Chronic Myeloid Leukemia (CML) 3

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Chronic myeloid   
leukemia (CML)
Dr Shumayla Aslam-Faiz
Jun. 01, 2019 • 74 likes • 29,695 views
  11 of 31  
chronic myeloid leukemia, CML, epidemiology, BCR

ABL1 gene, philadelphia chromosome, t(9;22), CML
incidence, etiology of CML, pathophysiology of CML,
phases of CML, treatment of CML, Allogenic stem cell
transplant, TKI therapy for CML, Sokal index for CML,
Health & Medicine
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 Chronic myeloid leukemia (CML)

1. Chronic MyeloidChronic Myeloid LeukemiaLeukemia
SHUMAYLA ASLAM-FAIZ, MDSHUMAYLA ASLAM-FAIZ, MD 33RDRD
YEAR RESIDENTYEAR RESIDENT DEPARTMENT OF INTERNAL
MEDICINEDEPARTMENT OF INTERNAL MEDICINE
EACMCCEACMCC Source: Harrisons 20th Edition, Ch 101, Pg 746-
757 MD Calc American Cancer Society
dr.shumaylaaslam@gmail.com
2. CMLCMLcan develop from any of these
3. Development of myeloid and lymphoid leukemias within the
context of hematopoietic cell hierarchy. Hematopoietic stem
cells (HSCs; S) produce granulocytic (G) and lymphocytic (L)
precursors, which then go on to generate smaller di!erentiated
cells. Genetic and/or epigenetic aberrancies (striped) in stem or
progenitor cells lead to a neoplastic accumulation of cells due to
hyperproliferation and decreased apoptosis.
4. WHAT’S WRONG • CML is defined by the presence of BCR-ABL1
fusion gene in a patient with a myeloproliferative neoplasm.
•Philadelphia chromosome (Ph) • the BCR-ABL1 chimeric gene
product, that codes for a constitutively active tyrosine kinase,
resulting from a reciprocal balanced translocation between the
long arms of chromosomes 9 and 22, t(9;22)(q34.1;q11.2)
5. INCIDENCE AND EPIDEMIOLOGY • CML accounts for 15% of all
cases of leukemia∼ • The annual incidence of CML is 1.5 cases
per 100,000 individuals • Male : female ratio 1.6:1 • The median
age at diagnosis is 55–65 years. • It is uncommon in children;
only 3% of patients with CML are younger than 20 years. • the
median survival in CML was 3–7 years but, with introduction of
TKI therapy (tyrosine kinase inhibitors) imatinib mesylate, the
first BCR-ABL1 TKI approved, is 85%. • The annual mortality has
been reduced from 10–20% to about 2%.
6. ETIOLOGY • No familial associations in CML • Exposure to
ionizing radiation (e.g., nuclear accidents, radiation treatment
for ankylosing spondylitis or cervical cancer) has increased the
risk of CML, which peaks at 5–10 years a"er exposure and is
dose-related (larger dose) • Because of adequate protection, the
risk of CML is not increased in individuals working in the nuclear
industry or among radiologists in recent times.
7. HEMATOPOI ETIC STEM CELLS hybrid oncogene, BCR-ABL1
kinase activity Excessive proliferation and reduced apoptosis
EXPOSURE TO RADIATIONS PATHOPHYSIOLOGY OF
CMLdr.shumaylaaslam@gmail.com
8. Phases of chronic myeloid leukemia • The phases are based
mainly on the number of immature WBC (blastsblasts) in the
blood or bone marrow. 1. Chronic phase • less than 10% blasts in
their blood or bone marrow. • fairly mild symptoms (if any) and
usually respond to standard treatments. • Most patients are
diagnosed in the chronic phase. 2. Blast phase (aka acute phase
or blast crisis) • 20% or more blasts • Large clusters of blasts are
seen in the bone marrow. • The blast cells have spread to tissues
and organs beyond the bone marrow. These patients o"en have
fever, poor appetite, and weight loss. In this phase, the CML acts
a lot like an acute leukemia. dr.shumaylaaslam@gmail.com
9. 3. Accelerated phase Patients are considered to be in
accelerated phase if any of the following are true: •15% or more,
but less than 30% blasts •Basophils make up 20% or more of the
blood •Blasts and promyelocytes combined make up 30% or
more of the blood •Very low platelet counts (100 x 1,000/mm3 or
less) that are not caused by treatment •New chromosome
changes in the leukemia cells with the Philadelphia
chromosome •symptoms such as fever, poor appetite, and
weight loss. CML in the accelerated phase doesn't respond as
well to treatment as CML in the chronic phase.
10. dr.shumaylaaslam@gmail.com
11. CML in Accelarated Phase dr.shumaylaaslam@gmail.com
12. CLINICAL PRESENTATION • Healthcare available areas 50–
60% of patients are diagnosed on routine blood tests and have
minimal symptoms at presentation, such as fatigue. • locations
where access to health care is more limited, patients o"en
present with high CML burden including splenomegaly,
anemiasplenomegaly, anemia, and related symptoms
(abdominalabdominal pain, weight loss, fatiguepain, weight
loss, fatigue), which translate into a higher frequency of high-risk
CML. dr.shumaylaaslam@gmail.com
13. • Less common presenting findings include thrombotic or
hyperviscosity-related events (from severe leukocytosis or
thrombocytosis) • cardiovascular complications, MI, VTE, visual
disturbances, dyspnea and pulmonary insu!iciency, drowsiness,
loss of coordination, confusion, or cerebrovascular accidents. •
Manifestations of bleeding diatheses include retinal
hemorrhages, gastrointestinal bleeding, and others. • Patients
who present with, or progress to, the accelerated or blastic
phases frequently have additional symptoms including
unexplained fever, significant weight loss, severe fatigue, bone
and joint pain, bleeding and thrombotic events, and infections.
15. Hematologic and Marrow Findings • CBC: • leukocytosis
ranging from 10–500 × 109/L. • predominance of neutrophils and
the presence of bands • Basophils and/or eosinophils are
frequently increased • Thrombocytosis • but thrombocytopenia
is rare and, when present, suggests a worse prognosis, disease
acceleration, or an unrelated etiology • Anemia is present in one-
third of patients. • PBS: • le"-shi"ed hematopoiesis with
predominance of neutrophils and the presence of bands,
myelocytes, metamyelocytes, promyelocytes, and blasts
(usually ≤5%). Anemia is present in one-third of patients.
17. • Bone Marrow • hypercellular with marked myeloid
hyperplasia and a high myeloid-to-erythroid ratio of 15–20:1. •
Marrow blasts are <5%; when >15 they carry a worse prognosis
or represent transformation to accelerated phase. • Increased
reticulin fibrosis (by Snook’s silver stain) is common, with 30–
40% of patients demonstrating grade 3–4 reticulin fibrosis. • With
TKI therapy, reticulin fibrosis resolves in most patients and is not
an indicator of poor prognosis • Biochemical abnormalities
include a low leukocyte alkaline phosphatase score and high
levels of vitamin B12, uric acid, lactic dehydrogenase, and
lysozyme. dr.shumaylaaslam@gmail.com
18. CMLCML dr.shumaylaaslam@gmail.com
19. Cytogenetic and Molecular Findings • The diagnosis of CML is
straightforward and depends on documenting the t(9;22)
(q34.1;q11.2), which is identified by G-banding in 90% of cases. •
Techniques such as FISH and PCR are now used to aid in the
diagnosis of CML. • Both FISH and PCR studies can be falsely
positive because of technical issues. Therefore, a diagnosis of
CML must always rely on a marrow analysis with routine
cytogenetics. dr.shumaylaaslam@gmail.com
20. TREATMENT dr.shumaylaaslam@gmail.com
21. • Serious side e!ects occur in <5–10% of patients. • With
imatinib therapy, common mild to moderate side e!ects include
fluid retention, weight gain, nausea, diarrhea, skin rashes,
periorbital edema, bone or muscle aches, fatigue, and others
(rates of 10–20%). • In general, second-generation TKIs are
associated with lower rates of these bothersome adverse events.
22. ALLOGENEIC STEM CELL TRANSPLANT • Allogeneic SCT, a
curative modality in CML, is associated with long-term survival
rates of 40– 60% when implemented in the chronic phase.
24. OTHER TREATMENTS AND SPECIAL THERAPEUTIC
CONSIDERATIONS • Chemotherapeutic Agents • Hydroxyurea
remains a safe and e!ective agent (at daily doses of 0.5–10 g) to
reduce initial CML burden, as a temporary measure in between
definitive therapies in combination with TKIs to sustain
complete hematologic or cytogenetic responses. • Busulfan is
o"en used in allogeneic SCT preparative regimens. Because of
its side e!ects (delayed myelosuppression, Addison- like
disease, pulmonary and cardiac fibrosis, myelofibrosis), it is now
only rarely used in the chronic management of CML.
25. • Interferon α: Interferon α is considered in combination with
TKIs, sometimes a"er CML failure on TKIs, occasionally in
patients during pregnancy, or as part of investigational
strategies with TKIs to eradicate residual molecular disease. •
Others Splenectomy is now seldom considered to alleviate
symptoms of massive splenomegaly and/or hypersplenism.
Splenic irradiation is rarely used, if at all, because of the
postirradiation adhesions and complications.
26. MONITORING THERAPY IN CML • Achievement of complete
cytogenetic response by 12 months12 months of imatinib
therapy • Failure to achieve a complete cytogenetic response by
12 months or occurrence of later cytogenetic or hematologic
relapse are considered as treatment failure and an indication to
change therapy. • Patients on frontline imatinib therapy should
be closely monitored until documentation of complete
cytogenetic response, every 6 months with peripheral blood
FISH and PCR studies (to check for concordance of results), or
more frequently (every 3 months) if there are concerns about
changes in BCR-ABL1 transcripts dr.shumaylaaslam@gmail.com
27. Discontinuation of TKIs and Treatment-Free Remissions or
“Molecular Cures” • Several studies have confirmed that TKI
discontinuation among patients who achieve undetectable BCR-
ABL1 transcripts for longer than 2–3 years can result in
treatment-free remission rates of 40– 60% • low Sokal-risk CML
in first chronic phase (no evidence of transformation)
28. Sokal Index for Chronic Myelogenous Leukemia (CML)
survival • Sokal Score = exp[0.0116 × (age in years – 43.4)] +
[0.0345 × (spleen size in cm – 7.51)] + [0.188 x ((platelets in 109 /L
/ 700)2 – 0.563)] + [0.0887 × (blasts in % – 2.10)]
29. PROGNOSIS AND CML COURSE • Before the TKI therapy,
imatinib era, the annual mortality in CML was 10% in the first 2
years and 15–20% therea"er. The median survival time in CML
was 3–7 years (with hydroxyurea-busulfan and interferon α). •
Without a curative option of allogeneic SCT, the course of CML
was toward transformation to, and death from, accelerated or
blastic phases. dr.shumaylaaslam@gmail.com
30. Adverse prognostic factors: • Accelerated phase or blast
phase • Enlarged spleen • Areas of bone damage from growth of
leukemia • Increased number of basophils and eosinophils
(certain types of granulocytes) in blood samples • Very high or
very low platelet counts • Age 60 years or older • Multiple
chromosome changes in the CML cells
31. Thank YouThank You dr.shumaylaaslam@gmail.com
Editor's Notes
No etiologic agents are incriminated, and no

associations exist with exposures to benzene or
other toxins, fertilizers, insecticides, or viruses
CML is not a frequent secondary leukemia
following therapy of other cancers with alkylating
agents and/or radiation
Cost of imatinib
P 1500 per tab
India: 28,000 for 1 year
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Jun. 01, 2019 • 74 likes • 29,695 views

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Copyright Cookie Preferences English 

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