Chapter 88 - Chronic Myelogenous Leukemia and Related Disorders

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Chapter 88: Chronic Myelogenous Leukemia and Related Disorders
Jane L. Liesveld; Marshall A. Lichtman
INTRODUCTION
SUMMARY
The chronic myelogenous leukemias (CMLs) include BCR rearrangementpositive CML, atypical CML, chronic myelomonocytic leukemia, juvenile
myelomonocytic leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, and chronic basophilic leukemia. The term chronic, in
contrast to acute, once had prognostic implications, but with advent of new treatments, the terms no longer reflect an invariable difference in
prognosis. For example, acute myelogenous leukemia in children and young adults has higher remission and cure rates than juvenile
myelomonocytic leukemia in children or chronic myelomonocytic leukemia in adults. BCR rearrangementpositive CML presents with anemia,
exaggerated granulocytosis; a large proportion of myelocytes and mature neutrophils; absolute basophilia; normal or elevated platelet counts; and,
frequently, splenomegaly. The marrow is intensely hypercellular, and marrow cells contain the Philadelphia (Ph) chromosome in approximately
90% of cases by cytogenetic analysis. A rearrangement of the BCR gene on chromosome 22 is present by molecular diagnostic analysis in
approximately 96% of cases that have a classic morphologic appearance. The BCRrearranged form of the disease usually responds to a tyrosine
kinase inhibitor (TKI), and median survival has been extended significantly. Allogeneic hematopoietic stem cell transplantation can cure the disease,
especially if the transplantation is applied early in the chronic phase, although this approach is now uncommonly utilized as a result of the
beneficial effect of TKI therapy. The effect of stem cell transplantation is related in part to a robust graftversusleukemia effect, engendered by
donor T lymphocytes. The natural history of the chronic phase is to evolve into an accelerated phase that often terminates in acute leukemia (blast
crisis), but the frequency of this progression has been markedly decreased by the application of TKIs. Blast crisis results in a myelogenous leukemic
phenotype in 75% of cases and a lymphoblastic leukemic phenotype in approximately 25% of cases. Phpositive acute myeloblastic leukemia (AML)
may appear de novo in approximately 1% of cases of AML, and Phpositive acute lymphocytic leukemia (ALL) may occur de novo in approximately
20% of cases of adult ALL and approximately 5% of childhood ALL cases. In Phpositive ALL, the translocation between chromosomes 9 and 22
results in the fusion gene encoding a mutant tyrosine kinase oncoprotein that may be identical in size to that in classic CML (210 kDa) in
approximately onethird of cases. A smaller mutant tyrosine kinase (190 kDa) is encoded in approximately twothirds of cases. In children, the cells
in approximately 90% of cases contain a 190kDa mutant tyrosine kinase. These acute leukemias may reflect (a) the presentation of CML in acute
blastic transformation without a preceding chronic phase or (b) de novo cases resulting from a BCRABL1 mutation occurring in a different early
hematopoietic cell from the event in CML or with as yet unidentified modifying gene alterations. Chronic myelomonocytic leukemia has variable
presenting features. Anemia may be accompanied by mildly or moderately elevated leukocyte counts; an elevated total monocyte count; a low,
normal, or elevated platelet count; and sometimes splenomegaly. Although cytogenetic abnormalities may be present, there is no specific genetic
marker of the disease. In a small proportion of cases, a translocation involving the plateletderived growth factor receptor (PDGFR)β gene is
associated with eosinophilia and is responsive to a TKI. Juvenile myelomonocytic leukemia occurs in infancy or very early childhood. Anemia,
thrombocytopenia, and leukocytosis with monocytosis are usual. The disease is refractory to treatment and, even with current maximal therapy and
stem cell rescue, cures are uncommon. Chronic neutrophilic leukemia presents with mild anemia and exaggerated neutrophilia, with very few
immature cells in the blood. Splenomegaly is very common; the disease is characterized by a mutation in the CSF3R gene. The disease usually occurs
after age 60 years. Chronic and juvenile myelomonocytic leukemia and chronic neutrophilic leukemia have a propensity to evolve into acute
myelogenous leukemia. Prior to that evolution, morbidity and mortality are related to infection, hemorrhage, and complicating medical conditions.
Chronic eosinophilic leukemia represents a subset of syndromes characterized by eosinophilia. It is a clonal disorder with a striking absolute
eosinophilia and often with neurologic and cardiac manifestations secondary to toxic effects of eosinophil granules. Some eosinophilic leukemias
have translocations involving the PDGFRα, PDGFRβ, or FGFR1 genes that encode mutant tyrosine kinases, imparting sensitivity to a TKI.
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Acronyms and Abbreviations
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ALL, acute lymphocytic leukemia; aCML, atypical chronic myelogenous leukemia; AML, acute myelogenous leukemia; ARCH, agerelated clonal
hematopoiesis; BCR, breakpoint cluster region; CCyR, complete cytogenetic response; CFUGM, colonyforming unit–granulocytemonocyte; CHR,
complete hematologic response; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic
Chronic eosinophilic leukemia represents a subset of syndromes characterized by eosinophilia. It is a clonal disorder with a striking absolute
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eosinophilia and often with neurologic and cardiac manifestations secondary to toxic effects of eosinophil granules. Some eosinophilic leukemias
have translocations involving the PDGFRα, PDGFRβ, or FGFR1 genes that encode mutant tyrosine kinases, imparting sensitivity to a TKI.
Acronyms and Abbreviations
ALL, acute lymphocytic leukemia; aCML, atypical chronic myelogenous leukemia; AML, acute myelogenous leukemia; ARCH, agerelated clonal
hematopoiesis; BCR, breakpoint cluster region; CCyR, complete cytogenetic response; CFUGM, colonyforming unit–granulocytemonocyte; CHR,
complete hematologic response; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic
leukemia; CMR, complete molecular response; DLI, donor lymphocyte infusion; DMR, deep molecular response; ERK, extracellular signal related
kinase; FISH, fluorescence in situ hybridization; FGF; fibroblast growth factor, GCSF, granulocyte colonystimulating factor; GMCSF, granulocyte
monocyte colonystimulating factor; GRB2, growth factor receptor–bound protein2; GTP, guanosine triphosphate; GTPase, guanosine
triphosphatase; GVHD, graftversushost disease; HLA, human leukocyte antigen; HPRT, hypoxanthine phosphoribosyltransferase; hsp, heat shock
protein; HUMARA, human androgen receptor assay; IFN, interferon; Ig, immunoglobulin; IL, interleukin; IRIS, International Randomized Study of
Interferon; JAK, Janusassociated kinase; LDH, lactic acid dehydrogenase; LSC, leukemia stem cells; LTCIC, longterm culture–initiating cell; MHC,
major histocompatibility complex; MCP, monocyte chemotactic protein; MCyR, major cytogenetic response; MDS, myelodysplastic syndrome; MIP,
macrophage inflammatory protein; MMR, major molecular response; MR4,4 log molecular response; MR4.5, 4.5 log molecular response; OS, overall
survival; NFκB, nuclear factorκB; NF1, neurofibromatosis tumorsuppressor gene; NK, natural killer; NOD, nonobese diabetic; OCT1, organic
cation transporter 1; PCR, polymerase chain reaction; PCyR, partial cytogenetic response; PDGFR, plateletderived growth factor receptor; Ph,
Philadelphia chromosome; PI3K, phosphatidylinositol 3'kinase; Rb, retinoblastoma; RTPCR, reverse transcriptase polymerase chain reaction;
SCID, severe combined immunodeficiency; 2G TKI, second generation TKI STAT, signal transducer and activator of transcription; TBI, totalbody
irradiation; TdT, terminal deoxynucleotidyl transferase; TERT, Telomerase reverse transcriptase; TGF, transforming growth factor; 3GT, third
generation TKI; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; WHO, World Health Organization; WT, Wilms tumor.
DEFINITION AND HISTORY
Chronic myelogenous leukemia (CML) is a multipotential hematopoietic stem cell disease characterized by anemia, extreme blood granulocytosis and
granulocytic immaturity, basophilia, often thrombocytosis, and splenomegaly. The hematopoietic cells contain a reciprocal translocation between
chromosomes 9 and 22 in more than 90% of patients with classic morphologic findings, which leads to an overtly foreshortened long arm of one of the
pair of chromosome 22 (ie, 22,22q−), referred to as the Philadelphia chromosome (Ph). A rearrangement of the breakpoint cluster region gene (BCR)
on the long arm of chromosome 22 defines this form of CML and is present even in the 10% of patients without an overt 22q abnormality by Giemsa
chromosome banding. The natural history of the disease is to undergo clonal evolution into an accelerated phase and/or a rapidly progressive blast
phase, an acute leukemia, highly refractory to therapy, which had been a frequent event prior to the introduction of tyrosine kinase inhibitors (TKIs) in
2001.
In 1845, Bennett1 in Scotland and Virchow2 in Germany described patients with splenic enlargement, severe anemia, and enormous concentrations of
leukocytes in their blood at autopsy. Additional cases were reported by Craige3 and others, and in 1847 Virchow4 introduced the designation weisses
Blut (white blood) and leukämie (leukemia). In 1878, Neumann5 proposed that the marrow not only was the site of normal blood cell production, but
also was the site from which leukemia originated and used the term myelogene (myelogenous) leukemia. Subsequent observations amplified the
clinical and laboratory features of the disease, but few fundamental insights were gained until the discovery by Nowell and Hungerford, working at the
University of Pennsylvania in Philadelphia,6 who reported in 1960 that 2 patients with the disease had an apparent loss of the long arm of chromosome
21 or 22, an abnormality that was quickly confirmed7–9 and designated the Philadelphia (subsequently nicknamed the Ph) chromosome after the city in
which it was discovered.7 Advanced cytogenetic techniques confirmed that it was chromosome 22. This observation led to a new approach to
diagnosis, a marker to study the pathogenesis of the disease, and a focus for future studies of the molecular pathology of the disease. The availability
of banding techniques to define the fine structure of chromosomes10,11 led to the discovery by Rowley12 that the apparent lost chromosomal material
on chromosome 22 was part of a reciprocal translocation between chromosomes 9 and 22. The discovery that the cellular oncogene ABL1 on
chromosome 9 and a segment of chromosome 22, the BCR, fuse as a result of the translocation provided a basis for the study of the molecular cause of
the disease.13,14 The appreciation that the fusion gene encoded a constitutively active tyrosine kinase (BCRABL1) that was capable of inducing the
disease in mice established the fusion gene product as the proximate cause of the malignant transformation. The search for, identification of, and
clinical development of a small molecule inhibitor of the mutant tyrosine kinase provided a specific agent, imatinib mesylate (STI571), with which to
inhibit the molecule that incites the disease.15 Several more potent congeners also have been synthesized (see “Etiology and Pathogenesis” below).
Thomas and colleagues established that allogeneic hematopoietic stem cell transplantation could cure the disease.16 An engaging monograph on the
17
discoveries and the scientists involved from the identification of the Ph chromosome to the development of imatinib has been published.
EPIDEMIOLOGY
on chromosome 22 was part of a reciprocal translocation between chromosomes 9 and 22. The discovery that the cellular oncogene ABL1 on
chromosome 9 and a segment of chromosome 22, the BCR, fuse as a result of the translocation provided a basis for the study of the molecular cause of
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the disease.13,14 The appreciation that the fusion gene encoded a constitutively active tyrosine kinase (BCRABL1) that was capable of inducing the
disease in mice established the fusion gene product as the proximate cause of the malignant transformation. The search for, identification of, and
clinical development of a small molecule inhibitor of the mutant tyrosine kinase provided a specific agent, imatinib mesylate (STI571), with which to
inhibit the molecule that incites the disease.15 Several more potent congeners also have been synthesized (see “Etiology and Pathogenesis” below).
Thomas and colleagues established that allogeneic hematopoietic stem cell transplantation could cure the disease.16 An engaging monograph on the
discoveries and the scientists involved from the identification of the Ph chromosome to the development of imatinib has been published.17
EPIDEMIOLOGY
CML accounts for approximately 15% of all cases of leukemia, or approximately 9000 new cases estimated to occur in the United States in 2019. The
ageadjusted incidence rate in the United States is approximately 2.7 per 100,000 persons for males and approximately 1.6 per 100,000 persons for
females. The incidence around the world varies by a factor of approximately twofold,18 but whether this is a true difference or represents variation in
methods of reporting is unclear.18 The agespecific incidence rate for CML in the United States increases logarithmically with age, from approximately
0.1 per 100,000 per year in persons younger than 20 years to a rate of approximately 10.0 per 100,000 in octogenarians (Fig. 88–1). Although CML
occurs in children and adolescents, less than 10% of all cases occur in persons between 1 and 20 years old. CML represents approximately 3% of all
childhood leukemias. The incidence of CML has not changed with time, but prevalence has been estimated at 10–12 per 100,000 persons with a steady
increase with time as a result of improvement in survival with the advent of TKI therapies.19 One study from France predicts a prevalence of 24 per
100,000 in 2030.20 The death rate per 100,000 persons per year has decreased dramatically (~70%) since 1998 as a result of the introduction of TKI
therapy around 2001. Multiple occurrences of CML in families are rare. There is no concordance of the disease in identical twins. There is no analytical
epidemiologic evidence for a familial predisposition to CML in Swedish databases.21 There is some evidence that being overweight or obese can
increase the incidence of CML.22
Figure 88–1.
Incidence of chronic myelogenous leukemia by age. Note the exponential increase in incidence with age from approximately teenage years to
octogenarian years. The exponential character of this arithmetic plot can be inferred, but was confirmed by showing a virtually linear increase in
incidence when the variable incidence rate is plotted on a log scale (not shown). Rare cases occur in younger children but too few to generate an
incidence rate.
ETIOLOGY AND PATHOGENESIS
ENVIRONMENTAL LEUKEMOGENS
Exposure to very high doses of ionizing radiation can increase the occurrence of CML above the expected frequency in comparable populations. Three
major populations—the Japanese exposed to the radiation released by the atomic bomb detonations at Nagasaki and Hiroshima,23 British patients
with ankylosing spondylitis treated with spine irradiation,24 and women with uterine cervical carcinoma who received radiation therapy25—had a
frequency of CML (as well as acute leukemia) significantly above the frequency expected in comparable unexposed groups. The median latent period
was approximately 4 years in patients irradiated for spondylitis, among whom approximately 20% of the leukemia cases were CML; 9 years in the
patients with uterine cervical cancer, of whom approximately 30% had CML; and 11 years in the Japanese survivors of the atomic bombs, of whom
approximately 30% of the patients with leukemia had CML.26 Patients who receive radioactive iodine for thyroid cancer may have an increased
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ENVIRONMENTAL LEUKEMOGENS
Exposure to very high doses of ionizing radiation can increase the occurrence of CML above the expected frequency in comparable populations. Three
major populations—the Japanese exposed to the radiation released by the atomic bomb detonations at Nagasaki and Hiroshima,23 British patients
with ankylosing spondylitis treated with spine irradiation,24 and women with uterine cervical carcinoma who received radiation therapy25—had a
frequency of CML (as well as acute leukemia) significantly above the frequency expected in comparable unexposed groups. The median latent period
was approximately 4 years in patients irradiated for spondylitis, among whom approximately 20% of the leukemia cases were CML; 9 years in the
patients with uterine cervical cancer, of whom approximately 30% had CML; and 11 years in the Japanese survivors of the atomic bombs, of whom
approximately 30% of the patients with leukemia had CML.26 Patients who receive radioactive iodine for thyroid cancer may have an increased
incidence of myeloproliferative neoplasms.27 Chemical leukemogens, such as benzene and alkylating agents, are not causative agents of CML,
presumably because of their inability to induce the specific chromosome translocation required to cause the disease.28 A metaanalysis suggested that
smoking may increase the risk of CML.29 An association of CML with chemotherapy administered for germ cell tumors has been suggested.30 The
evidence against chemically induced CML is substantial and, thus, these studies would require substantial verification to be accepted.28 CML does not
generally arise as a secondary malignancy.31
ORIGIN FROM A MUTANT HEMATOPOIETIC STEM CELL
CML results from the malignant transformation of a single hematopoietic stem cell. The disease is acquired (somatic mutation), given that the identical
twins of patients with CML and the offspring of mothers with the disease neither carry the Ph chromosome nor develop the disease.32 The origin of
CML from a single hematopoietic stem cell is supported by the following lines of evidence:
Involvement of erythropoiesis, neutrophilopoiesis, eosinophilopoiesis, basophilopoiesis, monocytopoiesis, and thrombopoiesis in chronic
phase CML.33
Presence of the Ph chromosome (22q−) in erythroblasts; neutrophilic, eosinophilic, and basophilic granulocytes; macrophages; and
megakaryocytes.34
Presence of a single glucose6phosphate dehydrogenase isoenzyme in red cells, neutrophils, eosinophils, basophils, monocytes, and platelets,
but not in fibroblasts or other somatic cells in women with CML who are heterozygotes for isoenzymes A and B.35
Presence of the Ph translocation only on a structurally anomalous chromosome 9 or 22 of each chromosome pair in every cell analyzed in
occasional patients with a structurally dissimilar 9 or 22 chromosome within the pair.36
Presence of the Ph chromosome in one, but not the other, cell lineage of patients who are a mosaic for sex chromosomes, as in Turner syndrome
(45X/46XX)37 and Klinefelter syndrome (46XY/47XXY).38
Molecular studies showing variation in the breakpoint of chromosome 22 among different patients with CML but precisely the same breakpoint
among cells within a single patient with CML.39
Combined DNA hybridization–methylation analysis of women who have restriction fragment length polymorphisms at the Xlinked locus for
hypoxanthine phosphoribosyltransferase, which enables distinction of the two alleles of the hypoxanthine phosphoribosyltransferase gene in
heterozygous females, coupled with methylationsensitive restrictionenzyme cleavage patterns that permits delineation of whether cells contain
either the maternally derived or the paternally derived copy of the gene.40
The foregoing observations place the parent cell of the clone at least at the level of the hematopoietic multipotential cell. Whether endothelial cells can
express BCRABL1, indicating an origin in a hemangioblastic cell, is controversial.41 Mesenchymal stromal cells do not belong to the Phpositive clone
but may harbor aberrant gene expression profiles at diagnosis.42
THE CHRONIC MYELOGENOUS LEUKEMIA STEM CELL
Acquisition of the BCRABL1 fusion gene as a result of the t(9;22) (q34;q11.2) in a single primitive multipotential hematopoietic cell (possibly the
pluripotential stem cell) results in the CML stem cell, necessary for the initiation and maintenance of the chronic phase of CML.43 The phenotype of the
CML stem cell is not fully defined but they are among the CD34+CD33−Lin−Thy1+ KIT− fraction of CML cells.43 A proportion of CML stem cells is in the G0
phase of the cell cycle and is resistant to therapy with BCRABL1 inhibitors. These cells represent a pool for the regrowth of the tumor in some patients,
if suppressive therapy is interrupted. The leukemia stem cell is resistant to TKI therapy, but a panBCL1 inhibitor has been found to sensitize marrow
Chapter 88: Chronic Myelogenous Leukemia and Related Disorders, Jane L. Liesveld; Marshall A. Lichtman
44 Ncadherin and WNT–βcatenin signaling are also thought to mediate microenvironmental
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leukemia stem cells to tyrosine kinase inhibition.
protection of CML stem cells from TKIs.45 Similarly, interleukin (IL)1 has been found to be involved in the maintenance of CML stem cells46 as has hsa
mir183/EGR1 (early growth response 1)mediated E2 transcription factor 1 regulation.47 The marrow microenvironment is thought to preserve the
THE CHRONIC MYELOGENOUS LEUKEMIA STEM CELL
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Acquisition of the BCRABL1 fusion gene as a result of the t(9;22) (q34;q11.2) in a single primitive multipotential hematopoietic cell (possibly the
pluripotential stem cell) results in the CML stem cell, necessary for the initiation and maintenance of the chronic phase of CML.43 The phenotype of the
CML stem cell is not fully defined but they are among the CD34+CD33−Lin−Thy1+ KIT− fraction of CML cells.43 A proportion of CML stem cells is in the G0
phase of the cell cycle and is resistant to therapy with BCRABL1 inhibitors. These cells represent a pool for the regrowth of the tumor in some patients,
if suppressive therapy is interrupted. The leukemia stem cell is resistant to TKI therapy, but a panBCL1 inhibitor has been found to sensitize marrow
leukemia stem cells to tyrosine kinase inhibition.44 Ncadherin and WNT–βcatenin signaling are also thought to mediate microenvironmental
protection of CML stem cells from TKIs.45 Similarly, interleukin (IL)1 has been found to be involved in the maintenance of CML stem cells46 as has hsa
mir183/EGR1 (early growth response 1)mediated E2 transcription factor 1 regulation.47 The marrow microenvironment is thought to preserve the
quiescence of CML stem cells.48 Singlecell molecular analysis of leukemia stem cells in CML has shown considerable heterogeneity at diagnosis and
differences in response to TKI treatment. As would be expected, the subpopulations with myeloid and proliferative signatures are more responsive to
TKIs than are those with primitive and quiescent signatures.49 The acquisition of genetic and epigenetic events in a derivative BCRABL1–positive cell
can result in evolution to accelerated phase and blastic transformation50,51 (see “Accelerated Phase and Blast Crisis of Chronic Myelogenous
Leukemia” below).
PLURIPOTENTIAL STEM CELL LESION
Some patients in chronic phase CML have lymphocytes that are derived from the primordial malignant cell. Evidence for this finding includes the
following: A single isoenzyme for glucose6phosphate dehydrogenase has been found in some T and B lymphocytes in women with CML who are
heterozygous for isoenzymes A and B,51 and fluorescence in situ hybridization (FISH) has detected the BCRABL1 fusion gene in approximately 25% of B
lymphocytes in some, but not all, patients in chronic phase.52 These findings suggest that B lymphocytes are derived from the malignant clone, placing
the lesion closer to, if not in, the pluripotential lymphohematopoietic stem cell.51 Previous studies found that the Blymphocyte pool is a mosaic,
containing both Phpositive and BCRABL1–positive cells and Phnegative or BCRABL1–negative cells.52 Results of studies examining the derivation of
T lymphocytes from the malignant clone are more ambiguous but indicate that T lymphocytes are derived from the malignant clone in some
patients.51,53–56 Natural killer (NK) cells isolated from patients with chronic phase CML do not contain the BCRABL1 fusion gene.57 It is possible that
myelopoiesis is invariably clonal and lymphopoiesis is an unpredictable mosaic derived largely from normal residual stem cells. This conclusion is
supported by the finding that progenitors of T, B, and NK lymphocytes contain the Ph chromosome and BCRABL1, but most Bcell and all Tcell
progenitors derived from the leukemic clone undergo apoptosis, leaving unaffected cells in the blood.58,59
The cell in which the mutation occurs may be even more primitive in that some endothelial cells generated in vitro express the BCRABL1 fusion gene,
as do some cells in the patient’s vascular endothelium.60
ETIOLOGIC ROLE OF THE Ph CHROMOSOME
Nearly all, if not all, patients with CML have an abnormality of chromosome 22 at a molecular level (BCR rearrangement). Thus, earlier studies
indicating an absence of a Ph chromosome were not valid measures of the normality of chromosome 22. The molecular abnormality in CML involving
the ABL1 gene on chromosome 9 and the BCR gene on chromosome 22 has been established as being the proximate cause of the chronic phase of the
disease (see “Molecular Pathology” below).
COEXISTENCE OF NORMAL STEM CELLS
Most, if not all, patients with CML have hematopoietic stem cells that, after treatment61–63 or culture in vitro,64–66 use of special cell isolation
techniques,62,63 or use of cell transfer to nonobese diabetic/severe combined immunodeficiency (SCID) mice67 do not have the Ph chromosome68,69 or
the BCRABL1 fusion gene.70–74 The switch to Phnegative cells in vitro is associated with a loss of monoclonal glucose6phosphate dehydrogenase
isoenzyme patterns, indicating the persistence and reemergence of normal polyclonal hematopoiesis rather than reversion to a Phnegative clone.75 In
confirmation, BCRABL1+, CD34+, human leukocyte antigen (HLA)DR− cells isolated from women with early phase CML are polyclonal using the human
androgen receptor assay to assess X chromosome inactivation patterns.76 Very primitive hematopoietic cells, the longterm culture–initiating cells, are
present in Phnegative cytapheresis samples collected during early recovery after chemotherapy for CML.77 These longterm culture–initiating cells are
most commonly present when samples are collected within 3 months of diagnosis.78 Variable levels of BCRABL1–negative progenitors are found in the
CD34+DR− population, but low levels are found in the CD34+CD38− population.79 Preprogenitors for the CD34+DR− cells are predominantly BCRABL1–
negative in both marrow and blood at diagnosis.80 Both normal and leukemic SCIDrepopulating cells coexist in the marrow and blood from CML
patients in chronic phase, whereas only leukemic SCIDrepopulating cells are detected in blast crisis.81,82
PROGENITOR CELL CHARACTERISTICS
Progenitor Cell Dysfunction
present in Phnegative cytapheresis samples collected during early recovery after chemotherapy for CML.77 These longterm culture–initiating cells are
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most commonly present when samples are collected within 3 months of diagnosis.78 Variable levels of BCRABL1–negative progenitors are found in the
CD34+DR− population, but low levels are found in the CD34+CD38− population.79 Preprogenitors for the CD34+DR− cells are predominantly BCRABL1–
negative in both marrow and blood at diagnosis.80 Both normal and leukemic SCIDrepopulating cells coexist in the marrow and blood from CML
patients in chronic phase, whereas only leukemic SCIDrepopulating cells are detected in blast crisis.81,82
PROGENITOR CELL CHARACTERISTICS
Progenitor Cell Dysfunction
The leukemic transformation resulting from the BCRABL1 fusion oncogene is maintained by a relatively small number of BCRABL1 stem cells that
favor differentiation over selfrenewal.83 This predisposition to differentiation and progenitor cell expansion is mediated by an autocrine IL3–
granulocyte colonystimulating factor (GCSF) loop.84 The earliest progenitors have the capacity to undergo marked expansion of erythroid,
granulocytic, and megakaryocytic cell populations, and have a decreased sensitivity to regulation.84 This expansion is especially dramatic in the more
mature progenitor cell compartment. BCRABL1 reduces growth factor dependence of progenitor cells.85
Erythroid progenitors are expanded, erythroid precursor maturation is blocked at the basophilic erythroblast stage, and the extent of erythropoiesis is
inversely proportional to the total white cell count.86
Progenitor Cell Characterization
Phenotypic differences of stem and progenitor cells in CML patients compared to normal subjects have been identified.87 Leukemic CD34+ cells
overexpress the P glycoprotein that determines the multidrug resistance phenotype,88 and demonstrate reduced Lselectin expression.89
BCRABL1–positive progenitors have a shorter survival in longterm culture than do their normal counterparts. Leukemic colonyforming unit
granulocytemonocyte colonies, unlike normal colonies, decrease in longterm cultures that are deficient in KIT ligand,90 whereas their proliferation is
favored in the presence of KIT ligand.91 macrophage inflammatory protein1α, renamed CCL3, does not inhibit growth factormediated proliferation of
CD34+ cells from CML patients, as it does CD34+ cells from normal individuals, even though the CCL3 receptor is expressed.92 Another chemokine,
monocyte chemotactic protein1 (CCL2), unlike CCL3, is an endogenous chemokine that cooperates with transforming growth factorβ to inhibit the
cycling of primitive normal, but not CML, progenitors in longterm human marrow cultures.93 Leukemic progenitors are less sensitive than normal
progenitors to the antiproliferative effects of transforming growth factorβ.94 CML stem and progenitor cells may evade immune surveillance through
downregulation of major histocompatibility complex expression, which may be restored by use of the Janus kinase (JAK) 1/2 inhibitor, ruxolitinib
(Jakafi).95
Effects of BCRABL1 on Cell Adhesion
Primitive progenitors and blast colonyforming cells from patients with CML have decreased adherence to marrow stromal cells.96 This defect is
normalized if stromal cells are treated with interferon (IFN)α.97 As a result, BCRABL1–negative progenitors are enriched in the adherent fraction of
circulating CD34+ cells in patients with chronic phase CML.
Phpositive colonyforming cells adhere less to fibronectin (and to marrow stroma) than do their normal counterparts. Adhesion is fostered as a result
of restoration of cooperation between activated β1 integrins and the altered epitopes of CD44.98,99 CML granulocytes have reduced and altered binding
to Pselectin because of modification in the CD15 antigens.100 BCRABL1–induced defects in integrin function may underlie the abnormal circulation
and proliferation of progenitors.101 IFNα restores normal integrinmediated inhibition of hematopoietic progenitor proliferation by the marrow
microenvironment.102 There are conflicting data regarding the effects of TKI on adhesion of CML cells to stroma.103,104 Adhesion of CML stem cells to
stroma maintains quiescence and resistance to imatinib through extracellular signalregulated kinase (ERK) and bone morphogenic signaling
pathways.105
BCRABL1–encoded fusion protein p210BCRABL binds to actin, and several cytoskeletal proteins are thereby phosphorylated. The p210BCRABL interacts
with actin filaments through an actinbinding domain. BCRABL1 transfection is associated with increased spontaneous motility, membrane ruffling,
formation of long actin extensions (filopodia), and accelerated rate of protrusion and retraction of pseudopodia on fibronectincoated surfaces. IFNα
treatment slowly converts the abnormal motility phenotype of BCRABL1–transformed cells toward normal.106 The p210BCRABL1 abrogates the
anchorage requirement but not the growth factor requirement for proliferation.107
The sum of evidence suggests that defects in adhesion (contact and anchoring) of CML primitive cells remove them from their controlling signals
normally received from microenvironmental cells via cytokine messages. These signals retain the balance among cell survival, cell death, cell
proliferation, and cell differentiation. Inappropriate phosphorylation of cytoskeletal proteins, possibly independent of the mutant tyrosine kinase, is
BCRABL1–encoded fusion protein p210BCRABL binds to actin, and several cytoskeletal proteins are thereby phosphorylated. The p210BCRABL interacts
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with actin filaments through an actinbinding domain. BCRABL1 transfection is associated with increased spontaneous motility, membrane ruffling,
formation of long actin extensions (filopodia), and accelerated rate of protrusion and retraction of pseudopodia on fibronectincoated surfaces. IFNα
treatment slowly converts the abnormal motility phenotype of BCRABL1–transformed cells toward normal.106 The p210BCRABL1 abrogates the
anchorage requirement but not the growth factor requirement for proliferation.107
The sum of evidence suggests that defects in adhesion (contact and anchoring) of CML primitive cells remove them from their controlling signals
normally received from microenvironmental cells via cytokine messages. These signals retain the balance among cell survival, cell death, cell
proliferation, and cell differentiation. Inappropriate phosphorylation of cytoskeletal proteins, possibly independent of the mutant tyrosine kinase, is
thought to be the key factor in disturbed integrin function of CML cells.
MOLECULAR PATHOLOGY
Ph Chromosome
The genetic disturbance became evident with the knowledge that CML was derived from a primitive cell containing a 22q− abnormality.6,11,108,109 Using
quinacrine (Q) and Giemsa (G) banding, Rowley12 reported in 1973 that the material missing from chromosome 22 was not lost (deleted) from the cell,
but was translocated to the distal portion of the long arm of chromosome 9. The amount of material translocated to chromosome 9 was approximately
equivalent to that lost from chromosome 22, and the translocation was predicted to be balanced.12 Moreover, the breaks were localized to band 34 on
the long arm of chromosome 9 and band 11 on the long arm of chromosome 22. Therefore, the classic Ph chromosome is t(9;22)(q34;q11), abbreviated
t(Ph) (Fig. 88–2). The Ph chromosome can develop on either the maternal or the paternal member of the pair.110
Figure 88–2.
Schematic of normal chromosome 9 showing the ABL gene between bands q34 and qter of chromosome 22, which has the BCR and SIS genes between
bands q11 and qter. The t(9;22) is shown on the right. The ABL from chromosome 9 is transposed to the chromosome 22 Mbcr sequences, and the
terminal portion of chromosome 22 is transposed to the long arm of chromosome 9. The 22q− is the Ph chromosome. BCR, breakpoint cluster region;
cSiS, cellular homologue of the viral simian sarcoma virustransforming gene; IGL, gene for immunoglobulin light chains. (Reproduced with
permission from De Klein A. Oncogene activation by chromosomal rearrangement in chronic myelocytic leukemia. Mutat Res. 1987 Sep;186(2):161
172.)
Mutation of ABL1 and BCR Genes
Mutations of the ABL1 gene on chromosome 9 and of the BCR gene on chromosome 22 are central to the development of CML (Fig. 88–3).111–113
Figure 88–3.
Schematic of the normal ABL and BCR genes and of the BCRABL fusion transcripts. In the upper panel of the diagram, the possible breakpoint
positions in ABL are marked by vertical arrows. Note the position immediately upstream of the ABL locus of the 8604Met gene. The BCR gene contains
25 exons, including first (e1) and second (e2) exons. The positions of the 3 breakpoint cluster regions, mbcr, Mbcr, and μbcr, are shown. The lower
panel of the figure shows the structure of the BCRABL mRNA fusion transcripts. Breakpoints in μbcr result in BCRABL transcripts with an e19a2
junction. The associated number designates the exon (location) at which the break occurs in each gene.
Figure 88–3.
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Schematic of the normal ABL and BCR genes and of the BCRABL fusion transcripts. In the upper panel of the diagram, the possible breakpoint
positions in ABL are marked by vertical arrows. Note the position immediately upstream of the ABL locus of the 8604Met gene. The BCR gene contains
25 exons, including first (e1) and second (e2) exons. The positions of the 3 breakpoint cluster regions, mbcr, Mbcr, and μbcr, are shown. The lower
panel of the figure shows the structure of the BCRABL mRNA fusion transcripts. Breakpoints in μbcr result in BCRABL transcripts with an e19a2
junction. The associated number designates the exon (location) at which the break occurs in each gene.
In 1982, the human cellular homologue ABL1 of the transforming sequence of the Abelson murine leukemia virus was localized to human chromosome
9.114 In 1983, ABL1 was shown to be on the segment of chromosome 9 that is translocated to chromosome 22115 by demonstrating reaction to
hybridization probes for ABL1 only in somatic cell hybrids of human CML cells containing 22q− but not those containing 9q+. vabl is the viral
oncogenic homologue of the normal cellular ABL1 gene. This gene (vabl) can induce malignant transformation of cells in culture and can induce
leukemia in susceptible mice.116
The ABL1 gene is rearranged and amplified in cell lines from patients with CML.117 Cell lines and fresh isolates of CML cells contain an abnormal,
elongated 8kb RNA transcript,118 which is transcribed from the new chimeric gene produced by the fusion of the 5′ portion of the BCR gene left on
chromosome 22 with the 3′ portion of the ABL1 gene translocated from chromosome 9 (Fig. 88–4).115 The fusion mRNA leads to the translation of a
unique tyrosine phosphoprotein kinase of 210 kDa (p210BCRABL), which can phosphorylate tyrosine residues on cellular proteins similar to the action
of the vabl protein product.116–119 The ABL1 locus contains at least 2 alleles, one having a 500bp deletion.120 In normal cells, the ABL1 protooncogene
codes for a tyrosine kinase of molecular weight 145,000, which is translated only in trace quantities and lacks any in vitro kinase activity.116 The fusion
product expressed by the BCRABL1 gene is hypothesized to lead to malignant transformation because of the abnormally regulated enzymatic activity
of the chimeric tyrosine protein kinase.121,122
Figure 88–4.
Molecular effects of the (nè Ph1) chromosome translocation t(9;22)(q34;q11). The upper panel shows the physically joined 5′ BCR and the 3′ ABL
regions on chromosome 22. The exons are solid (from chromosome 22, BCR) and hatched (from chromosome 9, ABL). The middle panel depicts
transcription of chimeric messenger RNA. The lower panel shows the translated fusion protein with the aminoterminus derived from the BCR of
chromosome 22 and the carboxyterminus from the ABL of chromosome 9. (Reproduced with permission from De Klein A. Oncogene activation by
chromosomal rearrangement in chronic myelocytic leukemia. Mutat Res. 1987 Sep;186(2):161172.)
regions on chromosome 22. The exons are solid (from chromosome 22, BCR) and hatched (from chromosome 9, ABL). The middle panel depicts
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transcription of chimeric messenger RNA. The lower panel shows the translated fusion protein with the aminoterminus derived from the BCR of
chromosome 22 and the carboxyterminus from the ABL of chromosome 9. (Reproduced with permission from De Klein A. Oncogene activation by
chromosomal rearrangement in chronic myelocytic leukemia. Mutat Res. 1987 Sep;186(2):161172.)
p210BCRABL Fusion Protein
The breakpoints on chromosome 9 are not narrowly clustered, ranging from approximately 15 kb to more than 40 kb upstream from the most
proximate region (first exon) of the ABL1 gene.114,115,123 The breakpoints on chromosome 22 occur over a very short, approximately 5–6 kb, stretch of
DNA referred to as the breakpoint cluster region (Mbcr),124,125 which is part of a much longer BCR126,127 gene (see Fig. 88–4). Three main BCRs have
been characterized on chromosome 22: major (Mbcr), minor (mbcr), and micro (μbcr). The 3 different breakpoints result in a p210 (Mbcr), p190 (m
bcr), and p230 (μbcr) fusion protein (see Fig. 88–3). The overwhelming majority of CML patients have a BCRABL1 fusion gene that encodes a fusion
protein of 210 kDa (p210BCRABL1), for which mRNA transcripts have e14a2 or a e13a2 fusion junction (see Fig. 88–3).128 Rare e14a3 transcripts also have
been described.129 The “e” represents the BCR exon and “a” the ABL1 exon sites involved in the translocation. A BCRABL1 with an e1a2 type of junction
has been identified in approximately 50% of the Phpositive acute lymphoblastic leukemia cases and results in the production of a BCRABL1 protein of
190 kDa (p190BCRABL). Almost all CML cases at diagnosis that encode a p210BCRABL and some also express BCRABL transcripts for p190.130 Dual
transcripts may result in higher rates of resistance to imatinib and worse longterm outcomes.131 The presence of other splicing variants on outcome is
controversial.132 Transgenic mice expressing p210BCRABL develop acute lymphocytic leukemia (ALL) in the founder mice, but all transgenic progeny
have a myeloproliferative disorder resembling CML.133
The BCR gene encodes a 160kDa serinethreonine kinase, which, when it oligomerizes, autophosphorylates and transphosphorylates several protein
substrates.134 The first exon sequences of the BCR gene potentiate the tyrosine kinase of ABL when they fuse as a result of the translocation.135 The C
terminus of BCR has a guanosine triphosphatase (GTPase)activating protein for p21rac, a member of the RAS family of guanosine triphosphate (GTP)
binding proteins.136 A reciprocal hybrid gene ABLBCR1 is formed on chromosome 9q+ when BCRABL1 fuses on chromosome 22. The ABLBCR1 fusion
gene actively transcribes in most patients with CML.137
Variations in breakpoints involving smaller stretches of chromosome 9 and rearrangements outside the Mbcr of chromosome 22 can occur. In a few
cases of CML with no evident elongation of chromosome 9, molecular probes have shown that ABL1 still is translocated to chromosome 22.138 In
occasional patients with Phpositive CML, the break in chromosome 22 is outside the Mbcr, and transcription of a fusion RNA of the usual type fails or
a fusion RNA is transcribed that does not hybridize with the classic Mbcr complementary DNA probe.139
In cases in which the Ph chromosome is not found, BCRABL1 still may be located on chromosome 9 (a masked Ph chromosome).140 The BCR gene can
recombine with genomically distinct sites on band 11q13 in complex translocations in a region rich in Alu repeat elements.141 ETV6/ABL1 fusion genes
also have been found in BCRABL1–negative CML.142
The BCR breakpoint site has been examined as a factor in disease prognosis. Some studies have shown no correlation between CML chronicity and
breakpoint site, although thrombocytosis may be more common with 3′ breakpoint sites and basophilia with 5′ breakpoint sites.143 CML patients with
mbcr breakpoints develop a blast crisis with monocytosis and an absence of splenomegaly and basophilia.144 The p230 (e19a2 RNA junction) encoded
by μbcr is rarely expressed but has been associated with neutrophilic CML or thrombocytosis (see “Special Clinical Features” below). Other rare
a fusion RNA is transcribed that does not hybridize with the classic Mbcr complementary DNA probe.
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In cases in which the Ph chromosome is not found, BCRABL1 still may be located on chromosome 9 (a masked Ph chromosome).140 The BCR gene can
recombine with genomically distinct sites on band 11q13 in complex translocations in a region rich in Alu repeat elements.141 ETV6/ABL1 fusion genes
also have been found in BCRABL1–negative CML.142
The BCR breakpoint site has been examined as a factor in disease prognosis. Some studies have shown no correlation between CML chronicity and
breakpoint site, although thrombocytosis may be more common with 3′ breakpoint sites and basophilia with 5′ breakpoint sites.143 CML patients with
mbcr breakpoints develop a blast crisis with monocytosis and an absence of splenomegaly and basophilia.144 The p230 (e19a2 RNA junction) encoded
by μbcr is rarely expressed but has been associated with neutrophilic CML or thrombocytosis (see “Special Clinical Features” below). Other rare
breakpoints have been described.145–147 Typical CML also is associated with an e19a2 junction BCRABL1 transcript.148
BCRABL IN HEALTHY SUBJECTS
BCRABL1 fusion genes can be found in the leukocytes of some normal individuals using a 2step reverse transcriptase polymerase chain reaction
assay. Thus, although BCRABL1 may be expressed relatively frequently at very low levels in hematopoietic cells, only infrequently do the cells acquire
the additional changes necessary to produce leukemia. This may be a dosage effect.149
BCRABL1 AND SIGNAL TRANSDUCTION
The tyrosine phosphoprotein kinase activity of p210BCRABL1 has been causally linked to the development of Phpositive leukemia in humans.150–161
p210BCRABL1 is, unlike the ABL1 protein that is located principally in the nucleus, located in the cytoplasm making it accessible to a large number of
interactions, especially components of signal transduction pathways.154,155,162 It binds and/or phosphorylates more than 20 cellular proteins in its role
as an oncoprotein.155 A subunit of phosphatidylinositol 3′kinase (PI3K) associates with p210BCRABL; this interaction is required for the proliferation of
BCRABL1–dependent cell lines and primary CML cells.
The pathways and interactions invoked by BCRABL1 acting on mitogenactivated protein kinases (MAPKs) are multiple and complex.163,164 A RAF
encoded serinethreonine kinase activity is regulated by p210BCRABL. Downregulation of RAF expression inhibits both BCRABL1–dependent growth of
CML cells and growth factor–dependent proliferation of normal hematopoietic progenitors.157 The efficiency of cell transformation by BCRABL1 is
affected by an adaptor protein that can relate tyrosine kinase signals to RAS. This involves growth factor receptor–bound protein2 (GRB2). p210BCR
ABL also activates multiple alternative pathways of RAS.158 PI3K is constitutively activated by BCRABL1, generates inositol lipids, and is dysregulated
through the downregulation by BCRABL1 of polyinositol phosphate tumor suppressors, such as PTEN (phosphatase and tensin homologue) and
SHIP1 (Src homology 2containinginositolphosphatase1).162 Figure 88–5 demonstrates interaction of p210BCRABL with various mediators of signal
transduction.
Figure 88–5.
Major intracellular signaling events associated with BCR/ABL. Constitutive activation of ABL protein tyrosine kinase induces phosphorylation of the
tyrosine moiety of various substrates, including autophosphorylation of BCR/ABL and complex formation of BCR/ABL with adaptor proteins. This
process subsequently activates multiple intracellular signaling pathways, including RAS activation and phosphatidylinositol 3′kinase (PI3K) activation
pathways. BCR/ABL also activates the cMYC pathway, which involves ABLSH2 domain. BCRABL inhibits apoptosis, possibly in part through
upregulation of Bcl2, and alters cellular adhesive properties, possibly by interacting with focal adhesion proteins and the actin cytomatrix. Broken
lines indicate hypothetical pathways. ERK, extracellular signalregulated kinase; FAK, focal adhesion kinase; GRB2, growth factor receptor–bound
protein2; JNK, Jun Nterminal kinase; MEKK, mitogen activated protein/extracellular signalrelated kinase kinase; Sos, Sonofsevenless; STAT, signal
transducer and activator of transcription. (Reproduced with permission from Gotoh A, Broxmeyer HE. The function of BCR/ABL and related proto
oncogenes. Curr Opin Hematol. 1997 Jan;4(1):311.)
lines indicate hypothetical pathways. ERK, extracellular signalregulated kinase; FAK, focal adhesion kinase; GRB2, growth factor receptor–bound
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protein2; JNK, Jun Nterminal kinase; MEKK, mitogen activated protein/extracellular signalrelated kinase kinase; Sos, Sonofsevenless; STAT, signal
transducer and activator of transcription. (Reproduced with permission from Gotoh A, Broxmeyer HE. The function of BCR/ABL and related proto
oncogenes. Curr Opin Hematol. 1997 Jan;4(1):311.)
Reactive oxygen species are increased in BCRABL1–transformed cells and may act as a second messenger to modulate enzymes regulated by the
reduction–oxidation equilibrium. An increase in these reactive oxygen products is postulated to play a role in the acquisition of additional mutations
as a result of production of reactive oxygen species through the chronic phase, contributing to the progression to accelerated phase.162,165
The adaptor molecule CRKL (vcrk sarcoma virus CT10 oncogene homologue [avian]like) is a major in vivo substrate for p210BCRABL, and it acts to
relate p210BCRABL to downstream effectors. CRKL is a linker protein that has homology to the vcrk oncogene product. Antibodies to CRKL can
immunoprecipitate paxillin. Paxillin is a focal adhesion protein159 that is phosphorylated by p210BCRABL. The p210BCRABL may be physically linked to
paxillin by CRKL. CRKL binds to CBL, an oncogene product that induces B cell and myeloid leukemias in mice.160 The Src homology 3 domains of CRKL
do not bind to CBL, but they do bind BCRABL. Therefore, CRKL mediates the oncogenic signal of BCRABL to CBL. The p120CBL and the adaptor
proteins CRKL and cCRK also link cabl, p190BCRABL, and p210BCRABL to the PI3K pathway.161 The p120CBL also coprecipitates with the p85 subunit of
PI3K, CRKL, and cCRK. The p210BCRABL may, therefore, induce the formation of multimeric complexes of signaling proteins.166 These complexes
contain paxillin and talin and may explain some of the adhesive defects of CML cells.167
Hef2 also binds to CRKL in leukemic tissues of p190BCRABL transgenic mice. Hef2 is involved in the integrin signaling pathway168 and encodes a protein
that accelerates GTP hydrolysis of RASencoded proteins and neurofibromin. The latter negatively regulates granulocytemacrophage colony
stimulating factor (GMCSF) signaling through RAS in hematopoietic cells.169 p62DOK, a constitutively tyrosinephosphorylated p120RAS GAPassociated
protein that is rapidly tyrosine phosphorylated upon activation of the ckit receptor,170 is also associated with ABL1.171
Nuclear factor κB activation is also required for p210BCRABLmediated transformation.172 Expression of p210BCRABL leads to activation of nuclear
factor κB–dependent transcription via nuclear translocation.173
Cell lines that express p210BCRABL also demonstrate constitutive activation of JAKs and signal transducers and activators of transcription (STATs),
usually STAT5.174 STAT5 is also activated in primary mouse marrow cells acutely transformed by the BCRABL1175; p210BCRABL1 coimmunoprecipitates
with and constitutively phosphorylates the common β subunit of the IL3 and GMCSF receptors and JAK2.176 Both ABL1 and BCR are also
multifunctional regulators of the GTPbinding protein family Rho177,178 and the growth factorbinding protein GRB2, which links tyrosine kinases to
RAS and forms a complex with BCRABL1 and the nucleotide exchange factor Sos (Sonofsevenless) that leads to activation of RAS.179
The p210BCRABL1 also activates Jun kinase and requires Jun for transformation.180 In some CML cell lines, p210BCRABL1 is associated with the
retinoblastoma (Rb) protein.181 Loss of the neurofibromatosis (NF1) tumorsuppressor gene, a RAS GTPaseactivating protein, also is sufficient to
produce a myeloproliferative neoplasm in mice akin to human CML resulting from RASmediated hypersensitivity to GMCSF.182
EFFECTS OF BCRABL ON APOPTOSIS Page 11 / 124
Whether p210BCRABL1 influences the expansion of the malignant clone in CML by inhibiting apoptosis is uncertain. In one study, the survival of normal
183
multifunctional regulators of the GTPbinding protein family Rho177,178 and the growth factorbinding protein GRB2, which links tyrosine kinases to
RAS and forms a complex with BCRABL1 and the nucleotide exchange factor Sos (Sonofsevenless) that leads to activation of RAS.179
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The p210BCRABL1 also activates Jun kinase and requires Jun for transformation.180 In some CML cell lines, p210BCRABL1 is associated with the
retinoblastoma (Rb) protein.181 Loss of the neurofibromatosis (NF1) tumorsuppressor gene, a RAS GTPaseactivating protein, also is sufficient to
produce a myeloproliferative neoplasm in mice akin to human CML resulting from RASmediated hypersensitivity to GMCSF.182
EFFECTS OF BCRABL ON APOPTOSIS
Whether p210BCRABL1 influences the expansion of the malignant clone in CML by inhibiting apoptosis is uncertain. In one study, the survival of normal
and CML progenitors was the same after in vitro incubation in serumdeprived conditions and after treatment with Xirradiation or glucocorticoids.183
The p210BCRABL1 inhibits apoptosis by delaying the G2/M transition of the cell cycle after DNA damage.184 The p210BCRABL1 also may exert an
antiapoptotic effect in factordependent hematopoietic cells.185,186
p210BCRABL1 does not prevent apoptotic death induced by human NK or lymphokineactivated killer cells directed against CML or normal cells.187 In
accelerated and blast phases, apoptosis rates were lower in CML neutrophils. GCSF and GMCSF considerably decreased the rate of apoptosis in CML
neutrophils.188
TELOMERE LENGTH
Patients with CML present with a somewhat shortened mean telomere length in granulocytic cells but not blood T lymphocytes at diagnosis, but
considerable overlap exists in the distribution of telomere length with healthy individuals.189–191 Telomere shortening correlates with the leukemic
stem cell burden at diagnosis.192 The rate of shortening of telomere length during the chronic phase is correlated with a more rapid onset of
accelerated phase.189,191 Telomerase reverse transcriptase is the catalytic subunit, expression of which is closely correlated with telomerase activity. In
CML CD34+ cells containing BCRABL1, the expression of telomerase reverse transcriptase is significantly lower than in normal CD34+ cells, consistent
with accelerated shortening of telomeres in CML cells.193 A further significant decrease in telomere length occurs in the accelerated phase of CML.
Telomerase activity is increased in the accelerated phase.194 When therapy permits restoration of Phnegative cells in the blood, these cells have
telomere length comparable to that in matched healthy controls.195
CLINICAL FEATURES
SIGNS AND SYMPTOMS
In the 50% of patients who are symptomatic at diagnosis, the most frequent complaints include easy fatigability, loss of sense of wellbeing, decreased
tolerance to exertion, anorexia, abdominal discomfort, early satiety (related to splenic enlargement), weight loss, and excessive sweating.196–198 The
symptoms are vague, nonspecific, and gradual in onset (weeks to months). A physical examination may detect pallor and splenomegaly. With medical
care being sought earlier, the presence of splenomegaly at the time of diagnosis is decreasing in frequency.197 Sternal tenderness, especially the lower
portion, is common; occasionally, patients notice it themselves.
Uncommon presenting symptoms include those of dramatic hypermetabolism (night sweats, heat intolerance, weight loss) simulating thyrotoxicosis;
acute gouty arthritis, presumably related in part to hyperuricemia; priapism, tinnitus, or stupor from the leukostasis associated with greatly
exaggerated blood leukocyte count elevations199–201; left upper quadrant and left shoulder pain as a consequence of splenic infarction and
perisplenitis; vasopressinresponsive diabetes insipidus202,203; and acne urticata associated with hyperhistaminemia.204 Acute febrile neutrophilic
dermatosis (Sweet syndrome), a perivascular infiltrate of neutrophils in the dermis, can occur. In Sweet syndrome, fever accompanied by painful
maculonodular violaceous lesions on the trunk, arms, legs, and face are characteristic.205,206 Spontaneous rupture of the spleen is a rare event.207,208
Digital necrosis has been reported as a rare paraneoplastic event.209,210
In an increasing proportion of patients, the disease is discovered, coincidentally, when blood cell counts are measured at a periodic medical
examination.
CHILDHOOD AND ADOLESCENT OR YOUNG ADULT PRESENTATION
Hyperleukocytosis and symptoms or signs thereof are a more common feature in patients who present with CML before the age of 20 years. The mean
white cell count at diagnosis in all children is twice that of adults. The fraction of blood blasts, promyelocytes, and myelocytes is significantly higher;
and clinical manifestations of hyperleukocytosis are far more frequent in children than adults.200 Young adults also have been found to have increased
frequency of splenomegaly and greater spleen size as well as lower rates of disease response to TKIs and higher rates of transformation. 211,212
LABORATORY FINDINGS
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CHILDHOOD AND ADOLESCENT OR YOUNG ADULT PRESENTATION
Hyperleukocytosis and symptoms or signs thereof are a more common feature in patients who present with CML before the age of 20 years. The mean
white cell count at diagnosis in all children is twice that of adults. The fraction of blood blasts, promyelocytes, and myelocytes is significantly higher;
and clinical manifestations of hyperleukocytosis are far more frequent in children than adults.200 Young adults also have been found to have increased
frequency of splenomegaly and greater spleen size as well as lower rates of disease response to TKIs and higher rates of transformation.211,212
LABORATORY FINDINGS
Blood
The presumptive diagnosis of CML can be made from the results of the blood cell counts and examination of the blood film.196,197 The blood
hemoglobin concentration is decreased in most patients at the time of diagnosis. Red cells usually are only slightly altered, with an increase in variation
from small to large size and only occasionally misshapen (elliptical or irregular) erythrocytes. Small numbers of nucleated red cells are commonly
present. The reticulocyte count is normal or slightly elevated, but clinically significant hemolysis is rare.196,213,214 Rare cases of mild
erythrocytosis215,216 or erythroid aplasia217,218 have been documented.
The total leukocyte count is elevated at the time of diagnosis. Granulocytes at all stages of development are present in the blood and are generally
normal in appearance (Fig. 88–6). In the series shown in Table 88–1, the mean blast cell prevalence was approximately 3% but can range from 0% to
10%; progranulocyte prevalence was approximately 4%; myelocytes, metamyelocytes, and bands accounted for approximately 40%; and segmented
neutrophils accounted for approximately 35% of total leukocytes (Table 88–1). Often, there is a “myelocyte bulge” in which the differential count
shows an exaggerated proportion of myelocytes compared to the proportion observed in normal persons. Hypersegmented neutrophils are
commonly present.
Figure 88–6.
Blood and marrow cells characteristic of chronic myelogenous leukemia. A . Blood film. Elevated leukocyte count. Elevated platelet count (aggregates).
Characteristic array of immature (myelocytes, metamyelocytes, band forms) and mature neutrophils. B . Blood film. Elevated leukocyte count.
Characteristic array of immature (myelocytes, metamyelocytes, band forms) and mature neutrophils. Two basophils in the field. Absolute basophilia is
a constant finding in CML. C . Blood film. Elevated leukocyte count. Characteristic array of immature (promyelocytes, myelocytes, metamyelocytes, band
forms) and mature neutrophils. Basophil in the field. Two myeloblasts in upper center. Note multiple nucleoli (abnormal) and agranular cytoplasm. D .
Marrow section. Hypercellular. Replacement of fatty tissue (normally approximately 60% of marrow volume in adults of this patient’s age) with
hematopoietic cells. Intense granulopoiesis and evident megakaryocytopoiesis. Decreased erythropoiesis. (Reproduced with permission from
Lichtman’s Atlas of Hematology, www.accessmedicine.com.)
TABLE 88–1.
White Blood Cell Differential Count at the Time of Diagnosis in 90 Cases of Ph+ Chronic Myelogenous Leukemia
Percent of Total Leukocytes (Mean Values)
Myeloblasts 3.0
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TABLE 88–1.
White Blood Cell Differential Count at the Time of Diagnosis in 90 Cases of Ph+ Chronic Myelogenous Leukemia
Percent of Total Leukocytes (Mean Values)
Myeloblasts 3.0
Promyelocytes 4.0
Myelocytes 12.0
Metamyelocytes 7.0
Band forms 14.0
Segmented forms 38.0
Basophils 3.0
Eosinophils 2.0
Nucleated red cells 0.5
Monocytes 8.0
Lymphocytes 8.0
In these 90 patients, the mean hematocrit was 31 mL/dL, mean total white cell count was 160 × 109/L, and mean platelet count was 442 × 109/L at the time of
diagnosis.
Data from Hematology Unit, University of Rochester Medical Center, Rochester, NY.
Neutrophil alkaline phosphatase activity is low or absent in more than 90% of patients with CML.219 With the availability of specific markers, BCRABL1
in CML and JAK2 mutations in polycythemia, leukocyte alkaline phosphatase is no longer used for diagnostic purposes.
The proportion of eosinophils usually is not increased, but the absolute eosinophil count nearly always is increased. Rarely, eosinophils are so
prominent that they dominate the granulocytic cells and lead to the designation Phpositive eosinophilic CML. An absolute increase in the basophil
concentration is present in almost all patients, and this finding can be useful in preliminary consideration of the differential diagnosis.220 Basophilic
progenitor cells are increased in the blood.221 The proportion of basophils usually is not greater than 15% during the chronic phase but may, in rare
patients, represent 30% to 80% of the total leukocyte count during chronic phase and lead to the designation of Phpositive basophilic CML.222 Flow
cytometry using antiCD203c provides very accurate assessment of the basophil frequency.223 Basophils may be hypogranulated or have an immature
phenotype and may be left uncounted in an optical differential white cell count. AntiCD203c recognizes these cells as basophils.224 Granules of
basophils in patients with CML, unlike normal basophils, contain mast cell αtryptase.224,225 Granulocytes containing both eosinophilic and basophilic
granules (mixed granulation) are commonly present.225
The total absolute lymphocyte count is increased (mean: approximately 15 × 109/L) in patients with CML at the time of diagnosis226 as a result of the
balanced increase in Thelper and Tsuppressor cells.227 B lymphocytes are not increased.228 T lymphocytes are increased in the spleen.228 NK cell
activity is defective in CML patients as a result of decreased maturation of these cells in vivo.229 The platelet count is elevated in approximately 50% of
patients at the time of diagnosis and is normal in most of the rest.230 The median value in patients at diagnosis is approximately 400 × 109 cells/L. The
platelet count may increase during the course of the chronic phase. Platelet counts greater than 1000 × 109/L are not unusual, and platelet counts as
high as 5000–7000 × 10 9/L have occurred. Thrombohemorrhagic complications of thrombocytosis are infrequent. Occasionally, the platelet count may
be below normal (<150 × 109/L) at the time of diagnosis, but this finding usually signals an impending progression to the accelerated phase of the
disease (see “Accelerated Phase and Blast Crisis of Chronic Myelogenous Leukemia” below) and may also occur with massive splenomegaly.
granules (mixed granulation) are commonly present.225
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The total absolute lymphocyte count is increased (mean: approximately 15 × 109/L) in patients with CML at the time of diagnosis226 as a result of the
balanced increase in Thelper and Tsuppressor cells.227 B lymphocytes are not increased.228 T lymphocytes are increased in the spleen.228 NK cell
activity is defective in CML patients as a result of decreased maturation of these cells in vivo.229 The platelet count is elevated in approximately 50% of
patients at the time of diagnosis and is normal in most of the rest.230 The median value in patients at diagnosis is approximately 400 × 109 cells/L. The
platelet count may increase during the course of the chronic phase. Platelet counts greater than 1000 × 109/L are not unusual, and platelet counts as
high as 5000–7000 × 109/L have occurred. Thrombohemorrhagic complications of thrombocytosis are infrequent. Occasionally, the platelet count may
be below normal (<150 × 109/L) at the time of diagnosis, but this finding usually signals an impending progression to the accelerated phase of the
disease (see “Accelerated Phase and Blast Crisis of Chronic Myelogenous Leukemia” below) and may also occur with massive splenomegaly.
Functional abnormalities of neutrophils (adhesion, emigration, phagocytosis) are mild; are compensated for by high neutrophil concentrations; and
do not predispose patients in chronic phase to infections by either usual or opportunistic organisms.231–233 Platelet dysfunction can occur, but is not
associated with spontaneous or exaggerated bleeding. A decrease in the second wave of epinephrineinduced platelet aggregation is the most
common abnormality and is associated with a deficiency of adenine nucleotides in the storage pool.234,235
Marrow
Morphology
The marrow is markedly hypercellular, and hematopoietic tissue takes up 75% to 90% of the marrow volume, with fat markedly reduced (see Fig. 88–7
below in “Cytogenetics”).236,237 Granulopoiesis is dominant, with a granulocytictoerythroid ratio between 10:1 and 30:1, rather than the normal 2:1 to
4:1. Erythropoiesis usually is decreased, and megakaryocytes are normal or increased in number. Eosinophils and basophils may be increased, usually
in proportion to their increase in the blood. Mitotic figures are increased in number. Mast cells are often seen, and uncommonly a juxtamembrane
domain mutant of KIT coincides with BCRABL1 in CML.238 Rare reports of marrow mastocytosis have been explained by a KIT mutation as an additional
genetic abnormality or by dual clones in the marrow.239,240 Macrophages that mimic Gaucher cells in appearance are sometimes seen. This finding is a
result of the inability of normal cellular glucocerebrosidase activity to degrade the increased glucocerebroside load associated with markedly
increased cell turnover.241 Macrophages also can become engorged with lipids, which, when oxidized and polymerized, yield ceroid pigment. This
pigment imparts a granular and bluish cast to the cells after polychrome staining; such cells have been referred to as seablue histiocytes.241
Collagen type III (reticulin fibrosis), which takes the silver impregnation stain, is increased at the time of diagnosis in nearly half the patients,242 and is
correlated with the proportion of megakaryocytes in the marrow.243,244 Increased fibrosis also is correlated with larger spleen size, more severe
anemia, and a higher proportion of marrow and blood blast cells.
The marrows of patients with CML have a mean doubling of microvessel density compared to healthy controls and have more angiogenesis in marrow
than other forms of leukemiaa.245–247 This increased marrow vascularity decreases to normal after treatment.248
Cytogenetics
The marrow and nucleated blood cells of approximately 90% of patients with clinical and laboratory signs that fall within the criteria for the diagnosis
of CML contain the Ph chromosome (22q−) as measured by Gbanding, and virtually all patients have the t(9;22)(q34;q11)(BCRABL1) by FISH. The Ph
chromosome is present in all blood cell lineages (erythroblasts, granulocytes, monocytes, megakaryocytes, Tcell and Bcell progenitors) but is not
present in the majority of blood B lymphocytes or in most T lymphocytes.53 Approximately 70% of patients in the chronic phase have only the classic Ph
chromosome in their cells.249 The remaining 20% also have a missing Y chromosome [t(Ph),−Y]; an additional Cgroup chromosome, usually number 8
[t(Ph),+8]; an additional chromosome 22q− but without the 9q+ [t(Ph), 22q−]; or t(Ph) plus either another stable translocation or another minor clone.
These variations have not been shown to affect the duration of the chronic phase. Deletion of the Y chromosome occurs in approximately 10% of
healthy men older than 60 years.250,251
Variant Ph chromosome translocations occur in approximately 5% of individuals with CML and involve complex rearrangements (3 chromosomes), and
every chromosome except the Y chromosome can be involved.252–256 The Ph chromosome, that is, 22q−, is present, but the gross exchange of
chromosomal material involves a chromosome other than 9 (simple variant) or involves exchange of material among chromosomes 9 and 22 and a
third or more chromosomes (complex variant; Fig. 88–7). Highresolution techniques have indicated that 9q34qter is transposed to 22q11 in simple
and in complex translocations.257,258 Thus, the fusion of 9q34 with 22q11 seems to occur in the cells of most patients with CML.259 Complex
translocations involving chromosome 3 have been notable.260,261 In rare cases, a reciprocal translocation with a chromosome other than 9 to
chromosome 22 is larger than usual, and the posttranslocation shortening of the long arms of 22 is not apparent. This circumstance has been referred
to as a masked Ph chromosome or masked translocation because the 22q− is not evident by microscopic examination,262,263 although t(9;22) may
occur as judged by banding techniques or molecular probes.264
Variant Ph chromosome translocations occur in approximately 5% of individuals with CML and involve complex rearrangements (3 chromosomes), and
every chromosome except the Y chromosome can be involved.252–256 The Ph chromosome, that is, 22q−, is present, but the gross exchange of
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chromosomal material involves a chromosome other than 9 (simple variant) or involves exchange of material among chromosomes 9 and 22 and a
third or more chromosomes (complex variant; Fig. 88–7). Highresolution techniques have indicated that 9q34qter is transposed to 22q11 in simple
and in complex translocations.257,258 Thus, the fusion of 9q34 with 22q11 seems to occur in the cells of most patients with CML.259 Complex
translocations involving chromosome 3 have been notable.260,261 In rare cases, a reciprocal translocation with a chromosome other than 9 to
chromosome 22 is larger than usual, and the posttranslocation shortening of the long arms of 22 is not apparent. This circumstance has been referred
to as a masked Ph chromosome or masked translocation because the 22q− is not evident by microscopic examination,262,263 although t(9;22) may
occur as judged by banding techniques or molecular probes.264
Figure 88–7.
Translocations involved in chronic myelogenous leukemia. The positions of the ABL gene in each of the chromosomes before and after the
translocation are noted. The origin of the chromosomal segments in each of the translocated chromosomes is indicated by a bracket on the side of the
chromosome. (Reproduced with permission from Rosson D, Reddy EP. Activation of the abl oncogene and its involvement in chromosomal
translocations in human leukemia. Mutat Res. 1988 May;195(3):231243.)
Approximately 10% of patients have a deletion of the derivative 9 chromosome adjacent to the chromosome breakpoint. Although this deletion is
thought to be an important factor in resistance to drug effects with IFN therapy, it does not appear to be significant with the use of imatinib.163
Molecular Probes
In a small proportion of patients with a clinical disease analogous to CML, cytogenetic studies do not disclose a classic, variant, or masked Ph
chromosome. In these cases, use of a panel of restriction enzymes and Southern blot analyses with a molecular probe for the breakpoint cluster
region on chromosome 22 nearly always detects rearrangement of fragments. This finding has led to the conclusion that almost all cases of CML have
an abnormality of the long arm of chromosome number 22 (BCR rearrangement).265–270 Phnegative CML cells with BCR rearrangement can express
p210BCRABL1, and such patients have a clinical course similar to Phpositive CML.265,270–273
The ability to identify the molecular consequences of the t(9;22), that is, BCR rearrangement, mRNA transcripts of the mutant fusion gene, and p210BCR
ABL1, has resulted in diagnostic tests supplementary to cytogenetic analysis.269 These tests include Southern blot analysis of BCR rearrangement,271–275
polymerase chain reaction (PCR) amplification of the abnormal mRNA,276 and a lesscomplex variation on PCR, a hybridization protection assay.277
PCR can achieve a sensitivity of 1 positive cell in approximately 500,000 to 1 million cells. This extreme sensitivity requires special care in analysis and
the inclusion of negative controls.278–281 Fusions e13a3, e14a3, and e19a2 are not detectable with standard PCR primers.282
an abnormality of the long arm of chromosome number 22 (BCR rearrangement).265–270 Phnegative CML cells with BCR rearrangement can express
p210BCRABL1, and such patients have a clinical course similar to Phpositive CML.265,270–273
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The ability to identify the molecular consequences of the t(9;22), that is, BCR rearrangement, mRNA transcripts of the mutant fusion gene, and p210BCR
ABL1, has resulted in diagnostic tests supplementary to cytogenetic analysis.269 These tests include Southern blot analysis of BCR rearrangement,271–275
polymerase chain reaction (PCR) amplification of the abnormal mRNA,276 and a lesscomplex variation on PCR, a hybridization protection assay.277
PCR can achieve a sensitivity of 1 positive cell in approximately 500,000 to 1 million cells. This extreme sensitivity requires special care in analysis and
the inclusion of negative controls.278–281 Fusions e13a3, e14a3, and e19a2 are not detectable with standard PCR primers.282
A multicolor FISH method to detect the BCRABL1 fusion in patients with CML is a rapid and sensitive alternative to Southern blot and PCRdependent
methods.283 For diagnostic purposes, FISH is simple, accurate, and sensitive, and can detect the various molecular fusions (eg, e13a2, e14a2, e1a2).284–
288 Interphase FISH is faster and more sensitive than cytogenetics in identifying the Ph chromosome. If the concentration of CML cells is very low,
interphase FISH may not detect BCRABL1, so it has limited use for detecting minimal residual disease.289 Hypermetaphase FISH allows analysis of up to
500 metaphases per sample in 1 day. Several factors influence the falsepositive and falsenegative rates of FISH identification of BCRABL1, including
definition of a fusion signal, nuclear size, and the genomic position of the ABL1 breakpoint.290 Double BCRABL fusion signals (doublefusion [D]FISH)
have been proposed as being more accurate than the fusion signal used in dual color (singlefusion) SFISH, because in the latter case a small
percentage of the normal BCR and ABL1 signals overlap.291
The frequency of cytogenetic analysis can be reduced if patients are monitored by molecular methods such as competitive reverse transcriptase (RT)
PCR. Molecular analyses can be performed on blood samples and therefore are much easier to use than cytogenetic analysis of marrow cell
metaphases. Quantitative RTPCR is the method of choice for monitoring patients for residual disease or reappearance of disease after marrow
transplantation and for following response to TKIs. Documentation that routine cytogenetics have become negative for the Ph chromosome has
traditionally been thought to be important, but this paradigm is being questioned as a complete cytogenetic response (CCyR) is equivalent to a
negative FISH test and BCRABL1 transcripts <1%.19 Competitive PCR can detect reappearance of or increasing levels of BCRABL1 RNA transcripts prior
to clinical relapse in patients after transplantation.284,292,293
Chemical Abnormalities
Uric Acid
An increased production of uric acid with hyperuricemia and hyperuricosuria occurs in untreated CML.294 Uric acid excretion often is 2–3 times normal
in patients with CML. If aggressive therapy leads to rapid cell lysis, excretion of the additional purine load may produce urinary tract blockage from uric
acid precipitates. Formation of urinary urate stones is common in patients with CML, and some patients with latent gout may develop acute gouty
arthritis or uric acid nephropathy.295 The likelihood of complications from urate overproduction is greatly increased by starvation, acidosis, renal
disease, or diuretic drug therapy.
Serum Vitamin B12–Binding Proteins and Vitamin B12
Neutrophils contain vitamin B12–binding proteins, including transcobalamins I and III (synonym: Rtype B12binding protein or cobalophilin).296–299
Patients with myeloproliferative neoplasms have an increased serum level of vitamin B12–binding capacity, and the source of the protein is principally
mature neutrophilic granulocytes.296–299
Pernicious anemia and CML may rarely coexist. In this situation, the tissues are vitamin B12 deficient, but the serum vitamin B12 level may be normal
because of the elevated level of transcobalamin I, a binder with a very high affinity for vitamin B12.300
Whole Blood Histamine
Mean histamine levels can be markedly increased in patients in chronic phase (median: approximately 5000 ng/mL) compared to healthy individuals
(median: approximately 50 ng/mL); and, this elevation is correlated with the blood basophil count.301 Cases of exaggerated basophilia and disabling
pruritus, urticaria, and gastric hyperacidity have occurred, associated with enormous increases (several hundredfold) of blood histamine
concentration.302,303
Serum Lactic Acid Dehydrogenase, Potassium, Calcium, and Cholesterol
The level of serum lactic acid dehydrogenase (LDH) is elevated in CML.304 Pseudohyperkalemia resulting from the release of potassium from white cells
during clotting and spurious hypoxemia or pseudohypoglycemia from in vitro use of oxygen or glucose by granulocytes can occur. Hypercalcemia306
305
or hypokalemia307 has occurred during the chronic phase of the disease, but such complications are very rare until the disorder transforms to acute
(median: approximately 50 ng/mL); and, this elevation is correlated with the blood basophil count.301 Cases of exaggerated basophilia and disabling
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pruritus, urticaria, and gastric hyperacidity have occurred, associated with enormous increases (several hundredfold) of blood histamine
concentration.302,303
Serum Lactic Acid Dehydrogenase, Potassium, Calcium, and Cholesterol
The level of serum lactic acid dehydrogenase (LDH) is elevated in CML.304 Pseudohyperkalemia resulting from the release of potassium from white cells
during clotting305 and spurious hypoxemia or pseudohypoglycemia from in vitro use of oxygen or glucose by granulocytes can occur. Hypercalcemia306
or hypokalemia307 has occurred during the chronic phase of the disease, but such complications are very rare until the disorder transforms to acute
leukemia. Elevated serum and urinary lysozyme levels are features of leukemia with greater monocytic components and are not features of CML.308
Serum cholesterol is decreased in patients with CML.309,310
Serum Angiogenic Factors
Angiogenin, endoglin (CD105), vascular endothelial growth factor (VEGF), βfibroblast growth factor, and hepatocyte growth factor are increased
strikingly in the serum of CML patients.246,247,311,312
SPECIAL CLINICAL FEATURES
BCRABL1–POSITIVE THROMBOCYTHEMIA
Either of 2 syndromes—thrombocythemia with the Ph chromosome and BCRABL1 rearrangement or thrombocythemia without a Ph chromosome but
with the BCRABL1 rearrangement—may precede the overt signs of CML or its accelerated phase.313–316 In general, the disease closely mimics classic
essential thrombocythemia initially: marked platelet elevation, extreme megakaryocytic hyperplasia, normal or mildly elevated white cell count, no or
very slight myeloid immaturity in the blood, and minimal anemia. Minor bleeding, such as epistaxis, erythromelalgia, or signs of thrombosis, such as
cerebral or limb ischemia, are occasionally present. In some cases, the absolute basophil count is mildly elevated. Approximately 5% of patients with
apparent essential thrombocythemia have a Ph chromosome.313 Evolution to blast crisis may occur.317,318 In one study of 87 Phpositive patients out of
1591 patients with extreme thrombocytosis, there was a female predominance, an e14a2 subtype, and high or intermediate risk by Sokal or Euro
prognostic scoring (see “Course and Prognosis” below for details of these scores). Those cases demonstrated good cytogenetic and molecular
responses to TKIs.319 The diseases in these patients were JAK2 negative, but there are reports of the coexistence of JAK2 or calreticulin mutations in
CML, which can affect TKI responses.320
NEUTROPHILIC CHRONIC MYELOGENOUS LEUKEMIA
A rare variant of BCRABL1–positive CML has been described in which the elevated white cell count is composed principally of mature
neutrophils.321,322 The white cell count is lower (30–50 × 109/L) at the time of diagnosis than is the case with classic CML (100–150 × 109/L). Moreover,
patients with neutrophilic CML usually do not have basophilia, notable myeloid immaturity in the blood, prominent splenomegaly, or low leukocyte
alkaline phosphatase scores. The cells of these patients have the Ph chromosome but have an unusual BCRABL1 fusion gene in that the breakpoint in
the BCR gene is between exons 19 and 20. This breakpoint location results in fusion of most of the BCR gene with ABL1 (e19a2 type BCRABL1), which
leads to a larger fusion protein (230 kDa) compared to the fusion protein in classic CML (210 kDa; see Fig. 88–3). This correlation between genotype and
phenotype has not been observed in all cases.323 This CML variant usually has an indolent course, which may be the result of very low levels of mRNA
for p230 and the undetectable or barely detectable p230 protein in cells.324
MINORBCR BREAKPOINT–POSITIVE CHRONIC MYELOGENOUS LEUKEMIA
A small portion of patients with BCRABL1–positive CML have the breakpoint on the BCR gene in the first intron (mbcr), resulting in a 190kDa fusion
protein instead of the classic 210kDa protein observed in most patients with CML (see Fig. 88–3). The mbcr molecular lesion is similar to that
observed in approximately 60% of patients with BCR rearrangementpositive ALL. In patients with mbcr CML, monocytes are more prominent, the
white cell count is lower on average, and basophilia and splenomegaly are less prominent than in disease with classic BCR breakpoint (Mbcr). The few
reported cases had a short interval before either myeloid or lymphoid blast transformation developed.325,326
HYPERLEUKOCYTOSIS
A small percentage of patients present with symptoms or signs referable to leukostasis as a result of the intravascular flowimpeding effects of white
cell counts greater than 300 × 109/L.199 Hyperleukocytosis is more prevalent in children with Phpositive CML.200 The effects of total leukocyte counts
from 300–800 × 109/L include impaired circulation of the lung, central nervous system, special sensory organs, and penis, resulting in some
combination of tachypnea, dyspnea, cyanosis, dizziness, slurred speech, delirium, stupor, visual blurring, diplopia, retinal vein distention, retinal
hemorrhages, papilledema, tinnitus, impaired hearing, and priapism.201 In asymptomatic patients with hyperleukocytosis, initial treatment with
reported cases had a short interval before either myeloid or lymphoid blast transformation developed.325,326 Access Provided by:
HYPERLEUKOCYTOSIS
A small percentage of patients present with symptoms or signs referable to leukostasis as a result of the intravascular flowimpeding effects of white
cell counts greater than 300 × 109/L.199 Hyperleukocytosis is more prevalent in children with Phpositive CML.200 The effects of total leukocyte counts
from 300–800 × 109/L include impaired circulation of the lung, central nervous system, special sensory organs, and penis, resulting in some
combination of tachypnea, dyspnea, cyanosis, dizziness, slurred speech, delirium, stupor, visual blurring, diplopia, retinal vein distention, retinal
hemorrhages, papilledema, tinnitus, impaired hearing, and priapism.201 In asymptomatic patients with hyperleukocytosis, initial treatment with
hydration and hydroxyurea usually can be used to decrease the white cell count. Hydroxyurea treatment should be designed to accomplish a gradual
decrease in white cell count over a few days so as to avoid the tumor lysis syndrome. If signs of hyperleukocytosis are present, hydration,
leukapheresis, and hydroxyurea can be used simultaneously; hydroxyurea dose should be selected to avoid exaggerated tumor lysis.
CONCURRENCE OF LYMPHOID MALIGNANCIES
CML may emerge in patients with established chronic lymphocytic leukemia (CLL).327–329 A few patients have presented with simultaneous occurrence
of the 2 diseases.330,331 A single case of lymphocytic leukemoid reaction simulating CLL that regressed as CML emerged has been reported.332 In some
cases, the CLL lymphocytes did not contain the Ph chromosome, whereas the CML cells did, suggesting the presence of 2 independent clonal
disorders.327,328,332,333 In other cases, the Ph chromosome was present in the myeloid and lymphoid cells, indicating a common origin.331 Concomitant
imatinib and ibrutinib have been used to treat a patient with both CML and CLL.334
DIFFERENTIAL DIAGNOSIS
Diseases Mimicking Chronic Myelogenous Leukemia
The diagnosis of CML is made based on the characteristic granulocytosis, white cell differential count, increased absolute basophil count, and
splenomegaly coupled with the presence of the Ph chromosome or its variants (90% of patients) or a BCR rearrangement on chromosome 22 (>95% of
patients).
Patients with other chronic hematopoietic stem cell diseases, such as polycythemia vera, essential thrombocythemia, or primary myelofibrosis, only
occasionally have closely overlapping features. For example, the total white cell count is greater than 30 × 109/L in more than 90% of patients with CML
and increases inexorably over weeks or months of observation, whereas the total white cell count is less than 30 × 109/L in more than 90% of patients
with the 3 other classic chronic clonal myeloid diseases and usually does not change significantly over months to years. Polycythemia vera is associated
with increased red cell mass and hemoglobin concentration and displays clinical signs of plethora; CML does not have these features. Patients with
primary myelofibrosis invariably have marked teardrop poikilocytes and other severe red cell shape, size, and chromicity changes, as well as
prominent nucleated red cells in the blood; CML rarely has these features. Patients with essential thrombocythemia have a platelet count greater than
450 × 109/L and usually only mild neutrophilia (<20 × 109/L); the slight neutrophilia distinguishes it from the proportion (approximately 25%) of CML
patients with platelet counts greater than 450 × 109/L, who at the time of diagnosis have white cell counts higher than 25 × 109/L. In addition, patients
with the clinical features of polycythemia vera or primary myelofibrosis do not have the Ph chromosome or BCR rearrangement in their blood and
marrow cells, except in extremely rare cases. A very small proportion of patients with apparent essential thrombocythemia has BCRABL1 transcripts in
their marrow and blood cells, and occasionally a Ph chromosome and may represent an atypical initial phase of CML (see “BCRABL1–Positive
Thrombocythemia” above). The presence of a mutation in the JAK2 gene in more than 95% of patients with polycythemia vera is an important
distinguishing feature (Chap. 83). The blood cells of approximately 50% of patients with primary myelofibrosis or essential thrombocythemia carry the
JAK2 gene mutation and in those with primary myelofibrosis who do not, another 40% have a mutation in the calreticulin or the cMPL gene (Chap. 85).
Increased awareness of the features of related disorders, such as chronic myelomonocytic leukemia (CMML) and chronic neutrophilic leukemia (CNL),
and an appreciation that older patients are prone to atypical clonal myeloid diseases, have minimized the inappropriate diagnosis of Phnegative CML,
which should be avoided unless the clinical features are characteristic of classic CML and a masked Ph chromosome or BCR rearrangement is not
found.
Reactive leukocytosis can occur with absolute neutrophil counts of 30–100 × 109/L. Usually these leukemoid reactions occur in the setting of an overt
inflammatory disease (eg, pancreatitis), cancer (eg, lung), or infection (eg, pneumococcal pneumonia). If the incitant is not apparent, the absence of
granulocytic immaturity, basophilia, or splenomegaly, and the absence of BCRABL1 in blood cells virtually eliminates classic CML as a consideration.
THERAPY
HYPERURICEMIA
Hyperuricemia and hyperuricosuria are frequent features of CML at diagnosis or in relapse.335 The need for treatment of hyperuricemia is a function of
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Reactive leukocytosis can occur with absolute neutrophil counts of 30–100 × 109/L. Usually these leukemoid reactions occur in the setting of an overt
inflammatory disease (eg, pancreatitis), cancer (eg, lung), or infection (eg, pneumococcal pneumonia). If the incitant is not apparent, the absence of
granulocytic immaturity, basophilia, or splenomegaly, and the absence of BCRABL1 in blood cells virtually eliminates classic CML as a consideration.
THERAPY
HYPERURICEMIA
Hyperuricemia and hyperuricosuria are frequent features of CML at diagnosis or in relapse.335 The need for treatment of hyperuricemia is a function of
the elevated pretreatment serum uric acid concentration, blood white cell concentration, spleen size, and dose of cytolytic therapy planned. If these
variables suggest a high risk for a significant amount of cell lysis, allopurinol (Zyloprim) 300 mg/day orally and adequate hydration to maintain a good
urine flow should be instituted prior to therapy. Allopurinol is associated with a high frequency of allergic skin reactions and should be discontinued
after the blood leukocyte count and spleen size have decreased and the risk of exaggerated cell lysis has passed. If hyperuricemia is extreme, usually
over 9 mg/dL, rasburicase (Elitek) can be administered.336 Rasburicase is a recombinant urate oxidase that converts uric acid to allantoin. Rasburicase,
unlike allopurinol, reduces the uric acid pool very rapidly, does not result in the accumulation of xanthine or hypoxanthine, and does not require
alkalinization of urine, thus facilitating phosphate excretion.337 Although the manufacturer recommends a dose every day for 5 days, several reports
have indicated that 1 injection will produce a rapid and sustained decrease in serum uric acid, significantly decreasing the cost of therapy.338 Another
alternative is to use allopurinol for a few days after 1 injection of rasburicase. A dose of 0.2 mg/kg of ideal body weight of rasburicase intravenously has
been used.339
INITIAL CYTOREDUCTION THERAPY
A TKI is now used as initial therapy in patients with CML. In cases where the white cell count is markedly elevated, hydroxyurea can be used prior to or
in conjunction with a TKI. If rapid cytoreduction is required because of signs of the hyperleukocytic syndrome, leukapheresis and hydroxyurea often
are combined.
Leukapheresis
Leukapheresis can control CML only temporarily. For this reason, it is rarely used in chronic phase CML and is useful in only 2 types of patients: the
hyperleukocytic patient in whom rapid cytoreduction can reverse symptoms and signs of leukostasis (eg, stupor, hypoxia, tinnitus, papilledema,
priapism),199–201 and in the pregnant patient with CML who can be controlled by leukapheresis treatment without other therapy either during the early
months of pregnancy when therapy poses a higher risk to the fetus or, in some cases, throughout the pregnancy.340,341 Because of the large body
burden of leukocytes in marrow, blood, and spleen, and the high proliferative rate in CML, leukocyte reduction by apheresis is less efficient than in
other types of leukemia.199,201 Leukapheresis reduces the burden of tumor cells subject to chemotherapeutically induced cytolysis and thus the
production and the excretion of uric acid. In hyperleukocytic nonpregnant patients, leukapheresis is best used in conjunction with hydroxyurea to
ensure rapid and optimal reduction in white cell count.
Hydroxyurea
Hydroxyurea (Droxia, Hydrea) 1–6 g/day orally, depending on the height of the white cell count, can be used to initiate elective therapy.342 Urgent
treatment of extraordinary total white cell counts may require higher doses. The dose of hydroxyurea should be decreased as the total white cell count
decreases and usually is given at 1–2 g/day when the total white cell count reaches 20 × 109/L. The drug should be temporarily discontinued if the white
cell count drops below 5 × 109/L. If hydroxyurea is being used in combination with a TKI, it is usually tapered and discontinued once a hematologic
response to the TKI is observed.
Anagrelide
Anagrelide (Agrylin) can be used for platelet reduction in patients who present with elevated platelet counts. This agent acts directly to decrease
megakaryocyte mass, and it can lead to a precipitous fall in platelet counts. In occasional patients who still have significant thrombocythemia after a
TKI is initiated, combination with anagrelide is associated with a normalization of platelet counts.343
INITIAL THERAPY WITH A TYROSINE KINASE INHIBITOR
Multiple kinases are now available for initial therapy of CML, making the choice of therapy difficult at times. Imatinib mesylate (imatinib, Gleevec) was
the first TKI developed, and it was approved by the FDA for initial therapy of CML in 2002. Subsequently, 2 secondgeneration TKIs (2GTKIs), nilotinib
(Tasigna) and dasatinib (Sprycel), were approved for initial therapy in 2010, and in 2017, bosutinib (Bosulif), a thirdgeneration TKI (3GTKI) received
such approval. These approvals were based on superior cytogenetic and molecular response rates at benchmark time points and lower rates of
conversion to accelerated or blast phase as compared with imatinib. Thus far, however, an overall survival (OS) advantage of dasatinib, nilotinib, or
megakaryocyte mass, and it can lead to a precipitous fall in platelet counts. In occasional patients who still have significant thrombocythemia after a
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TKI is initiated, combination with anagrelide is associated with a normalization of platelet counts.343
INITIAL THERAPY WITH A TYROSINE KINASE INHIBITOR
Multiple kinases are now available for initial therapy of CML, making the choice of therapy difficult at times. Imatinib mesylate (imatinib, Gleevec) was
the first TKI developed, and it was approved by the FDA for initial therapy of CML in 2002. Subsequently, 2 secondgeneration TKIs (2GTKIs), nilotinib
(Tasigna) and dasatinib (Sprycel), were approved for initial therapy in 2010, and in 2017, bosutinib (Bosulif), a thirdgeneration TKI (3GTKI) received
such approval. These approvals were based on superior cytogenetic and molecular response rates at benchmark time points and lower rates of
conversion to accelerated or blast phase as compared with imatinib. Thus far, however, an overall survival (OS) advantage of dasatinib, nilotinib, or
bosutinib compared with imatinib has not been shown. Ponatinib (Iclusig) is not yet approved for initial therapy. Table 88–2 compares these
inhibitors.
TABLE 88–2.
Comparison of Tyrosine Kinase Inhibitors
Nilotinib Bosutinib
Imatinib (Gleevec) Dasatinib (Sprycel) Ponatinib (Iclusig)
(Tasigna) (Bosulif)
Indications Firstline therapy (CP, Firstline therapy Firstline therapy (CP), Firstline therapy Resistance or

AP, BP); (CP), resistance or resistance or intolerance to (CP); secondline intolerance to prior TKI
relapsed/refractory intolerance to other TKIs (CP, AP, or BP); Ph+ therapy (CP, AP, BP or Ph+ ALL; resistant or
Ph+ ALL; approved in imatinib (CP and ALL with resistance or with resistance or intolerant to all other
children with CML AP) intolerance to prior therapy intolerance) TKIs; all T315I+ cases
Usual dosing CP 400 mg/day CP 300 mg BID CP 100 mg/day 500 mg/day 45 mg/day

AP/BP/progression AP/BP 400 mg BID AP/BP 140 mg/day
600–800 mg/day
Common GI disturbance, edema Rash, GI Edema, pleural effusions, GI GI (diarrhea), rash, HBP, rash, GI, fatigue,

toxicities (including periorbital), disturbances, symptoms, rash, low edema, fatigue, low headache
(nonhematologic) muscle cramps, elevated lipase, phosphorus phosphorus,
arthralgia, hyperglycemia, low elevated LFTs
hypophosphatemia, phosphorus,
rash increased LFTs
Other significant Elevated LFTs (usually Peripheral vascular Pulmonary arterial Arterial and venous

toxicities appear in first month); disease, PT hypertension, QTc thrombosis, pancreatitis,
rare cardiac toxicity prolongation, prolongation liver failure, ocular
reported pancreatitis toxicity, cardiac failure
Drug–drug CYP3A4 inducers CYP3A4 inhibitors CYP3A4 inhibitors increase CYP3A inhibitors Strong CYP3A inhibitors

interactions decrease levels increase levels levels and inducers may increased serum levels
CYP3A4 inhibitors may CYP3A4 inducers CYP3A4 inducer decrease levels alter levels
increase levels may decrease Antacids decrease levels Acidreducing
It is an inhibitor of levels H2 antagonists/proton pump medication may
CYP3A4 and CYP2D6 Inhibitor of CYP3A4, inhibitors decrease levels lower levels
Pgp substrate CYP2C8, CYP2C9,
CYP2D6
Induces CYP2B6,
CYP2C8, and
CYP2C9
Administration Taken with food Taken on empty Can be taken with or without a Taken with food Taken with and without

considerations stomach; avoid meal food
food 2 h before and
2 h after dose Page 21 / 124
Black box None QT prolongation None None Arterial thrombosis;
warnings and sudden death hepatotoxicity
CYP2C8, and
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CYP2C9
Administration Taken with food Taken on empty Can be taken with or without a Taken with food Taken with and without

considerations stomach; avoid meal food
food 2 h before and
2 h after dose
Black box None QT prolongation None None Arterial thrombosis;

warnings and sudden death hepatotoxicity
Other Approved in pediatric Keep potassium, Ascites and pericardial effusion Has activity with T315I

considerations patients (340 Mg, calcium, can also occur; has CSF mutations; available in
mg/m2/day) in CP phosphorus replete penetration U.S. through ARIAD PASS
program
ALL, acute lymphocytic leukemia; AP, accelerated phase; ARIAD PASS, ARIAD Pharmaceutical’s Patient Access and Support Services; BP, blast phase; CP, chronic
phase; CSF, cerebrospinal fluid; CYP, cytochrome P450; GI, gastrointestinal; HBP, high blood pressure; LFT, liver function tests; Mg, magnesium; Pgp, Pglycoprotein;
Ph+, Philadelphia chromosome–positive; PT, prothrombin time; TKI, tyrosine kinase inhibitor.
All information is from the commercial package insert of the TKIs as listed.
Imatinib Mesylate
Patients with newly diagnosed, chronic phase CML can be started on imatinib, 400 mg/day by mouth. The goal of imatinib therapy is to decrease the
cells bearing the t(9;22) translocation (leukemic cells) to the lowest levels possible, during which process normal (polyclonal) hematopoiesis is
restored. The efficacy of imatinib is judged by measuring 3 benchmarks: hematologic response, cytogenetic response, and molecular response as
defined in Table 88–3.344,345 These benchmarks are used to determine its maximal therapeutic effect. The time to achieve a maximal effect is variable,
but as long as a patient is having a continued reduction in the size of the leukemic clone as judged by cytogenetic or PCR measurements, and has met
response benchmarks, the drug is continued at 400 mg/day. If the patient stops responding before a CCyR or complete molecular remission (CMR) is
achieved, the dose can be increased or, preferably, another TKI can be used. Approximately twothirds of patients who do not have a significant
hematologic response or who relapse while receiving imatinib at a dose of 400 mg/day achieve a complete or partial hematologic response with higher
doses, but few cytogenetic responses occur.346 Some patients without a cytogenetic response can enter a partial or CCyR with higher doses of imatinib.
Unfortunately, the responses to higher doses of imatinib in patients lacking a hematologic or cytogenetic response at 400 mg/day usually are
transient.347,348
TABLE 88–3.
Definition of a Treatment Response to a Tyrosine Kinase Inhibitor
Complete White cell count <10 × 109/L, platelet count <450 × 109/L, no immature myeloid cells in the blood, and disappearance of all signs
hematologic and symptoms related to leukemia (including palpable splenomegaly) lasting for at least 4 weeks
response (CHR)
Minor cytogenetic >35% of cell metaphases are Philadelphia (Ph) chromosome–positive by cytogenetic analysis of marrow cells
response (mCyR)
Partial cytogenetic 1–35% of cell metaphases are Phpositive by cytogenetic analysis of marrow cells
response (pCyR)
Major cytogenetic <35% of cell metaphases contain the Ph chromosome by cytogenetic analysis of marrow cells
response (MCyR)
Complete No cells containing the Ph chromosome by cytogenetic analysis of marrow cells
cytogenetic
response (CCyR)
Major molecular BCRABL1/ABL1 ratio <0.1% or a 3log reduction in quantitative polymerase chain reaction (qPCR) signal from mean pretreatment
response (MMR) baseline value, if International Standard (IS)based PCR not available
hematologic response or who relapse while receiving imatinib at a dose of 400 mg/day achieve a complete or partial hematologic response with higher
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doses, but few cytogenetic responses occur.346 Some patients without a cytogenetic response can enter a partial or CCyR with higher doses of imatinib.
Unfortunately, the responses to higher doses of imatinib in patients lacking a hematologic or cytogenetic response at 400 mg/day usually are
transient.347,348
TABLE 88–3.
Definition of a Treatment Response to a Tyrosine Kinase Inhibitor
Complete White cell count <10 × 109/L, platelet count <450 × 109/L, no immature myeloid cells in the blood, and disappearance of all signs
hematologic and symptoms related to leukemia (including palpable splenomegaly) lasting for at least 4 weeks
response (CHR)
Minor cytogenetic >35% of cell metaphases are Philadelphia (Ph) chromosome–positive by cytogenetic analysis of marrow cells
response (mCyR)
Partial cytogenetic 1–35% of cell metaphases are Phpositive by cytogenetic analysis of marrow cells
response (pCyR)
Major cytogenetic <35% of cell metaphases contain the Ph chromosome by cytogenetic analysis of marrow cells
response (MCyR)
Complete No cells containing the Ph chromosome by cytogenetic analysis of marrow cells
cytogenetic
response (CCyR)
Major molecular BCRABL1/ABL1 ratio <0.1% or a 3log reduction in quantitative polymerase chain reaction (qPCR) signal from mean pretreatment
response (MMR) baseline value, if International Standard (IS)based PCR not available
Complete molecular BCRABL1 mRNA levels undetectable by qPCR with assay sensitivity at least 4.5 logs below baseline (IS)
response (CMR)
Early molecular BCRABL1 ≤10% at 3 or 6 months

response (EMR)
Deep molecular Major molecular response (MMR) 4.5log reduction or not detected
response (DMR)
All BCR/ABL values should be tested using International Standard methodology.
Data from Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013
Aug 8;122(6):872884; NCCN Practice Guidelines in Oncology. Version 1.2019. Accessed June 3, 2020. https://www.nccn.org/professionals/physician_gls/default.aspx.
Several studies have examined initial use of imatinib at doses higher than 400 mg/day at time of diagnosis. Patients with newly diagnosed chronic
phase CML treated with imatinib, 800 mg/day, administered in two 400mg doses, every 12 hours, had a frequency of 90% CCyR, and 96% had at least a
major cytogenetic response (MCyR). At a median of 15 months, no patient had progressed and 63% of patients showed blood BCRABL1/ABL1
percentage ratios of less than 0.05%; 28% of patients had undetectable BCRABL1 blood levels.349 In one trial, major molecular remission (MMR) at 12
and 24 months was higher in those receiving doses of imatinib greater than 600 mg/day.350 In another trial, patients receiving 400 mg twice per day had
MCyRs of 90% at 12 months and 96% at 18 months; MMR rates were 48% at 6 months and 54% at 12 months. These results compared favorably to
historical data in the IRIS (International Randomized Study of Interferon and STI571) trial studying 400 mg/day of imatinib, and in which responses
were more rapid with the higher doses. More edema, gastrointestinal symptoms, rash, fatigue, and myelosuppression occurred at the higher doses.351
Despite these reports the current starting dose is customarily 400 mg/day, which balances effectiveness and tolerability in newly diagnosed patients.
Moreover, the more rapid response with higher doses of imatinib may not translate into better longterm results.352,353 For example, in another trial,
MMR and CCyR at 12 months were not significantly different between standard and highdose patients, although patients in higherrisk categories
based on Sokal scores fared better with highdose imatinib.352 (See “Course and Prognosis” below for an explanation of the Sokal score.) The
availability of 2GTKIs and 3GTKIs for initial therapy has diminished the enthusiasm for doses of imatinib higher than 400 mg daily. Some researchers
suggest, however, that new TKIs should be compared with higher doses of imatinib in trials of initial therapy, as the 400 mg dose of imatinib may not be
354
optimal.
Doses of imatinib lower than 400 mg/day result in fewer CCyR and a shorter duration of that response. Patients who are older and who have lower
were more rapid with the higher doses. More edema, gastrointestinal symptoms, rash, fatigue, and myelosuppression occurred at the higher doses.351
Despite these reports the current starting dose is customarily 400 mg/day, which balances effectiveness and tolerability in newly diagnosed patients.
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Moreover, the more rapid response with higher doses of imatinib may not translate into better longterm results.352,353 For example, in another trial,
MMR and CCyR at 12 months were not significantly different between standard and highdose patients, although patients in higherrisk categories
based on Sokal scores fared better with highdose imatinib.352 (See “Course and Prognosis” below for an explanation of the Sokal score.) The
availability of 2GTKIs and 3GTKIs for initial therapy has diminished the enthusiasm for doses of imatinib higher than 400 mg daily. Some researchers
suggest, however, that new TKIs should be compared with higher doses of imatinib in trials of initial therapy, as the 400 mg dose of imatinib may not be
optimal.354
Doses of imatinib lower than 400 mg/day result in fewer CCyR and a shorter duration of that response. Patients who are older and who have lower
body weight may only tolerate a lower dose, but they are less likely to achieve a CCyR.355 If however, a patient is on a lower dose (eg, 300 mg/day) for a
special reason (body size or tolerance level) and achieves a complete hematologic response (CHR) and CCyR within 12 months of onset of therapy,
acceptable outcomes without excess toxicity can result.356
Some patients were followed for more than 10 years on imatinib in the pivotal IRIS trial (IFNα plus cytarabine vs. STI571 [imatinib]).357 With a median
followup of 10.9 years, the best observed CCyR rate was 83%. Only 7% had progressed to accelerated or blast phase, and OS rate was 83%.
Approximately 37% of patients (204/553) had molecular assessments at 10 years, and 93% (190/204) of those had a MMR. By 10 years of followup on the
IRIS trial, 23% of patients (127/553) had discontinued imatinib treatment because of an unsatisfactory response or toxicity, and only 47% (260/553)
completed the study. The estimated OS rate at 10 years in the imatinib arm was 83%, but those with a MMR at 12 months had a 10year OS rate of 91%.
No cumulative toxicity was noted, and most serious adverse events occurred in the first year of treatment.357 The CML Study IV randomized patients
between imatinib at 400 mg/day, imatinib at 800 mg/day, imatinib plus IFNα, or imatinib plus cytarabine.358 After a median followup of 9.5 years, there
was no difference in OS between the imatinib 400 mg alone arm and any comparison group. In a multivariate analysis, poorrisk group, presence of
chromosomal aberrations, comorbidities, or smoking history decreased survival, and treatment rendered in an academic medical center increased
survival.358
Use of Imatinib in Patients with Variant Chromosomal Translocations or Breakpoints
Patients with variant Ph chromosome translocations who are treated with imatinib have a similar prognosis to that of patients with classic Ph
BCRABL
chromosome translocations.359 (See Fig. 88–3 for a diagram of breakpoints.) Patients with the e13a3, p210 translocation can respond well to
imatinib, with similar rates of complete cytogenetic remission.360 Overall, studies suggest that e14a2 patients have a faster and deeper response to
imatinib, and 2 groups found better OS on imatinib in those with the e14a2 transcript,361–363 but no influence of transcript on OS has been found in
other studies.364 The e1a2 transcript in CML is found in approximately 1.3% of patients, and these patients are more likely to have monocytosis and
more likely to present in blast phase. An inferior response to TKI therapy and inferior OS and transformationfree survival was found.365 In a patient
with both e1a2 and e14a2 fusion transcripts, only the p210 e14a2 transcript disappeared with treatment, whereas the e1a2 transcript persisted during
progression to blast phase. No mutation in the kinase domain of ABL1 was found.366 Thus, different clones in a patient may have a different sensitivity
to imatinib. Deletions of the derivative chromosome 9 do not influence the response and outcomes in CML chronic phase when using imatinib.367
Response to Imatinib in Children and Older Patients
More than 80% of children with chronic phase CML who are treated with imatinib, 260–570 mg/m2, enter a CCyR. This conclusion was based on the
study of persons aged 1 to 17 years (median 12 years) at diagnosis and and aged 3 to 20 years (median 14 years) at study entry. Imatinib is now
approved for use in pediatric patients. Weight gain is the most common side effect of imatinib in younger patients.368 Musculoskeletal pain also may be
greater in pediatric populations.369 As CML is rare in younger patients, there is a need for evidencebased guidelines regarding management of CML in
children and adolescents.370 A study from Japan found inferior outcomes in adolescent and young adult populations, but further study is required to
determine if this finding is due to biologic difference in the disease.371
Side Effects and Special Treatment Considerations
Imatinib is usually tolerated. Most adverse effects are manageable and seldom require permanent cessation of therapy. Reduction to subtherapeutic
doses is not recommended; it is better to interrupt therapy for a time.372
Myelosuppression is common, especially at treatment onset when the CML clone accounts for most of the blood cells. Dose reduction to less than 300
mg/day is not advisable for myelosuppression. The drug should be stopped until blood counts recover. GCSF or GMCSF can prevent or treat
neutropenia.373,374 Platelet transfusion may be used for severe thrombocytopenia. Patients with imatinibinduced chronic cytopenias have inferior
responses.375 Myelosuppression is an independent adverse factor for achieving cytogenetic responses with imatinib.376 Erythropoiesisstimulating
agents may be used to raise hemoglobin levels, and their use does not appear to affect CML outcomes, but may increase the risk of thrombosis.377
Severe irreversible marrow aplasias after imatinib exposure can occur.378
Imatinib is usually tolerated. Most adverse effects are manageable and seldom require permanent cessation of therapy. Reduction to subtherapeutic
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doses is not recommended; it is better to interrupt therapy for a time.372
Myelosuppression is common, especially at treatment onset when the CML clone accounts for most of the blood cells. Dose reduction to less than 300
mg/day is not advisable for myelosuppression. The drug should be stopped until blood counts recover. GCSF or GMCSF can prevent or treat
neutropenia.373,374 Platelet transfusion may be used for severe thrombocytopenia. Patients with imatinibinduced chronic cytopenias have inferior
responses.375 Myelosuppression is an independent adverse factor for achieving cytogenetic responses with imatinib.376 Erythropoiesisstimulating
agents may be used to raise hemoglobin levels, and their use does not appear to affect CML outcomes, but may increase the risk of thrombosis.377
Severe irreversible marrow aplasias after imatinib exposure can occur.378
The main side effects noted with imatinib include fatigue, edema, nausea, diarrhea, muscle cramps, and rash.379 Elevated hepatic transaminases can
occur. Mild transaminase elevations often respond to glucocorticoid use.380 Hepatotoxicity is uncommon, occurring in approximately 3% of patients,
usually within 6 months of onset of imatinib use. Acute liver failure has been described.381 The severe periorbital edema occasionally observed is
postulated to be a drug effect on the function of plateletderived growth factor receptor (PDGFR) and KIT expressed by dermal dendrocytes. Surgical
decompression of severe edema rarely has been required.382 Weight gain is associated with imatinib use.383 Patients with renal impairment require
lower doses of imatinib.384 Hypophosphatemia385 and altered bone and mineral metabolism have occurred.386,387 Cutaneous reactions with imatinib
therapy occur in approximately 15% of patients.388,389 Except for severe reactions (approximately 5% of patients), such as StevensJohnson syndrome,
exfoliative dermatitis, and erythema multiforme, cutaneous reactions rarely require permanent discontinuation of therapy. With milder reactions,
concomitant glucocorticoid therapy or brief discontinuation of imatinib with gradual reintroduction at a lower dose and then a gradual increase in
dose can be accomplished.390,391 With very mild cases, concurrent treatment with antihistamine or other symptomatic therapy may be successful. Oral
desensitization regimens have been described that allow some patients to continue imatinib therapy. Hair depigmentation392 and hypopigmentation
of the skin,393 probably related to the inhibition of the KIT receptor tyrosine kinase by imatinib, have been reported.
Other Effects of Imatinib
Imatinib has been found to cause regression of marrow fibrosis.394 One study found that the extent of marrow fibrosis in CML is not a prognostic factor
with imatinib therapy,395 whereas another study observed that although imatinib reverses marrow fibrosis in patients with CML, it does not change the
unfavorable prognosis associated with fibrosis.396
Imatinib reverses exaggerated VEGF secretion in patients with CML,397 and it may reverse exaggerated marrow angiogenesis.398 It can reduce marrow
cellularity and normalize morphologic features regardless of cytogenetic response. BCRABL1–positive cells persist in patients despite prolonged
treatment responses with imatinib.399
Pharmacokinetic Considerations During Imatinib Therapy
Mean plasma trough concentration of imatinib and its metabolite, CGP74588, obtained at about 1 month (presumptive steadystate) was 979 ± 530
ng/mL. The rate of CCyR and MMR was higher within the highest quartiles of imatinib trough levels.400 Some physicians suggest that imatinib plasma
levels be checked in cases of suboptimal response to adjust the dose, but access to this monitoring is not routinely available.401 Comedications and
population covariates, such as body weight and white cell count, had no, or minimal, effect on imatinib clearance.402 Patients with CML on
hemodialysis have been successfully treated with imatinib.403 Therapy interruptions and nonadherence with oral imatinib usage are common, and
patient education and close monitoring are important to ensure compliance.404
Initiation of Therapy with SecondGeneration and ThirdGeneration Tyrosine Kinase Inhibitors
Dasatinib
Dasatinib is a 2GTKI oral BCRABL1 inhibitor with dual inhibition of ABL1 and SRC.405 It can bind to both the active and inactive conformation of the
ABL1 kinase domain, so it may be affected by mutations resulting in resistance.405
Dasatinib, administered orally, was first studied for use in initial therapy in a phase II trial that accrued 62 patients. Of the 62 patients, 61 (98%)
achieved a CCyR, and the median time to CCyR was 3 months. The MMR rate was 82%. Responses were durable, and the recommended treatment
schedule based on a safety profile was 100 mg, once daily.406 A randomized phase III trial compared the efficacy of dasatinib to imatinib.407 In this
study, 259 patients received dasatinib, 100 mg/day, and 260 received imatinib, 400 mg/day. After 12 months of followup, the rates of CCyR by 3 months
was 54%, by 6 months was 73%, and by 9 months was 78 for patients on dasatinib as compared to 31% (3 months), 59% (6 months), and 67% (9
months) for those on imatinib. The 24month CCyR was 80% for patients using dasatinib, as compared to 74% for those on imatinib. The MMR showed
a similar trend, and the median time to MMR was 15 months for those using dasatinib, compared to 36 months for those using imatinib. A final 5year
analysis of this trial, called Dasatinib Versus Imatinib Study in TreatmentNaïve Chronic Myeloid Leukemia Patients (DASISION), found that 61% of
ABL1 kinase domain, so it may be affected by mutations resulting in resistance.405
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Dasatinib, administered orally, was first studied for use in initial therapy in a phase II trial that accrued 62 patients. Of the 62 patients, 61 (98%)
achieved a CCyR, and the median time to CCyR was 3 months. The MMR rate was 82%. Responses were durable, and the recommended treatment
schedule based on a safety profile was 100 mg, once daily.406 A randomized phase III trial compared the efficacy of dasatinib to imatinib.407 In this
study, 259 patients received dasatinib, 100 mg/day, and 260 received imatinib, 400 mg/day. After 12 months of followup, the rates of CCyR by 3 months
was 54%, by 6 months was 73%, and by 9 months was 78 for patients on dasatinib as compared to 31% (3 months), 59% (6 months), and 67% (9
months) for those on imatinib. The 24month CCyR was 80% for patients using dasatinib, as compared to 74% for those on imatinib. The MMR showed
a similar trend, and the median time to MMR was 15 months for those using dasatinib, compared to 36 months for those using imatinib. A final 5year
analysis of this trial, called Dasatinib Versus Imatinib Study in TreatmentNaïve Chronic Myeloid Leukemia Patients (DASISION), found that 61% of
dasatinibtreated patients and 63% of imatinib treated patients remained on their initial assigned therapy.408 Molecular responses of 4.0log or 4.5log
reduction in BCRABL1 transcripts were higher in the dasatinib group, but there was no difference in progressionfree or OS at 5 years. Twentyeight
percent of dasatinib patients had pleural effusion, most often in the first year. Sixteen percent discontinued dasatinib because of adverse events,
whereas 7% discontinued imatinib for intolerance.408 The achievement of an early molecular response was predictive of improved progressionfree
survival and OS in both arms.409
Toxicity of Dasatinib
Most grade 3 or 4 adverse events with dasatinib are hematologic and all cell lines can be affected. Some patients may have bleeding from inhibition of
platelet aggregation.410 Adverse events noted less often with dasatinib than imatinib include nausea, vomiting, myalgia, rash, and fluid retention,
including superficial edema. Pleural effusions can be seen with dasatinib use. In one trial of dasatinib, 14% of patients had grade 1 or 2 pleural
effusions at 24 months, but grade 3 or 4 effusions occurred in only 2 patients. This toxicity did not affect drug efficacy. Dasatinib may also increase the
risk of pulmonary arterial hypertension at any time, and this is an indication to discontinue dasatinib.411 A study of 21 patients with dasatinibrelated
pulmonary arterial hypertension showed persistence in 8 patients (37%) after discontinuation, but improvement occurred in the majority of affected
patients. The onset was from 8 to 74 months after first exposure.412 Dasatinib may prolong the QTc interval, and it should be used with caution in those
who have long QT syndrome or those taking drugs that may lengthen the QT interval.407 Hypophosphatemia was found in 7% of patients.407
Dasatinib is metabolized primarily by hepatic cytochrome P450 3A4 enzymes, so inducers of this enzyme may decrease the effective dose, and
inhibitors may increase the effective dose. Increases or decreases in administered dose may be needed to compensate for these effects. Antacids can
also reduce dasatinib effects.413 Lymphocytosis from the clonal expansion of NK/T cells has occurred during dasatinib treatment.414 The presence of
lymphocytosis may be associated with a higher response rate and improved OS.415 In a population of dasatinibtreated patients with large granular
lymphocyte expansion, 90% had Tcell receptor delta rearrangements, the functional significance of which is unknown.416 Lymph node follicular
hyperplasia has been noted in patients on dasatinib therapy.417 Unlike the case with imatinib, dasatinib cellular uptake is not affected by octamer
binding protein1 (OCT1) activity, which is a substrate of the efflux proteins, ABCB1 and ABCG2. Resistance to dasatinib is often found with point
mutations in ABL1 at residue 315 or 317.
Nilotinib
Unlike dasatinib, nilotinib is a selective, orally bioavailable, ATPcompetitive inhibitor of BCRABL1 which is 20–50 times more potent than imatinib in
vitro.418 Like imatinib, it does not induce apoptosis in CD34+ CML cells.419 As with dasatinib, nilotinib was first tested as initial oral therapy in phase II
trials,420,421 which were followed by a randomized phase III trial. The phase III trial compared nilotinib, 300 mg twice daily, 400 mg twice daily, and
imatinib 400 mg daily.422 At 12 months, the MMR, which had been chosen as the primary end point, was 44% (nilotinib, 300 mg dose), 43% (nilotinib,
400 mg dose), and 22% (imatinib, 400 mg daily). The CCyR rates were 15% higher with nilotinib than imatinib. The rate of progression to accelerated or
blast phase was 4% at 1 year with imatinib and less than 1% with nilotinib. These improvements were observed in each prognostic group based on
Sokal risk groups (see “Course and Prognosis” below for definition of Sokal risk groups). The patients using either 300 or 400 mg doses had minimal
differences, so in 2010, nilotinib was approved at a dose of 300 mg twice daily for initial CML therapy. At a minimum followup of 5 years, 54% of those
on the 300 mg twice per day nilotinib arm compared with 31% in the imatinib arm achieved a molecular response of 4.5423 Nilotinib use led to fewer
(less than half as many) treatmentemergent BCRABL1 mutations than did imatinib treatment, and to reduced rates of progression to accelerated
phase and blast crisis in patients with these mutations.424 Other studies also have shown that 39% of patients initially treated with nilotinib had a 4log
reduction (MR4) in BCRABL at 18 months with cardiovascular events in 6%,425 and another showed MR4 in 46% at 2 years with an acceptable safety
profile.426 In those patients on nilotinib for newly diagnosed CML, dose escalation from 300 mg to 400 mg twice daily after suboptimal response or
dose reductions due to adverse events can also achieve MMR by 24 months.427
Toxicity of Nilotinib
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Nilotinib is rarely associated with edema or muscle cramps. Grades 3 and 4 cytopenias were seen in 29% of cases in one trial. Significant elevations
in lipase, bilirubin, and hyperglycemia were observed in 17% (lipase), 8% (bilirubin), and 12% (hyperglycemia) of patients, and hypophosphatemia was
phase and blast crisis in patients with these mutations.424 Other studies also have shown that 39% of patients initially treated with nilotinib had a 4log
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reduction (MR4) in BCRABL at 18 months with cardiovascular events in 6%,425 and another showed MR4 in 46% at 2 years with an acceptable safety
profile.426 In those patients on nilotinib for newly diagnosed CML, dose escalation from 300 mg to 400 mg twice daily after suboptimal response or
dose reductions due to adverse events can also achieve MMR by 24 months.427
Toxicity of Nilotinib
Nilotinib is rarely associated with edema or muscle cramps. Grades 3 and 4 cytopenias were seen in 29% of cases in one trial.422 Significant elevations
in lipase, bilirubin, and hyperglycemia were observed in 17% (lipase), 8% (bilirubin), and 12% (hyperglycemia) of patients, and hypophosphatemia was
seen in 16%. QTc prolongation can occur, so one should monitor the electrocardiogram readings at 7 days after starting therapy and with dose
changes.418 Electrolyte abnormalities should be corrected at outset of treatment. Nilotinib may be associated with an increased risk of peripheral
vascular disease, which may be arterial or venous.428 If thrombosis occurs, it should no longer be used for therapy. The vascular changes occur as a
result of direct endothelial cell toxicity.429
Bosutinib
Bosutinib, a dual SRC/ABL kinase inhibitor, was approved for oral use in initial therapy in 2017. This was on the basis of a randomized trial in which 268
patients received 400 mg bosutinib once daily or imatinib 400 mg daily.430 The MMR rate at 12 months was 47% for bosutinib versus 37% for imatinib
which was statistically significant. Grade 3 diarrhea and increased transaminases were more common with bosutinib. Vascular and cardiac events are
of low incidence with bosutinib therapy.431
Ponatinib and Other SecondGeneration and ThirdGeneration Tyrosine Kinase Inhibitors
Ponatinib is not approved for initial therapy for CML, but a phase 2 study of 51 patients receiving between 15 mg/day and 30 mg/day, orally, were
treated for newly diagnosed CML. Of evaluable patients, 48 (94%) achieved a CCyR at 6 months but with a high incidence of rash and serum lipase
elevations and a 50% incidence of cardiovascular events (mainly hypertension). The trial of ponatinib was discontinued because of concern for
thromboembolic events.432 Radotinib (Supect)433 and flumatinib (HHGV678)434 are also being explored as initial therapy. Asciminib (ABL001) is an
allosteric BCRABL1 kinase inhibitor that is designed to inhibit BCRABL1 in a nonATP competitive fashion.435 Combined with the standard TKIs, it
suppresses early leukemia progenitors and decreases emergence of mutations conferring drug resistance. ABL001 is susceptible to ABCB1 and ABCG2
efflux transporter overexpresson,436 a rationale for combining it with nilotinib, which is not susceptible to these mutations. Combining asciminib with
ponatinib may be effective in preventing emergence and in suppressing resistant and compound BCRABL1 mutations.437 This combination has yet to
be examined in patients. As a single agent, it has been found in a phase I study to have activity in those patients with resistance to or intolerance of at
least 2 prior TKIs.438
Summary of Tyrosine Kinase Inhibitor Selection for Initial Therapy of Chronic Phase Chronic Myelogenous Leukemia
The goal of initial TKI therapy is to achieve a CCyR within 12 months or no later than 18 months of therapy, and to prevent progression to the
accelerated or blast phase. How best to achieve these goals remains controversial. Hence, the National Comprehensive Cancer Network (NCCN)
guidelines list imatinib, nilotinib, dasatinib, and bosutinib as all being acceptable TKIs for initial treatment of CML.345 Many clinicians would choose a
2GTKI, given the rapidity and depth of response and the lower rates of transformation to advanced phases of the disease, but others use imatinib
because of the lack of proof of prolongation of survival with nilotinib or dasatinib.439 In those with intermediate or highrisk disease as assessed by
the Sokal and Hasford models (see “Course and Prognosis” below for details of these scores), nilotinib or dasatinib may be preferred over imatinib to
achieve rapid, better responses—the “hit hard, hit early” approach.440 There have been no prospective CML treatment comparisons of nilotinib to
dasatinib, but retrospective analysis has shown comparable efficacies as initial therapy.441 Choice of agent may be dependent on cost considerations,
ease of administration, patient risk scores or perceived risk,442 and the drug’s sideeffect profile (Table 88–4). Cardiovascular events with the use of
2GTKIs and 3GTKIs continue to be of concern with their longterm use and continue to be studied.443,444 It is unclear whether the availability of
generic imatinib has had an impact on costs or upon initial therapy choice.445
TABLE 88–4.
Considerations for Initial Tyrosine Kinase Inhibitor Therapy
Characteristic Preferred Tyrosine Kinase Inhibitor
Availability of longterm toxicity data Imatinib (Gleevec)
Rapidity and depth of CCR/MMR 2GTKI
dasatinib, but retrospective analysis has shown comparable efficacies as initial therapy.441 Choice of agent may be dependent on cost considerations,
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ease of administration, patient risk scores or perceived risk,442 and the drug’s sideeffect profile (Table 88–4). Cardiovascular events with the use of
2GTKIs and 3GTKIs continue to be of concern with their longterm use and continue to be studied.443,444 It is unclear whether the availability of
generic imatinib has had an impact on costs or upon initial therapy choice.445
TABLE 88–4.
Considerations for Initial Tyrosine Kinase Inhibitor Therapy
Characteristic Preferred Tyrosine Kinase Inhibitor
Availability of longterm toxicity data Imatinib (Gleevec)
Rapidity and depth of CCR/MMR 2GTKI
Decreased risk of transformation Possibly 2GTKI
Cost Imatinib when available in generic form in most, but not all, instances
Age Possibly 2GTKI in younger patients
Possibility of early discontinuation Possibly 2GTKI but can be achieved with imatinib
Probability of survival Each TKI equivalent
High Sokal, Hasford, or EUTOS score 2GTKI
Fewer vascular events Imatinib
Once per day administration/adherence Imatinib, dasatinib (Sprycel), bosutinib (Bosulif)
Desire for pregnancy Possibly 2GTKI
Tolerability/quality of life Variable from patient to patient
2GTKI, secondgeneration tyrosine kinase inhibitor; CCR, complete cytogenetic remission; EUTOS, European Treatment and Outcomes Study; MMR, major molecular
response; TKI, tyrosine kinase inhibitor.
Because a significant fraction of patients with CML who are treated with TKIs are living nearly normal life spans, emphasis on issues related to adverse
effects and quality of life take on greater importance.446–448 The age of the patient, which will dictate potential years of exposure, likelihood of
successful treatmentfree remission (see “Discontinuation of tyrosine kinas inhibitor therapy”), and desire to have a child, which would require
discontinuation of TKI therapy, also may be considerations.449–454 In the future, molecular markers, such as somatic variants in epigenetic modifiers,
may predict failure of the initial response to imatinib, but this approach has not been used clinically and has not predicted failure of response to 2G
TKIs.455
Defining a Response to Tyrosine Kinase Inhibitors
Table 88–3 contains definitions of hematologic, cytogenetic, and molecular responses. The guidelines for periodic monitoring of patients who are in
chronic phase and receiving TKI therapy are shown in Table 88–5. The median BCRABL1 levels for imatinibtreated patients can decrease over at
least 5 years. Table 88–6 lists the milestones at 3, 6, 12, and 18 months expected of patients as indicators of an appropriate response in patients
treated initially with a TKI.344,345 There is variation in an individual patient’s time to maximal response. Consequently, if a patient has not met those
precise milestones but shows a continued decrease in the proportion of Phpositive cells on cytogenetic examination of marrow, or if in a CCyR, a
continued decrease in the level of the PCR signal for BCRABL1, which is near the benchmark, the treatment can be continued. Only (a) failure to meet
the benchmarks at 3, 6, or 12 months, (b) loss of response as defined as loss of a CHR or CCyR, (c) development of new cytogenetic abnormalities, (d)
acquisition of a BCRABL1 mutation, or (e) an increase in the BCRABL1/ABL1 ratio of 1log or more on serial RTPCR testing or into the range
associated with reappearance of the Ph chromosome on Gbanding should generate a change in treatment to limit the risk of progression of the
disease. Because of the variability in PCR testing, those changes should be confirmed within 1 month. Patients who had no decrease in BCRABL1 after
1 month had only 18% versus 64% MMR at 12 months and 55% versus 87% at 24 months, which was statistically significant, as compared with socalled
responders.456 Patients who have 100% Phpositive cells after 6 months of therapy have a minimal chance of achieving a MCyR or CCyR and may be
offered allogeneic hematopoietic cell transplantation, if applicable.345,457 Studies have concluded that cytogenetic assessment is unnecessary after the
treated initially with a TKI.344,345 There is variation in an individual patient’s time to maximal response. Consequently, if a patient has not met those
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precise milestones but shows a continued decrease in the proportion of Phpositive cells on cytogenetic examination of marrow, or if in a CCyR, a
continued decrease in the level of the PCR signal for BCRABL1, which is near the benchmark, the treatment can be continued. Only (a) failure to meet
the benchmarks at 3, 6, or 12 months, (b) loss of response as defined as loss of a CHR or CCyR, (c) development of new cytogenetic abnormalities, (d)
acquisition of a BCRABL1 mutation, or (e) an increase in the BCRABL1/ABL1 ratio of 1log or more on serial RTPCR testing or into the range
associated with reappearance of the Ph chromosome on Gbanding should generate a change in treatment to limit the risk of progression of the
disease. Because of the variability in PCR testing, those changes should be confirmed within 1 month. Patients who had no decrease in BCRABL1 after
1 month had only 18% versus 64% MMR at 12 months and 55% versus 87% at 24 months, which was statistically significant, as compared with socalled
responders.456 Patients who have 100% Phpositive cells after 6 months of therapy have a minimal chance of achieving a MCyR or CCyR and may be
offered allogeneic hematopoietic cell transplantation, if applicable.345,457 Studies have concluded that cytogenetic assessment is unnecessary after the
diagnosis is confirmed and only molecular monitoring is required thereafter. Cytogenetic reassessment, however, should be done if the molecular
response is suboptimal.458
TABLE 88–5.
Guidelines for Monitoring of Patients in Chronic Phase Who are Undergoing Tyrosine Kinase Inhibitor Therapy
1. At diagnosis, before starting therapy, obtain Giemsabanding cytogenetics and measure BCRABL1 transcript numbers by qPCR using marrow cells. If
marrow cannot be obtained, use FISH on a blood specimen to confirm the diagnosis. Qualitative RTPCR should also be obtained to look for minor
transcripts as well.
2. At 3, 6, 9, and 12 months after initiating therapy, measure qPCR for BCRABL1 transcripts. (If qPCR using the International Standard is not available,
perform marrow cytogenetics.) If there is a rising level of BCRABL1 transcript or 1log increase after MMR achieved, qPCR should be repeated in 1–3
months.
3. Once CCyR is obtained, monitor qPCR on blood cells every 3 months for 3 years and then every 3–6 months, thereafter. If there is a rising level of
BCR/ABL1 transcripts (1log increase after MMR achieved), repeat qPCR in 1–2 months for confirmation.
4. These guidelines presume continued response to a TKI until CCyR achieved. If this does not occur see text for approach.
5. Mutation analysis should be performed with loss of chronic phase, loss of any previous level of response, inadequate initial response (BCR/ABL1
transcripts >10%) at 3 or 6 months or no CCyR at 12 or 18 months, and a 1log increase in BCR/ABL after MMR once achieved.
CCyR, complete cytogenetic response; CP, chronic phase; FISH, fluorescence in situ hybridization; MMR, major molecular response; Ph, Philadelphia chromosome;
qPCR, quantitative polymerase chain reaction; TKI, tyrosine kinase inhibitor.
Data from NCCN Practice Guidelines in Oncology. Version 1.2019. Accessed June 3, 2020. https://www.nccn.org/professionals/physician_gls/default.aspx
TABLE 88–6.
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CCyR, complete cytogenetic response; CP, chronic phase; FISH, fluorescence in situ hybridization; MMR, major molecular response; Ph, Philadelphia chromosome;
qPCR, quantitative polymerase chain reaction; TKI, tyrosine kinase inhibitor.
Data from NCCN Practice Guidelines in Oncology. Version 1.2019. Accessed June 3, 2020. https://www.nccn.org/professionals/physician_gls/default.aspx
TABLE 88–6.
Milestones for Assessing Response to Tyrosine Kinase Inhibitors4 1 6,4 9 7
Disease Response
Time of Observation (months) Unsatisfactory Suboptimal Response/Warning Optimal Response
3 No CHR and/or Ph+ >95% BCR/ABL1 >10% and/or Ph+ 36–95% BCR/ABL1 ≤10% and/or MCyR
6 BCR/ABL1 >10% and/or no MCyR BCR–ABL1 1–10% and/or MCyR BCR/ABL1 <1% and/or CCyR
12 BCR/ABL1 >1% and/or no CCyR BCR–ABL1 <0.1–1% BCR/ABL1 <0.1%
18 No CCyR CCyR if no MMR CCyR or MMR
CHR, complete hematologic response; CCyR, complete cytogenetic response; MCyR, major cytogenetic response; MMR, major molecular response.
Response is defined in Table 89–3. These data were derived from studies with imatinib (Gleevec) but are applicable to therapy with any tyrosine kinase inhibitor
(TKI) as initial therapy in chronic phase. “Unsatisfactory” implies the need to consider change in treatment approach, as appropriate for that patient. Usually this
change is an increase in the dose of imatinib, a shift to an alternative TKI, or allogeneic hematopoietic stem cell transplantation, if eligible. These guidelines are
approximate in that a patient showing continued response to a TKI can be continued on that therapy until a response plateau has been reached, at which time the
response can be evaluated using the milestones described. The suboptimal category indicates at least closer monitoring is recommended. See text for further
details.
Achieving a cytogenetic response is associated with progressionfree survival in patients treated with imatinib and is an important goal of therapy (97%
in those with a CCyR vs 81% in those without a MCyR).459 A complete remission at 1 year may be the major predictor of OS and progressionfree
survival.460 In patients in chronic phase treated with imatinib, nilotinib, or dasatinib, early responses (at 3 months) in BCRABL1 transcript reduction or
decrease of Ph chromosome frequency predicted for better outcomes as measured by eventfree survival or OS. For example, patients with less than
10% BCRABL1 transcripts at 3 months had a 3year eventfree survival of 95% or greater, whereas those with greater than 10% transcript level at 3
months had a 61% eventfree survival.461
Molecular response is determined by the decrease in BCRABL1 mRNA by PCR. This is the only means to measure the depth of the response once a
CCyR is attained. The achievement of MMR after treatment with imatinib is associated with durable longterm CCyR and a lower rate of disease
progression. Only 5% of patients achieving a MMR with imatinib lost a CCyR, compared to 37% who did not achieve that degree of response.462 Also, the
5year followup of the IRIS trial showed that no patient with a CCyR and MMR at 12 months had progressed to a more advanced phase of the disease.459
The IRIS study 7year followup also showed that in those with a MMR at that time, progression was rare. The estimated eventfree survival was 95% for
those with MMR at 18 months compared with 86% in those without a MMR.463 As of this writing, there is no evidence that a change of therapy would
improve survival in those with CCyR but not a MMR. Patients in CCyR have similar survival whether or not MMR has been achieved.464 In those with
stable CCyR after treatment with a 2GTKI, achievement of MMR may not have significance as a predictor of survival.461 There is evidence, however, that
patients who sustain a MR4 for 12 months versus those who have sustained MR3 have only a 2.6% versus 25.0% chance of losing MR3 by 5 years.465
Some patients who have MMR with imatinib can be converted to deep molecular responses (DMRs) with dasatinib.466 (A DMR is a MMR of 4.5 logs or
undetectable BCRABL transcripts.)
The time taken to achieve MMR is also thought to have prognostic significance. In the IRIS study, the chance of disease progression was higher in those
who failed to achieve a 1log reduction in BCRABL1 transcripts by 3 months or a 2log reduction by 6 months.467 A BCRABL1 transcript level greater
than 10% after 3 months is a significant predictor for longterm outcomes.468 Others have shown that even a 3month BCRABL1 of 1% or less or a 6
month BCRABL1 of 0.1% or less have predictive value for achieving a DMR.469 There is also evidence that early molecular response to initial therapy
with dasatinib or nilotinib in patients with CML is a predictor of overall response. In one trial with dasatinib, patients with BCRABL1 transcripts of 10%
or less at 3 months had significantly better 5year progressionfree survival (92% vs. 67%) and 4year OS than did those with greater than 10%
transcripts (95% vs.83%).470 Some studies have validated the halving time of BCRABL1 transcripts as a predictor of both MMR and DMR.471 In another
study with nilotinib, patients with BCRABL1 of 10% or less at 3 months also had improved 4year progressionfree survival compared to those with
BCRABL1 greater than 10% at 3 months (95% vs 85%).472 Progression was defined as transformation to accelerated or blast phase. There is evidence
The time taken to achieve MMR is also thought to have prognostic significance. In the IRIS study, the chance of disease progression was higher in those
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who failed to achieve a 1log reduction in BCRABL1 transcripts by 3 months or a 2log reduction by 6 months.467 A BCRABL1 transcript level greater
than 10% after 3 months is a significant predictor for longterm outcomes.468 Others have shown that even a 3month BCRABL1 of 1% or less or a 6
month BCRABL1 of 0.1% or less have predictive value for achieving a DMR.469 There is also evidence that early molecular response to initial therapy
with dasatinib or nilotinib in patients with CML is a predictor of overall response. In one trial with dasatinib, patients with BCRABL1 transcripts of 10%
or less at 3 months had significantly better 5year progressionfree survival (92% vs. 67%) and 4year OS than did those with greater than 10%
transcripts (95% vs.83%).470 Some studies have validated the halving time of BCRABL1 transcripts as a predictor of both MMR and DMR.471 In another
study with nilotinib, patients with BCRABL1 of 10% or less at 3 months also had improved 4year progressionfree survival compared to those with
BCRABL1 greater than 10% at 3 months (95% vs 85%).472 Progression was defined as transformation to accelerated or blast phase. There is evidence
that additional time points are needed to accurately assess the initial rate of the decrease in BCRABL1.473 The slope between diagnosis and 3 months
cannot use ABL1 as an internal gene control (>10% positive), but the rate of decline between 3 and 6 months can be associated with eventfree survival
and failurefree survival.474
Increasing BCRABL1 Transcript Levels
An increase in BCRABL1 transcripts can indicate a new mutation or cytogenetic relapse. A significant change is defined as either a twofold increase,
serially increasing levels, or a 1log increase.344,345 There are no current recommendations for therapy changes based on an increase in BCRABL1
transcripts. Serial increases or increases of 1log or more should trigger ABL mutational analysis and more frequent monitoring of BCRABL1
transcripts.
Suboptimal Therapeutic Responses
The initial European LeukemiaNet guidelines defined suboptimal response as no cytogenetic response at 3 months, less than a partial cytogenetic
response (PCyR) at 6 months, a PCyR at 12 months, and less than a MMR at 18 months.344,475 The significance of a suboptimal response is dependent on
the cause. For example, this may be insignificant if it is the result of drug intolerance or noncompliance as opposed to drug resistance (see “Acquired
Resistance” below). The significance also depends on time of suboptimal response with earlier time points indicating a worse prognosis. Currently,
CCyR and PCyR at 3 months are considered optimal and suboptimal responses. Suboptimal responses are labeled as a “warning” response in the
Network guidelines.344 These response levels may trigger ABL mutation analysis or closer monitoring.
There is still limited data or agreement on how to manage suboptimal responses.458 Several studies have compared standarddose imatinib to
imatinib dose escalation or to nilotinib. One study showed that a switch in TKI therapy within 6 months was associated with a higher likelihood of
achieving a MMR. This was especially true in those with long halving times.476 The patients switching to nilotinib may have a higher cumulative MMR
rate.477 In the Therapeutic Intensification in De Novo Leukaemia (TIDEL)II study, patients who switched from 600 mg imatinib, daily, to 400 mg
nilotinib, twice per day, had high rates of subsequent MMR (73%) and DMR (34%) at 24 months.478 In the LASOR trial, 191 patients who had suboptimal
response to imatinib were randomly assigned to nilotinib, 400 mg, twice per day, versus imatinib, 600 mg/day. A higher percentage of patients achieved
improved cytogenetic or molecular response with the nilotinib, but differences were not statistically significant.426 A higher rate of development of a
CCyR after 2 years of imatinib therapy was observed with a switch to nilotinib instead of continuing imatinib.479,480 Continuing imatinib may be
acceptable in terms of survival, but switching to a 2GTKI may provide a greater chance of a DMR and of eventually discontinuing treatment.481
Milestones are expected to undergo further revision once it is better understood what the optimal initial rate of decline and ultimate depth of
molecular remission should be, and what implications these have for discontinuing TKI therapy and for OS.482 Chronic phase patients with “warning
responses” after 12 months may have an improvement in molecular responses after changing to a 2GTKI, but there was no effect on progressionfree
survival or OS.483 Only CCyR, and not a DMR, has been associated with survival.484
Secondary Chromosomal Changes with Tyrosine Kinase Inhibitors
The presence of additional chromosomal abnormalities has traditionally been considered to be a feature of the accelerated phase of CML. The
significance of additional chromosomal abnormalities at diagnosis in the TKI era is lesswell understood. Approximately 5% of patients may present
with these.485 These changes seen at diagnosis do not alter the probability of a MMR or a good OS.485 In some patients, clonal evolution may be related
to imatinib resistance.486 Clonal abnormalities may be present in up to 10% of patients taking imatinib.487 Some of these cases may be associated with
a myelodysplastic syndrome, especially in those patients with previous exposure to cytarabine and idarubicin. The antiproliferative effect of imatinib
allows restoration of polyclonal hematopoiesis in CCyR, which could permit the manifestation of a Phnegative disorder.488 Some investigators have
found that, with the possible exception of +8, +Ph, and i(17), additional chromosomal abnormalities at diagnosis are not associated with an inferior
outcome to imatinib therapy.489,490 In contrast, another group found that development of trisomy 8 in patients taking imatinib, while associated with
pancytopenia, did not result in signs of disease progression.491–517 The most unfavorable cytogenetic abnormalities observed in more than 2000
patients with de novo CML were i16(q10), 3q26, and −7.492 Of patients who were treated at diagnosis with imatinib, 9% developed chromosomal
abnormalities in Phnegative metaphases. These appeared at a median of 18 months, and the most common abnormalities were −Y and +8. Most were
with these.485 These changes seen at diagnosis do not alter the probability of a MMR or a good OS.485 In some patients, clonal evolution may be related
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to imatinib resistance.486 Clonal abnormalities may be present in up to 10% of patients taking imatinib.487 Some of these cases may be associated with
a myelodysplastic syndrome, especially in those patients with previous exposure to cytarabine and idarubicin. The antiproliferative effect of imatinib
allows restoration of polyclonal hematopoiesis in CCyR, which could permit the manifestation of a Phnegative disorder.488 Some investigators have
found that, with the possible exception of +8, +Ph, and i(17), additional chromosomal abnormalities at diagnosis are not associated with an inferior
outcome to imatinib therapy.489,490 In contrast, another group found that development of trisomy 8 in patients taking imatinib, while associated with
pancytopenia, did not result in signs of disease progression.491–517 The most unfavorable cytogenetic abnormalities observed in more than 2000
patients with de novo CML were i16(q10), 3q26, and −7.492 Of patients who were treated at diagnosis with imatinib, 9% developed chromosomal
abnormalities in Phnegative metaphases. These appeared at a median of 18 months, and the most common abnormalities were −Y and +8. Most were
temporary and disappeared within 5 months. Only 1 patient with −7 progressed to acute myelogenous leukemia (AML).493 Cytogenetic clonal evolution
may not be an important impediment to achieving a MCyR or CCyR with imatinib, but it is an independent poor prognostic factor for survival of patients
in chronic and accelerated phases of CML.494 Imatinib therapy may overcome the poor prognostic significance of derivative chromosome 9 in CML.495
The appearance of aberrations such as monosomy 7 and trisomy 8 during treatment does not appear to have impact on long term outcomes.496
Adherence to Tyrosine Kinase Inhibitor Therapy
Unsurprisingly, noncompliance with therapy results in poorer outcomes. In one trial, patients with a suboptimal response had higher nonadherence
(23%) than did those with optimal responses (7%).497 In another study, adherence was the only independent predictor for achieving a CMR on imatinib.
Patients with an adherence rate of 85% or less had a greater chance of losing their CCyR at 2 years (27%) than did those with better adherence (1.5%).
They also had a lower chance of remaining on imatinib.498 Adherence also has been correlated with level of molecular response. In patients using a TKI
for approximately 5 years, median adherence was 98% (range: 24–100%). If adherence was greater than 90%, there was a higher probability for a 3log
reduction in BCRABL1 transcripts and a CMR. If adherence was less than 80%, no MMRs occurred.499 The poor adherence to 2GTKIs has not been
studied for a sufficient duration to determine its impact. Management of side effects is important for maintaining a high rate of adherence. One study
found there was a 29% rate of nonadherence in patients on Medicare Part D in the United States, with higher rates among those with lower outof
pocket costs.500 In the current era, patients whose disease is controlled by TKIs will have greater effects from the TKI on quality of life and adverse
events than from the disease itself, and this no doubt contributes to noncompliance.501,502 Thus, patientreported outcomes are now incorporated
into CML trials.503
Development of Tyrosine Kinase Inhibitor Resistance
The development of resistance to imatinib is not surprising.504,505 Its specificity and “snug fit” into the ABL1kinase pocket provide the ideal
circumstance for resistance.504 Some cases demonstrate primary resistance to imatinib, and gene profiling has demonstrated differential expression
of approximately 46 genes in responders compared to nonresponders.505 Even in patients with CCyR, malignant progenitors at the longterm culture–
initiating cell stage persist. Chronic phase CML stem cells are resistant to imatinib and are genetically unstable.506 Mathematical models suggest that
imatinib rapidly eliminates leukemic progenitors, but does not deplete CML stem cells. Such models predict the probability of developing resistant
mutations and can estimate the time that resistance will emerge.507 Several potential mechanisms of resistance include BCRABL1 amplification in the
presence of imatinib, Pglycoprotein–mediated drug efflux, altered drug metabolism, acquisition of BCRABL1–independent signaling characteristics,
and point mutations in the ABL1 kinase domain that decrease imatinib binding. Each of these mechanisms of resistance may have clinical relevance.
Primary Resistance
Primary resistance to imatinib is defined as lack of CHR at 6 months or failure to achieve any level of cytogenetic response at 6 months, a MCyR at 12
months, or a CCyR at 18 months. This may occur in 15% to 25% of patients. Primary resistance may often be the result of inadequate plasma
concentration because of binding of the drug to proteins, such as albumin or α1acid glycoprotein. In an analysis of the IRIS study, plasma levels of
imatinib following the first month of treatment proved to be a significant predictor for clinical response. Plasma levels are not available for clinical use,
however, so these have minimal influence on treatment decisions when responses are not as expected. Only 1 gene, prostaglandinendoperoxide
synthase 1/cyclooxygenase1 (PTGS1/COX1) was found to differentiate primary imatinib resistance. Eleven genes were associated with secondary
resistance after imatinib therapy in those without an ABL1 kinase domain mutation.508 Expression of OCT1, which mediates drug influx, is thought to
be important for imatinib but not dasatinib effectiveness.509,510 Many CML patients who have a suboptimal response to imatinib have low OCT1
activity, but this can be overcome with higher doses of imatinib or use of dasatinib, which uptake is not dependent on OCT1 expression.510 OCT1
expression is associated with MMR at 12 and 24 months, and it is a predictor of the longterm risk of resistance and of transformation in patients
treated with imatinib.511 CML CD34+ cells overexpress the drug transporter ABCG2, and imatinib, dasatinib, and nilotinib are substrates for ABCB1 and
ABCG2. Overexpression of MDR1 is associated with decreased intracellular concentration of imatinib.512 Both OCT1 and ABCB1 polymorphisms can be
513
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predictors of efficacy and toxicity of imatinib.
Acquired Resistance
resistance after imatinib therapy in those without an ABL1 kinase domain mutation.508 Expression of OCT1, which mediates drug influx, is thought to
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be important for imatinib but not dasatinib effectiveness.509,510 Many CML patients who have a suboptimal response to imatinib have low OCT1
activity, but this can be overcome with higher doses of imatinib or use of dasatinib, which uptake is not dependent on OCT1 expression.510 OCT1
expression is associated with MMR at 12 and 24 months, and it is a predictor of the longterm risk of resistance and of transformation in patients
treated with imatinib.511 CML CD34+ cells overexpress the drug transporter ABCG2, and imatinib, dasatinib, and nilotinib are substrates for ABCB1 and
ABCG2. Overexpression of MDR1 is associated with decreased intracellular concentration of imatinib.512 Both OCT1 and ABCB1 polymorphisms can be
predictors of efficacy and toxicity of imatinib.513
Acquired Resistance
Acquired resistance is that which occurs after exposure to TKIs or other treatments. Amplified gene expression and increased BCRABL1 protein
expression are often reported in resistant patients. Duplication of the Ph chromosome and isodicentric chromosomes are a possible mechanism of
resistance to imatinib.514,515
Mutations in the ABL1 kinase domain are a frequent mechanism of resistance. Kinase domain mutations were the only independent predictor for the
loss of CCyR and progression when compared to those without a mutation.516 Mutations in the ABL1 kinase domain may predate imatinib treatment,517
and several BCRABL1 kinase domain mutants associated with imatinib resistance remain sensitive to the drug, suggesting a need for characterization
before a resistant phenotype can be attributed to the given mutation.518 The mutant clone does not always have a proliferative advantage.519 Some of
these mutations may lie outside the kinase domain, and more than 40 such mutations have been described. Screening early phase CML patients for
mutations before the start of imatinib therapy is not costeffective because of their low incidence, but in patients with evidence of an increase in CML
cells while on imatinib, mutation searches are indicated.520 BCRABL1 kinase domain point mutations are rare in those who have had good cytogenetic
responses to imatinib, and when detected in that setting, their presence does not always predict relapse.521 Mutations in the ABL1 portion of the BCR
ABL1 oncogene are present in approximately 40% of patients who do not achieve a CHR or CCyR to imatinib. ABL1 mutations were found in those
patients with both primary and acquired resistance. Amino acid substitutions in seven residues accounted for 85% of all mutations associated with
resistance.522 The mutations most associated with resistance are Thr315ILe, Gly250Glu, Glu255Lys, and Thr253His substitutions. Few of the described
mutations directly affect imatinib binding.523 Mutations in the ABL1–ATP phosphatebinding loop (Ploop) are most closely associated with a poor
prognosis,524 and these Ploop mutations predict for disease progression. OS is worse for Ploop and for T315I mutations, but not significantly
different when other mutations are present.525
Ultradeep sequencing approaches show that routine Sanger sequencing underestimated BCRABL1 mutation in 55% of samples where the missed
mutations had low abundance.526 Mass spectrometry can detect a 0.05% to 0.5% level of mutations, as well.527 For many mutations, the concentration
that inhibits 50% (IC50) of various TKIs and response have not been documented.528
Secondgeneration BCRABL1 inhibitors (see “SecondGeneration Tyrosine Kinase Inhibitor Therapy: Dasatinib and Nilotinib” below) are able to
overcome imatinibresistant mutants, with the exception of the T315I mutations (Table 88–7). Mutations F317L and V299L are resistant to dasatinib
and mutations Y253H, E255K, and F359I are resistant to nilotinib. Ponatinib was active against T315I and against other BCRABL1 mutations resistant to
dasatinib or nilotinib.529 Ponatinib may be effective against individual ABL1 point mutations but may not overcome some compound mutations, which
are 2 or more mutations in the same BCRABL1 molecule. Some mutations may be polyclonal as well.516 The T315I mutation results in steric hindrance,
which precludes access of some TKIs to the ATPbinding pocket of the ABL1 kinase domain.530 In a series of 27 patients with T315I mutation, survival
was dependent on stage of disease, with many of the patients with chronic phase disease described as having an indolent course.531 In addition to
ponatinib, agents such as IFNα and homoharringtonine (omacetaxine, Synribo) also have been proposed as therapy for those with the T315I
mutation.532 Hematopoietic cell transplantation can be offered, but one retrospective comparison of OS between ponatinib and transplantation
showed higher OS rates for those treated with ponatinib.533 Other investigators have suggested, however, that stem cell transplantation may be the
treatment of choice with this mutation.534 There are distinct resistance profiles for secondgeneration ABL inhibitors, and computational analysis can
predict outcomes for distinct drugsensitivity profiles.535 Dynamic models of mutated CML cells after imatinib therapy may, also, predict response to
imatinib or dasatinib.536
TABLE 88–7.
Prevalent A B L 1 Mutations Conferring Resistance to a Tyrosine Kinase Inhibitor
Mutation Treatment Recommendation
T315I Ponatinib (Iclusig) or stem cell transplantation
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V299L, T315A, F317L/V/I/C Consider nilotinib (Tasigna) over dasatinib (Sprycel); bosutinib (Bosulif) and ponatinib may be effective
showed higher OS rates for those treated with ponatinib.533 Other investigators have suggested, however, that stem cell transplantation may be the
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treatment of choice with this mutation.534 There are distinct resistance profiles for secondgeneration ABL inhibitors, and computational analysis can
predict outcomes for distinct drugsensitivity profiles.535 Dynamic models of mutated CML cells after imatinib therapy may, also, predict response to
imatinib or dasatinib.536
TABLE 88–7.
Prevalent A B L 1 Mutations Conferring Resistance to a Tyrosine Kinase Inhibitor
Mutation Treatment Recommendation
T315I Ponatinib (Iclusig) or stem cell transplantation
V299L, T315A, F317L/V/I/C Consider nilotinib (Tasigna) over dasatinib (Sprycel); bosutinib (Bosulif) and ponatinib may be effective
F359V/C/I Consider dasatinib rather than imatinib (Gleevec); bosutinib and ponatinib may be effective
Others Any tyrosine kinase inhibitor not previously used or highdose imatinib
The reader is referred to the text, which includes references describing listings of known sensitivities of reported mutations.
In some cases of resistance associated with imatinib, other signal pathways independent of BCRABL1 may become important in cell proliferation.537
These include heat shock protein70,538 survivin,539 LYN kinase,540 SRC,541 and GRB2, among others.542 Mutations in genes other than BCRABL1, such
as ASXL1, TET2, RUNX1, DNMT3A, EZH2, and TP53, could also be involved in response to TKIs, but whether they are relevant for therapeutic decisions
and outcomes is unclear.543
Dose escalation, combination therapy, and treatment interruption have been proposed as means to overcome drug resistance.544 Combination
therapy from the outset545 also has been proposed to prevent development of resistance. Treatment interruption to stop clonal selection of resistant
cells has been proposed.541 Geneexpression profiles may be useful to predict the clinical effectiveness of imatinib for CML treatment, thereby allowing
individualized therapy from the outset.545 In patients with relapse or resistance, alternative approaches include increasing the dose of imatinib or
switching to dasatinib or nilotinib.546 Allogeneic hematopoietic stem cell transplantation is not recommended unless patients have inadequate
response or intolerance to multiple TKIs or have the T315I mutation. Mutational analysis is not recommended at diagnosis but is of help in selecting
TKI therapy for patients with an inadequate initial response or loss of response to TKI therapy. Mutation type may dictate choice of the next TKI.547
Management of Resistance and Intolerance to Tyrosine Kinase Inhibitors
Dose Escalation If the patient is on imatinib, 400 mg/day, dose escalation to 800 mg/day can be tried. This may be most efficacious in patients with
cytogenetic relapse who had achieved a cytogenetic response with the initial dose of imatinib, but is not likely to benefit those who have not had a
cytogenetic response with imatinib at 400 mg/day.
SecondGeneration Tyrosine Kinase Inhibitor Therapy: Dasatinib and Nilotinib Several TKIs are approved for use in the case of imatinib
resistance or intolerance. In general, outcome with each is comparable, so the choice of agent often depends on its sideeffect profile or, in some
cases, on mutation type (see Tables 88–2 and 88–7).547
The 3month molecular response after initiation of a second generation TKI is also a predictor of overall and eventfree survival for those patients in
chronic phase when switched from imatinib to another TKI.472 A BCRABL1 level of 10% or less at 3 months is desirable. In patients treated with
nilotinib after imatinib resistance or intolerance, the 4year progressionfree survival was 85% and OS was 95% if BCRABL1 transcripts were 10% or
less as compared to 42% and 71% for those with BCRABL1 transcripts greater than 10% at 3 months.548
Either dasatinib or nilotinib can be used in cases of imatinib resistance or intolerance. Dasatinib is 325fold more potent than imatinib; and, as a dual
inhibitor of SRC and ABL1 kinases, dasatinib is able to bind to BCRABL1 with lessstringent conformational requirements.549 In patients resistant to
imatinib, dasatinib, 140 mg/day (70 mg q12h), resulted in a higher proportion of MCyR, CCyR, and MMR than did 800 mg/day (400 mg q12h) of imatinib.
Treatment failure was decreased and progressionfree survival was improved with dasatinib.550 Unlike imatinib, dasatinib penetrates the blood–brain
barrier.551 In longterm followup of 670 patients with imatinibresistant or intolerant CML, treated with various doses of dasatinib, 188 (28%) of the
patients remained on study treatment at 6 years. Survival was in the range of 76% to 83%, and a MMR was achieved in 45% (85 of the 188 patients who
remained on study treatment after 6 years) on a dose of 100 mg/day. Molecular and cytogenetic responses at 3 and 6 months were predictive of
survival. For those with BCRABL1 transcripts less than 10% at 3 months, progressionfree survival was 68%, whereas it was only 26% for those with
BCRABL1 transcripts greater than 10%.552 In patients who switch to dasatinib because of lowgrade adverse events using imatinib, efficacy was
553
Either dasatinib or nilotinib can be used in cases of imatinib resistance or intolerance. Dasatinib is 325fold more potent than imatinib; and, as a dual
inhibitor of SRC and ABL1 kinases, dasatinib is able to bind to BCRABL1 with lessstringent conformational requirements.549 In patients resistant to
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imatinib, dasatinib, 140 mg/day (70 mg q12h), resulted in a higher proportion of MCyR, CCyR, and MMR than did 800 mg/day (400 mg q12h) of imatinib.
Treatment failure was decreased and progressionfree survival was improved with dasatinib.550 Unlike imatinib, dasatinib penetrates the blood–brain
barrier.551 In longterm followup of 670 patients with imatinibresistant or intolerant CML, treated with various doses of dasatinib, 188 (28%) of the
patients remained on study treatment at 6 years. Survival was in the range of 76% to 83%, and a MMR was achieved in 45% (85 of the 188 patients who
remained on study treatment after 6 years) on a dose of 100 mg/day. Molecular and cytogenetic responses at 3 and 6 months were predictive of
survival. For those with BCRABL1 transcripts less than 10% at 3 months, progressionfree survival was 68%, whereas it was only 26% for those with
BCRABL1 transcripts greater than 10%.552 In patients who switch to dasatinib because of lowgrade adverse events using imatinib, efficacy was
maintained and symptom burden improved.553 A 7year followup study of dasatinib at 100 mg/day as secondline therapy showed that only 19% of
patients remained on study treatment, but the OS was 65%. Of those who remained on the study treatment, 28% had pleural effusions and pulmonary
hypertension, but arterial ischemic events were of low incidence.554 Nilotinib, 300 mg BID, showed little cross intolerance and 50% of patients achieved
a MR4.5 in up to 24 months in those intolerant to nilotinib.555 In the SENSOR study, where patients with suboptimal imatinib responses were switched
to nilotinib, 400 mg BID, 51% by 12 months and 67% by 24 months had achieved MMR.556 Quality of life and adherence to secondline nilotinib have
been found to be acceptable.557
ThirdGeneration Tyrosine Kinase Inhibitor Therapy: Bosutinib and Ponatinib In addition to the 2gTKIs dasatinib and nilotinib, the 3GTKIs,
bosutinib and ponatinib, are active against many of the imatinibresistant BCRABL1 kinase domain mutations and are effective treatment options for
CML resistant to standarddose imatinib. Both were FDA approved for this indication in 2012. Bosutinib is active with F317L, Y253H, and F359C/I/V
mutations. Ponatinib is also effective against many mutations resistant to nilotinib or dasatinib and has activity in cases with a T315I mutation (see
Table 88–7).
Bosutinib is a dual SRCABL1 TKI that resulted in a CCyR in 24% and CHR in 73% of patients who had used 2 prior TKIs.558 In a secondline trial after
imatinib resistance or intolerance, the MCyR rate was 59%, and the probability of maintaining MCyR at 4 years was 75%.559 All mutations except T315I
were responsive. It is approved for chronic phase, accelerated phase, or blast phase in those resistant or intolerant to prior TKI therapy. The dose is
500 mg/day, orally, with food. Diarrhea, nausea, decreased platelet count, other gastrointestinal complaints, rash, and anemia were the most common
adverse events, and most of these were of low grade. Ponatinib blocks native and mutated BCRABL1, including the gatekeeper mutation T315I. In a
phase I doseescalation study, pancreatitis, rash, and myelosuppression were major toxicities. In 12 patients with T315I mutations, 11 (92%) had a
MCyR. In those with accelerated or blast phase, or Phpositive ALL, 36% had a major hematologic response and 32% had a MCyR. Arterial thrombotic
events occurred, however.529 Retrospective analyses of these incidents led to temporary withdrawal of this medication, which is now used primarily in
cases of T315I mutation or in patients for whom no alternative TKI is available.560 If vascular occlusion occurs, therapy should be halted
immediately.561 Trials are underway to see if reduced doses will be effective while mitigating the vascular complications.560 Ponatinib has a black box
warning for vascular occlusion, heart failure, and hepatotoxicity. There is evidence that ponatinib inhibition of AKT and ERK can induce apoptosis of
cardiomyocytes,562 and it has been shown to reduce viability and migration of human endothelial cells.563
A thirdline TKI should be considered in patients who have failed 2 prior generations of TKI therapy, but responses tend to be infrequent and are
usually not durable, so clinical trials, other agents, or allogeneic hematopoietic cell transplantation should be considered. A prior CCyR on either
imatinib or subsequent nilotinib or dasatinib therapy was the only predictor of a cytogenetic remission on a thirdline therapy.563 Ponatinib can be
effective after use of 2 TKIs with a MMR of 82% at 18 months.564 In a comparison of ponatinib to the TKIs bosutinib, dasatinib, and nilotinib in the
chronic phase of CML, patients who were resistant or intolerant to 1 or more of the 2GTKIs, were found to derive little benefit from further use of 2G
TKIs (24% CCyR) as compared with 60% frequency of CCyR with ponatinib.565 Bosutinib, also, has been examined as a fourthoption TKI after prior
therapy with imatinib, nilotinib, and dasatinib. A prior CCyR at start of therapy predicted for a MMR (64%), but in those without a CCyR, the probability
of obtaining CCyR was 25% and of obtaining MMR was 14%. Diarrhea and pleural effusions were the main side effects.566 There is evidence that
switching TKIs increases costs and healthcare use.567
Sequencing Tyrosine Kinase Inhibitor Therapy Analyses of optimal therapy sequencing are now available.568 Some 2GTKIs and 3GTKIs are not
available in certain countries, so sequencing may be restricted. Because 2GTKIs may give a faster response, but with associated longterm safety
concerns, especially arterial vascular events,569 some investigators have found that switching to imatinib after an optimal response to a 2GTKI can be
done safely and without sacrifice of efficacy.570
Non–Tyrosine Kinase Inhibitor Therapies
Omacetaxine
Omacetaxine (homoharringtonine, Synribo) is a Cephalotaxus alkaloid that has activity against the T315I mutation. Omacetaxine was approved on the
basis of a study that recruited patients who had already been on 2 or more TKIs. In those enrolled in chronic phase, 67% of patients had a CHR; 22%
achieved a MCyR and 4% achieved a CCyR. Median OS was 30 months.571 In those with T315I mutations enrolled in a separate study, MMR was achieved
572
done safely and without sacrifice of efficacy.570 Access Provided by:
Non–Tyrosine Kinase Inhibitor Therapies
Omacetaxine
Omacetaxine (homoharringtonine, Synribo) is a Cephalotaxus alkaloid that has activity against the T315I mutation. Omacetaxine was approved on the
basis of a study that recruited patients who had already been on 2 or more TKIs. In those enrolled in chronic phase, 67% of patients had a CHR; 22%
achieved a MCyR and 4% achieved a CCyR. Median OS was 30 months.571 In those with T315I mutations enrolled in a separate study, MMR was achieved
in 17% of patients and the T315I clone was reduced in 61% of patients.572 The most common side effects with this medication are cytopenias, which are
usually managed with dose delays or reductions.573 This agent also has activity in accelerated phase CML, but little in blast phase. It was approved by
the FDA in October 2012 for chronic and accelerated phase patients intolerant of other therapy or in cases not responding to 2 or more TKIs.
Several inhibitors of signal transduction mediators involved in the downstream effects of BCRABL have been proposed for use in imatinibresistant
CML. These inhibitors include the JAK2 inhibitor AG490,574 SRC kinase inhibitors, mTOR (mammalian target of rapamycin) inhibitors, such as
rapamycin,575 the proteasome inhibitor bortezomib (Velcade),576 and histone deacetylators.577,578 PI3K or MEK (mitogenactivated kinase) inhibitors
and inhibitors of the WNT/βcatenin pathway are thought to be active in CML stem cells.575 Imatinib resistance often is associated with restored
activation of the BCRABL1 signal transduction pathway, suggesting that BCRABL1 remains a valid target to overcome resistance in these cases.579 BCR
ABL1 point mutations isolated from patients with imatinibresistant CML are sensitive to inhibitors of the BCRABL1 chaperone heat shock protein90,
such as geldanamycin (alvespimycin).580 Many of these agents have not yet entered clinical trials, but some are in early phase trials, such as inhibitors
of the hedgehog pathway, which is activated in CML but not in normal hematopoietic stem cells.581 Some are being used in conjunction with imatinib in
resistant cases.
Combined Therapy
Agents that have been proposed for use in combination to improve response rates or to overcome resistance to imatinib include IFNα, cytarabine,
omacetaxine multiagent chemotherapy, arsenic trioxide (Trisenox), and decitabine (Dacogen), with some supporting in vitro data.582–587 Studies of
concurrent use of lowdose imatinib with nilotinib also have been reported.588 Combining imatinib with chemotherapeutic agents is more
myelosuppressive, and final effects on response rates and survival have yet to be determined. This approach is rarely used in chronic phase CML, but is
used in accelerated or blast phase or in Phpositive acute lymphoblastic leukemia.589
Disease Prognosis and Monitoring During Tyrosine Kinase Inhibitor Therapy
Treatment failure should lead to alterations in therapeutic strategy.590 Among patients treated initially with imatinib, BCRABL1 expression in
cytogenetic responders and nonresponders was similar. BCRABL1 expression became significantly different 3 months after treatment and became
increasingly different between responders and nonresponders with continued therapy at 6, 9, and 12 months.591
Monitoring during TKI therapy includes obtaining quantitative RTPCR every 3 months on a blood sample. A 1log increase in the level of BCRABL1
reactivity, confirmed on a repeat sample at least 1 month later, suggests a loss of response to treatment. Other therapeutic options are considered for
patients who do not have a CHR at 3 months or a MCyR after 6–12 months.592,593 The molecular response after 2–3 months of therapy is a strong
predictor of clinical and cytogenetic response.594 Sequencing the BCRABL1 kinase domain can reveal emergence of resistant clones and is useful if
there is an insufficient initial response to imatinib or a 2GTKI (see Table 88–6) or any sign of loss of response, such as relapse to Phpositive status, a 1
log increase in BCR/ABL1 transcript ratio, or loss of a MMR.344,345
In patients receiving 2GTKIs as secondline therapy, those who have no cytogenetic response at 3–6 months should be considered for allogeneic
transplantation or switched to an alternative therapy in a clinical trial. After CCyR is attained, molecular monitoring is recommended every 3 months for
3 years and every 4–6 months thereafter.345 After 12 months, those with a MCyR had a significant survival advantage over those with lesser
responses.595 Those patients with BCRABL1 transcripts greater than 10% following initial imatinib treatment should be switched to dasatinib,
nilotinib, or bosutinib. If this is not an option because of cost or availability, highdose imatinib can be considered, but it also unlikely to have benefit
for more than a few months. For those already on a 2GTKI, a clinical trial or alternative TKI could be tried or patients may continue the same TKI with
very careful followup, as the impact of this benchmark on OS is not yet known.345 The 6month evaluation should identify patients with a poor
outcome. For those who have MCyR or BCRABL1 of less than 10% at 6 months, OS was 100% as compared to 79% for those with no response.596 At 12
and 18 months, CCyR is the optimal response.345 In those who have achieved CCyR, MMR may not be of prognostic significance.464
Rising BCRABL1 levels may be associated with an ABL1 mutation or relapse of disease. Those with more than a twofold rise in BCRABL1 are more likely
597
to have a mutation. A serial rise in the BCRABL1 level may also indicate loss of response to therapy. 19
OTHER AGENTS USED IN TREATMENT OF CHRONIC PHASE
responses. Those patients with BCRABL1 transcripts greater than 10% following initial imatinib treatment should be switched to dasatinib,
nilotinib, or bosutinib. If this is not an option because of cost or availability, highdose imatinib can be considered, but it also unlikely to have benefit
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for more than a few months. For those already on a 2GTKI, a clinical trial or alternative TKI could be tried or patients may continue the same TKI with
very careful followup, as the impact of this benchmark on OS is not yet known.345 The 6month evaluation should identify patients with a poor
outcome. For those who have MCyR or BCRABL1 of less than 10% at 6 months, OS was 100% as compared to 79% for those with no response.596 At 12
and 18 months, CCyR is the optimal response.345 In those who have achieved CCyR, MMR may not be of prognostic significance.464
Rising BCRABL1 levels may be associated with an ABL1 mutation or relapse of disease. Those with more than a twofold rise in BCRABL1 are more likely
to have a mutation.597 A serial rise in the BCRABL1 level may also indicate loss of response to therapy.19
OTHER AGENTS USED IN TREATMENT OF CHRONIC PHASE
Interferonα
IFNα, formerly the most effective agent, is rarely used in the treatment of CML. A CCyR with IFNα was uncommon (13%), but 10year survival rates in
responders were approximately 70%.598 CCyRs to IFNα were stable and durable.598 Approximately 50% of complete responders become longterm
survivors. Common toxicities of IFNα use include fatigue, lowgrade fever, weight loss, liver function test abnormalities, hematologic changes, and
neuropsychiatric symptoms. OS is improved in imatinibtreated patients compared with patients treated with IFNα or IFNα plus cytarabine.599
Nevertheless, among all patients who attained a MCyR or CCyR at 12 months, the survival rate was comparable in either case. IFNα also has been
proposed as an immune stimulant to consolidate imatinib remissions because additive effects have been noted.600,601 Conversely, those treated
initially with IFNα who achieve a CCyR have an improved molecular response with imatinib.602,603 Some patients intolerant to a TKI may be treated
successfully with IFNα. Studies continue to understand the optimal current role of IFN in the treatment of CML.604
Use of Other Chemotherapeutic Agents in Chronic Phase
Hydroxyurea
The major side effect of hydroxyurea is an extension of its pharmacologic effect, that is, reversible suppression of hematopoiesis, often with
megaloblastic erythropoiesis. The median survival of patients with CML treated with hydroxyurea alone is approximately 5 years. Studies with high
dose hydroxyurea indicate that marrow metaphase cells in some patients lose the Ph chromosome either partially or completely after such therapy.605
Hydroxyurea often is used for initial cytoreduction, but it has few other indications in the TKI era of CML therapeutics. Chronic use of hydroxyurea is
associated with leg ulcers.606
Cytarabine
IFNα2b combined with cytarabine (araC) (20 mg/m2 per day SQ for 10 days per month) in the chronic phase was associated with a greater proportion
of MCyRs at 12 months and greater survival prolongation than IFN alone.607 Toxicities with these drug combinations were greater, and this
combination has been replaced by TKI therapy and is rarely used.
Busulfan
Once the mainstay of treatment for the chronic phase, busulfan (Busulfex, Myleran) usage now is rare.608 It is used primarily as part of the preparative
regimen for allografting or autografting. It may be used occasionally in older patients who do not tolerate TKIs.
Other Cytotoxic Agents
Intensive multidrug regimens have been used in an attempt to eradicate the Phpositive clone and, occasionally, have led to prolongation of remission
or cure of the disease. This approach did not significantly increase population survival.609
Other Potential Therapeutic Agents in Chronic Phase Chronic Myelogenous Leukemia
Several classes of agents have been explored in an attempt to suppress CML stem and progenitor cells.610,611 These include inhibitors of the hedgehog
signaling pathway,612,613 JAKSTAT pathway inhibitors,614,615 and inhibitors of peroxisome proliferatoractivated receptors.616,617 BCL2 inhibition may
enhance imatinibinduced progenitor death in CML.618 IL1RAP (IL1 receptor accessory protein) is associated with stem cell burden in CML,619 and
antibodies to IL1RAP may block stem cell expansion in CML.620 Epigenetic reprogramming in CML may sensitize stem cells to EZH2 inhibitors in
combination with TKIs.621 The hypomethylation agent decitabine has activity in imatinib refractory CML. The histone deacetylase inhibitor,
suberoylanilide hydroxamide acid (SAHA) has been found to suppress proliferation of TKIresistant CML stem cells through hsamiR196a by targeting
BCRABL1,622 CD36 is expressed on primitive CML stem cells and antibodies to CD36 may increase their vulnerability to imatinib.623 For control of T315I
mutant CML, JNJ026854165, an inhibitor of MDM2 has been examined preclinically.624 Axitinib (Inlyta) has also shown activity in gatekeeper mutation
Several classes of agents have been explored in an attempt to suppress CML stem and progenitor cells.610,611 These include inhibitors of the hedgehog
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signaling pathway,612,613 JAKSTAT pathway inhibitors,614,615 and inhibitors of peroxisome proliferatoractivated receptors.616,617 BCL2 inhibition may
enhance imatinibinduced progenitor death in CML.618 IL1RAP (IL1 receptor accessory protein) is associated with stem cell burden in CML,619 and
antibodies to IL1RAP may block stem cell expansion in CML.620 Epigenetic reprogramming in CML may sensitize stem cells to EZH2 inhibitors in
combination with TKIs.621 The hypomethylation agent decitabine has activity in imatinib refractory CML. The histone deacetylase inhibitor,
suberoylanilide hydroxamide acid (SAHA) has been found to suppress proliferation of TKIresistant CML stem cells through hsamiR196a by targeting
BCRABL1,622 CD36 is expressed on primitive CML stem cells and antibodies to CD36 may increase their vulnerability to imatinib.623 For control of T315I
mutant CML, JNJ026854165, an inhibitor of MDM2 has been examined preclinically.624 Axitinib (Inlyta) has also shown activity in gatekeeper mutation
situations,625 and aurora A kinase inhibitors may induce senescence in CML cells with T315I mutations.626
RADIOTHERAPY
Palliative splenic irradiation may be useful occasionally in subjects who have entered the accelerated or advanced chronic phase and are troubled with
extreme splenomegaly with splenic pain, perisplenitis, and encroachment of the spleen on the gastrointestinal tract.627 Splenic irradiation may palliate
symptoms for a short time.628 Spleen size associated with chronic phase disease usually is decreased with TKI therapy.
Palliative radiotherapy may be useful for extramedullary myeloid sarcomas, which may occur occasionally in bone or soft tissue during the late chronic
or accelerated phase.
SPLENECTOMY
Splenectomy does not prolong the chronic phase of CML, delay the onset of the accelerated phase, enhance sensitivity to TKIs or chemotherapy, or
prolong survival of patients.629 In carefully selected patients with symptomatic thrombocytopenia unresponsive to therapy, mechanical discomfort,
hypercatabolic symptoms, and portal hypertension, splenectomy may be useful. Postoperative morbidity from infection, thrombosis, or hemorrhage
has been high, with mortality rates up to 10% reported.630 Splenectomy performed before allografting does not influence the severity of either graft
versushost disease (GVHD) or survival after allogeneic hematopoietic stem cell transplantation.631
TREATMENT OF CHRONIC PHASE CHRONIC MYELOGENOUS LEUKEMIA DURING PREGNANCY
Rarely, in the current era, is urgent treatment of chronic phase CML during pregnancy required to prevent placental insufficiency from
hyperleukocytosis.632 In the era of TKI therapy, where chronic phase CML is a chronic, controllable condition, desire to achieve pregnancy is more
common,633 but that goal is counterbalanced by the fact that TKIs are potentially teratogenic. Normal newborns have been delivered by patients who
conceived and ingested imatinib during early pregnancy.634–637 However, in a series of 125 women exposed to imatinib during pregnancy, 63 (50%)
delivered normal infants, and 31 (25%) underwent elective terminations, 3 of the 31 doing so following the identification of fetal abnormalities. Twelve
additional infants had abnormalities evident after delivery.638 The majority of patients who discontinue imatinib during pregnancy lose their complete
hematologic remission and their cytogenetic responses.639 Case series of pregnancy outcomes in women taking 2GTKIs also suggest risks to the
fetus.640,641 In pregnant women who are diagnosed with CML or conceive while on a TKI, discussion of early termination of the pregnancy can occur, as
well as consideration of risks of CML progression during pregnancy. If the decision is made to continue the pregnancy, TKIs should be discontinued
immediately as data indicate safety of discontinuation of TKIs after prolonged DMRs. This step may be taken during attempts to conceive and during a
pregnancy. In those who do not meet criteria for discontinuation, IFN can be used to maintain the response.641 Consultation with a fertility expert is
useful. If the clinical situation allows, embryo or ovary/oocyte cryopreservation for females or sperm banking for males can be considered.641,642
Males treated with imatinib have fathered healthy infants.643 If a pregnancy occurs unintentionally, termination of pregnancy is not recommended,
generally, because of the lack of evidence of increased rates of fetal anomalies.644 Males with CML show sperm alterations at diagnosis that are not
improved with imatinib treatment.645 Imatinib does cross the blood–testis barrier, and it may reduce sperm density, counts, survival, and motility in
chronic phase CML.646 Current recommendations are for both males and females to practice contraception during treatment with any TKI. Male
patients trying to conceive do not need to stop TKIs, however.647 If conception is desired, attaining a MMR before the TKI therapy is discontinued and a
3month washout period are recommended. Frequent molecular monitoring is recommended during this time, and the patient should be made aware
of the risk for CML progression during the pregnancy. In the event of an unplanned pregnancy, individual risks and preferences need to be taken into
account.647
If a female is pregnant at the time of CML diagnosis, IFN treatment can be considered until delivery.648 IFN can be used during pregnancy with minimum
risk of teratogenicity. Eight patients treated with IFN from the first trimester have been described, and each of these pregnancies resulted in normal
Chapter 88: Chronic Myelogenous Leukemia and Related Disorders, Jane L. Liesveld; Marshall A. Lichtman 648
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infants, except for 1 with mild neonatal thrombocytopenia. All infants had normal growth patterns.
©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Hydroxyurea may be useful during the second
and third trimester but should be avoided in the first trimester.639,649 Leukapheresis in the first trimester (or longer) also can be used to avoid fetal
drug exposure early in pregnancy (see “Leukapheresis” above). It is important to use a TKI after delivery to achieve the best outcome for the mother.
patients trying to conceive do not need to stop TKIs, however.647 If conception is desired, attaining a MMR before the TKI therapy is discontinued and a
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3month washout period are recommended. Frequent molecular monitoring is recommended during this time, and the patient should be made aware
of the risk for CML progression during the pregnancy. In the event of an unplanned pregnancy, individual risks and preferences need to be taken into
account.647
If a female is pregnant at the time of CML diagnosis, IFN treatment can be considered until delivery.648 IFN can be used during pregnancy with minimum
risk of teratogenicity. Eight patients treated with IFN from the first trimester have been described, and each of these pregnancies resulted in normal
infants, except for 1 with mild neonatal thrombocytopenia. All infants had normal growth patterns.648 Hydroxyurea may be useful during the second
and third trimester but should be avoided in the first trimester.639,649 Leukapheresis in the first trimester (or longer) also can be used to avoid fetal
drug exposure early in pregnancy (see “Leukapheresis” above). It is important to use a TKI after delivery to achieve the best outcome for the mother.
Imatinib does appear in breastmilk.650
TREATMENT OF OLDER PATIENTS
Although the median age at diagnosis of CML is 64 years, there are few studies focused on treatment in patients over 64 years of age. One study showed
that older patients are more likely to discontinue dasatinib than nilotinib, but both drugs were often used at doses less than the recommended in older
patients.651 Proposals have been made that the older patient with CML should be assessed for frailty652 (Chap. 1), but chronological age should not be
a contraindication to TKI therapy, and initial imatinib or a 2GTKI can be effective.653 In a study where patients were stratified by age and started on
nilotinib in chronic phase, age did not impact attainment of DMR or the eventual eligibility for treatment discontinuation.654 Older patients can receive
TKI at the same dose and schedule as those younger than 65 years,655 but in the event of intolerance, studies have started to look at alternative doses
and schedules. The incidence of adverse events such as pleural effusions may be higher in the older than in younger patients on dasatinib, and older
patients may benefit from dasatinib doses as low as 20 mg/day. In one study, this low dose was associated with a 94% chance of achieving a MMR and
74% of patients achieved MR4.656 In another study of intermittent imatinib use in the older patients (1 month on and 1 month off), side effects were less
and all patients who lost CCyR or MMR were restarted at the same dose continuously after which they regained their previous response level or
better.655
DISCONTINUATION OF TYROSINE KINASE INHIBITOR THERAPY
Patients responding to TKI therapy are likely to maintain their response. TKIs are associated with a significant symptom burden, however,658 and one
third have persistent moderate to severe symptoms. Furthermore, the lifelong costs of TKIs can be prohibitive. Longstanding CMR is seen in only a
minority of patients, and the vast majority of patients on TKIs have minimal residual disease even if their BCRABL1 transcripts are undetectable, and
this may lead to relapse if the drug is stopped. Despite disease persistence, approximately half of patients in a DMR for 2 years or more have been able
to discontinue imatinib without relapse.659,660 This has been called a “functional cure” because quiescent leukemia stem cells persist.661 It remains
uncertain why this is successful, but it has been postulated to be related to cancer latency, stochastic events, clonal exhaustion, or possibly to immune
mechanisms.662 The persistence of leukemia stem cells in a DMR has been demonstrated.663
In a trial from the Australasian Leukaemia and Lymphoma Group, 40 patients with MR4.5 had imatinib stopped and 18 (45%) remained in continuous
treatmentfree remission with a median followup of 8.6 years.664 The latest relapse was 27 months after stopping. Of those who met the requirement
for retreatment, all regained MR4.5. Of those who could be monitored with precision methods, BCRABL1 DNA decreased to MR6.1 in the sixth year of
treatmentfree remission.664 In the STIM (Stop Imatinib) study of 100 patients with a CMR (>5log reduction in BCRABL1 transcripts) for at least 2 years
who stopped imatinib, 69 (69%) patients had at least 12 months of followup. Of these 69 patients, 27 (39%) were stable and 42 (61%) relapsed, most
within the first 6 months. The outcome of stopping was better for those with a lower Sokal risk score at diagnosis (see “Course and Prognosis” below
for details of this score).660 In another study, 40 patients were evaluated, and treatmentfree remission at 24 months was 47.1% for all patients and was
higher if patients had prior IFN treatment.659 Female sex and early molecular response predict stable undetectable BCRABL1 transcripts in chronic
phase CML, and are 2 criteria for early stopping.665 In one of the larger discontinuation trials, the socalled EUROSKI (Europe Stop Tyrosine Kinase
Inhibitors) trial, 758 European patients who had received any TKI for at least 3 years and had a confirmed DMR for at least 1 year were enrolled.
Molecular relapsefree survival for the group was 50% at 24 months. In the 49% who lost a MMR after TKI discontinuation, only 2 (<1%) lost a MMR after
restarting TKI therapy. Longer treatment duration and longer DMR durations were associated with increasing probability of a persistent MMR.666 In a
study of 236 patients with CML in Spain, treatmentfree remission was 64% at 4 years, and cumulative incidence of molecular relapse at 3 years was
33%. TKI treatment for greater than 5 years and MR4.5 duration shorter than 4 years were associated with higher incidence of molecular recurrence.667
In a study from Japan in which patients with at least 3 years of imatinib therapy and 2 years of DMR had imatinib discontinued, the treatmentfree
remission at 12 months was 67.6%.668 There is evidence that if TKI is discontinued for unplanned reasons such as toxicity or pregnancy, if an MR4 or
deeper had been attained, the 2year treatmentfree remission (67%) was comparable to that observed on clinical trials with a planned discontinuation
of treatment.669,670 The French Stop Imatinib (STIM1) study with a median followup of over 6 years found that the molecular recurrencefree survival
671
was 38% at 60 months. A metaanalysis of 15 cohort studies that included 509 patients treated with imatinib who had a TKI discontinued showed a
mean molecular relapse rate of 51%; 80% of relapses occurred in the first 6 months.672
restarting TKI therapy. Longer treatment duration and longer DMR durations were associated with increasing probability of a persistent MMR. In a
study of 236 patients with CML in Spain, treatmentfree remission was 64% at 4 years, and cumulative incidence of molecular relapse at 3 years was
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33%. TKI treatment for greater than 5 years and MR4.5 duration shorter than 4 years were associated with higher incidence of molecular recurrence.667
In a study from Japan in which patients with at least 3 years of imatinib therapy and 2 years of DMR had imatinib discontinued, the treatmentfree
remission at 12 months was 67.6%.668 There is evidence that if TKI is discontinued for unplanned reasons such as toxicity or pregnancy, if an MR4 or
deeper had been attained, the 2year treatmentfree remission (67%) was comparable to that observed on clinical trials with a planned discontinuation
of treatment.669,670 The French Stop Imatinib (STIM1) study with a median followup of over 6 years found that the molecular recurrencefree survival
was 38% at 60 months.671 A metaanalysis of 15 cohort studies that included 509 patients treated with imatinib who had a TKI discontinued showed a
mean molecular relapse rate of 51%; 80% of relapses occurred in the first 6 months.672
A model to analyze the risk of molecular relapse after cessation of TKIs has been developed.673 Patients with the e13a2 BCRABL1 transcript may have
less possibility to stop TKI therapy.674 Several studies have shown that treatmentfree remission can be achieved after initial administration of a 2GTKI
as well. For patients who had achieved MR4.5 and had been on nilotinib for a median of 43.5 months, at 48 weeks after stopping nilotinib, 52%
remained in MMR or better.675 This study was updated at a 96 weeks analysis and showed that 48.9% remained in treatmentfree remission.676 In
another study of patients on nilotinib or dasatinib for at least 3 years and with MR4.5 for at least 2 years, 26 (43%) of 60 patients had a molecular
relapse with median time to recurrence of 4 months. Treatmentfree remission at 48 months was 53%.677 Treatmentfree remission after imatinib can
occur in pediatric patients,678 and after discontinuation of TKIs in blast phase CML.679
Use of reduced doses or intermittent dosing as compared to stopping TKIs also has been attempted. Intermittent imatinib dosing has been explored in
selected older patients with CML without adverse impact on overall and progressionfree survival.680 In patients with intolerable side effects on
imatinib, the dose may be reduced in some cases without the loss of a CMR.681 Reduceddose dasatinib, 50 mg/day, can result in a MMR and DMR
without severe toxicity in those unable to achieve MMR with lowdose imatinib and may be especially relevant to those who may have later treatment
discontinuation.682 For those with stable MMR but not MR4, treatment deescalation of imatinib, dasatinib, or nilotinib is effective with dosing at half
standard.683
Anxiety and depression are associated with TKI discontinuation and are exacerbated at time of required reintroduction in those who require it.684
Moreover, not all chronic phase CML patients are inclined to discontinue TKIs, even if they meet the criteria for doing so.685 Musculoskeletal pain can
occur after discontinuation of a TKI, and this has been dubbed the “TKI withdrawal syndrome.”686 Some investigators have associated this pain with a
lower risk of molecular relapse.687 A French observational study of 70 patients who reattempted TKI discontinuation after an unsuccessful first attempt
showed that at a median followup of 38.3 months, 45 (64%) patients had lost MMR at a median of 5.3 months. The speed of molecular relapse after the
first TKI was stopped was the only factor associated with outcome. No patient progressed toward an advanced phase of CML, and TKI efficacy on
restarting therapy was adequate.688
In the United States, the LAST (Life After Stopping Tyrosine Kinase Inhibitors) study, now underway, is a prospective, longitudinal study of 173 patients
who discontinue any of the TKIs approved for upfront therapy with the primary end point being molecular recurrence. Samples from these patients
with undetectable BCRABL will be examined by digital PCR and will include patientreported outcomes.689 Genetic markers that might predict stability
of molecular remission after TKI discontinuation are also being examined.690 Completion of these and other studies are anticipated to better define
the frequency and value of successful TKI discontinuation. Multiple prospective trials have now shown that patients who maintain a DMR for at least 2
years with TKI treatment may be eligible for discontinuation. Approximately 40% of those who discontinue TKIs will remain in remission for at least 1
year.691 Table 88–8 outlines key concepts regarding TKI discontinuation. Safety is important in this setting, and stopping TKIs should not be
considered without (a) prior TKI therapy for several years, (b) a stable MR4.0 for at least 2 years, and (c) the availability of BCRABL testing.492,692
Frequent molecular monitoring is required after TKI discontinuation; monthly for at least 6 months, so that therapy can be rapidly reinstituted in the
event of loss of MMR. Combination therapies with agents such as IFN, venetoclax, or ruxolitinib, along with TKIs, may allow more effective CML clonal
elimination and greater success with TKI discontinuation.693
TABLE 88–8.
Requirements for Consideration of TreatmentFree Remission (Tyrosine Kinase Inhibitor Stoppage)
Should have typical b2a2 or b3a2 BCRABL1 transcripts, which can be quantified to <4.5log reduction levels by qPCR using the International Standard
Should be in chronic phase
Duration of TKI >3 years (some studies recommend 5 years)
MR4.5 reached
MR4 or MR4.5 maintained for >2 years
considered without (a) prior TKI therapy for several years, (b) a stable MR4.0 for at least 2 years, and (c) the availability of BCRABL testing.492,692
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Frequent molecular monitoring is required after TKI discontinuation; monthly for at least 6 months, so that therapy can be rapidly reinstituted in the
event of loss of MMR. Combination therapies with agents such as IFN, venetoclax, or ruxolitinib, along with TKIs, may allow more effective CML clonal
elimination and greater success with TKI discontinuation.693
TABLE 88–8.
Requirements for Consideration of TreatmentFree Remission (Tyrosine Kinase Inhibitor Stoppage)
Should have typical b2a2 or b3a2 BCRABL1 transcripts, which can be quantified to <4.5log reduction levels by qPCR using the International Standard
Should be in chronic phase
Duration of TKI >3 years (some studies recommend 5 years)
MR4.5 reached
MR4 or MR4.5 maintained for >2 years
Should have availability of accurate qPCR which should be obtained on a monthly basis at the beginning of discontinuation. This must have a sensitivity of
detection of at least MR4.5 (≤0.0032% IS).
The qPCR assay must have a rapid turnaround time (2 weeks or less)
Monthly monitoring is recommended for the first year, then every 6 weeks for 1 year, and then every 3 months thereafter
Should have capability to rapidly intervene if BCR/ABL level is rising; if MMR is lost, TKI should be resumed within 4 weeks of loss with close monitoring
thereafter
IS, International Standard; MR, molecular remission; MMR, major molecular remission; qPCR, quantitative polymerase chain reaction; TKI, tyrosine kinase inhibitor.
Data from Tough IM, Court Brown WM, Buckton KE, et al9; NCCN Practice Guidelines in Oncology345; Mahon FX 661; Saussele S, Richter J, Guilhot J, et al666; Etienne G,
Guilhot J, Rea D, et al671; Bhalla S, Tremblay D, Mascarenhas J.691
HIGHDOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL INFUSION
Since the availability of imatinib, autografting in CML is rarely used.694 Phnegative stem cells are present in most patients with CML at the time of
diagnosis. Techniques that use these cells to reconstitute hematopoiesis after highdose therapy have been developed.695
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Until imatinib became available in 2001, allogeneic transplantation was used in most new patients with CML who were younger than 65 years of age and
who had a suitable donor. The advent of imatinib resulted in a marked reduction in number of transplantations performed for CML worldwide and a
decline in the proportion performed in first chronic phase.696 There is circumstantial evidence that survival is superior for populations of patients
treated with drugs who have a CCyR as compared to transplantation.697 However, one study in which CML patients who were newly diagnosed (1997–
2004), had matched family donors, and were randomized to either stem cell transplantation or to best available drug treatment, found that survival
probabilities were not different between groups; 76% 10year survival in the transplantation group and 69% in the drugtreated group. More patients
in the transplantation group were in molecular remission and were free of drug treatment (56% vs 6%).698 Not all patients in this trial received TKI
therapy. There has not been a randomized study published that compared TKI treatment with transplantation.
Allografting continues to play a role in the treatment of patients who are refractory or intolerant to serial TKIs, and remains the optimal therapy in
those who progress to accelerated or blast crisis in the face of treatment with a series of TKIs.696 In those who have significant intolerance to TKIs,
primary or secondary resistance to TKIs, or a T35I mutation, search for a donor should be started in case response to a subsequent TKI or to other
pharmacologic interventions is suboptimal.696 In those presenting with accelerated or blast phase, this process should start at diagnosis.
Contemporary studies have shown that in those in the chronic phase of CML who achieve CMR after transplantation, outcomes are excellent, but only
50% of those in accelerated phase at transplantation are longterm survivors, indicating that early donor search is important in those anticipated to
progress on TKIs. 699
Patients in the chronic phase of CML who are younger than approximately 75 years and who have a histocompatiblerelated or alternative donor can
Allografting continues to play a role in the treatment of patients who are refractory or intolerant to serial TKIs, and remains the optimal therapy in
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those who progress to accelerated or blast crisis in the face of treatment with a series of TKIs.696 In those who have significant intolerance to TKIs,
primary or secondary resistance to TKIs, or a T35I mutation, search for a donor should be started in case response to a subsequent TKI or to other
pharmacologic interventions is suboptimal.696 In those presenting with accelerated or blast phase, this process should start at diagnosis.
Contemporary studies have shown that in those in the chronic phase of CML who achieve CMR after transplantation, outcomes are excellent, but only
50% of those in accelerated phase at transplantation are longterm survivors, indicating that early donor search is important in those anticipated to
progress on TKIs.699
Patients in the chronic phase of CML who are younger than approximately 75 years and who have a histocompatiblerelated or alternative donor can
be transplanted after conditioning therapy. In younger fit patients, this usually consists of a combination of busulfan and cyclophosphamide or
cyclophosphamide and fractionated totalbody irradiation. Busulfan can be administered as an IV preparation and as a single daily dose.700 When
targeted steadystate busulfan levels are used, a 3year survival rate of 86% and a diseasefree survival rate of 78% with no age effect is achieved.701
With nonmyeloablative or “reducedintensity” conditioning regimens, patients over 60 years and those with comorbidities can undergo successful
allografting.702 With the success of TKI therapy, allogeneic stem cell transplantation is no longer recommended as a treatment option in chronic phase
CML responding to any sequence of TKIs.696 Allogeneic transplantation should be considered for patients with disease progression to accelerated or
blast phase on TKI therapy or in those who have not responded optimally to TKIs. In those cases, TKIs to which the patient has not been previously
exposed and for which they do not possess a resistant mutation can be used to bridge or prepare for the transplantation.703 Allogeneic transplantation
can be used in those rare patients who present with blast crisis and in those with T315I mutations who do not respond to ponatinib.704,705 In those who
do not respond to their first TKI exposure and are switched to a second TKI, transplantation in chronic phase would be indicated for those patients
with BCRABL1 transcripts greater than 10% or less than a PCyR at 3 and 6 months, minor or no cytogenetic response at 12 months, and only a PCyR at
18 months or cytogenetic relapse at 12 or 18 months.345 Splenic irradiation before transplantation has no effects on posttransplantation outcomes,
including relapse incidence.706
Myeloablative Allogeneic Transplantations
Stem cell transplantation from HLAcompatible siblings results in engraftment and an actual or projected longterm survival in 45% to 85% of
recipients.707–709 In patients older than 50 years, survival rates are slightly less at 5 years. The risk of CML relapse is approximately 20%, with a plateau
of relapse at 5–7 years. Transplanted T lymphocytes, especially if activated by a (mild) GVHD, may be an important factor in preventing leukemic
relapse. This phenomenon, referred to as graftversusleukemia effect, is thought to suppress the leukemic process through Tcell–mediated
cytotoxicity. The relative benefit of marrow compared to mobilized blood stem cells as the source of the allograft has not been established.710,711
Mobilized blood stem cells engraft more rapidly but may be associated with more chronic GVHD. The majority of survivors have no evidence of residual
leukemia.712 In children and adolescents undergoing myeloablative transplantation in chronic phase, the best outcomes are with marrow grafts and
matched sibling donors.713
Pretransplantation imatinib is not associated with increased transplantationrelated morbidity or decreased survival, but those who are transplanted
and have a suboptimal response to imatinib or loss of response to imatinib fare worse, which is probably related to a higher disease burden at the time
of transplantation and more aggressive disease.714,715 2GTKIs do not increase transplantrelated toxicity.716 The use of 3 TKIs before transplantation
was found in one series to be an adverse prognostic factor after transplantation in terms of nonrelapse mortality.717 Disease status after allografting
can be monitored with cytogenetic studies, PCR, or FISH analysis. A positive PCR assay 3 months after allogeneic transplantation has not been found to
correlate with an increased risk of relapse compared with PCRnegative patients. A positive assay at 6 months and beyond is associated with
subsequent relapse. In one series, 42% of patients with a positive PCR assay at 6–12 months relapsed versus 3% with a negative assay.718 Paradoxically,
patients who remain BCRABL1—positive more than 36 months after transplantation have little propensity for relapse.718 Serial quantitative RTPCR
analysis of blood specimens has been proposed to distinguish patients destined to relapse.719 Patients who remain in remission have undetectable,
low, or falling BCRABL1 levels on sequential analysis. After 6–9 months, these levels are undetectable in most cases. Recognition of relapse at the
molecular level may allow for early therapeutic intervention.
Killer immunoglobulinlike receptor (KIR) ligand mismatch also is an important prognostic factor in achieving molecular responses after
transplantation for CML.720 Increased frequency of regulatory T cells characterized as CD4+, CD25high are associated with higher rates of relapse after
allografting in CML.721
Nonmyeloablative Allogeneic Transplantations
Nonablative regimens have been developed in an attempt to expand the indication for allogeneic transplantation for patients over 60 years and those
with comorbidities. These regimens rely on immunosuppressive therapy to allow engraftment of cells that potentially will generate a graftversus
722
leukemia effect. Approximately 60% of patients, mostly in initial chronic phase (median age: 50 years) and transplanted with reducedintensity
conditioning regimens, had a 3year survival and approximately 33% had a 3year progressionfree survival.723 Patients no longer in first chronic phase
transplantation for CML.720 Increased frequency of regulatory T cells characterized as CD4+, CD25high are associated with higher rates of relapse after
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allografting in CML.721
Nonmyeloablative Allogeneic Transplantations
Nonablative regimens have been developed in an attempt to expand the indication for allogeneic transplantation for patients over 60 years and those
with comorbidities. These regimens rely on immunosuppressive therapy to allow engraftment of cells that potentially will generate a graftversus
leukemia effect.722 Approximately 60% of patients, mostly in initial chronic phase (median age: 50 years) and transplanted with reducedintensity
conditioning regimens, had a 3year survival and approximately 33% had a 3year progressionfree survival.723 Patients no longer in first chronic phase
do not fare as well.724 There is evidence that nonablative transplantations can be effective when used in conjunction with imatinib in patients less than
50 years in early or late chronic phase with comparable OS and eventfree survival as compared with imatinib and with a lower cost over a 10year
period in these patients with long life expectancy.725 Transplantations performed with nonablative or reducedintensity conditioning regimens have
not been compared with ablative transplantations in chronic phase CML, but they may have less transplantrelated morbidity and mortality, although
GVHD rates are thought to be comparable and relapse rates may be higher.722
USE OF TYROSINE KINASE INHIBITORS AFTER STEM CELL TRANSPLANTATION
Both donor leukocyte infusions (DLIs) and TKIs can be used to treat posttransplantation relapse. Complete responses after imatinib therapy have been
noted in accelerated or blast phase CML persisting after stem cell transplantation.726 In one series, imatinib was able to generate CMRs in 26% of
chronic phase patients after allografting, with full donor chimerism usually observed.727 One study found that more patients with relapsed disease had
a molecular remission with DLI at 5 years than with imatinib alone. Most of these patients had cytogenetic relapses only.728 In a retrospective
comparison of 37 patients with hematologic or molecular relapse of CML who received imatinib, DLI, or a combination of both in concurrent or
sequential regimens, the OS was 100% for imatinib plus DLI, 89% for imatinib alone, and 54% for DLI alone.729 Some of these studies included patients
who have not had TKI therapy before transplantation. 2GTKIs and 3GTKIs also can be used to treat posttransplantation relapse.730 The choice of TKI
is dependent on the patient’s prior TKI exposure and on mutation status, which should be checked at relapse. Patients who have ABL kinase mutations
before transplantation often relapse with the same mutation.731
Prophylactic administration of imatinib after transplantation has been used for patients at high risk of relapse.732 Posttransplantation imatinib is
usually welltolerated; pancytopenia is the principal toxicity. The cytopenias resolve with dose adjustments or temporary drug discontinuation.
Nilotinib prophylaxis appears to be safe and may control minimal residual disease and convert patients to a complete molecular response.733 Nilotinib
was not associated with altered immune function or reconstitution posttransplantation.734 Dasatinib also has been used postallograft in CML and may
be associated with increased risk of cytomegalovirus reactivation.735 The choice of agent to use as prophylaxis may be dictated by the presence of
pretransplantation ABL kinase domain mutations as those with kinase mutations before transplantation relapse predominately with the same
mutation.731 TKIs are usually started 30–100 days after allografting once established engraftment occurs and they are often started at 50% dose
reductions compared with pretransplantation doses to avoid toxicity.736 Questions remain regarding the use of posttransplantation TKIs. When should
they be started? Which drug is superior? For how long should the drugs be used? Should they only be started in cases of molecular relapse? How can
they be best combined with DLI in cases of relapse?
IMMUNOTHERAPY: ADOPTIVE CELL THERAPY FOR POSTTRANSPLANTATION RELAPSE
Substantial evidence indicates that the effectiveness of allografting in CML does not result solely from the eradication of the leukemic clone with high
dose chemoradiotherapy conditioning regimens, but also from adoptive immunotherapy provided by lymphocytes in the allograft, the graftversus
leukemia effect (see “Myeloablative Allogeneic Transplantations” above).737 This phenomenon has been recreated to produce a therapeutic response
by infusing the lymphocytes from the stem cell donor after a relapse following allogeneic stem cell transplantation.738,739 The overall response rate to
DLI is approximately 75%. The response rate is higher when this approach is used early after detecting a relapse by PCR,740,741 compared to use after a
hematologic or cytogenetic relapse. Patients with a short interval between transplantation and DLI have a higher probability of response than patients
with longer intervals. Responses are the same with related versus unrelated donors.742 Some patients show a very rapid decline of BCRABL1 transcript
levels (<6 months after DLI), whereas other patients demonstrate PCR negativity only over a longer period.743 The responses to DLI can be durable.744
Molecular responses can occur in up to twothirds of patients.745
The main toxicities of DLI are the induction of GVHD and myelosuppression. Chronic GVHD can occur in up to 60% of cases.746 Attempts to diminish
these toxicities have included use of CD8depleted DLIs and infusion of smaller numbers of T cells.747,748 Lower initial cell dose is associated with less
myelosuppression, the same response rate, better survival, and less DLIrelated mortality, leading to suggestions that the initial dose should not
8 mononuclear cells/kg body weight.749 The initial doses should be lower when matched unrelated donors are used. Immune
Page 43 / 124
exceed 0.2 × 10
suppression should first be tapered before DLIs are administered. As noted above, imatinib may synergize with DLI to foster rapid molecular
responses after relapse.729
with longer intervals. Responses are the same with related versus unrelated donors.742 Some patients show a very rapid decline of BCRABL1 transcript
levels (<6 months after DLI), whereas other patients demonstrate PCR negativity only over a longer period.743 The responses to DLI can be durable.744
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Molecular responses can occur in up to twothirds of patients.745
The main toxicities of DLI are the induction of GVHD and myelosuppression. Chronic GVHD can occur in up to 60% of cases.746 Attempts to diminish
these toxicities have included use of CD8depleted DLIs and infusion of smaller numbers of T cells.747,748 Lower initial cell dose is associated with less
myelosuppression, the same response rate, better survival, and less DLIrelated mortality, leading to suggestions that the initial dose should not
exceed 0.2 × 108 mononuclear cells/kg body weight.749 The initial doses should be lower when matched unrelated donors are used. Immune
suppression should first be tapered before DLIs are administered. As noted above, imatinib may synergize with DLI to foster rapid molecular
responses after relapse.729
COURSE AND PROGNOSIS
Imatinib was first used experimentally for CML treatment in June 1998.
With the advent of TKI treatment, life expectancy of patients with chronic phase CML has approached that of the general population. One study found
those persons, regardless of age, diagnosed in 2013 would on average lose less than 3 years of life expectancy as a result of CML.750 TKIs also increased
diseasespecific survival in those diagnosed before and alive at the introduction of TKIs.751 The prevalence of CML in the TKI era is estimated to reach a
plateau 35 times the annual incidence, with a plateau estimated to occur in 2050. Therefore, the prevalence of CML is predicted to increase by a factor
of 10.752 Using the Swedish Cancer Registry, over a 36year period, relative survival rates compared with the total population for CML improved from
0.21 in 1973–1979 to 0.80 for 2001–2008; imatinib was introduced in Sweden in 2001.753 Another study from the Swedish CML registry of 779 patients
showed that the mean survival ratio at 5 years was close to 1.0 for those younger than 60 years and 0.9 for those 60–80 years old.754 Resistance rates
decline with each passing year, and adverse effects have not emerged over time.459 Those who require 1 year or more of imatinib therapy to attain a
CCyR have comparable rates of molecular response, progressionfree survival, and OS to those who achieve a CCyR sooner.755 In patients with failure
to respond or intolerance to imatinib the estimated 3year survival rate after a median of 2 years of observation was approximately 70% for patients in
chronic phase. Survival in chronic phase was better when subsequent therapy was nilotinib or dasatinib as compared to allogeneic hematopoietic
stem cell transplantation or to others agents.756 For those patients who require a secondline or thirdline TKI for therapy, diseaserelated mortality
was greater than that resulting from treatmentrelated adverse events, suggesting usefulness of subsequent TKIs in those who are resistant to or
intolerant of initial TKI therapy.757 Older patients (>64 years) have lower response rates when treated in late chronic phase, but if they attain a CCyR, no
difference was found in the level of molecular response.755 Smokers with CML are at a higher risk of disease progression and premature death than
those with CML who do not smoke.758
In one analysis of 559 newly diagnosed patients with CML treated initially with imatinib, at a minimum followup of 66 months, 363 (65%) were still on
imatinib and the 6year survival was 89%; leukemiarelated deaths were 5% of the 559 patients treated.759 In another study of longterm imatinib use,
with a median followup of 83 months, the 10year survival rate was 82% and 21% of patients had reached MR4 for longer than a year and 6.5% reached
MR4.5.760 In the longest followup of the IRIS trial published thus far, at a median followup of 10.9 years, among patients originally assigned to the
imatinib group, the 10year estimated OS rate was 83.3%, and 82.8% had a CCyR. Most serious adverse events related to imatinib occurred in the first
year of treatment.427 Table 88–9 shows the 5year relative survival data by age at diagnosis in the United States. In general, longterm use of tyrosine
kinases is thought to be safe.761 With improved survival in CML, some patients are developing second malignancies. One study showed a relative
incidence slightly higher than in the general population,762 whereas other studies showed no evidence of such an increase.763,764 Opportunistic
infections have been reported with TKI use, but these are rare; even so, some investigators recommend screening for chronic hepatitis B virus infection
and for prophylactic therapy.765 Even though longterm outcomes can be similar in CML regardless of the initial TKI used, severe adverse events (grade
IIIIV) can shorten survival times.766 Those who develop CML after having had a prior malignancy have similar eventfree survivals and failurefree
survivals as those without prior cancer.767,768
TABLE 88–9.
Chronic Myelogenous Leukemia: 5Year Period Relative Survival Rates (2009–2015) by Age at Diagnosis
Age (years) Percent of Patientsa
<45 90
45–54 87
55–64 77
infections have been reported with TKI use, but these are rare; even so, some investigators recommend screening for chronic hepatitis B virus infection
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and for prophylactic therapy.765 Even though longterm outcomes can be similar in CML regardless of the initial TKI used, severe adverse events (grade
IIIIV) can shorten survival times.766 Those who develop CML after having had a prior malignancy have similar eventfree survivals and failurefree
survivals as those without prior cancer.767,768
TABLE 88–9.
Chronic Myelogenous Leukemia: 5Year Period Relative Survival Rates (2009–2015) by Age at Diagnosis
Age (years) Percent of Patientsa
<45 90
45–54 87
55–64 77
65–74 61
>75 33
a Percent rounded to nearest whole number.
Data from Surveillance, Epidemiology, End Results Cancer Statistics: 5Year Survival Rates, All Races and Sexes. National Cancer Institute, Washington, DC. Available
at http://www.seer.cancer.gov.
The introduction of imatinib has minimized the impact of prognostic factors at diagnosis of chronic phase CML.769 Several prognostic scales have been
proposed in CML, including the Sokal and Hasford systems for patients at the time of diagnosis (Table 88–10). The European Bone Marrow
Transplantation Consortium Risk Score was introduced for patients undergoing allogeneic hematopoietic stem cell transplantation,770 in which
performance status is added to 5 variables (age, spleen size, blood blast cell count, basophil and eosinophil count, and platelet count [Hasford score]),
and has been validated with good discrimination for survival.770 The Sokal score based on age, spleen size, platelet count, and percent blasts was
published in 1984 during the busulfan era of treatment and was less accurate in patients treated with IFN. The European Treatment and Outcomes
Study (EUTOS) score uses basophils and spleen size and can be calculated using an online algorithm (http://www.mdcal.com/etosscoreichronic
myelogenousleukemiacml). This was validated in a study from China in 220 patients with CML on imatinib. The EUTOS score predicted progression
free survival and duration of CCyR. It did not discriminate the intermediaterisk from the highrisk group in survival or attainment of CCyR.772 There is
evidence that a patient with chronic phase CML and a favorable Sokal score at the time of diagnosis has a higher proportion of CHR and CCyR with
imatinib treatment than other patients.773 The score of a patient may be calculated, easily, using an online website (https://www.mdcalc.com) (Table
88–10). Some studies also suggest that in certain healthcare systems, the healthcare setting may influence survival time, especially for those in
advanced phases of the disease.774
TABLE 88–10.
The Variables Used to Calculate the Risk Group (High, Intermediate, Low) at Diagnosis in Patients with Chronic Phase Chronic Myelogenous
Leukemia to Estimate Prognosis
The Sokal score, which is a hazard ratio, is calculated using the following formula based on age, spleen size, platelet count, and blood percent blast cells:
exp (0.0116 × (age [years] − 43.4)) + (0.0345 × (spleen size [cm] − 7.51) + (0.188 × ((platelets [109/L]/700)^2 − 0.563)) + (0.0887 × (blasts [%] − 2.10)). There are 3
risk groups: lowrisk (Sokal score <0.8), intermediaterisk (Sokal score 0.8–1.2), and highrisk (Sokal score >1.2).
The Hasford score (or Euro score) is calculated using the following formula based on the 4 Sokal variables plus percent eosinophils and basophils in the
blood: (0.6666 × age [0 when age <50 years; 1 otherwise]) + (0.0420 × spleen size [cm]) + (0.0584 × blasts [%]) + (0.0413 × eosinophils [%]) + (0.2039 × basophils
[0 when basophils <3%; 1 otherwise]) + (1.0956 × platelet count [0 when platelets <1500 × 109/L; 1 otherwise]) × 1000). Three risk groups are: lowrisk (score
≤780, 40.6% of patients), intermediaterisk (score 781–1480, 44.7% of patients), and highrisk (score ≥1481, 14.6% of patients).
These scores may be calculated electronically by insertion of the individual variables, such as age, spleen size, blood blast percentage, etc. at the following website.
http://bloodref.com/myeloid/cml/sokalhasford.
Outcomes after allogenic hematopoietic stem cell transplantation have also improved in the imatinib era, but those in chronic phase have better 3year
survival rates than those in advanced phases (91% [chronic phase] vs 59% [advanced phases]).775 There is favorable longterm survival after 5 years
evidence that a patient with chronic phase CML and a favorable Sokal score at the time of diagnosis has a higher proportion of CHR and CCyR with
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imatinib treatment than other patients.773 The score of a patient may be calculated, easily, using an online website (https://www.mdcalc.com) (Table
88–10). Some studies also suggest that in certain healthcare systems, the healthcare setting may influence survival time, especially for those in
advanced phases of the disease.774
TABLE 88–10.
The Variables Used to Calculate the Risk Group (High, Intermediate, Low) at Diagnosis in Patients with Chronic Phase Chronic Myelogenous
Leukemia to Estimate Prognosis
The Sokal score, which is a hazard ratio, is calculated using the following formula based on age, spleen size, platelet count, and blood percent blast cells:
exp (0.0116 × (age [years] − 43.4)) + (0.0345 × (spleen size [cm] − 7.51) + (0.188 × ((platelets [109/L]/700)^2 − 0.563)) + (0.0887 × (blasts [%] − 2.10)). There are 3
risk groups: lowrisk (Sokal score <0.8), intermediaterisk (Sokal score 0.8–1.2), and highrisk (Sokal score >1.2).
The Hasford score (or Euro score) is calculated using the following formula based on the 4 Sokal variables plus percent eosinophils and basophils in the
blood: (0.6666 × age [0 when age <50 years; 1 otherwise]) + (0.0420 × spleen size [cm]) + (0.0584 × blasts [%]) + (0.0413 × eosinophils [%]) + (0.2039 × basophils
[0 when basophils <3%; 1 otherwise]) + (1.0956 × platelet count [0 when platelets <1500 × 109/L; 1 otherwise]) × 1000). Three risk groups are: lowrisk (score
≤780, 40.6% of patients), intermediaterisk (score 781–1480, 44.7% of patients), and highrisk (score ≥1481, 14.6% of patients).
These scores may be calculated electronically by insertion of the individual variables, such as age, spleen size, blood blast percentage, etc. at the following website.
http://bloodref.com/myeloid/cml/sokalhasford.
Outcomes after allogenic hematopoietic stem cell transplantation have also improved in the imatinib era, but those in chronic phase have better 3year
survival rates than those in advanced phases (91% [chronic phase] vs 59% [advanced phases]).775 There is favorable longterm survival after 5 years
free of relapse after allogeneic hematopoietic stem cell transplantation.776 Prognostic factors in the TKI era for allogeneic transplantation are also
being defined, and in addition to disease phase, donormatch, age, sex, and calculated comorbidity indices are of importance.777
DETECTION OF MINIMAL RESIDUAL DISEASE
Detection of minimal residual disease by molecular probes makes possible the identification of approximately 1 cell in 1 million that is derived from the
CML clone.778 Techniques used to monitor residual disease have been reviewed.779,780 PCR permits observation of regression or persistence of
subclinical disease following therapy and of progression of subclinical disease prior to the disease becoming overt, and it is therefore critical for
monitoring responses to CML treatment.781,782 The stable persistence of subclinical disease does not invariably predict early relapse.783,784 With the
advent of treatmentfree remission, this has become a goal of therapy for many, and this has made depth and duration of MMR (eg, MR4.5 or
undetectable BCRABL) a target that necessitates accurate molecular monitoring.785
Efforts continue to standardize the technique for measuring and reporting RTPCR,786 and serial measurements are required for treatment decisions
based on increases in transcript numbers.787 This has led to development of an international reporting scale (International Standard).786 In patients on
imatinib, who have MMR confirmed by realtime quantitative PCR, no marrow cell cytogenetic abnormalities were found, indicating that patients with
MMR do not require regular marrow examinations for cytogenetics.458,788 The International Standard uses baseline diagnosis levels in the IRIS study as
100% and fixes a 3log reduction from a standardized baseline (MMR) at 0.1%. Widespread use of the International Standard requires laboratories to
send in specimens for analysis,786 which is a priority to ascertain response to therapy accurately and to analyze responses among treatment centers.789
Challenges to standardization persist.790,791 There is also evidence outside academic medical centers that less than 40% of patients undergo
quantitative PCR every 3 months as recommend by the NCCN/European LeukemiaNet guidelines.792 One analysis showed that 0.35% of patients who
have regular monitoring versus 5.12% of those without regular monitoring have progression to accelerated phase or blast crisis, so this has important
survival implications.793 Quantitative PCR is technically demanding and liable to assay variations, but its importance has risen as clinical decisions,
such as whether to discontinue TKI therapy, hinge upon its accuracy.794,795 The GeneXpertTM system has an accuracy at levels lower than 10% BCR
ABL1. It, also, has the capability of predicting CCyR and MMR at 12 months, based on a cutoff of 1.5% at 3 months as compared with the 10%
International Standardization quantitative PCR method with a 10% cutoff at 3 months.796 The role that such automated systems will play in the future
has not been determined.592
Patients who achieve a MMR (expressed as a 3log reduction from median baseline value) at the time of achieving a CCyR have been found to have
longer cytogenetic remissions than those without this magnitude of molecular response.797 Other studies, however, show that patients who achieve
CCyR do not derive additional benefit from a CMR.798 The treatment response to imatinib, nilotinib, and dasatinib showed that the 3year eventfree
survival was 95% for those with BCRABL1 transcripts of 1% or less at 3 months, 98% for greater than 1% to 10%, and 61% for greater than 10%. These
3month responses translated into OS of 98%, 96%, and 92%, respectively.799
ABL1. It, also, has the capability of predicting CCyR and MMR at 12 months, based on a cutoff of 1.5% at 3 months as compared with the 10%
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International Standardization quantitative PCR method with a 10% cutoff at 3 months.796 The role that such automated systems will play in the future
has not been determined.592
Patients who achieve a MMR (expressed as a 3log reduction from median baseline value) at the time of achieving a CCyR have been found to have
longer cytogenetic remissions than those without this magnitude of molecular response.797 Other studies, however, show that patients who achieve
CCyR do not derive additional benefit from a CMR.798 The treatment response to imatinib, nilotinib, and dasatinib showed that the 3year eventfree
survival was 95% for those with BCRABL1 transcripts of 1% or less at 3 months, 98% for greater than 1% to 10%, and 61% for greater than 10%. These
3month responses translated into OS of 98%, 96%, and 92%, respectively.799
Interphase FISH is not standardized, but up to 500 cells can be rapidly analyzed. Fixation, specimen preparation, and hybridization conditions may
account for differing falsepositive ranges and scoring criteria.800 In CML patients treated with imatinib, FISH for BCRABL1 on interphase blood
neutrophils, but not unselected white cells, correlates with marrow cytogenetics.801 FISH is not suitable for monitoring minimal residual disease.802
For patients who are undergoing allogeneic hematopoietic stem cell transplantation, the kinetics of minimal residual disease in either standard or
nonmyeloablative transplants differ. BCRABL1/ABL1 ratios were 0.2% with reducedintensity transplantations versus 0.01% in transplantation
patients with traditional conditioning regimens in the first 3 months. By 12 months, however, 20% of patients who received standard transplantations
and 50% of patients who received reducedintensity transplantations had reached a level less than 0.01%, supporting the concept of different kinetics
of disease eradication between the 2 transplantation modalities.724 Patients who relapse after allografting have reappearance and/or rising levels of
BCRABL1 transcripts.803 Use of quantitative RTPCR early (3–5 months) after stem cell transplantation can project longterm outcomes.804 When RT
PCR was negative, the 3year risk of relapse was 16.7%; when RTPCR was positive at a ratio of less than 0.02%, the relapse rate was 42.9%; and when
RTPCR was positive at a level greater than 0.02%, the relapse rate was 86.5%. Another group found that detection of blood BCRABL1 at 18 or more
months after transplantation was associated with a highly significant risk of relapse and that patients who had a positive test result but failed to
relapse generally had only 1 positive test result at a low copy number.805 Performance of quantitative PCR at regular intervals after allogeneic
transplantation (every 2–4 months in the first year and every 6 months thereafter) is appropriate. If the PCR results are persistently positive or become
positive, quantitative PCR should be performed at monthly or shorter intervals. Molecular relapse is defined as a 10fold increase of PCR positivity
without any signs of cytogenetic relapse. Detection of increasing recipient chimerism by FISH for the male chromosome in sexmismatched donor–
recipient pairs or variable number of tandem repeats after allogeneic transplantation or after DLI infusion also is usually associated with a relapse.806
In an imatinibtreated patient, the absence of BCRABL1 transcripts should not be interpreted as an absence of the leukemic clone.807 In response to
2GTKIs, there was no difference in eventfree survival and CCyR duration between patients with CCyR with and without MMR up to 18 months, with
followup at 3month intervals.808 One study examined 116 patients with durable cytogenetic responses on imatinib who had increased PCR levels on at
least two occasions. Only 10 (9%) of the 116 patients had CML progression. Ten patients (9%) had lost MMR or had never had it, and all of these had
more than 1log increase in quantitative PCR.464 With 2GTKI, the BCRABL1 transcript levels at 3 months are also correlated with CCyR and MMR by 24
months, with levels less than 10% at 3 months being optimal.809 Only 60% of patients in the IRIS trial were in CCyR on imatinib after 6 years of therapy,
indicating the need for close monitoring and for alternative therapies.810 There is also evidence that the BCRABL1 transcript doubling time more
reliably assesses CML relapse as compared to the fold rise in BCRABL1 transcripts. A short doubling time for a patient in chronic phase should raise
suspicion of nonadherence.811
ACCELERATED PHASE AND BLAST CRISIS OF CHRONIC MYELOGENOUS LEUKEMIA
DEFINITION
In all patients with chronic phase CML, the disease has the potential to evolve into a more aggressive, more symptomatic, and troublesome phase,
which is poorly responsive to the therapy that formerly controlled the chronic phase. The failure of therapy to restore or maintain nearnormal red cell
and white cell counts, increased spleen size, increased numbers of marrow blasts and blood basophils, loss of the sense of wellbeing, and
appearance of extramedullary tumors are the most consistent clinical hallmarks of the metamorphosis of the chronic to the accelerated phase of CML.
The most objective findings are a blood blast percentage greater than 10, a platelet count lower than 100 × 109/L, blood basophils higher than 20%,
and new clonal cytogenetic abnormalities accompanying the Ph chromosome.812
Several criteria have been published to define accelerated phase and blast crisis.813–815 The terminology used has included accelerated phase, acute
phase, acute transformation, or, in its most dramatic expression, blast crisis, but the metamorphosis, which can be acute, often is more gradual, hence
the preference for transformation or accelerated phase to describe this transition from a controllable to a poorly controlled malignancy. Blast phase is
the severest manifestation of the accelerated phase and can occur abruptly or after a period of worsening disease. Blast crisis is in effect the evolution
to overt acute leukemia, either myeloid or lymphoid.
PATHOGENESIS
and new clonal cytogenetic abnormalities accompanying the Ph chromosome.812
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Several criteria have been published to define accelerated phase and blast crisis.813–815 The terminology used has included accelerated phase, acute
phase, acute transformation, or, in its most dramatic expression, blast crisis, but the metamorphosis, which can be acute, often is more gradual, hence
the preference for transformation or accelerated phase to describe this transition from a controllable to a poorly controlled malignancy. Blast phase is
the severest manifestation of the accelerated phase and can occur abruptly or after a period of worsening disease. Blast crisis is in effect the evolution
to overt acute leukemia, either myeloid or lymphoid.
PATHOGENESIS
Effect of Tyrosine Kinase Inhibitors in Rate of Progression
The advent of TKI therapy for CML has resulted in a marked increase in the duration of a subclinical chronic phase, with normal blood counts and
spleen size, often with the loss of identifiable Ph chromosome–bearing cells in blood and marrow, and sometimes with the loss of laboratory evidence
of the BCRABL1 oncogene as judged by PCR. This therapeutic advance has greatly delayed the evolution to accelerated phase and blast crisis, but the
risk for such a conversion exists since under experimental conditions. CML stem cells do not undergo apoptosis when exposed to TKIs. BCRABL1–
positive cells return in virtually all patients if TKI therapy is interrupted; even in those patients able to sustain a treatmentfree remission. There is
evidence that genomic instability and clonal evolution may derive from an imatinibrefractory CML stem cell.816
Blast Crisis Stem Cells
The onset of accelerated phase is thought to occur in a BCRABL1–bearing granulocytemonocyte progenitor. Experimental817,818 and theoretical819
evidence supports this concept. This progenitor for clonal evolution also could explain the reversion to chronic phase in some patients in whom the
suppression of the advanced phase of the disease is achieved.
Molecular and Genetic Alterations
The transformation of chronic phase CML to accelerated and then blast crisis, or directly to blast crisis, is thought to be the result of 7 molecular
processes: (a) maturation arrest, (b) failure of genome surveillance, (c) failure of adequate DNA repair, (d) development of a mutated phenotype, (e)
telomere shortening, (f) loss of tumorsuppressor function, and (g) unknown factors.820,821
Progression of chronic phase to accelerated phase is marked by an increase in BCRABL1 expression.822,823 Superimposed on the increased
transcription of mRNABCRABL1 are additional cytogenetic abnormalities that are added to the persistent Ph chromosome in approximately 50% to 65%
of patients.824–826 In lymphoid blast crisis, in which the blast cells have a lymphocytic phenotype, acquisition of mutations in tumorsuppressor genes,
such as p16/ARF, occurs in approximately 50% of cases, and RB gene mutations occurs in approximately 20% of cases. In myeloid blast crisis, in which
blast cells have a myeloid phenotype, approximately 25% of cases have cells containing a p53 mutation.827 The possible role of loss of p53 function in
fostering transformation of a human chronic phase CML clone has been demonstrated in transgenic mice in which p53 function was abrogated.828,829
Progression of the clone to a more malignant clone is reflected in a more disordered growth and maturation pattern of progenitor cells in culture,
ultimately mimicking the cell development failure of acute leukemia,824 and in increased morphologic and functional abnormalities of blood
cells,830,831 eventuating in a block in maturation and replacement of blood and marrow by blast cells.
Approximately 65% of patients have cytogenetic abnormalities in addition to the Ph chromosome. A double Ph chromosome, trisomy 8, and
isochromosome 17p are the secondary changes most commonly seen.827,832 Because the frequency of trisomy 8 was greater after treatment with
busulfan compared to hydroxyurea, the frequency of secondary chromosomal changes may be quite different after imatinib therapy.827 Clonal
instability also has been found in cases of lymphoid blast crisis. Clones distinct from those identified later may be detected before overt lymphoid
transformation. Identification of these abortive clones suggests clonal instability before the onset of transformation, which might have prognostic
value.833 FISH has been used to determine which cells have secondary cytogenetic abnormalities, and these cells often are not the blast cells. This
finding suggests that some chromosomal abnormalities merely denote genomic instability.834 The abnormal mRNA and protein product p210BCRABL1
are present in the marrow and blood cells of patients who have transformed to acute leukemia.835–837
Although the breakpoint site on Mbcr was thought to be correlated with the time of the onset of the accelerated phase,838 subsequent studies have
not indicated a correlation between length of chronic phase and the specific site of the BCRABL1 fusion.839 Rare cases have displayed deletion of the
BCRABL1 fusion gene, loss of transcription of the message, and loss of expression of the p210 tyrosine kinase after transformation, the latter finding
indicating the abnormal protein kinase may not always play a unique role in sustaining the acute state.840 In contrast, the frequent response, albeit
temporary, to imatinib suggests that the mutant BCRABL1 product usually plays a role at this stage of the disease.
Numerous molecular changes identified in the cells of patients with acute transformation that might contribute to the increased malignant behavior of
the CML clone, include activation of the NRAS gene,841,842 rearrangement of the p53 gene,842–845 hypermethylation of the calcitonin gene,846 and
847
Although the breakpoint site on Mbcr was thought to be correlated with the time of the onset of the accelerated phase,838 subsequent studies have
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not indicated a correlation between length of chronic phase and the specific site of the BCRABL1 fusion.839 Rare cases have displayed deletion of the
BCRABL1 fusion gene, loss of transcription of the message, and loss of expression of the p210 tyrosine kinase after transformation, the latter finding
indicating the abnormal protein kinase may not always play a unique role in sustaining the acute state.840 In contrast, the frequent response, albeit
temporary, to imatinib suggests that the mutant BCRABL1 product usually plays a role at this stage of the disease.
Numerous molecular changes identified in the cells of patients with acute transformation that might contribute to the increased malignant behavior of
the CML clone, include activation of the NRAS gene,841,842 rearrangement of the p53 gene,842–845 hypermethylation of the calcitonin gene,846 and
methylation of the ABL1 gene.847 One report described p53 mutations in 17% of blast crisis patients. An association between the failure of CML cells to
express the RB1 gene product and acute blast crisis with a megakaryoblastic phenotype has been reported.848 Homozygous deletions of the p16 gene
are associated with lymphoid transformation of CML,849 but such deletions are not seen in the chronic phase and in myeloid blast crisis. p16 is also
known as the cyclindependent kinase 4 inhibitor gene and is located on chromosome 9p21.850,851 This gene inhibits the kinase CDK4, which regulates
a cellcycle checkpoint prior to commitment to DNA synthesis. The Wilms tumor (WT) gene on chromosome 11p13 encodes a zinc finger motif
containing transcription factor found in CML patients only after progression to blast crisis.852 Overexpression of the EVI1 gene also has been found in
CML blast crisis.853,854 Microsatellite instability has not been found to be involved with progression to blast crisis.855 BCL2, cMYC, RUNX1, IKZF1,
ASXL1, WT1, TET2, IDH1, NRAS, KRAS, CBL, and various other genes also have been implicated in the evolution of CML.50,856–858 Thus far, no
characteristic mutation or combination of mutations has emerged, and progression may occur in the absence of BCRABL1 mutations, suggesting
involvement of alternative pathways.859
Approximately 50 genes have been identified that could play a role in the progression to accelerated phase or blast crisis,820 including genes identified
by expression profiling that are dysregulated in accelerated phase compared to chronic phase.857,858 These include the WNTβcatenin and JunB
pathways. In patients with TKIresistant progression to advanced stage where no ABL1 mutations are expressed, mutations in genes associated with
epigenetic regulation, such as DNMT3A and ASXL1, have been reported.860 Mutations may be found during chronic phase in Phnegative and Ph
positive clones, such as those affecting ASXL1, DNMT3A, RUNX1, and TET2 genes.861 CpG (cytosinephosphateguanine) site methylation may also
increase during CML progression to accelerated or blastic phase.862
CLINICAL FEATURES
Signs and Symptoms
The features that might signal the conversion of the chronic to the accelerated phase include unexplained fever, bone pain, weakness, night sweats,
weight loss, loss of sense of wellbeing, arthralgia, and left upper quadrant pain related to splenic enlargement or infarcts. These features may occur
weeks in advance of laboratory evidence of the accelerated phase. Localized or diffuse lymphadenopathy or enlarging masses in extralymphatic and
extramedullary sites containing BCRABL1–positive myeloblasts or lymphoblasts may develop. A poor response of blood cell counts and splenic
enlargement despite previously effective therapy may be evident.863–865 Symptoms caused by histamine excess in basophilic crisis can be present.866
Several of these changes may occur in series or in parallel. The time of onset of transformation and the appearance of a blast crisis and its clinical
expression are unpredictable.
LABORATORY FEATURES
Blood Findings
Quantitative and qualitative blood cell abnormalities are varied.827,864,865 Anemia may worsen and be associated with increasing poikilocytosis,
anisocytosis, and anisochromia. The number of nucleated red cells in the blood may increase. These red cell changes may be accentuated further if
advancing marrow fibrosis is a feature of the disease.
The total leukocyte count may fall without treatment. The proportion of blasts increases to greater than 10% in blood and marrow in the accelerated
phase, and when blast crisis ensues, represents 20% to 90% of the cells. The morphology of the blast cells may be lymphoid or myeloid. Myelocytes
decrease in number. Hyposegmented neutrophils (PelgerHuët cells) and other dysmorphic changes may become evident. Basophils increase and can
represent 20% to 80% of the total blood leukocytes. A decrease of the platelet count to less than 100 × 109/L develops. Giant platelets,
micromegakaryocytes, and megakaryocyte fragments may enter the blood. Decreased progenitor cell growth in culture is present, akin to that in acute
leukemia.
Marrow Findings
The marrow findings are widely variable.827,864,865 Marked dysmorphic changes in 1, 2, or 3 of the major cell lineages; an increase in blast count to
greater than 10%; marrow morphology simulating subacute myelomonocytic leukemia; or, in the extreme, florid blastic transformation with blast
phase, and when blast crisis ensues, represents 20% to 90% of the cells. The morphology of the blast cells may be lymphoid or myeloid. Myelocytes
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decrease in number. Hyposegmented neutrophils (PelgerHuët cells) and other dysmorphic changes may become evident. Basophils increase and can
represent 20% to 80% of the total blood leukocytes. A decrease of the platelet count to less than 100 × 109/L develops. Giant platelets,
micromegakaryocytes, and megakaryocyte fragments may enter the blood. Decreased progenitor cell growth in culture is present, akin to that in acute
leukemia.
Marrow Findings
The marrow findings are widely variable.827,864,865 Marked dysmorphic changes in 1, 2, or 3 of the major cell lineages; an increase in blast count to
greater than 10%; marrow morphology simulating subacute myelomonocytic leukemia; or, in the extreme, florid blastic transformation with blast
counts greater than 30% can occur. Reticulin fibers may increase in prominence, and occasionally severe reticulin and collagen fibrosis develop.
Additional clonal cytogenetic abnormalities develop in as many as half the patients in accelerated phase (see “Cytogenetic Studies” below).
EXTRAMEDULLARY BLAST CRISIS
A variety of symptoms or signs may occur as a result of the specific effects of new extramedullary blastic tumors, referred to as extramedullary blast
crisis.866–869 Extramedullary blast crisis is the first manifestation of accelerated phase in approximately 10% of patients with CML. Lymph nodes,867–869
serosal surfaces,870,871 skin and soft tissue,866–869 breast,869,872 gastrointestinal or genitourinary tract,867,869 bone,867,869–876 and central nervous
system867,877–881 are among the principal areas involved. Isolated or diffuse lymphadenopathy may occur. Bone involvement may lead to severe pain,
tenderness, and pathologic fracture, and may be evident on imaging of the involved area. Central nervous system involvement usually is meningeal
and may be preceded by headache, vomiting, stupor, cranial nerve palsies, and papilledema and is associated with an increase in cells, protein, and the
presence of blasts in the spinal fluid.869,877–879
Appropriate histochemical and immunologic tests are required to determine if the extramedullary disease is composed of phenotypic myeloblasts or
lymphoblasts. Because the tumor cells may have features of lymphoma cells, the terms myeloid or granulocytic sarcoma, chloroma, and
myeloblastoma can be misnomers, and the term extramedullary blast crisis is used for this circumstance in CML.878,880–882 The lymphoblasts, like the
myeloblasts, are Phpositive. A combination of morphology, histochemistry (eg, peroxidase, lysozyme), terminal deoxynucleotidyl transferase (TdT)
assay, and monoclonal antibodies specific for lymphoid or myeloid cells can be used to classify the extramedullary blast cells.
MARROW BLAST CRISIS
Approximately half of patients with CML enter the accelerated phase by developing acute leukemia. The onset of blast crisis can develop from days883–
885 to decades after diagnosis of CML. The signs and symptoms may include fever, hemorrhage, bone pain, and lymphadenopathy.883–885 The
morphology of the acute leukemia usually is myeloblastic or myelomonocytic.886,887 A substantial proportion of myeloid leukemia in this setting may
not have myeloperoxidase demonstrable by cytochemistry.887 The proportion of cases classified as erythroblastic leukemia is approximately 10%,
based on morphologic features,888 but may be as high as 20% if expression of glycophorinA is used as the determinant.889 Occasional cases have
megakaryoblastic transformation.848,890 These cases may be difficult to identify by light microscopy because the megakaryoblasts may be mistaken for
lymphoid cells or undifferentiated blasts. Myelofibrosis is a feature of this variant. Antiplatelet glycoprotein antibodies and other monoclonal
antiplatelet antibodies are available as reagents to identify megakaryoblasts without the need for ultrastructural studies.890 Promyelocytic891–893 and
eosinophilic894 blast crises also can occur. Basophilic leukemia is a known variant of CML.222 Patients with promyelocytic crisis often have t(15;17) in
addition to the Ph chromosome, and some have presented with disseminated intravascular coagulation.895
CML may transform into ALL in approximately 30% of blastic crisis cases.812,896,897 The lymphoid cells generally express TdT896 and are of the Bcell
lineage,898 as judged by antiimmunoglobulin staining. TdT is a DNA polymerase that adds deoxynucleoside monophosphates from triphosphate
substrates to singlestranded DNA by end addition, differing in the latter respect from replicative polymerases.899 The enzyme is present in normal
immature thymocytes and in the blast cells of nearly all patients with acute lymphoblastic leukemia. Rare patients have blasts with a Tlymphocyte
phenotype.900 Some cases are biphenotypic; the blasts have both lymphoid and myeloid markers.901–903 A case with concurrent, T, B, and myeloid
features has been described.904 Patients with lymphoid blast crisis seldom have an intermediate accelerated phase, have less splenomegaly and
basophilia, and usually have a higher degree of marrow blast infiltration. With nonTKI therapy, remission rate and survival were somewhat longer in
cases of lymphoid than in myeloid blast crisis.905
CYTOGENETIC STUDIES
Most large studies have shown 7 recurrent changes in patients’ cells prior to, or during, the accelerated phase: trisomy 8 (33% of cases), additional 22q
− (30% of cases), isochromosome 17 (20% of cases), trisomy 19 (12% of cases), loss of Y chromosome (8% of males), trisomy 21 (7% of cases), and
monosomy 7 (5% of cases).906–908 In addition, a large number of other chromosome abnormalities have been described.909–913 In one study, 46 (63%)
of 73 blast crisis patients had secondary cytogenetic abnormalities. These abnormalities were more common in myeloid blast crisis and were
associated with shorter remission.833 The changes may be features of myeloid blast crisis compared to lymphoid crisis.907–912 Some abnormalities,
basophilia, and usually have a higher degree of marrow blast infiltration. With nonTKI therapy, remission rate and survival were somewhat longer in
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cases of lymphoid than in myeloid blast crisis.905
CYTOGENETIC STUDIES
Most large studies have shown 7 recurrent changes in patients’ cells prior to, or during, the accelerated phase: trisomy 8 (33% of cases), additional 22q
− (30% of cases), isochromosome 17 (20% of cases), trisomy 19 (12% of cases), loss of Y chromosome (8% of males), trisomy 21 (7% of cases), and
monosomy 7 (5% of cases).906–908 In addition, a large number of other chromosome abnormalities have been described.909–913 In one study, 46 (63%)
of 73 blast crisis patients had secondary cytogenetic abnormalities. These abnormalities were more common in myeloid blast crisis and were
associated with shorter remission.833 The changes may be features of myeloid blast crisis compared to lymphoid crisis.907–912 Some abnormalities,
such as inv16, are associated with early transformation to AML.914 A significant proportion (50%) of patients in the accelerated phase or blast crisis
have no additional cytogenetic abnormalities beyond t(9;22)(q34;q11) after banding and multicolor FISH analysis.915 There may be a differential impact
of additional chromosomal abnormalities in myeloid versus lymphoid blast phase in the TKI era.916 Certain chromosome abnormalities with poor
prognosis in AML have especially poor prognosis in CML blast phase as well and do not respond well to TKIs. These include 3q26.2 abnormalties.917 In
cases where the blastic transformation is in extramedullary sites, such as lymph nodes or spleen, the additional cytogenetic abnormalities may be in
the cells at those sites but not in cells in the blood or marrow.918
TREATMENT
Optimal treatment is allogeneic stem cell transplantation if the patient is eligible based on patient’s age and donor availability. The role of stem cell
transplantation is also evolving as TKI use in these phases of diseases becomes better defined, and some patients who present in early accelerated
phase may respond well to TKIs alone, meeting the treatment benchmarks that have been described for chronic phase CML. Thus far, treatment with
TKIs has improved survival only modestly in blast crisis, and most longterm survivors have received stem cell transplantation. At present, it is
recommended that patients in blast crisis be treated with TKIs with or without chemotherapy to a second chronic phase and proceed to stem cell
transplantation as soon as possible once a donor is identified. One of the major goals of treatment of chronic phase CML is the prevention of evolution
to an accelerated or blast phase of the disease.
Tyrosine Kinase Inhibitors in Accelerated and Blast Crisis
The initial dose of imatinib in accelerated phase is 600 mg/day.919 Imatinib 600 mg/day, dasatinib 140 mg/day, and nilotinib 400 mg BID, bosutinib 500
mg daily or ponatinib 45 mg/day single agents have been used as bridging therapies to permit allogeneic stem cell transplantation in accelerated
phase.920 Dasatinib and nilotinib can achieve MMR, and thus the role for and timing of transplantation in accelerated phase CML is being redefined.920
Imatinib or other TKIs can be combined with an anthracycline plus cytarabine for patients in myeloid blast crisis.921 Imatinib has produced complete
hematologic remissions in approximately 20% of patients.922,923 However, CCyRs are uncommon. Central nervous system and other extramedullary
blast crisis can occur during imatinib therapy for accelerated phase disease.924,925 Compared to historical controls in which various combinations of
chemotherapy were used, imatinib used alone results in comparable outcomes (6month median survival of patients in blast crisis).926 Although
dasatinib therapy can result in CCyRs in 29% of blast crisis CML, and nilotinib can result in CCyRs in 27% of myeloid blast crisis and in 43% of lymphoid
blast crisis, these responses are rarely durable, so in a patient of appropriate age with an acceptable donor, transplantation options should be
considered with the secondline TKIs used as a bridge to transplantation therapy.927,928 The choice of TKI in accelerated phase is based on prior
therapy and/or mutational status. If response to TKI therapy is inadequate in accelerated phase, allogeneic hematopoietic stem cell transplantation
should be considered. In lymphoid or myeloid blast phase, allogeneic hematopoietic stem cell transplantation is recommended if there is a suitable
donor.345 Omacetaxine has shown activity in patients with disease progression to accelerated phase CML after prior TKI use.929
Chemotherapy
The treatment approach is predicated on the phenotype of the blast cells in CML patients with blast crisis and is rarely used in accelerated phase. In
patients with myeloid phenotypes, the approach has been similar to that used for AML: combinations of an anthracycline antibiotic, such as idarubicin
(Idamycin) or daunorubicin (Cerubidine), with cytosine arabinoside (CytosarU) and sometimes etoposide (Toposar).930 A CHR is observed in only a
quarter to a third of patients with this approach, and a TKI is almost always combined with the chemotherapy regimen.
In patients with lymphoid phenotypes, vincristine sulfate 1.4 mg/m2 (not to exceed 2 mg/dose) given intravenously once per week and prednisone 60
mg/m2 per day given orally are the mainstay of treatment. A minimum of 2 cycles of treatment (2 weeks) should be given to judge responsiveness.
Other ALL chemotherapy regimens in conjunction with TKIs also have been used as would be employed in Phpositive ALL.931,932 Approximately one
third of patients with lymphoid blast transformation reenter the chronic phase after such treatment. The benefit of intensive chemotherapy has been
small because remission durations have been modest.933 Hypomethylating agents, such as azacytidine (Vidaza), have been combined with TKIs in
advanced phase CML, with some hematologic responses and some patients stabilized so as to have time to receive a hematopoietic cell transplant.934
(Idamycin) or daunorubicin (Cerubidine), with cytosine arabinoside (CytosarU) and sometimes etoposide (Toposar).930 A CHR is observed in only a
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quarter to a third of patients with this approach, and a TKI is almost always combined with the chemotherapy regimen.
In patients with lymphoid phenotypes, vincristine sulfate 1.4 mg/m2 (not to exceed 2 mg/dose) given intravenously once per week and prednisone 60
mg/m2 per day given orally are the mainstay of treatment. A minimum of 2 cycles of treatment (2 weeks) should be given to judge responsiveness.
Other ALL chemotherapy regimens in conjunction with TKIs also have been used as would be employed in Phpositive ALL.931,932 Approximately one
third of patients with lymphoid blast transformation reenter the chronic phase after such treatment. The benefit of intensive chemotherapy has been
small because remission durations have been modest.933 Hypomethylating agents, such as azacytidine (Vidaza), have been combined with TKIs in
advanced phase CML, with some hematologic responses and some patients stabilized so as to have time to receive a hematopoietic cell transplant.934
Allogeneic Hematopoietic Stem Cell Transplantation
Stem cell transplantation from an appropriately HLAmatched donor has been used in some patients after entry into the blastic crisis. Occasional
patients have had longterm survival. The 3year survival rate is approximately 15% to 20%,935–937 unlike transplantation in the chronic phase, in which
the 3year survival rate is 50% to 60%. Relapse of accelerated phase after allogeneic stem cell transplantation has responded to infusion of donor
cytotoxic T lymphocytes.938 Use of TKIs before allogeneic stem cell transplantation for patients in advanced phases of disease may favorably improve
transplantation outcomes, especially when MCyR occurs before transplantation.939
Autologous Hematopoietic Stem Cell Transplantation
Autografting in the accelerated phase or blast crisis, either with stem cells collected during chronic phase or with mobilized Phnegative progenitor
cells collected upon cell rebound after intensive chemotherapy, has resulted in prolonged remission in some patients, but this procedure is rarely
used in advanced disease because of the high rate of relapse.940 Whether Phnegative cells collected during imatinib therapy have the same potential is
unknown.
Splenectomy
Splenectomy may be performed for palliation of painful splenic infarctions or hemorrhage. However, the complication rates are high, and the
procedure performed in this setting should be avoided if possible.31,941
COURSE AND PROGNOSIS
The accelerated phase of CML generally is very poorly responsive or refractory to treatment. Those who are in accelerated phase at diagnosis will do
better than those who progress from chronic phase while on TKI.942 Patients with myeloid blast crisis have a median survival of approximately 6
months, whereas patients with lymphoid blast crisis have a median survival of approximately 12 months.943 A worse survival was seen with
abnormalities of chromosome 17, other superimposed translocations, or a high percentage of abnormal metaphases.944 Of patients resistant to a
prior TKI and switched to ponatinib, those who did not respond to ponatinib in accelerated phase had poor longterm outcomes.945 While TKIs have
moderately improved survival in blast phase, the median survival is still less than 1 year..863 Transplantation offers the best longterm prognosis for
patients in blasts crisis.933 In a cohort study of 477 patients, 381 (80%) of whom progressed to blast from chronic phase, the median OS was 12 months
and median progressionfree survival was 5 months. Obtaining major hematologic or CCyR to the initial therapy was predictive of better survival, and
the combination of a TKI with induction chemotherapy followed by hematopoietic stem cell transplantation gave the best overall outcomes.946
RELATED CLONAL MYELOID DISEASES WITHOUT THE BCR REARRANGEMENT
In addition to classic CML with the BCRABL1 fusion gene, there are several other chronic myeloid leukemias; they are listed in Table 88–11. The World
Health Organization (WHO) category of myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPNUC) is discussed in Chap.
86.
TABLE 88–11.
Types of Chronic Myelogenous Leukemia
Type of
Chronic Further
Molecular Genetics Major Clinical Features
Myelogenous Details
Leukemia
BCR >95% p210BCRABL; <5% p190 or p230 Splenomegaly in 80% of cases; WBC >25 × 109/L; blood blasts <5%; Pages
rearrangement absolute basophilia in virtually all cases; Ph chromosome in 90% of 1523
TABLE 88–11.
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Types of Chronic Myelogenous Leukemia
Type of
Chronic Further
Molecular Genetics Major Clinical Features
Myelogenous Details
Leukemia
BCR >95% p210BCRABL; <5% p190 or p230 Splenomegaly in 80% of cases; WBC >25 × 109/L; blood blasts <5%; Pages

rearrangement absolute basophilia in virtually all cases; Ph chromosome in 90% of 1523
positive chronic cases; BCR gene rearrangement in 100% of cases 1553
myelogenous
leukemia
Chronic >40% mutation in SRSF2 gene and 90% have a Anemia, monocytosis >1.0 × 109/L; blood blasts <10%; increased Page

myelomonocytic mutation in 1 of 9 genes1027; various cytogenetic plasma and urine lysozyme; BCR rearrangement absent; rare cases 1554
leukemia abnormalities with PDGFRβ mutation respond to imatinib
Chronic Various cytogenetic abnormalities; PDGFRα/β, Blood eosinophil count >1.5 × 109/L; cardiac and neurologic Page

eosinophilic FGFR1, and JAK mutations in some cases manifestations common; a proportion of cases have PDGFRα 1556
leukemia mutations and are responsive to imatinib mesylate
Chronic Various cytogenetic abnormalities Only 5 cases reported; hemoglobin 6–13 g/dL; basophilia of 3.4–41 × Page

basophilic 109/L; 2 of 5 cases with splenomegaly; very cellular marrow (>90%) 1557
leukemia in each case with mild increase in type III collagen, and
megakaryocytic dysmorphia; increase in marrow mast cells in 3 of 5
cases
Juvenile RAS pathway mutations (PTPN11, NF1, NRAS, Infants and children <4 years; eczematoid or maculopapular rash; Page

myelomonocytic KRAS, and CBL) in 89% of cases1028; various anemia and thrombocytopenia; increased HbF in 70% of cases; 1558
leukemia cytogenetic changes neurofibromatosis in 10% of cases; abnormality of chromosome 7
(eg, del 7, del 7q, etc) in approximately 20% of patients; BCR
rearrangement absent
Chronic Colonystimulating factor 3 receptor gene (CSF3R) Segmented neutrophilia ≥20 × 109/L; splenomegaly >90% of cases; Page

neutrophilic alone (~30% of cases); a combination of mutated no blood blasts; platelets >100 × 109/L; 75% of cases have normal 1559
leukemia CSF3R and a SET binding protein gene (SETBP1)
cytogenetics; BCR rearrangement absent
mutation (~60% of cases); the JAK2V617F mutation
alone (~10% of cases)984–986
BCR Various cytogenetic changes Clinical findings indistinguishable from BCR rearrangementpositive Page

rearrangement CML; Ph chromosome and BCRABL fusion gene absent 1560
negative chronic
myelogenous
leukemia
Atypical chronic Various cytogenetic changes Patient usually >65 years; variable blood cell changes: anemia, Page

myelogenous granulocytosis, normal or decreased platelet counts; hypercellular 1560
leukemia marrow, marrow blasts <10%; dysmorphia of blood and marrow
cells common (eg, PelgerHuët neutrophils, dyserythropoiesis, and
megakaryopoiesis; often splenomegaly)
CML, chronic myelogenous leukemia; HbF, fetal hemoglobin; JAK, Janus kinase; PDGFR, plateletderived growth factor receptor; Ph, Philadelphia chromosome;
WBC, white blood cells.
CHRONIC MYELOMONOCYTIC LEUKEMIA
cells common (eg, PelgerHuët neutrophils, dyserythropoiesis, and Access Provided by:
megakaryopoiesis; often splenomegaly)
CML, chronic myelogenous leukemia; HbF, fetal hemoglobin; JAK, Janus kinase; PDGFR, plateletderived growth factor receptor; Ph, Philadelphia chromosome;
WBC, white blood cells.
CHRONIC MYELOMONOCYTIC LEUKEMIA
Definition and History
This disease shares the feature of all clonal myeloid diseases as originating in the clonal expansion of a primitive multipotential hematopoietic cell.947
It is part of the spectrum of clonal myeloid diseases that may have findings that simulate CML. In the past, when rigorous criteria for the diagnosis of
CML were not applied, CMML was among a heterogenous group of related diseases that sometimes were referred to as Phnegative CML. CMML is
characterized by an accumulation of leukemic monocytes in the blood, and a predilection for transformation to AML.948 CMML was once included in
myelodysplastic syndrome (MDS) disorders because a significant fraction of cases showed characteristic dysplasia of marrow and blood cells, but in
2001, the WHO placed it in the category of myelodysplastic/myeloproliferative (MDS/MPN [myeloproliferative neoplasm]) overlap group because in
some cases there is minimal white cell elevation or leukopenia and myelodysplastic features, while in others there is an increased white cell count and
absence of dysplastic features. The “dysplastic” variant of CMML has been characterized as a leukocyte count ≤13 × 109/L, but often presents with
cytopenias, whereas the “proliferative” variant has a leukocyte count >13 × 109/L. In the WHO 2016 classification, CMML is now divided into CMML0
(<5% blasts in marrow), CMML1 (5–9% blasts in marrow), and CMML2 (10–19% blasts in marrow).949 CMML variants with JAK2 or KIT mutations and
preCMML conditions also have been described and reviewed.948
Epidemiology
The median age of onset of CMML is approximately 72 years, and approximately 90% of patients are older than 60 years at the time of diagnosis.950
Occasional cases have been reported in older children and younger adults. Men are affected more frequently than women (approximately 2:1).950 An
evaluation of exogenous factors that might increase the incidence of CMML did not find an association with benzene or other occupational or
nonoccupational risk factors.951
The disease may occur following therapy for an unrelated malignancy, most commonly lymphoma, breast, or prostate cancer. The prior therapy was
radiation, combined radiation and chemotherapy, or chemotherapy, alone. The median time of onset of CMML was 6 years.952
Clinical Findings
Signs and Symptoms
The onset usually is insidious, and weakness, infection, or exaggerated bleeding may bring patients to medical attention.953 Hepatomegaly and
splenomegaly occur in approximately 50% of patients. Leukemia cutis occurs in a small proportion of patients and the skin cellular infiltrate usually
has a monocytic phenotype: CD45, CD68+ and is lysozyme positive by immunostaining. Immune manifestations, such as vasculitis, pyoderma
gangrenosum, immune cytopenias, and connective tissue diseases, may occur in coincidence with CMML.954 These are usually only transiently
responsive to glucocorticoids but may respond to hypomethylating agent therapy.954
Blood and Marrow Findings
The disease is characterized by anemia and a consistent blood monocytosis greater than 1 × 109/L and relative proportion of monocytes of at least 10%
of blood leukocytes.948 The white cell count may be decreased, normal, or elevated. In one study of 275 patients, the range in 247 informative patients
was 0.9–160.0 × 109/L.950 Occasional patients, however, may have hyperleukocytosis with total white cell counts of 250–300 × 109/L associated with
respiratory insufficiency resulting from pulmonary leukostasis.955 Promonocytes and monocytes are present in blood and may have dysmorphic
features. Immature granulocytes (promyelocytes and myelocytes) may be present in the blood. Blood myeloblasts are absent in approximately 75% of
patients or, when present, usually do not exceed 10% of total white cells. Most patients have thrombocytopenia, but normal or elevated platelet counts
may occur (range: 3.0–1385.0 × 109/L among 227 patients in one series).950 Eosinophilia may be so prominent in occasional cases that the designation
chronic eosinophilic leukemia (CEL) may be appropriate.956 Patients with monocytosis and eosinophilia should be evaluated for t(5;12)(q31or32;p13)
translocation, which encodes for ETV6(TEL)PDGFβ fusion oncogene. The FGR1 and PCM1JAK2 fusion also may be associated with a clonal myeloid
disease that expresses monocytosis and eosinophilia.948
The marrow is hypercellular as a result of granulomonocytic hyperplasia; the dominant cells are early myelocytes. Blasts cells are less than 5% in about
twothirds of patients and are from 5% to 19% in onethird.950 The proportion of promyelocytes is increased. Promonocytes and monocytes also are
respiratory insufficiency resulting from pulmonary leukostasis. Promonocytes and monocytes are present in blood and may have dysmorphic
features. Immature granulocytes (promyelocytes and myelocytes) may be present in the blood. Blood myeloblasts are absent in approximately 75% of
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patients or, when present, usually do not exceed 10% of total white cells. Most patients have thrombocytopenia, but normal or elevated platelet counts
may occur (range: 3.0–1385.0 × 109/L among 227 patients in one series).950 Eosinophilia may be so prominent in occasional cases that the designation
chronic eosinophilic leukemia (CEL) may be appropriate.956 Patients with monocytosis and eosinophilia should be evaluated for t(5;12)(q31or32;p13)
translocation, which encodes for ETV6(TEL)PDGFβ fusion oncogene. The FGR1 and PCM1JAK2 fusion also may be associated with a clonal myeloid
disease that expresses monocytosis and eosinophilia.948
The marrow is hypercellular as a result of granulomonocytic hyperplasia; the dominant cells are early myelocytes. Blasts cells are less than 5% in about
twothirds of patients and are from 5% to 19% in onethird.950 The proportion of promyelocytes is increased. Promonocytes and monocytes also are
increased in number. Distinction between poorly granulated myelocytes and promonocytes with primary granules can be difficult and use of
immunohistochemical stains for monocytic cells should be used. Macronormoblasts and hypersegmented or hyposegmented, often bilobed (acquired
PelgerHuët anomaly) neutrophils may be evident, but are more frequent in cases with lower white cell counts. Despite thrombocytopenia,
megakaryocytes usually are present in the marrow and are frequently micromegakaryocytes with abnormal nuclear lobulations. Reticulin fibrosis in
the marrow occurs in approximately onethird of patients. Flow cytometry can reveal an increased percentage (>94%) of classical monocytes
(CD14+CD16+) (Chap. 70). This finding has a high specificity and sensitivity (>91%) in identifying monocytosis associated CMML as compared to
monocytosis in other clonal myeloid diseases.957 “Spontaneous” cluster/colony growth of granulocytemonocyte colonyforming cells occurs in vitro.
The spontaneous growth may result from autocrine or paracrine production of GMCSF, based on anti–GMCSF inhibition of colony growth.958 There is
evidence that blastic plasmacytoid dendritic cell neoplasm and CMML may have a common clonal origin.959
Cytogenetic and Genetic Findings
Patients with CMML have an approximately 35% frequency of chromosomal abnormalities. By definition, the Phchromosome and rearrangements
involving PDGFR1, PDGFRβ or FGFR1 are absent as is a PCM1JAK2 fusion gene.948 Trisomy 8 and, to a lesser extent, monosomy 7 and −Y are the most
prevalent findings. A low–risk karyotype is either a normal pattern or isolated −Y, an intermediaterisk is any other abnormality, and highrisk is
trisomy 8 or complex karyotypes (more than 3 abnormalities). Approximately 35% of patients have point mutations of the KRAS or NRAS gene.950 The
RAS gene may be involved in the transforming events. The RAF kinase inhibitor protein is often lost in CMML and results in RASdriven myeloid
leukemogenesis.960 Disease progression is associated with TET2 and RAS mutations,961 and those with MDS like features often have SF3B1 and U2AF1
mutations.961 Abnormal methylation of p15INK4B is a common finding in CMML.962 Somatic mutations in CMML cells include SRSF2, TET2, ASXL1,
RUNX1, SETBP1, KRAS, EZH2, CBL, DNMT3A, UTX, JAK2, IDH1/2, and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2, and CSMD1, each
mutated in 10% or more of patients.950 The gene SRSF2 (serine/argininerich splicing factor 2), was found to be the most frequently mutated gene in
patients with CMML, and some studies suggest it does not affect prognosis.963 Many of the genes commonly mutated in CMML have been associated
with agerelated clonal hematopoiesis (ARCH). Most CMML patients (71%) had mutations in 2 or more ARCH genes and 52% had 7 or more mutations
overall. Higher mutation burden was associated with shorter survival. ARCH is characterized by a myelomonocytic differentiation bias. These findings
are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired agerelated mutations have
accumulated. CMML appears to represent the leukemic conversion of the myelomonocyticlineagebiased aged hematopoietic system.964 In an effort
to determine the frequency of the mutation in a large sample of patients and to look for coincident mutations with SRSF2 in cells of patients with
CMML, 8 other genes known to be mutated in some patients with CMML were studied among 275 patients with the disease.950 SRSF2 was mutated in
129 (47%) patients in this large series, and had a significantly increased coincidence with EZH2 and TET2. Of the 275 patients, 256 (93%) had at least 1
mutated gene. Targeted sequencing and flow cytometry can distinguish CMML from reactive monocytosis965 and may help to distinguish it from
atypical CML.966 The causes of reactive (polyclonal) monocytosis are described in Chaps. 69 and 70.967
Serum and Urine Findings
Plasma and urine lysozyme concentrations nearly always are elevated. Lysozyme nephropathy can occur.968 Plasma levels of VEGF, hepatocyte growth
factor, and tumor necrosis factorα are elevated. Serum vitamin B12, β2microglobulin, and LDH levels often are elevated.953
Treatment
Treatment of most patients with CMML has been unsatisfactory, and remissions of any duration are uncommon. The age and performance status of
the patient are considered in determining the intensity of treatment. In those patients who present with consequential anemia, erythroid stimulating
agents can be used.969 Cytarabine, either standard or lowdose, etoposide, hydroxyurea, and other approaches have been attempted in proliferative
cases, but with little success. Decitabine and 5azacytidine have been useful in a small proportion of patients.953 One study of azacytidine treatment
reported a complete response in 11%, a partial response in 3%, and hematologic improvement in 25% of patients. The median survival of responders
was 15 months compared to 12 months among nonresponders, a modest result. 970 In a phase 2 trial of decitabine, the overall response rate was 48%,
and the complete response rate was 16.6%.971 In a series of 151 CMML cases treated with either decitabine or azacytidine, the overall response rate was
75% and 41% achieved a complete remission. More patients treated with decitabine achieved a complete remission than those treated with azacitidine.
Treatment
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Treatment of most patients with CMML has been unsatisfactory, and remissions of any duration are uncommon. The age and performance status of
the patient are considered in determining the intensity of treatment. In those patients who present with consequential anemia, erythroid stimulating
agents can be used.969 Cytarabine, either standard or lowdose, etoposide, hydroxyurea, and other approaches have been attempted in proliferative
cases, but with little success. Decitabine and 5azacytidine have been useful in a small proportion of patients.953 One study of azacytidine treatment
reported a complete response in 11%, a partial response in 3%, and hematologic improvement in 25% of patients. The median survival of responders
was 15 months compared to 12 months among nonresponders, a modest result.970 In a phase 2 trial of decitabine, the overall response rate was 48%,
and the complete response rate was 16.6%.971 In a series of 151 CMML cases treated with either decitabine or azacytidine, the overall response rate was
75% and 41% achieved a complete remission. More patients treated with decitabine achieved a complete remission than those treated with azacitidine.
The median OS was 24 months. After lack of response to hypomethylating agents, the OS was only a median of 7 months.972 In another study of 121
patients treated with hypomethylating agents, the overall response rate was 41% and complete response rates were less than 20%. Of the 121 patients,
35 (29%) progressed to AML with a median OS of 8 months. ASXL1 and TET2 mutation status had no effect in this series.973 Outcomes reported after
hypomethylating agent use have been variable, but one study showed in a retrospective analysis of 1378 older adults with CMML, median OS times
improved after the introduction of hypomethylating agents.974 The addition of lenalidomide (Revlimid) to azacitidine did not improve results in
patients with CMML,975 and a phase I study with singleagent lenalidomide showed 5 mg to be the maximum tolerated daily dose.976 Ruxolitinib, the
JAK1/2 inhibitor, has shown responses in some cases.977 Omacetaxine has shown some responses in CMML after failure of hypomethylating agents.978
Allogeneic stem cell transplantation is an option for the small proportion of younger patients with an appropriate matchedrelated or unrelated
donor.979 In one series of 211 patients with CMML who underwent allografting, higher CMMLspecific prognostic scoring system score at time of
transplantation, lower Karnofsky performance status, and receipt of a transplant using marrow cells versus a transplant using blood stem cells was
associated with poorer survival. In the lowrisk group, the 5year survival rate was 44% and in the highrisk group, it was 19%.980 Small series have
suggested that use of hypomethylating agents before allografting can improve progressionfree survival for patients with CMML.981,982
Course and Prognosis
Median survival in CMML is approximately 12 months, with a range from approximately 1 month to more than 60 months. Approximately 30% of
patients progress to frank AML. The CMML0 and CMML1 division has no impact on outcome,983 but the myeloproliferativetype of CMML (vs MDStype
of CMML) is associated with shorter OS and shorter duration to AML transformation.984 Clusters of prognostic variables have been used to stratify
patients into risk groups for survival duration. A CMMLspecific prognostic scoring system has been proposed, and one model by the Groupe Francais
des Myelodysplasies uses age older than 65 years, white blood cell (WBC) greater than 15 × 109/L, platelets less than 100 × 199/L, and ASXL1 mutation
status to separate the patients into 3 groups. An alternate Mayo Molecular Model uses a different set of 5 variables.967 (Both classifications are
reviewed in reference 967.) Cytogenetic abnormalities and mutations in the ASXL1, RUNX1, NRAS, and SETBP1 genes have been independently
associated with OS, and when combined with anemia requiring red cell transfusion, the leukocyte count, and marrow blast percentage, defined 4
prognostic groups.985 In a series of CMML patients treated with hypomethylating agents, ASXL1 mutations predicted a lower overall response rate,
whereas TET2 mutations predicted a higher complete remission rate.986 Another study also found that EZH2 mutations, which cluster with ASXL1
mutations in CMML, have poor prognostic implications.987 DNMT3A mutations (present in only 5% of cases) also are associated with inferior overall
and leukemiafree survival.988 DNA methylation profiles discriminate between those with low and intermediate/highrisk karyotypes and between
those with mutated or wildtype TET2.989 In an individual patient, the variability in outcome is based on such prognostic variables; careful clinical
observation for progression is most important. In those who present with inflammatory and autoimmune manifestations, increased cardiovascular
comorbidities can occur.990 Splenectomy does not affect survival in CMML, but it can have a palliative role and result in improvements in cytopenias.991
Its application should be made judiciously.
CHRONIC EOSINOPHILIC LEUKEMIA
History and Definition
The recognition of eosinophilic lineage prominence in myelogenous leukemia dates to a case published in 1912.992 In 1968, the term hypereosinophilic
syndrome was introduced to encompass a group of disorders with (a) prolonged exaggerated eosinophilia without an apparent cause, (b) frequent
cardiac and neurologic tissue damage, (c) a poor or transient response to therapy, and (d) a progressive course and a high fatality rate. Shortly
thereafter, Benvenisti and Ultmann993 presented 5 cases of eosinophilic leukemia and reviewed the literature regarding that phenotypic designation.
In 1975, Chusid and colleagues994 described 14 cases of hypereosinophilic syndrome, highlighted the frequency of secondary cardiac and neurologic
disorders, and suggested the existence of a continuum of manifestations. Because some cases had clonal cytogenetic abnormalities and hematologic
findings compatible with a clonal myeloid disease, the presence of eosinophilic leukemia was suspected in this apparently heterogeneous group of
patients.
The relationship of blood eosinophilia to clonal myeloid diseases is complex because the blood eosinophilia can be reactive or represent acute
The recognition of eosinophilic lineage prominence in myelogenous leukemia dates to a case published in 1912. In 1968, the term hypereosinophilic
syndrome was introduced to encompass a group of disorders with (a) prolonged exaggerated eosinophilia without an apparent cause, (b) frequent
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cardiac and neurologic tissue damage, (c) a poor or transient response to therapy, and (d) a progressive course and a high fatality rate. Shortly
thereafter, Benvenisti and Ultmann993 presented 5 cases of eosinophilic leukemia and reviewed the literature regarding that phenotypic designation.
In 1975, Chusid and colleagues994 described 14 cases of hypereosinophilic syndrome, highlighted the frequency of secondary cardiac and neurologic
disorders, and suggested the existence of a continuum of manifestations. Because some cases had clonal cytogenetic abnormalities and hematologic
findings compatible with a clonal myeloid disease, the presence of eosinophilic leukemia was suspected in this apparently heterogeneous group of
patients.
The relationship of blood eosinophilia to clonal myeloid diseases is complex because the blood eosinophilia can be reactive or represent acute
eosinophilic leukemia, CEL, or eosinophilia associated with a different category of disease, such as BCRABL1–positive CML, primary myelofibrosis,
oligoblastic leukemia (MDS), or mastocytosis.995 CEL is a BCRABL1–negative, clonal myeloid disease with a striking eosinophilia in the blood and
marrow, often with clonal cytogenetic abnormalities that have features including, when present, cytogenetic findings that usually distinguish CEL from
other clonal myeloid diseases that may have an associated eosinophilia, such as CMML. The phenotype of the eosinophilic variant of CMML overlaps
somewhat with that of CEL. The WHO 2016 classification of eosinophilic disorders now places those cases with PDGFRα, PDGFRβ, FGFR1, or with PCM1
JAK2 fusion genes in a separate class of diseases.996 Four patients with eosinophilia and polycythemia vera with a 4aminoacid deletion in the JAK2
gene have been described.997 This deletion results in activation of STAT5 and ERK and, subsequently, the IL5 receptor, with resultant eosinophilia.
CELnototherwisespecified is classified with other MPNs. It requires an eosinophilia of less than 15.0 × 109/L, in the absence of other MPNs, no
rearrangement of PDGFRα or PDGFRβ, FGFR1, or JAK2 fusion genes. AML (M4Eo) with inv16 or t(16;16) (p13;q22) should not be present, and there
should be evidence of clonality or blasts in blood must be greater than 2% or marrow blasts must be greater than 5%.996 The diagnostic evaluation of
eosinophilia is further discussed in Chap. 65.998
Signs and Symptoms
Fever, cough, weakness, easy fatigability, dyspnea, abdominal pain, maculopapular rash, cardiac symptoms and signs of heart failure, and a variety of
neurologic manifestations ranging from peripheral neuropathy to cerebral encephalomalacia may occur, ranging from mild to severe in expression.
Splenomegaly often is evident.
Laboratory Findings
Eosinophilia is a constant finding. Anemia is usually but not always present at the time of presentation. The leukocyte count may be highnormal or
more often elevated. Platelet counts often are normal or mildly decreased. The marrow shows myelocytic and eosinophilic hyperplasia and,
occasionally, CharcotLeyden crystals. Mast cells, often spindleshaped, may be increased. In the FIP1L1–PDGFRα type of CEL, which may make up
approximately 14% of cases of primary eosinophilia not found to be reactive to another disease, marrow aggregates of spindleshaped mast cells are
invariably found (see “Cytogenetic Findings” below).999 Megakaryocytes usually are present but may appear dysmorphic. Reticulin fibrosis is common.
Immunophenotyping and PCR do not show evidence of either a clonal Tcell population or Tcell–receptor rearrangement as would be present in the
lymphocytic variant of hypereosinophilic syndrome. Pulmonary function studies may provide evidence of fibrotic (restrictive) lung disease.
Echocardiography may detect mural thrombi, thickening (fibrosis) of the ventricular wall, valvular dysfunction from papillary muscle, and chordae
fibrosis. Magnetic resonance imaging can detect subendocardial fibrosis, thickening of ventricles, and markedly reduced ventricular lumen volume.
Serum immunoglobulin E, vitamin B12, and tryptase levels usually are elevated. Skin biopsy of lesions uncovers intense eosinophilic infiltrates. Neural
or brain biopsy may disclose eosinophilic infiltrates, often perivascular, with microthrombi, axonal degeneration, and gliosis.
Cytogenetic Findings
A wide array of cytogenetic findings have been reported in cases of CEL.1000 Notable translocations include a high frequency of translocations involving
chromosome 5, t(1;5), t(2;5), t(5;12), t(6;11), 8p11, and trisomy 8, and numerous others infrequently. Chromosome 5 often is translocated at the site of
the PDGFRβ gene, and the phenotype usually is more compatible with CMML with eosinophilia. Chromosome 5 from band q3135 contains several
genes relevant to eosinophilopoiesis, including those encoding IL5, IL3, GMCSF, and PDGFRβ. A cryptic interstitial CHIC2 deletion on chromosome 4
(q12;q12) results in the fusion gene FIL1L1–PDGFRα, normally separated by the CHIC2 gene, and in a phenotype that can be considered a form of CEL,
virtually always associated with marrow mastocytosis, which is of particular note because of a nearuniversal response to treatment with imatinib.1000–
1002
Serum Tryptase Level Elevation Versus Normal Levels
The elevation of serum tryptase level (>11.5 ng/mL) has been used to distinguish a subset of patients who (a) are male, (b) have marrows that are
intensely hypercellular with a higher proportion of immature eosinophils and with dysmorphic mast cells with a CD117−CD25+CD2− genotype and
phenotype (distinguishing these cells from classic mastocytosis, which are CD117+CD25+CD2+), (c) have dramatically higher serum vitamin B12 and
immunoglobulin E levels, (d) are more prone to restrictive pulmonary disease and endomyocardial fibrosis, (e) have the FIP1L1–PDGFRα fusion gene,
and (f) are responsive to imatinib.1003
virtually always associated with marrow mastocytosis, which is of particular note because of a nearuniversal response to treatment with imatinib. 1000–
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1002
Serum Tryptase Level Elevation Versus Normal Levels
The elevation of serum tryptase level (>11.5 ng/mL) has been used to distinguish a subset of patients who (a) are male, (b) have marrows that are
intensely hypercellular with a higher proportion of immature eosinophils and with dysmorphic mast cells with a CD117−CD25+CD2− genotype and
phenotype (distinguishing these cells from classic mastocytosis, which are CD117+CD25+CD2+), (c) have dramatically higher serum vitamin B12 and
immunoglobulin E levels, (d) are more prone to restrictive pulmonary disease and endomyocardial fibrosis, (e) have the FIP1L1–PDGFRα fusion gene,
and (f) are responsive to imatinib.1003
Differential Diagnosis
Eosinophilia can occur for many reasons (Chap. 65). The first step is to identify signs that may point to a clonal myeloid disease. These signs include
anemia, thrombocytopenia, splenomegaly, immature eosinophils in the marrow examination, evidence of dysmorphic cells in blood or marrow, for
example, atypical megakaryocytes or dysmorphic mast cells, cardiac or pulmonary manifestations, which may occur secondary to CEL, and markedly
elevated serum tryptase or vitamin B12 level. The former signs, especially in the aggregate, are highly suggestive, but the presence of a cytogenetic
abnormality in myeloid cells is diagnostic of a clonal myeloid disease (leukemia). If the latter is not evident, PCR and/or flow cytometry to search for a
clonal Tlymphocyte abnormality should be performed. Whether the eosinophilic leukemia is typical or represents an eosinophilia with idiopathic
myelofibrosis, CMML, or MDS is less important than if it has a mutation that is imatinib sensitive (eg, a PDGFR mutation).
Therapy
An eosinophil count of 1.5–2.0 × 109/L has been proposed as a threshold for treatment initiation, but others recommend starting treatment with any
degree of eosinophil elevation in the setting of a clonal process to avoid later tissue damage.996 Patients (nearly always men) whose cells display a
FIP1L1–PDGFRα have a very high probability of responding to imatinib at a dose of 100–400 mg/day.1001–1005 The tyrosine kinase activity of this fusion
protein is 2 orders of magnitude more sensitive to imatinib than that of BCRABL1. However, because not all patients taking 400 mg/day achieve a MR,
and that goal may be more likely to result in longterm remission, initial therapy remains at 400 mg/day or an equivalent dose of another TKI, such as
dasatinib or nilotinib, with PCR monitoring as appropriate. Dose adjustment upward if MR is not achieved can be considered. Unlike the case in CML,
patients with CEL with significant side effects when taking imatinib, 400 mg/day, have a reasonable probability of having a good response at lower
doses.1005 Dasatinib and nilotinib are also active.1006
In patients with CEL without a TKIsensitive translocation, therapy with glucocorticoids, hydroxyurea, or IFNα can be used. Those with FGFR1
rearrangements often require intensive chemotherapy, and pemigatinib (Pemazyre), an oral FGFR1 inhibitor, is being examined.1007 Ruxolitinib has
been used in patients with PCM1JAK2 fusion gene expression.1008 In patients who become resistant to treatment and who are progressing, ablative or
nonablative allogeneic stem cell transplantation can be considered if they are in an acceptable age range and have access to a matchedrelated or
matchedunrelated donor. The role of transplantation in CEL is uncertain.1009 Antibodies to IL5, such as mepolizumab1010 and benralizumab1011 are
being examined in eosinophilic disorders in which IL5 is a principal eosinopoietin.
If CEL is not TKIsensitive, the longterm outlook is one of probable progressive cardiac and neurologic disability. Transformation to acute eosinophilic
or myelogenous leukemia can occur. Allogeneic stem cell transplantation is potentially curative. In tyrosine kinase–sensitive cases, hematologic
normalization, reversal of marrow fibrosis and mastocytosis, resolution of skin lesions, normalization of spleen size, and restoration of wellbeing
occurs in the great preponderance of cases. Cardiac, neurologic, and pulmonary changes usually cannot be reversed but should be stabilized. For
those who have a TKIsensitive eosinophilic neoplasm, the prognosis is better. Patients with CEL, in general, had a survival of approximately 14
months. The survival time is predicated on the presence of clonality (a neoplasm) as determined by negative or positive nextgeneration sequencing,
as some patients with neoplastic hypereosinophilia will have mutations in ASXL1, TET2, EZH2, SETBP1, or other mutations, not sensitive to TKIs.1012
CHRONIC BASOPHILIC LEUKEMIA
This type of clinical disorder, in which the patient has marrow and blood basophilia and other findings compatible with a clonal myeloid disease
without evidence of the BCRABL1 translocation, is rare. Two reports of such a syndrome occurring in 5 patients have been published.1013,1014 The
marrow was intensely hypercellular in the 3 major lineages. Dysmorphic megakaryocytes were evident. Basophilia in marrow and blood was striking,
although eosinophilia also was evident in 2 patients and increased mast cells was evident in 3 patients. The clinical effects of basophilic mediator
release were evident in 2 patients. One patient evolved to AML; the other recovered after allogeneic transplantation. The cases had similar findings,
leading to the suggestion they represented Phnegative chronic basophilic leukemia. In one case, a PRKG2–PDGFRβ fusion gene was evident and the
patient responded to imatinib. There are no accepted criteria for either classification of basophilic leukemias or to distinguish acute and chronic forms
of the disease where no evidence exists for another hematologic malignancy. The term hyperbasophilia is proposed for cases with a persistent
CHRONIC BASOPHILIC LEUKEMIA
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This type of clinical disorder, in which the patient has marrow and blood basophilia and other findings compatible with a clonal myeloid disease
without evidence of the BCRABL1 translocation, is rare. Two reports of such a syndrome occurring in 5 patients have been published.1013,1014 The
marrow was intensely hypercellular in the 3 major lineages. Dysmorphic megakaryocytes were evident. Basophilia in marrow and blood was striking,
although eosinophilia also was evident in 2 patients and increased mast cells was evident in 3 patients. The clinical effects of basophilic mediator
release were evident in 2 patients. One patient evolved to AML; the other recovered after allogeneic transplantation. The cases had similar findings,
leading to the suggestion they represented Phnegative chronic basophilic leukemia. In one case, a PRKG2–PDGFRβ fusion gene was evident and the
patient responded to imatinib. There are no accepted criteria for either classification of basophilic leukemias or to distinguish acute and chronic forms
of the disease where no evidence exists for another hematologic malignancy. The term hyperbasophilia is proposed for cases with a persistent
peripheral basophil count greater than 1 × 109/L.1015 This cutoff was thought to at least distinguish malignant from reactive forms, but does not allow
determination of primary or secondary cases.
JUVENILE MYELOMONOCYTIC LEUKEMIA
Epidemiology
A disorder different from adulttype CMML, designated juvenile myelomonocytic leukemia, represents approximately 1.5% of childhood leukemias. It
occurs most often in infants and children younger than 4 years and is similar in some respects to adult CMML, because the 2 diseases share a
prominent monocytic component in the leukemic cell population.1016,1017 The WHO classifies it as a myeloproliferative/myelodysplastic overlap
syndrome.1018
Pathogenesis
This disorder is a clonal myeloid disease that originates in an early hematopoietic multipotential cell. Evidence indicates this cell may be pluripotential
(myeloidlymphoid) in some cases, and myeloid in others.1018,1019 Patientderived induced pluripotential stem cells recapitulated the growth patterns
in vitro of the human disease and drug inhibition of MEK kinase reduced their GMCSF growth potential.1020 RAS mutations in hematopoietic cells are
present in approximately 20% of patients.1021 Approximately 1 in 10 patients with juvenile myelomonocytic leukemia have mutations of NF1 and
manifest type 1 neurofibromatosis. This frequency is approximately 400 times the expected occurrence in a comparable pediatric population.1022 The
linkage between neurofibromin, the protein encoded by the NF1 gene, GTPase activity proteins, and the activation state of RASencoded proteins has
led to a postulated sequence of events that may be triggered by the extraordinarily heightened sensitivity of the colonyforming cells in the marrow and
blood of infants with the disease to the proliferative effects of GMCSF. The latter initiates signal transduction from the cell membrane to the nucleus
via RAS protein activation.1022,1023 Mutations in the PTPN11 gene have been found in approximately onethird of children with juvenile myelomonocytic
leukemia, and the mutations in NF1, RAS, and PTPN11 usually do not coincide.1024 However, they each may act through a common pathway. PTPN11
encodes SHP2, a phosphatase, which is an upstream regulator of RAS; thus, all 3 mutations can contribute to deregulation of RAS signaling. As an
aside, children with Noonan syndrome, which is characterized by short stature, dysmorphic facies, skeletal abnormalities, and cardiac defects, have a
germcell mutation of PTPN1. These children may have a transient disorder that closely mimics juvenile myelomonocytic leukemia.1024 Gene mutation
profiling can be used to determine subtypes. Those with PTPN11, NRAS, and KRASmutated juvenile myelomonocytic leukemia have a heterozygous
gainof function genotype and are not associated with any characteristic syndrome. Juvenile myelomonocytic leukemia in those with NF1 or CBL
mutations have germline RAS activation and biallelic inactivation of the respective genes in hematopoietic cells.1018 There is evidence that epigenetics
play a role in prognosis as well.1025 Cases with a high methylation pattern often have somatic PTPN11 mutations and a poor clinical outcome; the low
methylation group has NRAS and CBL mutations, and includes Noonan syndrome patients, and is associated with good prognosis. The intermediate
methylation group showed monosomy 7 and somatic KRAS mutations.1026 The number of somatic mutations present at diagnosis is a major
determinant of prognosis.1027
Clinical Findings
Symptoms and Signs
Infants present with failure to thrive, and children present with malaise, fever, persistent infections, and exaggerated skin, oral, or nasal bleeding.
Hepatomegaly can occur. Splenomegaly, sometimes massive, is present in almost all cases. Lymphadenopathy is frequent.1016,1017 More than half of
the patients have eczematoid or maculopapular skin lesions1018 and xanthomatous lesions, and multiple caféaulait spots (neurofibromatosis type 1)
may occur.1016 The xanthomas may be the earliest signs of neurofibromatosis.1016 Noonan syndrome (dysmorphic facies, short stature, heart disease,
mental retardation, cryptorchidism, webbed neck, chest deformities, and bleeding diathesis) may coexist.1016
Laboratory Findings
Anemia, thrombocytopenia, and mild to moderate leukocytosis are common. The leukocyte count usually is greater than 10 × 109/L with a median
Infants present with failure to thrive, and children present with malaise, fever, persistent infections, and exaggerated skin, oral, or nasal bleeding.
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Hepatomegaly can occur. Splenomegaly, sometimes massive, is present in almost all cases. Lymphadenopathy is frequent.1016,1017 More than half of
the patients have eczematoid or maculopapular skin lesions1018 and xanthomatous lesions, and multiple caféaulait spots (neurofibromatosis type 1)
may occur.1016 The xanthomas may be the earliest signs of neurofibromatosis.1016 Noonan syndrome (dysmorphic facies, short stature, heart disease,
mental retardation, cryptorchidism, webbed neck, chest deformities, and bleeding diathesis) may coexist.1016
Laboratory Findings
Anemia, thrombocytopenia, and mild to moderate leukocytosis are common. The leukocyte count usually is greater than 10 × 109/L with a median
leukocyte count at diagnosis of approximately 35 × 109/L. The blood has an increased monocyte concentration of 1–100 × 109/L, immature
granulocytes including a small percentage of blast cells, and nucleated red cells. Fetal hemoglobin concentration is increased in approximately two
thirds of the patients.1028 The marrow aspirate is hypercellular as a result of granulocytic hyperplasia; the number of erythroblasts and
megakaryocytes usually are decreased. Monocytic cells are increased but may not be as striking as in the blood. Leukemic blast cells are present in
modest proportions (<20%).
Cell culture of blood and marrow shows a striking preponderance of monocytic progenitors, even in the absence of overt monocytosis in the
marrow.1029 Granulocytemonocyte colonyforming cells show a marked tendency to spontaneous growth if adherent (monocytic) cells are not
depleted from culture.1029 The effect is mediated by a release of large quantities of GMCSF by monocytes in culture.1030
Although clonal chromosome abnormalities have been found in some cases,1031 the cytogenetic abnormalities have no consistent pattern, and more
than half of the patients have normal karyotypes. The BCRABL1 fusion gene is not present.1031,1032 The phenotype of monosomy 7 syndrome overlaps
with juvenile myelomonocytic leukemia, and an abnormality of chromosome 7 (del 7, del 7q, others) is present in approximately onefifth of
patients.1031
Course, Prognosis, and Treatment
The median survival of patients with juvenile myelomonocytic leukemia has been less than 2 years.1016 Children younger than 2 years are more likely to
have a protracted course. The disease has been refractory to most chemotherapy. Even in the treated patients, complete suppression of the disease
did not occur, and treatment protocols to induce and sustain remissions were lacking.1029 The resistance of these cells to currently available therapy is
distressingly highlighted by the sense of success in prolonging the life of infants and young children by a few years. Intensive therapy can control
disease, but curative chemotherapy has been elusive.1033 Azacitidine can target leukemiainitiating cells in juvenile myelomonocytic leukemia.1034 The
GMCSF antagonist E21R, inhibitors of RAF1 gene expression, retinoids, blockers of RAS protein farnesylation, and angiogenesis inhibitors are among
other drug approaches to the disease being studied.1035–1037
Allogeneic stem cell transplantation is an important approach to therapy and may provide the best chance of longterm survival in selected
children.1038–1040 Hence, a rapid search for a matchedunrelated donor, including cord blood sources, is important in patients without matched sibling
donors. Transplantation from a histocompatible sibling or matchedunrelated donor resulted in an eventfree survival at 5 years of approximately
50%, and from matchedcord blood stem cells of approximately 45%, unless monosomy 7 was present, which lowers 5year survival to approximately
25%.1045 Children transplanted before age 1 year had better results (approximately 50%) than did older children (approximately 30%).1040 Early stem
cell transplantation is recommended for all children with NF1, somatic PTPN11 and KRAS mutations, and for most with somatic NRAS mutations. A
“watchandwait” strategy should be employed in those with germline CBL mutations, certain NRAS mutations, and in Noonan syndrome patients as
spontaneous resolution has been reported.1037 A minority of patients have a smoldering course for 2–4 years. Thereafter, the disease usually rapidly
progresses, and patients die of infection or hemorrhage. Occasional patients have a very long survival (>10 years) despite persistence of abnormal
blood counts and splenomegaly, independent of the type or intensity of therapy. Some children convert to a fullblown AML with a rapidly fatal
outcome. Cases of juvenile myelomonocytic leukemia also may be associated with transformation to acute lymphoblastic leukemia.1041 The disease
may resolve spontaneously in approximately 15% of cases, so better understanding of the genomic features of the disease to predict outcome is
important.1018
CHRONIC NEUTROPHILIC LEUKEMIA
History, Features, Pathogenesis, and Epidemiology
In 1920, Tuohey1042 described the first recorded case of an unusual sustained neutrophilia with splenomegaly without fever, inflammation, cancer, or
other cause of a leukemoid reaction.1043 Some cases may arise in the hematopoietic multipotential cell, others in a neutrophil progenitor cell.1042–1045
1046 As in most clonal myeloid diseases, men are affected more
The median age at onset is approximately 65 years. Younger patients may be affected.
frequently than are women.
important.
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CHRONIC NEUTROPHILIC LEUKEMIA
History, Features, Pathogenesis, and Epidemiology
In 1920, Tuohey1042 described the first recorded case of an unusual sustained neutrophilia with splenomegaly without fever, inflammation, cancer, or
other cause of a leukemoid reaction.1043 Some cases may arise in the hematopoietic multipotential cell, others in a neutrophil progenitor cell.1042–1045
The median age at onset is approximately 65 years. Younger patients may be affected.1046 As in most clonal myeloid diseases, men are affected more
frequently than are women.
Clinical Features
Symptoms and Signs
Patients may complain of weakness, anorexia, weight loss, abdominal pain, and easy bruising. Symptoms and signs of gouty arthritis occur in
approximately onethird of cases. The spleen is enlarged in almost all cases, and the liver frequently is enlarged. Lymphadenopathy is very infrequent.
A hemorrhagic tendency is present in some patients.
Laboratory Findings
Although some patients have a normal hemoglobin concentration at the time of presentation, most have mild to moderate anemia on
presentation1043. The platelet count rarely is less than 125 × 109/L and usually is normal. Coagulation times are normal. The total leukocyte count
usually is between 25 × 109/L and 100 × 109/L in most cases, and only rarely is less than 20 × 109/L or more than 100 × 109/L. Neutrophils compose 85%
to 95% of the white cells. Although segmented cells usually dominate, occasional cases have a high proportion of band forms. Very infrequently,
metamyelocytes, myelocytes, and nucleated red cells may be present in patients. Basophil and eosinophil counts are not increased. Blasts are nearly
always absent from the blood. Neutrophil alkaline phosphatase activity is increased in almost all cases.
The marrow invariably shows granulocytic hyperplasia with myeloidtoerythroid ratios as high as 10:1. Myeloblasts are not overtly increased in
number (0.5–3.0%). Megakaryocytes are either normal or slightly increased in number and have normal distribution and morphology. Erythropoiesis
usually is mildly decreased. Unlike CML, reticulin fibrosis is unusual. A few cases with dysmorphic features in the marrow (acquired PelgerHüet
anomaly, erythroid, dysplasia, micromegakaryocytes) have been reported. Serum vitamin B12binding protein and vitamin B12 levels both are markedly
increased above normal. Serum uric acid concentration is increased, and serum LDH activity may be increased.
Almost every case examined postmortem had liver and splenic enlargement. Portal hepatic and splenic red pulp infiltrates of neutrophils or islands of
extramedullary hematopoiesis with immature myeloid cells and megakaryocytes are characteristic.
Cytogenetic and Genetic Findings By definition, the Ph chromosome, BCR gene rearrangements, and BCRABL1 transcripts are absent.1043 Most
patients have normal karyotypes, but approximately 25% of patients have nonrandom abnormalities of chromosomes.1043 Deletions of chromosome
20q and trisomy 21 or 9 are the most common abnormalities. The disease is associated with a mutation in the colonystimulating factor 3 receptor gene
(CSF3R) alone (approximately 30% of cases), or a combination of mutated CSF3R and a SET binding protein gene (SETBP1) mutation (approximately
60% of cases) or the JAK2V617F mutation alone (approximately 10% of cases).1047,1048 Two principal mutations were observed in CSF3R: the membrane
proximal CSF3RS783fs mutation and the truncated CSF3RT618I or CSF3RT615A mutation. The CSF3RS783fs mutation results in deregulation of the SRC
family TNK2 kinases and may respond to SRC inhibitors, whereas the CSF3RT618I or CSF3RT615A mutation deregulates JAKSTAT kinases and may confer
sensitivity to ruxolitinib.1047 The CSF3RT618I mutation is thought to represent a distinct entity that may or may not demonstrate marrow cell
dysplasia.1049 Genetic landscaping suggests that CNL, atypical CML, and MDS/MPNU represent a continuum of disease rather than discrete diagnostic
entities.1050,1051 Commonalities include SETBP1, SRSF2, U2AF1, TET2, and ASXL1 mutations, and order of acquisition is not yet understood in terms of
clinical presentation or outcomes.1052
Differential Diagnosis
Most leukemoid reactions are associated with an obvious underlying cause, such as pancreatitis, carcinoma, immunologic disease, smoker’s
neutrophilia, and chronic bacterial or fungal infection. The leukocyte alkaline phosphatase level usually is markedly elevated in CNL and markedly
decreased in CML. More to the point, molecular studies identifying BCR gene rearrangement or the presence of BCRABL1 transcripts should
distinguish CNL (BCRABL1–negative) from neutrophilic CML (BCRABL1–positive; see “Special Clinical Features” above). In CML, more than half of the
patients have thrombocytosis and megakaryocytic hyperplasia, which are uncharacteristic of CNL. The presence of a CSF3R or JAK2 mutation with a
classical clinical picture would be strong diagnostic evidence for the CNL. Atypical CML or another MPN/MDS overlap syndromes are differential
diagnostic considerations. 1051
Treatment
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Most leukemoid reactions are associated with an obvious underlying cause, such as pancreatitis, carcinoma, immunologic disease, smoker’s
neutrophilia, and chronic bacterial or fungal infection. The leukocyte alkaline phosphatase level usually is markedly elevated in CNL and markedly
decreased in CML. More to the point, molecular studies identifying BCR gene rearrangement or the presence of BCRABL1 transcripts should
distinguish CNL (BCRABL1–negative) from neutrophilic CML (BCRABL1–positive; see “Special Clinical Features” above). In CML, more than half of the
patients have thrombocytosis and megakaryocytic hyperplasia, which are uncharacteristic of CNL. The presence of a CSF3R or JAK2 mutation with a
classical clinical picture would be strong diagnostic evidence for the CNL. Atypical CML or another MPN/MDS overlap syndromes are differential
diagnostic considerations.1051
Treatment
No systematic studies of treatment have been reported. Although hydroxyurea, IFNα, or cytarabine may decrease the white count and spleen size,
longterm benefit is unusual.1043,1053 Intensive induction therapy has led to early posttreatment deaths, and splenectomy is not recommended. With
identification of specific genetic mutations, either a JAK2 inhibitor (eg, ruxolitinib) (for the CSF3RT618I mutation) or dasatinib (for the CSF3RS783fs
mutation) should be considered.1043 Ruxolitinib can reduce the allelic burden of the CSF3R mutation in certain cases of CNL.1054,1055 SETBP1 mutations
can offset ruxolitinib response in those with concurrent CSF3RT618I mutations.1056 Some patients who harbor both membraneproximal and truncation
CSF3R mutations may have activation of MAPK pathways, and could be sensitive to MAPK inhibitors.1057 These inhibitors may include the MEK1/2
inhibitor, trametinib (Mekinist). The disease is rare and clinical trials have only recently been attempted now that the CSF3R mutation can be used for
more precise disease identification. Allogeneic stem cell transplantation in eligible patients may be curative.1058 CSF3R allele burden may serve as a
minimal residual disease marker posttransplantation.1056
The disease is fatal, with a median survival of approximately 2.5 years and a range of 0.5–6.0 years.1043,1046 Blast transformation may occur in up to 20%
of cases.1043 The prognosis is considerably worse than the prognosis for CML despite the prevalence of mature neutrophils and the paucity of blasts.
Newer approaches with dasatinib or ruxolitinib for the appropriate genetic mutations (see “Treatment” above) may provide better outcomes. Causes
of death have included intracranial hemorrhage, sometimes in the presence of adequate platelet counts and coagulation times. The disease usually
afflicts older persons, and cardiac, pulmonary, and vascular diseases contribute to a fatal outcome.
A remarkable frequency of concordant essential monoclonal gammopathy or myeloma has been described.1059,1060 CNL has evolved from
polycythemia vera or myelodysplasia.1061,1062 There is evidence that the presence of ASXL1 and SETBP1 mutations and thrombocytopenia may be
associated with a worse prognosis.1043,1063
BCR REARRANGEMENTNEGATIVE PHENOTYPICALLY TYPICAL CHRONIC MYELOGENOUS LEUKEMIA
A small proportion of patients (approximately 4%) with clinical manifestations within the limits usually applied to the diagnosis of CML have neither a
Ph chromosome (classic, variant, or masked) nor evidence of rearrangement of BCR on chromosome 22. This circumstance represents BCRnegative
CML. The literature describing Phnegative CML prior to 1987 is difficult to evaluate because many cases were not studied carefully for masked or
variant translocations and for the BCR gene rearrangement. Phnegative CML is a clonal disease that has the propensity for lymphoid and myeloid
transformation.1064,1065 Exhaustive molecular diagnostic evaluation must be negative in these cases, and there is controversy as to whether this is a
distinct entity as most series did not have exhaustive nextgeneration sequencing data.1066,1067 In a report of 76 such patients with phenotypic CML but
no BCR/ABL rearrangement, the median age was 66 years (range: 24–88 years), splenomegaly was present in 38 (50%) of patients, the median white cell
count was 38 × 109 cells/L (range: 11–296 × 109 cells/L), and the median hemoglobin was 110 g/L (range: 70–160 g/L), with classical morphologic
features in blood and marrow.1067 Median survival was 24 months and only 5 (7%) patients survived for more than 5 years. Some patients developed
cytopenias and myeloid blast phase occurred in onethird of those followed until their death. Occasional patients had extended complete remissions
with IFNγ therapy.1066 Hydroxyurea can be useful as palliative therapy.
ATYPICAL CHRONIC MYELOGENOUS LEUKEMIA
Definition
A neoplasm of a hematopoietic stem cell has many variations in expression (Chap. 82), and it is surprising that nearly all can be pigeonholed into a
generally agreed upon phenotype. Some cases do not fit a standard diagnostic pattern, and they have been classified by the WHO as atypical CML
(aCML) or, alternatively, myelodysplasticmyeloproliferative syndrome unclassifiable (MDS/MPN U), which category excludes BCRrearrangement–
positive CML, CMML, CNL, refractory sideroblastic anemia with thrombocytosis, and other classical syndromes, as judged phenotypically and
1068–1070 Myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRα, PDGFRβ, or FGFR1, or with PCM1
genotypically.
JAK2 have now been moved into a separate category in the WHO classification and are no longer considered aCML, CMML, or CEL. The
myelodysplastic/myeloproliferative syndromes are described in Chap. 86. Currently, aCML is defined by neutrophilic leukocytosis and
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Definition
A neoplasm of a hematopoietic stem cell has many variations in expression (Chap. 82), and it is surprising that nearly all can be pigeonholed into a
generally agreed upon phenotype. Some cases do not fit a standard diagnostic pattern, and they have been classified by the WHO as atypical CML
(aCML) or, alternatively, myelodysplasticmyeloproliferative syndrome unclassifiable (MDS/MPN U), which category excludes BCRrearrangement–
positive CML, CMML, CNL, refractory sideroblastic anemia with thrombocytosis, and other classical syndromes, as judged phenotypically and
genotypically.1068–1070 Myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRα, PDGFRβ, or FGFR1, or with PCM1
JAK2 have now been moved into a separate category in the WHO classification and are no longer considered aCML, CMML, or CEL. The
myelodysplastic/myeloproliferative syndromes are described in Chap. 86. Currently, aCML is defined by neutrophilic leukocytosis and
dysgranulopoiesis. It has a heterogeneous mutational landscape, and the JAK, MAPK, and ROCK pathways are postulated to be targets in these
patients.1071
Clinical Features
These patients are principally in the 60–90yearold age range, but atypical expression of a multipotential hematopoietic cell neoplasm can occur at
any age. Hepatomegaly and/or splenomegaly are present in a minority of patients. Anemia, and nearly always granulocytosis (granulocytes, notably
neutrophils, and granulocytic precursors), sometimes with neutrophilic dysmorphia (eg, acquired PelgerHuët neutrophils), are characteristic.
Neutrophilic precursors represent less than 15% of blood cells. The blast cell count in blood and marrow is low, usually less than 10%. Monocytes are
not increased and eosinophils or basophils are usually not increased but may be as high as 10% of total leukocytes. Transformation to AML may occur.
Laboratory Features
The LDH is often elevated. The marrow is hypercellular with variable evidence of dysmorphic granulopoiesis and dysmorphic megakaryocytopoiesis.
Mild marrow reticular fibrosis may be evident. Clonal cytogenetic abnormalities may occur but do not include translocations characteristic of classical
chronic myeloid neoplasms, such as a BCRABL1 or translocations involving PDGFRα, PDGFRβ, or FGFR1 seen in CEL with or without mastocytosis.
Common myeloidrelated cytogenetic abnormalities may occur, such as trisomy 8 and del (20q). Genes frequently mutated in aCML include RAS,
SETBP1, RUNX1, ASXL1, TET2, PTPN1, and CSF3R.1072,1073 ETNK1 mutations are found in approximately 9% of cases.1073 aCML is thought to have more
genetic heterogeneity than CNL, but cooccurrence of CSF3R and U2AF1 have been described in both disorders.1051
Therapy
This neoplasm has no specific treatment and is usually treated “symptomatically” with red cell or platelet transfusion and an agent to reduce the white
cell count, if that is a problem (eg, hydroxyurea, IFNα, 5azacytidine, decitabine, lowdose cytarabine).1074 Stem cell transplantation can be offered at
the time of diagnosis in those of appropriate age, who are fit, have highrisk disease, and have a suitable donor.1075 The role that cytoreduction plays in
influencing transplant outcomes is not well understood in aCML, nor is the influence of various mutations on outcomes. Nonmyeloablative allogeneic
stem cell transplantation also has been used. In a study of 42 patients between 1997 and 2006, 37 (87%) achieved a complete remission, and at 5 years,
the relapsefree survival was 36%. Young patients with better prognostic risk scores fared best.1075 Studies of targeted therapies such as ruxolitinib
(JAK and CSF3R mutations) and trametinib (RAS mutations) are underway.1076
Median survivals of 12–30 months have been reported in various series.1077 Approximately 40% of patients transform to AML, and increased leukocyte
count, increased blood myeloid immaturity, female sex, and older age are adverse prognostic features.1077
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Indications First­line therapy (CP, First­line therapy First­line therapy (CP), First­line therapy Resistance or

Usual dosing CP 400 mg/day CP 300 mg BID CP 100 mg/day 500 mg/day 45 mg/day

Common GI disturbance, edema Rash, GI Edema, pleural effusions, GI GI (diarrhea), rash, HBP, rash, GI, fatigue,

Other significant Elevated LFTs (usually Peripheral vascular Pulmonary arterial Arterial and venous

Drug–drug CYP3A4 inducers CYP3A4 inhibitors CYP3A4 inhibitors increase CYP3A inhibitors Strong CYP3A inhibitors

Administration Taken with food Taken on empty Can be taken with or without a Taken with food Taken with and without

Administration Taken with food Taken on empty Can be taken with or without a Taken with food Taken with and without

Black box None QT prolongation None None Arterial thrombosis;

Other Approved in pediatric Keep potassium, Ascites and pericardial effusion Has activity with T315I

Early molecular BCR­ABL1 ≤10% at 3 or 6 months

Time of Observation (months) Unsatisfactory Suboptimal Response/Warning Optimal Response

3 No CHR and/or Ph+ >95% BCR/ABL1 >10% and/or Ph+ 36–95% BCR/ABL1 ≤10% and/or MCyR

6 BCR/ABL1 >10% and/or no MCyR BCR–ABL1 1–10% and/or MCyR BCR/ABL1 <1% and/or CCyR

12 BCR/ABL1 >1% and/or no CCyR BCR–ABL1 <0.1–1% BCR/ABL1 <0.1%

18 No CCyR CCyR if no MMR CCyR or MMR

BCR >95% p210BCR­ABL; <5% p190 or p230 Splenomegaly in 80% of cases; WBC >25 × 109/L; blood blasts <5%; Pages

Chronic >40% mutation in SRSF2 gene and 90% have a Anemia, monocytosis >1.0 × 109/L; blood blasts <10%; increased Page

Chronic Various cytogenetic abnormalities; PDGFRα/β, Blood eosinophil count >1.5 × 109/L; cardiac and neurologic Page

Chronic Various cytogenetic abnormalities Only 5 cases reported; hemoglobin 6–13 g/dL; basophilia of 3.4–41 × Page

Juvenile RAS pathway mutations (PTPN11, NF1, NRAS, Infants and children <4 years; eczematoid or maculopapular rash; Page

Chronic Colony­stimulating factor 3 receptor gene (CSF3R) Segmented neutrophilia ≥20 × 109/L; splenomegaly >90% of cases; Page

BCR Various cytogenetic changes Clinical findings indistinguishable from BCR rearrangement­positive Page

Atypical chronic Various cytogenetic changes Patient usually >65 years; variable blood cell changes: anemia, Page

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Indications Firstline therapy (CP, Firstline therapy Firstline therapy (CP), Firstline therapy Resistance or

Early molecular BCRABL1 ≤10% at 3 or 6 months

BCR >95% p210BCRABL; <5% p190 or p230 Splenomegaly in 80% of cases; WBC >25 × 109/L; blood blasts <5%; Pages

Chronic Colonystimulating factor 3 receptor gene (CSF3R) Segmented neutrophilia ≥20 × 109/L; splenomegaly >90% of cases; Page

BCR Various cytogenetic changes Clinical findings indistinguishable from BCR rearrangementpositive Page

28. Lichtman MA. Is there an entity of chemically induced BCRABLpositive chronic myelogenous leukemia? Oncologist. 2008;13:645. [PubMed:

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