Chronic Leukemia Herfindal

93 Chronic Leukemias Page 1 of 40
93
Chronic Leukemias
Courtney W. Yuen
Chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia (CLL) are
hematologic malignancies that occur primarily in older adults. Patients usually survive
several years beyond the diagnosis of leukemia, even in the absence of treatment. Over
time, the chronic leukemias become more aggressive and less responsive to treatment.
CML is curable only with an allogeneic hematopoietic cell transplant (AHCT), which is
available to about 20% to 30% of patients. CLL is incurable at this time.
New therapies are emerging that contribute to prolonged survival and may possibly lead
to a cure for patients with chronic leukemia. Patients with chronic leukemia are
benefiting from the knowledge and application of new therapeutic approaches, including
the use of biologic agents, advances in hematopoietic cell transplants (HCTs), new
effective chemotherapy, and improved supportive care. As these advances in treatment
are made available for patients, care must be taken to safeguard patient quality of life.
The new approaches under development will warrant evaluations of cost to benefit
ratios.
Chronic Myelogenous Leukemia
CML is a hematologic malignancy originating from a leukemic transformation in a clonal

pluripotent stem cell. Ninety-five percent of patients display a characteristic t(9 S 2 2 )
chromosome translocation, the Philadelphia chromosome. The disease progresses
through three distinct phases.1 The first stage, lasting from 3 to 5 years, is an early
chronic phase in which the patient is minimally symptomatic. At this point, there is
usually less than 5% immature or blast cells present in the bone marrow. In this early
phase of the disease, the leukemic cells retain the ability to differentiate and mature
into granulocytes. The leukemia may then go through a transition phase or accelerated
phase (5%–30% blast cells) of several months' duration, in which the symptoms are
more pronounced and more refractory to medication. Finally, CML invariably progresses
to a blast phase (>30% blast cells), which causes a fatal leukemic blast crisis, unless
the leukemic clone has been eradicated and normal hematopoiesis is restored. Blast
crisis is characterized by fevers and bleeding complications, similar to the presentation
of acute leukemia, and unless the patient receives treatment, the risk of mortality is
extremely high. At this time, the only potential cure for CML is an AHCT.
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Treatment Goals: Chronic Myelogenous Leukemia
l Provide curative therapy by eradicating the leukemic cells and restoring

normal hematopoiesis. A cure for CML is currently available only by
allogeneic bone marrow (or hematopoietic stem cell) grafts, which are
available for about 20% to 30% of patients with CML.
l For patients who are not candidates for allogeneic stem cell grafting,
prolong the chronic phase of the disease as long as possible to prolong
survival with minimal symptoms.
Epidemiology
CML accounts for approximately 20% of all cases of leukemia with an incidence of 1 to
1.5 cases per 100,000 population. The median age at diagnosis is 67 years, although
patients may be diagnosed at any age.2 There is a slight male to female predominance
in a ratio of about 1.5:1.3
The etiology of the leukemogenic transformation is unclear. There appears to be no

hereditary component. Chemical leukemogens have not been distinctly identified, but
may include benzene and chemotherapy. No role for viral involvement has been
observed. Exposure to ionizing radiation appears to have an etiologic role in some
cases. Survivors of atomic bomb explosions, radiologists, and patients exposed to large
amounts of radiation have an increased incidence of CML.4
FIGURE 93.1 Oncogene activation by chromosomal relocation. A. Chronic

myelogenous leukemia. Breaks at the ends of the long arms of chromosomes 9 and
22 allow reciprocal translocations to occur. The c-abl proto-oncogene on
chromosome 9 is translocated to the breakpoint region (bcr) of chromosome 22.
The result is the Philadelphia chromosome, which contains a new fusion gene
coding for a hybrid oncogenic protein (BCR-ABL), presumably involved in the
pathogenesis of chronic myelogenous leukemia. B. Burkitt lymphoma. In this
disorder, chromosomal breaks involve the long arms of chromosomes 8 and 14.
The c-myc gene on chromosome 8 is translocated to a region on chromosome 14
adjacent to the gene coding for the constant region of an immunoglobulin heavy
chain (CH). The expression of c-myc is enhanced by its association with the
promoter/enhancer regions of the actively transcribed immunoglobulin genes.
(From
Rubin E, Farber JL. Pathology, 3rd ed. Philadelphia: Lippincott Williams & Wilkins,
1999
, with permission.)
Pathophysiology
The key event in the evolution of CML appears to be the translocation of the proto-
oncogene c-ABL located on the long arm of chromosome 9 to the BCR gene on the long
arm of chromosome 22. A reciprocal translocation occurs, and the BCR gene on
chromosome 22 is translocated to chromosome 9. A BCR-ABL gene is formed on
chromosome 22, and an ABL-BCR gene is formed on chromosome 9. The BCR-ABL gene
is transcribed into an 8.5-kb mRNA, which is translated into a 210-kD protein. The
expression of the BCR-ABL gene to the p210BCR/ABL tyrosine kinase protein is linked
to the oncogenic transformation to CML. The BCR-ABL fusion produces an abundance of
tyrosine kinase that results in the deregulation of cellular proliferation and reduction in
apoptosis to mutagenic stimuli.5 The resultant t(9 S 2 2 ) chromosomal translocation is
named the “Philadelphia (Ph)” chromosome (Fig. 93.1).
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Further chromosomal abnormalities occur as the disease progresses to the accelerated

and blast phase. Examples of these acquired abnormalities include trisomy 8, an
additional Ph chromosome, and isochromosome 17q.6
Clinical Presentation and Diagnosis
Signs and Symptoms
Chronic Phase
The onset of symptoms is usually gradual. Common presenting symptoms are fatigue,
weight loss, anorexia, abdominal fullness, early satiety, and sweating. Physical findings
commonly include splenomegaly, hepatomegaly, sternal tenderness, pallor, and
palpable lymph nodes. Laboratory findings include an elevated white blood cell (WBC)
count, often greater than 100 × 10 9 per liter. Basophilia, eosinophilia, and monocytosis
are typical. Most patients have normochromic, normocytic anemia. Many patients have
thrombocytosis. The lactic acid dehydrogenase (LDH), uric acid, and serum vitamin B 1 2
levels are usually above normal. The leukocyte alkaline phosphatase level is almost
always low. The bone marrow is hypercellular.3 , 4 , 6
Progression to Accelerated and Blast Phases
The disease may progress from the chronic phase to the accelerated phase and then to
blast crisis or may move directly from the chronic phase to the blast phase. The
transition may occur at any time in the course of the disease. Although the chronic
phase usually lasts several years, there is no guarantee that the CML will not rapidly
advance to blast crisis. As the disease moves into the accelerated phase, medication is
no longer as effective as in the chronic stage and laboratory test results and clinical
findings will worsen. New cytogenetic abnormalities will appear. Patients entering the
accelerated phase may report fever, night sweats, weight loss, myalgias, and
arthralgias.
Patients in the blast phase of CML have signs and symptoms of acute leukemia. Many
patients will present with fever (with or without infection), bone pain and enlarged
spleen. Often infection and bleeding occur due to bone marrow failure. CML will evolve
to acute myeloid leukemia (AML) in about two thirds of patients and to acute
lymphocytic leukemia (ALL) in about one third. The acute leukemic phase of CML is
more refractory to therapy than is de novo acute leukemia. CML that transforms into
ALL is more responsive to therapy than CML that transforms into AML.3 , 4 , 6
Diagnosis
CML is commonly diagnosed incidentally after the detection of a high WBC count on
routine screening. The patient with symptoms most frequently reports asthenia,
abdominal discomfort, weight loss, and fever. On physical examination, the majority of
patients have splenomegaly. Hepatomegaly is also common. The WBC count is elevated
in more than 90% of patients, with many having a WBC count greater than 100 × 10 9 per
liter. Anemia and thrombocytosis are usually present. The bone marrow shows
hyperplasia of myeloid cells. Analysis generally shows less than 5% blasts. Cytogenetic
analysis, an examination of the chromosomes in metaphase in the leukemic cells, is
necessary to confirm the presence of the Ph chromosome.3 , 4 , 6
Psychosocial Aspects
CML is usually diagnosed when patients have few symptoms. They will be told that they
have leukemia that is incurable without an AHCT and that the chance of a successful
HCT is greatest if it is performed during the chronic phase and within the first year of
diagnosis. Therefore, at a time in their disease when they are feeling well, patients have
to choose between the possibility of their CML remaining in the chronic phase for 3 to 5
years with a decreased chance of cure or undergoing an early HCT with its attendant
risk of early death but with the chance of cure. If the patient chooses to wait for disease
progression before undergoing HCT, the likelihood of cure with HCT is reduced. Family
members may feel guilty if they are not eligible as bone marrow donors. If the patient
undergoes a HCT and dies from transplant-related complications, the related donor may
feel that he or she contributed to patient harm. Patients who are too old for transplant
or without suitable donors will be faced with the knowledge that the leukemia is
incurable.
Therapeutic Plan
The only curative therapy available for a patient with CML is allogeneic bone marrow or
stem cell transplant. This approach is available only to patients who have a suitable
donor and who are young enough to tolerate the procedure and the subsequent toxic
effects of allogeneic transplant. All patients with chronic-phase CML who are younger
than 50 years of age with a matched sibling donor should undergo HCT. Although the
upper age limit at which a HCT is too dangerous is controversial, it has been advancing
over the years because supportive care has led to improved survival even in older
patients. The decision to perform a HCT in patients older than 50 years of age may be
based on the patient's functional status and overall health and not on age alone.
Treatment decisions are complicated more due to ever increasing treatment options
such as nonmyeloablative preparative regimens and imatinib (see below). The timing of
the transplant is also controversial. Survival is markedly improved if the transplant is
performed during the chronic phase of CML and in the first year from diagnosis.
However, the patient is often asymptomatic or minimally symptomatic during this time,
and it may be difficult for the patient to decide to undergo a life-threatening procedure
when he or she feels well.3 , 4 , 5 , 6
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The patient variables considered in treatment decisions include patient age, patient
functional status, phase of disease (chronic versus blast crisis), and donor availability.
Treatment options include chemotherapy and/or interferon (INF-α), imatinib, AHCT with
a matched sibling donor, AHCT with an unrelated donor, nonmyeloablative AHCT, or
experimental autologous HCT.
Treatment
Chronic Phase
If CML is in the chronic phase and an AHCT is unavailable or inappropriate because of

the patient's age or performance status, the standard treatment options are busulfan,
hydroxyurea, IFN-α, or imatinib alone or in combination with other chemotherapy
regimens. The goal of therapy for CML in the chronic phase is to prolong survival and
minimize symptoms by achieving a complete hematologic response and a complete
cytogenetic response. Complete hematologic response is generally defined as the return
to normal hematologic laboratory values and the absence of any signs or symptoms of
CML. A complete cytogenetic response is the disappearance of the Ph chromosome,
also described as the absence of all Ph-positive metaphases. A partial cytogenetic
response has been variously defined. A useful definition is the presence of the Ph
chromosome in less than 35% of the metaphases.4 Busulfan, hydroxyurea, INF-α, and
imatinib usually provide a complete hematologic response. A cytogenetic response is
rarely, if ever, achieved with busulfan or hydroxyurea. Interferon can provide a complete
cytogenetic response in 9% to 26% of patients and a partial cytogenetic response in
about the same percentage. Imatinib may also produce a complete cytogenetic
response, but the impact on overall survival is still debatable due to the development of
resistance and its potential for making future stem cell transplant less effective.
Busulfan
Busulfan was at one time the most effective agent available for the chronic phase of
CML, but its use has been supplanted by agents with less toxicity and more efficacy.
Busulfan is an alkylsulfonate alkylating agent, which is not cell cycle specific. It is well
absorbed orally. The half-life in adults is 2.1 to 2.6 hours. Busulfan is metabolized in the
liver, and the metabolites are renally cleared. The primary effect at low doses is to
suppress granulocytopoiesis. Busulfan use may lead to a delayed, prolonged, and
profound myelosuppression. This effect requires that patients receiving busulfan be
carefully monitored so that the dose can be decreased or the drug stopped before the
target WBC count is reached. Because blood counts continue to drop after busulfan is
discontinued, the drug must be stopped at about double the desired WBC count to
prevent dangerously low WBC counts. Pancytopenia from busulfan is frequently fatal.
Skin hyperpigmentation is common. An infrequent but serious complication of chronic
busulfan therapy is pulmonary fibrosis. The initial symptoms include fever, dry cough,
and dyspnea. Busulfan should be discontinued while other possible causes of
pulmonary symptoms, such as infection, are ruled out. If the patient is thought to have
busulfan-induced pulmonary dysplasia, further therapy with busulfan is absolutely
contraindicated. No effective treatment for the pulmonary complications of busulfan is
known. The patient may develop pulmonary failure, which usually results in death within
6 months of the onset of pulmonary symptoms. An Addison-like syndrome can rarely
develop with chronic busulfan therapy with symptoms of anorexia, weakness,
hypotension, and fatigue.7 , 8 , 9 , 10
Busulfan is commercially available as 2-mg tablets (Table 93.1). It may be given daily or
intermittently. On the intermittent schedule, the usual dose is 0.1 mg/kg/day orally
(PO).4 Once the WBC count decreases by half, the dose should be reduced by half.
When the WBC count falls below 20 × 10 9 per liter, busulfan should be stopped and
restarted when the WBC rises to 50 × 10 9 per liter. Alternatively, busulfan can be given
as a 4-mg per day dose, holding the dose when the WBC falls below 10 × 10 9 per liter.3
Advantages to the use of busulfan in chronic-phase CML are that it is effective in most
patients in achieving a hematologic remission, it is given orally, it is inexpensive, and it
is generally well tolerated. Busulfan's role in the treatment of chronic-phase CML has
been largely replaced by hydroxyurea, which has fewer side effects, has a dose that is
easier to titrate, and may result in improved survival.
Hydroxyurea
Hydroxyurea is a ribonucleotide diphosphate reductase inhibitor. Ribonucleotide

reductases catalyze the conversion of ribonucleotides to deoxyribonucleotides.
Hydroxyurea may have other mechanisms of action as well. Hydroxyurea is cell cycle
specific for the S phase, causing cell arrest at G 1 to S.7 , 8 , 9 , 10 , 11 Its oral bioavailability
is 73% to 127%.12 , 13 The half-life is about 3.5 to 4.5 hours. Hydroxyurea is hepatically
metabolized and renally excreted. The usual dose is 20 to 30 mg/kg/day or 1.5 to 2 g per
day (Table 93.1). The drug is commercially available in 500-mg capsules and 1,000-mg
tablets. The dose should be adjusted downward for patients with leukopenia or
thrombocytopenia. The primary adverse effect is bone marrow
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suppression. Gastrointestinal effects are uncommon at usual doses.7 , 8 , 9 , 10 , 11
TABLE 93.1 Agents Used in Chronic Myelogenous Leukemia
Summary of Suggested Dosing for Agents Used in CML
Busulfan3,4
Hydroxyurea7,8,9,10,11
Alpha Interferon17,18
Imatinib43,44
4 mg/day PO
20–30 mg/kg/day PO in divided dose (500 mg tid, 1,000 mg bid)
5 million units/m2/day Sq daily
400–800 mg/day PO
CML, chronic myelogenous leukemia; PO, by mouth; tid, three times daily; bid, twice
a day; Sq, subcutaneous.
An unusual and infrequent complication of chronic hydroxyurea use is the development

of cutaneous leg ulcers. The ulcers are usually painful and may be numerous. The
ulcers heal or markedly improve after hydroxyurea is discontinued.14
Hydroxyurea is used in chronic-phase CML to control blood counts. It does not delay or
prevent the transition to blast crisis. It has few side effects, and the dose is easily
titrated. It is preferred over busulfan because of its greater tolerability, no severe
adverse effects, ease of dose adjustment, and it appears to provide a survival
advantage compared to busulfan.15 It may be used as a single agent or combined with
INF-α or other agents.
Interferon-α
INF-α has been found to be useful in patients with CML for inducing a complete
hematologic remission and a major or complete cytogenetic response.16 , 17 Because
INF-α does not benefit all patients, is expensive, and has side effects that may make it
difficult for patients to continue therapy, careful attention to patient selection and
monitoring is important to achieve the best response with the least toxicity.
The side effects of INF-α may decrease the patient's sense of well-being. These side
effects include flu-like symptoms of malaise, fever, chills, and aching. The symptoms
are sometimes relieved by acetaminophen. Tachyphylaxis to these side effects usually
develops within weeks. Anorexia, nausea, and diarrhea are common. Fatigue and
depression may be significant. INF-α should be avoided in patients with clinical
depression.17 , 18
In general, the recommended dose of INF-α is 5 million units/m 2 /day, adjusted to the
patient's tolerance of side effects (Table 93.1). In at least one study, a dose lower than 5
million units/m 2 /day subcutaneously was used and equal efficacy was reported19;
however, other studies have observed a dose-response effect, suggesting a better
response with the standard dose (Table 93.2 lists interferon administration
recommendations).17 , 18
The best time to begin therapy for optimal response is in the early chronic phase when
the patient has more Ph-negative polyclonal hematopoiesis. Most patients achieving a
hematologic response will do so within the first 3 months of therapy. Most patients who
achieve a cytogenetic response will do so within the first 12 months of treatment, but it
may take as long as 18 months.20
For patients with chronic-phase CML, there is an improved 5-year survival rate when
INF-α is used, compared to chemotherapy.20 A comparison of INF-α to busulfan in the
early chronic phase found a 54% predicted survival rate at 5 years for patients receiving
INF-α and a 32% predicted 5-year survival rate for those receiving busulfan.21
In a meta-analysis of seven randomized trials, the 5-year survival rate with INF-α was
57% compared to 42% with chemotherapy.20 However, in some studies, no survival
advantage of INF-α over hydroxyurea was seen. One study found no advantage in
survival for the combination of INF-α and hydroxyurea compared to hydroxyurea
alone.22 Low-dose INF-α (3 million units subcutaneously 5 days/week) was used. The
survival of the INF-α group was similar to that seen in other studies. The hydroxyurea
group showed better survival than that seen in other studies. The German CML Study
Group also found no difference in survival between hydroxyurea and INF-α groups,23
while the Italian Cooperative Study Group found a significant survival advantage with
the use of INF-α.24 A comparison of the German and Italian studies suggested that the
different findings are based on differences of study design and that the combination of
INF-α and hydroxyurea is more effective than either agent used alone.25 The potential
benefits of the combination of INF-α and hydroxyurea include possible additive effects
that may provide a survival advantage and earlier hematologic remission, and therefore,
earlier relief of disease symptoms for the patient. A long-term follow-up of the Italian
Cooperative Study Group reported that the significant improvement in survival seen in
the INF-α study arm compared to the chemotherapy arm was maintained over time. Of
218 patients, 26% achieved a complete or major cytogenetic response. In nine (4%)
patients, the complete cytogenetic response has continued for more than 8 years.26 The
German CML Study Group found that INF-α 5 million units/m 2 /day plus hydroxyurea 40
mg/kg/day was associated with a long-term survival advantage over hydroxyurea
monotherapy in patients with chronic phase CML.27
TABLE 93.2 Recommendations for Interferon Administration
In general, the recommended dose of INF-α is 5 million units/m2/day, adjusted to the

patient's tolerance of side effects.
Try to give the full dose of INF-α if possible, adjusting to patient tolerance, to side
effects, and effect on quality of life.
Begin the INF-α at a low dose for several days to allow the patient time to adjust to the
side effects. A reasonable beginning dose is 3 million units subcutaneously daily, then
increase toward the intended dose.
Add hydroxyurea 0.5–2 g orally daily to decrease the WBC count to 10–20 × 109 per
liter. It is reasonable to continue both agents. If one drug needs to be stopped because
of a low WBC count, discontinue the hydroxyurea before altering the INF-α.
Give INF-α at bedtime.
Instruct the patient to take acetaminophen with each dose to decrease fever and
myalgias.
INF-α, interferon alpha; WBC, white blood cell.
In one study, the combination of low-dose cytarabine and INF-α appeared to increase
survival in patients with chronic-phase CML compared to treatment with INF-α alone.28
The
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dose of INF-α used was 5 million units/m 2 /day, and the dose of cytarabine was 20
mg/m 2 /day for 10 days out of every month. Patients also were given hydroxyurea 50
mg/kg/day until complete hematologic remission was obtained. There was an increase in
hematologic and cytogenetic remissions. However, there were more side effects in the
combination treatment group. Cytarabine contributed thrombocytopenia, nausea,
vomiting, diarrhea, mucositis, weight loss, asthenia, and skin rashes to the usual side
effects of INF-α therapy. About one half of the patients in the study receiving the
combination therapy discontinued treatment because of side effects compared to one
third of patients treated with INF-α alone. Patient quality of life or functional status
between combination therapy and INF-α alone was not compared. Because of the
observed increase in cytogenetic response and improved survival, it is reasonable to
provide combination therapy with low-dose cytarabine and INF-α, despite the increase in
side effects.
TABLE 93.3 Treatment Continuation/Discontinuation Algorithm for Interferon-α

in Patients with Chronic Myelogenous Leukemia
Evaluation
Time from IFN Therapy
Start of IFN-α Patient Characteristics Decision
3 mo Less than or equal to a partial hematologic Discontinue

response and poor pretreatment risk factors IFN-α
(splenomegaly ≥5 cm below the costal margin
or pretreatment platelet count ≥700 × 109/L)

response and poor pretreatment risk factors IFN-α
Complete hematologic response, no cytogenetic Continue IFN-α
response, and no pretreatment risk factors
or
Complete hematologic response, no cytogenetic
response, and poor pretreatment risk factors

response IFN-α
or May offer to
Complete hematologic response, no cytogenetic continue IFN-α
response, and poor pretreatment risk factors for 6 mo
Complete hematologic response, no cytogenetic

response, and no poor pretreatment risk factors
It appears that INF-α probably prolongs the survival of patients who achieve a major
cytogenetic response. However, it may take more than 12 months for the cytogenetic
response to occur, and it would be useful to be able to make an early prediction about
which patients are likely to eventually respond to continued INF-α therapy. Some
investigators have attempted this. Preliminary guidelines based on a large, single-
institution study have been developed (Table 93.3).29 The authors recommend that INF-α
therapy should be continued in patients who have more than a 10% chance of achieving
a major cytogenetic response if an allogeneic transplant is not available to them. They
found that pretreatment risk factors for a low chance of response are a spleen size more
than 5 cm below the costal margin and platelet count greater than 700 × 10 9 per liter.
The decision algorithm appears to be fairly complex. At 3 months, interferon should be
discontinued in patients who achieve no better than a partial hematologic response and
have pretreatment
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risk factors (splenomegaly or thrombocytosis). At 6 months, patients with a complete

hematologic response and a minor cytogenetic response have a 60% chance of
achieving a major cytogenetic response. Patients with a complete hematologic response
and no cytogenetic response and no pretreatment risk factors have a 38% to 45%
chance of achieving a major cytogenetic response. Both of these groups should
continue INF-α therapy. Patients with no cytogenetic response at 6 months and
pretreatment risk factors of thrombocytosis or splenomegaly have a less than 10%
chance of achieving a major cytogenetic response. INF-α should be stopped and other
treatment options offered. At 12 months, if patients with pretreatment risk factors have
no cytogenetic response, INF-α therapy should be stopped. However, patients with no
cytogenetic response at 12 months, but with a complete hematologic response and no
pretreatment risk factors, have a 16% to 26% chance of achieving a major cytogenetic
response and can be offered INF-α therapy for another 6 months. It is believed that
achieving a major cytogenetic response confers a survival advantage.17
These findings have been supported by a single institution trial reporting that failure to
have a hematologic response at 3 months predicted a low probability of a cytogenetic
response to INF-α and that a major or complete cytogenetic response to INF-α is
associated with prolonged survival.30
It is not known if patients with a long-term complete cytogenetic response from INF-α
can be considered cured. Patients may have no detectable Ph chromosome, yet still
have residual BCR-ABL transcript. The absence of the BCR-ABL transcript is a

molecular complete remission, which may be associated with a decreased relapse
rate.31 Molecular complete remissions have been observed in recipients of HCTs. There
are some patients with a long-term complete cytogenetic response from INF-α who also
have been observed to have nondetectable BCR-ABL.27 , 32 It is possible that these
patients have been cured of CML without a HCT, but further follow-up is required.
The cost-effectiveness of INF-α has been determined by two investigators.32 , 33 For a

therapy to be considered worthwhile, the marginal cost-effectiveness should be less
than $50,000 per quality-adjusted life year (QALY). One trial found the marginal cost-
effectiveness to be $34,800 per QALY saved.33 The model used $1,500 as the estimated
drug cost for INF-α for 1 month at a dose of 5 million units/m 2 /day. A second trial
estimated the marginal cost-effectiveness to be $89,500 or $63,000 per QALY saved,
depending on the scenario.34 The authors estimated the monthly cost of INF-α to be
$2,750 for a mean dose of 8 million units/m 2 /day. In the second analysis, therefore, INF-
α was not found to be a cost-effective therapy. Both groups of authors reported that the
models are most sensitive to manipulation of drug cost.
Imatinib
Imatinib is a tyrosine kinase inhibitor that shows promise in CML. The BCR-ABL
transcript of CML has tyrosine kinase activity, which is necessary for its ability to
cause leukemic transformation. Imatinib is an ABL protein tyrosine kinase inhibitor.
Imatinib is available as 100-mg PO capsules or 400-mg PO tablets. The parent compound
has a half-life of 18 hours, while its active N-demethyl metabolite has a half-life of 40
hours. It is primarily metabolized by CYP 3A4 enzymes. Imatinib is also a potent CYP3A4
inhibitor, and interactions with other drugs must be considered. Significant side effects
include neutropenia, fatigue, fluid retention, dermatologic reactions, nausea, vomiting,
and muscle cramps.35 A phase I study showed that patients with chronic phase CML,
who had failed treatment with interferon, demonstrated a 98% (53/54) hematologic
response rate for 4 weeks.36 In a phase II trial, 532 patients who had failed interferon
were placed on imatinib 400 mg PO once daily. Complete hematologic response was
found in 95% of patients and 60% had a major cytogenetic response.37
The International Randomized study of Interferon and Imatinib compared imatinib 400
mg PO daily versus interferon 5 million units/m 2 /day + cytarabine 20 mg/m 2 /day × 10
days every month in 1,106 newly diagnosed patients. The imatinib arm showed
significance in all end points including complete hematologic response (97% vs. 69%),
major cytogenetic response (87% vs. 35%), and complete cytogenetic response (76% vs.
14%).38 Long-term survival benefits have recently been shown in follow-up studies. In
newly diagnosed patients, survival was estimated at 15.3 years in patients who were
treated with imatinib versus 9.07 years in those who received interferon and
cytarabine.39 One study looked at 261 patients who had failed interferon therapy and
were subsequently treated with imatinib. After a median follow-up of 45 months, 73%
had a major cytogenetic response and 63% had a complete cytogenetic response, and an
estimated 4-year survival of 86%.40
Although the current recommended dose of imatinib for chronic phase CML is 400 mg
per day (Table 93.1) and 600 mg per day for CML in transformation, some studies
suggest that a higher starting dose of imatinib 400 mg twice a day may offer better
disease control and a reduction in the emergence of imatinib-resistant CML clones.41
Higher doses lead to earlier and more profound reduction in the BCR-ABL transcript
levels, which was associated with a higher probability of progression free survival.42
Newer studies will better determine the role of a higher dose imatinib. In addition, there
are new tyrosine kinase inhibitors in phase II and early phase III trials. These “super
imatinibs” are approximately 100 times more potent than imatinib.
Accelerated Phase
Patients with CML in the accelerated phase have a 6- to 18-month average survival.
There is no standard therapy for accelerated-phase CML. The treatment goal is to
provide symptom palliation and a return to chronic-phase CML. Generally, each patient
must be assessed and treated with an individualized treatment plan that is modified for
disease response and patient tolerance. A patient with accelerated-phase CML has
circulating blasts, and these blasts can be
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immunophenotyped to determine if the CML is transforming into a myeloid or lymphoid

blast crisis phase with associated development of AML or ALL. The patient may then
receive treatment appropriate for the associated acute leukemia. Imatinib has been used
in patients with accelerated phase CML with modest results. One study evaluating 200
patients showed a clinical response of 90% and a complete cytogenetic response in
24%.43 Patients receiving a HCT during the accelerated phase have a much lower
survival rate than during the chronic phase.
Blast Phase
Patients with blast-phase CML have an expected average survival of 2 to 3 months. The
goal of treatment is to provide symptom palliation and a return to chronic-phase CML.
Patients should be managed with therapy for acute leukemia. Many patients have
disease that is resistant to this therapy. Patients with a lymphoid blast crisis are more
likely to respond than patients with a myeloid blast crisis. HCT during a blast crisis
provides a 0% to 20% chance for long-term survival. For some patients with blast-phase
CML, a second chronic phase may be achieved, in which case a HCT should be
performed if there is an available donor. Patients in blast crisis may benefit from
imatinib. One study looking at 260 patients with CML in blast crisis, demonstrated a 52%
hematologic response while on 400 to 600 mg of imatinib. In addition, 31% of patients
had a sustained response for at least 4 weeks and 8% had a complete hematologic
response.44
Bone Marrow Transplant
Allogeneic Hematopoietic Cell Transplant
AHCT has the potential to cure CML and is the treatment of choice for young patients
with chronic-phase CML. A human leukocyte antigen (HLA)-matched sibling donor is
available for only 20% to 25% of patients with CML. HLA matching helps determine the
chance of acceptance of the donor cells by the recipient. A matched HLA sibling donor
has the highest chance of success, however, if a HLA-matched sibling is not available, a
matched unrelated donor may be used, but with a higher risk of rejection. The
probability of long-term survival for patients receiving a HCT in the chronic phase is
60% to 80%, but it is less than 20% for patients in blast crisis. Survival outcomes
appear to be more favorable if the patient receives a HCT within 1 year of diagnosis.
Younger patients have better outcomes, but the upper age limit is controversial and is
advancing as supportive care improves.2
A retrospective study compared survival after HLA- identical AHCT versus treatment
with INF-α or hydroxyurea. The group included patients from 15 to 55 years of age. The
study described better survival with INF-α or hydroxyurea in the first 18 months from
diagnosis. Survival figures for the HCT group did not surpass those of the
hydroxyurea/INF-α group until 5.5 years from the initial diagnosis. If HCT was delayed
for more than 1 year after diagnosis, the survival advantage from HCT decreased. At 7
years, the survival probability in the transplant group was 58% and in the
hydroxyurea/INF-α group the survival probability was 32%.45 Table 93.4 shows the
recommendations for stem cell transplantation by age. The usual preparative regimens
(treatment that the patient receives prior to transplant) for HCT in patients with CML are
cyclophosphamide and total body irradiation or cyclophosphamide and busulfan.
Modified preparative regimens with less toxic effects and equal efficacy continue to
show promise in reducing the mortality from HCT, making it available to an older age
group.46
Unrelated Donor Hematopoietic Cell Transplant
The use of unrelated bone marrow donors for HCT carries increased risk for the patient.
More failure to engraft the new marrow is seen, and graft-versus-host disease (GVHD)
occurs more frequently and is more severe. Because of the increased risk with
unrelated donor HCTs, the decision to perform this type of transplant in a patient with
CML who is feeling well can be difficult.47 , 48
Most recommendations for unrelated donor transplants for CML have included an upper
age limit for patients of 35 to 45 years. It is possible that this age limit may be raised. A
review of unrelated donor transplants for CML showed a 74% 5-year survival rate for
patients younger than 50 years who received matched unrelated donor transplants
within the first year of diagnosis.48 This high survival rate may reflect improved
supportive care, including antiviral and antifungal prophylaxis.
A decision analysis for unrelated donor HCT compared transplant within the first year
from diagnosis (early transplant), delayed transplant, and no transplant.47 The study
concluded that unrelated donor transplant performed within the first year was superior
in quality-adjusted expected survival to no transplant, but that it takes 4 years before
survival for patients receiving an early transplant is improved over that for patients with
no transplant. Delayed transplant (i.e., transplant later than 1 year from diagnosis) also
showed increased quality-adjusted expected survival compared to no transplant,
although it took 6 years to realize this difference.
A model of the cost-effectiveness of unrelated donor HCT compared to therapy with INF-
α or hydroxyurea has been developed.49 Compared to INF-α therapy, the cost-
effectiveness ratio for an unrelated donor HCT is $51,800 for each QALY gained and
compared to hydroxyurea it is $55,000. When the model parameter estimates were
manipulated to simulate changes in clinical scenarios, the cost-effectiveness ratio
ranged from $32,600 to $126,800 QALY. The authors concluded that while unrelated
donor HCT is very expensive, it is cost-effective for a carefully selected patient
population in whom it can significantly prolong life.
A patient with chronic-phase CML who is younger than 50 years old and who lacks a
matched sibling donor should be offered a matched, unrelated donor transplant, if a
donor is available, and the institution is experienced in performing unrelated donor
marrow transplants. Older patients in the same situation should be given a trial of
imatinib. Alternatively,
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nonmyeloablative HCT regimens may be considered (see below).
TABLE 93.4 Summary of Treatment Options: Chronic Myelogenous Leukemia
Treatment Options for CML Chronic Phase
Young (< 50)
Option 1 Option 2
HLA-matched sibling HSCT (Patients Imatiniba

may be started on imatinib while If no response to imatinib, consider
searching for donor) HLA-matched sibling donor
If no HLA-matched sibling donor, a MUD If no HLA-matched sibling donor, a
should be considered MUD should be considered
If no response to transplant, consider If no response to transplant, consider
experimental agents. experimental agents.
Age 50–60
Option 1 Option 2
HLA-matched sibling HSCT (Patients Imatiniba

may be started on imatinib while If no response to imatinib, consider
searching for donor) HLA-matched sibling donor
If no response to HLA-matched If no response to HLA-matched
transplant, consider experimental agents transplant, consider experimental
agents
MUDs are usually not recommended for patients over the age of 50, however, a
nonmyeloablative transplant may be indicated.
Older(> 60)
Option 1 Option 2
Nonmyeloablative transplant Imatinib

If no response to transplant, consider If poor response, consider
experimental agents nonmyeloablative transplant or
experimental agents
aFirst-line treatment will depend on age of patient, staging of disease (chronic, acute,
blast), and availability of HLA-matched donor. First-line therapy is still controversial.
Recent data suggest that imatinib should be first-line therapy, however there is still no
long-term survival data, curative ability is still unknown and there is a concern
regarding resistance.
CML, chronic myelogenous leukemia; HLA, human leukocyte antigen; HSCT,
hematopoietic stem cell transplant; MUD, matched unrelated donor.
Nonmyeloablative Hematopoietic Cell Transplant
An important change in the philosophy of preparative regimens for allogeneic transplant

is the realization that ablative regimens may not be absolutely necessary. Engraftment
can be accomplished by using less intensive and toxic regimens. This translates into a
decrease in treatment related mortality, which has been the major concern for patients
older than 50 years of age.50 Nonmyeloablative regimens rely more on the graft versus
leukemic effect than the cytotoxic effects of the traditional preparative regimens.
Experience is limited, and more trials are warranted.
Relapse After Hematopoietic Stem Cell Transplant
Relapse after HCT may be hematologic or cytogenetic. It is common for the Ph

chromosome to be detectable for several months after the transplant. This does not
necessarily herald relapse. The persistence of the Ph chromosome for more than 6
months after transplant, the reappearance of the Ph chromosome after it has
disappeared, or a rising proportion of Ph-positive metaphases are triggers to begin
therapy for relapse. Several approaches that have been successful for treating CML
relapse after HCT are donor lymphocyte infusion (DLI), and the use of INF-α or imatinib.
DLI appears to be more effective in eradicating the Ph chromosome compared to INF-α;
however, there is significant toxicity in the form of loss of engraftment or severe GVHD,
with as much as a 20% mortality rate. INF-α appears to provide cytogenetic remission in
a significant number of patients with cytogenetic relapse, without causing life-
threatening toxic effects.51 , 52 A reasonable strategy may be to offer INF-α therapy to
patients with cytogenetic relapse, and if they do
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not have remission within 1 year, to offer DLI. Patients with hematologic relapse may
receive either INF-α or DLI. There may be a role for combination therapy using a
modified dose of DLI and INF-α.52 There are also reports of patients who have failed
INF-α and DLI who have responded to imatinib. Twenty-eight patients with CML, who
relapsed after an allogeneic stem cell transplant, were placed on 400 to 1,000 mg
imatinib daily. The overall response rate was 79% with a 35% complete cytogenetic
response rate. The 1-year survival rate was 74%.53
Autologous Hematopoietic Stem Cell Transplant
It may be possible to obtain long-term survival in patients by using an infusion of Ph

chromosome-negative autologous peripheral blood progenitor cells.54 Some
investigators have reported that treatment in the early chronic phase, before initiation
of INF-α therapy, may allow for collection of more Ph-negative stem cells. In one study,
patients received a course of intensive conventional chemotherapy, followed by
granulocyte colony-stimulating factor. Peripheral blood progenitor cells were pheresed
(removed) when blood count results were beginning to improve. These patients then
received preparative regimens of high-dose chemotherapy with or without total body
irradiation, followed by infusion of the previously mobilized stem cells. Half of the
patients achieved Ph-negative marrow, but follow-up has been short.55 With AHCT, the
duration of remission seems to depend on the graft-versus-leukemia (GVL) effect. With
the GVL effect, the donor hematopoietic cells recognize persistent leukemia cells as
foreign and act to eradicate them. This effect is absent in autograft recipients. It may be
necessary to provide posttransplant maintenance therapy such as INF-α to patients
receiving autografts. Autografting may prove useful for patients without matched
donors or who are outside the age limit to tolerate allogeneic grafting. This procedure is
investigational and should be performed in the context of a clinical trial.
Hematopoietic Stem Cell Versus Imatinib
To date, only an allogeneic hematopoietic stem cell offers cure to a patient with CML,
however data from imatinib is revolutionizing treatment. Data suggests quick and
reliable decreases in surrogate markers traditionally associated with outcomes in
patients treated with interferon, but not yet proven with imatinib.56 Long-term outcomes
are unknown in patients treated with imatinib alone. Currently, there are two approaches
to the management of a newly diagnosed CML patient: (a) to offer a trial of imatinib and
offer a hematopoietic stem cell transplant to those who fail imatinib treatment, or (b) to
continue to discuss transplant up front to those for whom a more aggressive therapy is
thought to be appropriate.57
Chronic Lymphocytic Leukemia
CLL is a slowly progressing leukemia that may be quiescent for years and occurs
primarily in older adults. It is not curable, but in many patients does not decrease
survival compared to the normal population. Therefore, CLL is usually not treated
unless the patient is symptomatic or the rate of disease progression increases.
CLL is a malignancy of monoclonal small mature lymphocytes that have prolonged

survival and which proliferate and accumulate in the blood, bone marrow, lymph nodes,
spleen, and liver. Ninety-five percent of patients have B-cell CLL and 5% have T-cell
CLL.
Treatment Goals: Chronic Lymphocytic Leukemia
The treatment goal is to prolong survival and palliate disease symptoms, while
maintaining good quality of life.58 There is no known curative therapy for CLL.
Aggressive therapy with HCT may be an appropriate consideration in younger patients
with risk factors for poor survival, but this approach is investigational.
Epidemiology
The cause of CLL is unknown. Radiation and drug exposure do not seem to be risk
factors. There may be an increased risk with industrial exposure for agricultural and
asbestos workers.59 CLL is primarily a disease of older adults, and its incidence
increases with age. The median age at diagnosis is 65 years.58 More men than women
are affected by a ratio of about 2:1. CLL is the most commonly occurring leukemia in
Western Europe and North America, but it is uncommon in Japan and China. Immigrants
from Japan to the West do not acquire an increased risk for the disease.59
Pathophysiology
CLL may result from a mutational change that prevents normal programmed cell death
(apoptosis), rather than from increased cell proliferation.60 It is speculated that a
normal
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CD5-positive lymphocyte is transformed via multiple mutational steps into a monoclonal

leukemic cell line that lacks normal apoptotic mechanisms, which then accumulates.58
Most CLL cells (about 95%) are in the quiescent G 0 stage of the cell cycle. Symptoms of
CLL arise from accumulation of leukemic lymphocytes in organs and tissues and from
immune dysfunction.
Clinical Presentation and Diagnosis
Signs and Symptoms
Patients are often asymptomatic at diagnosis, with the diagnosis being made when a
routine complete blood count is done. Patients with symptoms may report typical “B”
symptoms of weight loss, fever, fatigue, and night sweats. They may experience early
satiety or a feeling of abdominal fullness from splenomegaly or hepatomegaly. They may
notice enlarged lymph nodes and may report frequent infections.
TABLE 93.5 Staging Systems Used for Chronic Lymphocytic Leukemia
Survival
Percentage of 10-
Patients With Median Year
System and Risk Stage Definition CLL in Stage (yr) (%)
Rai staging system
Low 0 Lymphocytosis only 31 <10 59
Intermediate I Lymphocytosis and 35 9

lymphadenopathy
II Lymphocytosis and 26 5 10
splenomegaly with or
without lymphadenopathy
or hepatomegaly
High III Lymphocytosis and 6 2 10

anemia, with or without
organomegaly
IV Lymphocytosis, anemia, 2 2 10
and thrombocytopenia,
with or without
organomegaly
Binet staging system
Low A Lymphocytosis, with 63 <10 51

enlargement of > lymphoid
areasa
A' Stage A with lymphocyte 49 <10 56

count of ≥30,000/mm3 and
hemoglobin concentration
of ≤120 g/L
A′ Stage A with lymphocyte 14 7 38

′ count of <30,000/mm3,
hemoglobin concentration
of >20 g/L, or both
Intermediate B Lymphocytosis, with 30 5

enlargement of ≥ lymphoid
areas
High C Lymphocytosis and 7 2

anemia, or
thrombocytopenia, or both
a The following lymphoid areas are included: cervical, axillary, and inguinal
(unilateral or bilateral), spleen, and liver.
Diagnosis
The diagnosis of CLL is based on an absolute lymphocyte count in the blood of 5 × 10 9

per liter. The leukemic cells are normal-appearing small mature lymphocytes. They have
monoclonal expression of either κ or λ light chains. There is a smaller than normal
amount of surface immunoglobulin.61 B lymphocytes in CLL express surface antigens
CD5, CD19, CD20, and CD23. If a bone marrow aspirate and biopsy are performed, more
than 30% of nucleated cells must be lymphoid for a diagnosis of CLL.
There are two staging systems for CLL: (a) the Rai system62 and (b) the Binet system.63
The Rai system is used primarily in the United States and the Binet system is used
mostly in Europe. Both systems are useful and either can be applied. The two systems
stage CLL based on evidence of lymphocyte infiltration into tissue and organs and on
evidence of impaired bone marrow function, as seen by anemia or thrombocytopenia.
Patients with low-risk disease exhibit lymphocytosis only and have a median survival of
longer than 10 years. Patients with high-risk disease have lymphocytosis with anemia or
thrombocytopenia and have a median
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survival of 2 years (Table 93.5).64 One useful prognostic indicator is lymphocyte

doubling time. A lymphocyte doubling time of less than 1 year is associated with a much
worse prognosis. The typical patient with CLL usually develops a higher stage of
disease slowly over several years. The patient then requires more treatment, and the
treatment gradually needs to be more aggressive to control symptoms, bringing with it
more side effects of therapy.
In a small percentage of patients CLL may transform abruptly into a large-cell non-
Hodgkin lymphoma that is resistant to treatment. This is called Richter transformation
or Richter syndrome. The patient will have fever, increased lymphadenopathy, a rising
LDH level, and widespread tissue infiltration of lymphoma cells. It occurs in 3% to 15%
of patients with CLL. Few patients with Richter transformation survive longer than 6 to 8
months. There is controversy over whether the lymphoma arises from the original
malignant clone or is from a separate, distinct clone. It appears that the lymphoma
arises from the original clone in at least two thirds of patients.59 , 65
Patients with CLL may develop autoimmune reactions against hematopoietic cells.
Autoimmune hemolytic anemia is estimated to occur in 5% to 37% of patients with
CLL.66 Pure red cell aplasia may be present in 6% of patients. Idiopathic
thrombocytopenia occurs in 2% to 3% of patients. The cause of the autoimmune
dysfunction is not well understood.
The immune dysfunction seen in patients with CLL contributes significantly to the
morbidity of the disease. The mechanism for the immune dysfunction is multifaceted
and includes impairment in humoral and cell-mediated immune function.67 The
malignant CLL B-cell functions poorly as an antigen-presenting cell. The B-cell to T-cell
interaction is weakened. There are a decreased number of normal B-cells, and their
immune function may be down regulated by cytokine production from the malignant B-
cell clone. This may contribute to the low levels of immunoglobulin usually seen in
patients with CLL. T cells in patients with CLL may be anergic. Natural killer (NK) cells
have a decreased ability to become activated and to lyse target cells. NK cell mediation
of antibody-dependent cell-mediated cytotoxicity is decreased. There is a proposed
mechanism in which the dysfunction of the NK cells and T cells in patients with CLL
may lengthen the survival of the malignant B-cell clone and so contribute to the
progression of the disease.
Infectious complications are a major manifestation of the immune dysfunction seen in

CLL. The majority of deaths in patients with CLL are actually due to bacterial infections.
The usual infecting organisms are Staphylococcus aureus, Streptococcus pneumoniae,
Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas
aeruginosa. With the recent increased use of purine analogs such as fludarabine,
cladribine, and pentostatin, new pathogens have been observed.68 These include
Listeria sp, Pneumocystis carinii, Mycobacterium tuberculosis, Nocardia sp, Candida
sp, Aspergillus sp, and herpes viruses. The risk for these infections increases if the
patient receives corticosteroids concurrently or before purine analog therapy.69
Psychosocial Aspects
Patients may be told that they have incurable leukemia and that they do not need
treatment. This confuses most patients. Patients with low-stage disease may have no
symptoms or have symptoms that are controlled with an oral medication taken once or
twice a month. The change to a more aggressive disease will develop gradually, usually
over several years. The patient is usually elderly and may have other medical problems,
some of which may be more life threatening or may affect the person's quality of life
more distinctly than does CLL. If the patient is young with high-risk disease, he or she
may be faced with a choice between a HCT with its multiple risks, which has not yet
been shown to improve survival, but may ultimately control the leukemia, or standard
therapy, which is usually well tolerated, but does not prolong survival.
Treatment
Patients with CLL are usually only treated if they develop uncomfortable symptoms,
such as increasing adenopathy, or constitutional symptoms, such as fatigue and weight
loss, develop significant anemia or thrombocytopenia, or show evidence of more rapid
disease progression, such as a lymphocyte doubling time of less than 1 year.
Pharmacotherapy
Alkylating Agents
When the decision is made to treat a patient with CLL, the initial therapy is usually
chlorambucil, an oral alkylating agent. It may be given at 0.1 mg per kilogram daily, or
at 4 mg per kilogram every 2 to 4 weeks, or as a 0.7 mg per kilogram total dose over 4
days every month (Table 93.6). It is available as a 2-mg tablet and is well absorbed
orally. Chlorambucil is hepatically metabolized with hepatic and renal clearance of the
metabolites. The half-life
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is 2 to 8 hours. The dose is adjusted for disease response and myelosuppression.

Chlorambucil is well tolerated and has mild side effects other than myelosuppression.
The use of chlorambucil in patients with CLL does not prolong survival, but does
control disease symptoms. It has been shown to be as effective as more aggressive and
more toxic combinations of chemotherapy such as cyclophosphamide, vincristine, and
prednisone (CVP) or cyclophosphamide, melphalan, and prednisone.70 , 71 , 72 No
advantage has been found for starting chlorambucil therapy in patients in the early
stage of disease.64 Prednisone may be added to chlorambucil at a dose of 40 mg/m 2 /day
PO for 5 days every month. Other schedules have also been used. The addition of
prednisone to chlorambucil does not prolong survival, but may increase symptom
improvement in lymphadenopathy and splenomegaly. It appears to have particular value

in patients who have immune-mediated anemia or thrombocytopenia. Because of
emerging evidence suggesting that prior steroid therapy may contribute to the risk of
opportunistic infection in patients who eventually receive one of the purine analogs,
such as fludarabine, an attempt should be made to limit the use of prednisone to those
patients who show response of CLL-related anemia or thrombocytopenia to steroid
therapy. Cyclophosphamide, another alkylating agent, appears to have efficacy similar
to that of chlorambucil. The usual dose is 1 to 2 mg/kg/day. There is no clear advantage
when cyclophosphamide is given in combination with other chemotherapy agents
compared to chlorambucil alone.
TABLE 93.6 Agents used in Chronic Lymphocytic Leukemia
Summary of Suggested Dosing for Agents Used in CLL
Chlorambucil59 0.1 mg/kg/day PO

Cyclophosphamide73 1–2 mg/kg/day PO
Fludarabine74 25 mg/m2/day IV over 30 minutes × 5 days every 4 weeks
0.1 mg/kg/day continuous IV infusion over 24 hours,
Cladribine83
375 mg/m2/day IV once every 4 weeks
Rituximab92 Dose escalation to 30 mg IV three times weekly for 16 weeks
Alemtuzumab95
CLL, chronic lymphocytic leukemia; PO, by mouth, IV, intravenously.
The alkylating agent (chlorambucil or cyclophosphamide) is usually continued until the

patient's symptoms have responded and no additional improvement is seen or until the
patient experiences myelotoxicity.73 The drug can then be stopped. If the patient's
disease symptoms recur or worsen after therapy is discontinued, it is reasonable to
renew treatment with the same agent. If the disease progresses while the patient is
receiving therapy, the alkylating agent should be discontinued, and another agent, such
as a purine analog, should be started.
Purine Analogs
Three purine analogs that have shown efficacy in CLL include (a) fludarabine, (b)
cladribine, and (c) pentostatin. The most experience is with fludarabine. It has been
approved for use in the treatment of CLL refractory to alkylating agents. Cladribine has
also been shown to be effective for this indication. Pentostatin has not been used as
extensively, and may be less effective than fludarabine or cladribine in the treatment of
CLL. There appears to be cross-resistance between fludarabine and cladribine. A patient
whose disease is refractory to one of these agents is unlikely to respond to the other.
Fludarabine phosphate is a water soluble analog of adenosine and a fluorinated analog

of the antiviral drug, vidarabine. It is resistant to adenosine deaminase. Fludarabine is
first dephosphorylated to 2-fluoro-ara-adenine, and is then converted intracellularly to
2-fluoro-ara-adenosine triphosphate (ATP), which is the active form. It inhibits DNA
polymerase, and ribonucleotide reductase. Fludarabine is also effective against the
nonproliferating cells of CLL, possibly by inducing apoptosis. The half-life of 2-fluoro-
ara-adenine is about 10 hours, with a clearance of 8.9 L/hr/m 2 and a volume of
distribution of 98 L/m 2 .74 Fludarabine is primarily cleared renally, and the dose should
be adjusted for renal impairment, although exact guidelines are not available. The usual
dose for the treatment of B-cell CLL is 25 mg/m 2 /day intravenously (IV) over 30 minutes
daily for 5 days every 4 weeks (Table 93.6). The drug should be continued for three
cycles after the maximal response has been achieved.8 , 9 , 75 It should be discontinued
for disease progression or for the development of hemolytic anemia. The usual and
expected side effect is myelosuppression, which may be cumulative. Following
fludarabine, colony-stimulating factors may be useful in reducing the
myelosuppression, allowing for the administration of fludarabine therapy to continue as
planned. The use of colony-stimulating factors may also decrease infections.76 At high
doses of fludarabine, severe irreversible neurotoxicity has been observed, but these
doses are no longer used.77 Rarely, patients may develop interstitial pneumonitis.
Opportunistic infections are common, especially in patients who have had extensive
prior therapy or have received steroids. Patients may even develop infections after the
first dose of fludarabine without a history of corticosteroid use.78 Patients should be
carefully monitored for infection, and care must be taken not to miss infections such as
P. carinii pneumonia (PCP), listeriosis, tuberculosis, herpes infections, and Candida or
Aspergillus infections.79 , 80 Consideration should be given for the use of PCP
prophylaxis in all patients receiving fludarabine. It should be required in patients with
CLL who have a current or previous history of corticosteroid use. The role for
prophylaxis against herpes and fungal infections has not been determined.
There may be an increased risk of hematologic immune manifestations such as

hemolytic anemia in fludarabine-treated patients. Although hemolytic anemia is common
in patients with CLL, the purine analogs appear to further promote its occurrence. A
causal relationship has not been firmly established. Most patients with fludarabine-
associated hemolytic anemia have a recurrence if the drug is given again, which carries
a high risk of mortality. Patients who develop hemolytic anemia with any of the purine
analogs should not receive further therapy with any drug in this class.80 , 81
In previously treated patients with high Rai-stage disease, the response rate to
fludarabine is 31% to 36%.82 The response rate is improved in patients who receive
fludarabine as first-line therapy and has been reported to be as high as 78% in one
series.83 Although fludarabine is effective in achieving a response, there is no evidence

that its use as first-line therapy instead of chlorambucil improves overall survival. It is
also unknown if there are quality of life differences between treatment with
chlorambucil and fludarabine regimens.
Cladribine is a chlorinated analog of adenosine. It is resistant to adenosine deaminase.

Deoxycytidine kinase phosphorylates cladribine intracellularly to 2-Cd-adenosine
monophosphate (2-Cd-AMP), which is then converted to 2-Cd-ATP.
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2-Cd-AMP is incorporated into DNA. 2-Cd-ATP inhibits ribonucleotide reductase.

Cladribine also shows activity in resting cells by depleting nicotinamide adenine
dinucleotide levels. Ultimately, the activity of cladribine results in apoptosis, even in
quiescent lymphocytes.8 , 9 The half-life is 5 to 6 hours; plasma clearance is about 980
mL/hr/kg, with a large amount of variability. The volume of distribution is about 9 L per
kilogram. It is not known how cladribine is cleared from the body, but there is some
renal clearance. Although approved for use in hairy cell leukemia where it is the drug of
choice, it has also shown substantial activity in CLL.84 , 85 The usual dose is 0.1
mg/kg/day as a continuous IV infusion daily for 7 days every 4 weeks (Table 93.6). Other
similar schedules have been used in clinical studies with a usual maximum dose of 0.7
mg per kiolgram per cycle (e.g., 0.12 mg/kg/day IV over 2 hours daily for 5 days).86
Bone marrow suppression is the usual and expected side effect. As with fludarabine,
infections are a common occurrence, and patients should be monitored closely. Fever,
even without infection, is common. Nausea may occur, but it is usually mild. High doses
of cladribine, which are not in clinical use, have produced neurotoxicity. Immune
hematologic effects have occurred with the use of cladribine in patients with CLL.
Cladribine has been associated with an increased risk of hemolytic anemia, which may
be fatal.87 If hemolytic anemia develops while the patient is receiving therapy, the drug
should be discontinued, and the patient should not be given additional therapy with
cladribine or another purine analog. If the patient has a history of disease (CLL)-related
autoimmune hemolytic anemia, it is appropriate to attempt therapy with a purine analog,
as some patients have shown resolution of disease-related autoimmune hemolytic
anemia when treated with fludarabine or cladribine. At this time, pentostatin for CLL
should be reserved for use in the context of a clinical trial.
Therapy for patients with CLL for whom treatment is indicated should begin with
chlorambucil. If the patient has a good performance status and is young, the use of
fludarabine as first-line therapy may be considered because it may provide a higher
response rate and a longer remission. However, it has more severe and dangerous side
effects, requires IV administration, and is expensive compared to chlorambucil. It is not
known if fludarabine improves survival compared to chlorambucil. If a patient receiving
chlorambucil fails to respond or has disease progression, the patient should be treated
with fludarabine or cladribine, because these agents are less toxic than combination
therapy such as cyclophosphamide, doxorubicin (Adria), and prednisone (CAP) or

cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), and prednisone (CHOP)
and may be more effective.88 At this time, fludarabine should probably be chosen over
cladribine for CLL, as their efficacy and safety profile are similar, but fludarabine is
approved for the indication, is easier to administer, and is less expensive. If a patient
fails to respond to a purine analog or shows disease progression while receiving
therapy, combination therapy such as CHOP may be considered. Careful consideration
must be given to the patient's quality of life and performance status before initiating
therapy that will not prolong survival and that has significant toxic effects in elderly,
heavily pretreated patients.
Intravenous Immunoglobulin
Hypogammaglobulinemia is a frequent finding in patients with CLL and may contribute

to the incidence of bacterial infections. The administration of IV immunoglobulin was
found to reduce the incidence of bacterial infections but not to prolong survival. The
study used immunoglobulin 400 mg per kilogram IV every 3 weeks. A lower dose may
also provide a similar benefit. In general, IV immunoglobulin is not recommended as
standard therapy for patients with CLL. It may be appropriate in a patient with advanced
disease and low immunoglobulin levels who has frequent bacterial infections requiring
hospitalization.89 IV immunoglobulin may be useful in the management of autoimmune
hemolytic anemia. One recommended dosing schedule is 400 mg/kg/day IV for 5 days,
repeated as needed.90
Monoclonal Antibodies
Rituximab
Monoclonal antibodies have been used for the treatment of CLL. Rituximab is a
monoclonal antibody against cell surface antigen CD20. It is currently approved for the
treatment of B-cell non-Hodgkin lymphoma, but has also been used for a variety of
CD20-positive B-cell lineage tumors. Studies have looked at rituximab in previously
untreated CLL91 and relapsed or refractory disease.91 Although there are no
randomized comparative trials, initial reports indicated a reasonable response rate with
rituximab (51%)90 compared to treatments with fludarabine(63%),86 and with less
toxicities. More recently, the combination of fludarabine with rituximab given
concurrently or sequentially was found to prolong progression free and overall survival
in previously untreated CLL.91 Generally, rituximab is well tolerated, however, there
have been reports of deaths, hypotension, and tumor lysis syndrome with the use of
this agent.92 , 93 This happens more often with the initial dose of rituximab. It is
recommended that patients be premedicated with acetaminophen and diphenhydramine
prior to each infusion to minimize risk. For rituximab dosing refer to Table 93.6. Overall,
rituximab may have a role in the treatment of CLL patients who cannot tolerate
traditional chemotherapy.
Alemtuzumab
Alemtuzumab is a human anti-CD52 monoclonal antibody. CD52 antigen is expressed on

the surface of more than 95% of human B and T lymphocytes. There appears to be some
activity of alemtuzumab even in heavily pretreated patients with CLL, including patients
who have received purine analogs.94 , 95 , 96 Some patients have achieved a complete
response to this agent. Alemtuzumab has been used in combination with fludarabine
with some success.97 In patients with bulky lymphadenopathy, alemtuzumab was not as
effective, suggesting a potential role in postremission therapy,98 but to date, there are
no set guidelines. The primary
P.2311
toxic effect is immune suppression and a high frequency of infections is seen with this
agent. The use of fluconazole, acyclovir, and trimethoprim/sulfamethoxazole for
prophylaxis has minimized infectious complications. For alemtuzumab dosing refer to
Table 93.6. Hypersensitivity is also a risk and premedication with acetaminophen and
diphenhydramine is recommended.
Bone Marrow Transplant
The role of HCT in the management of CLL is controversial. The age of most patients
with CLL is above the limit for AHCT. The value of autologous HCT in a disease in which
the bone marrow is heavily infiltrated with disease may be limited. Patients with low-
stage disease often have the same life expectancy as age-matched control subjects. No
survival advantage has yet been demonstrated using HCT in patients with CLL.
Nevertheless, in patients younger than 55 years of age with good performance status
and Rai stage III or IV disease, AHCT may be considered.99 , 100 In patients between 55
and 65 years of age with good performance status and high Rai stage disease, an
autologous HCT may be appropriate. Several investigators have reported the feasibility
of transplant under these conditions, reporting a high percentage of patients achieving
a complete response, and in some studies, low transplant-related mortality.101 , 102 , 103
One study reported that prior treatment with fludarabine might reduce the incidence of
GVHD, owing to its immunosuppressive effects.104 Patients undergoing autologous or
AHCT for CLL should be treated within the framework of a clinical study.
An exciting new development is the use of nonablative and less toxic preparative
regimens for AHCT. This approach harnesses the GVL effect to provide the antileukemic
response, instead of relying on the intensity of the chemotherapy and radiation therapy
to eradicate the leukemic cells. This milder preparative regimen decreases the toxic
risks of transplantation, making it more tolerable for older patients.105
Nonpharmacologic Therapy
Patients may sometimes benefit from the removal of their spleen. In particular, patients
with refractory anemia or thrombocytopenia often show improvement after
splenectomy.106 Splenic radiation has also been of value for patients with symptomatic
splenomegaly that does not respond to drug therapy.
Improving Outcomes
Infection is the leading cause of death in patients with CLL. Many of the infections are
common bacterial infections that can be treated with standard antibiotics. Patients need
to be educated about the signs and symptoms of infections and instructed to seek
medical evaluation when these signs and symptoms occur.
Key Points
Chronic Myelogenous Leukemia
l The earlier an allogeneic transplant is performed in the course of CML, the

better the chance for long-term disease-free survival
l Patients with chronic-phase CML who are younger than age 50 years with a
matched sibling donor should undergo an AHCT within the first year
following diagnosis
l Patients without a donor for a HCT and patients who are older and in poor
health are not candidates for HCT
l There are many patients with CML who do not fit into the above categories.
Making decisions about treatment of these patients is difficult and should be
done on a case-by-case basis
l Imatinib may be used as initial treatment in some patients, however, its
exact place in overall management is still under investigation
l Patients without a matched sibling donor or patients who are older than age
50 years should be given a trial of imatinib. In the absence of a complete
cytogenetic response, AHCT should be offered if age and functional status
allow and a donor is available
Chronic Lymphocytic Leukemia
l CLL is incurable at this time

l Many patients with CLL do not require treatment. Patients with low-stage
disease do not benefit from the addition of drug therapy
l Patients are at high risk for infection from the disease and from drug
therapy and, therefore, require careful monitoring
l Autoimmune hematologic disease is common

l Aggressive therapy, such as HCT, should be reserved for patients with good
performance status and progressive disease
Acknowledgment
The author acknowledges the contribution of Betsy Aulthaus, Pharm. D., who authored
the corresponding chapter in the Seventh Edition. Portions of that chapter have been
used in this edition.
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Chronic Leukemia Herfindal

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93 Chronic Leukemias Page 1 of 40

Chronic Myelogenous Leukemia

CML is a hematologic malignancy originating from a leukemic transformation in a clonal

Treatment Goals: Chronic Myelogenous Leukemia

l Provide curative therapy by eradicating the leukemic cells and restoring

The etiology of the leukemogenic transformation is unclear. There appears to be no

FIGURE 93.1 Oncogene activation by chromosomal relocation. A. Chronic

Further chromosomal abnormalities occur as the disease progresses to the accelerated

Clinical Presentation and Diagnosis

Signs and Symptoms

Progression to Accelerated and Blast Phases

If CML is in the chronic phase and an AHCT is unavailable or inappropriate because of

Hydroxyurea is a ribonucleotide diphosphate reductase inhibitor. Ribonucleotide

suppression. Gastrointestinal effects are uncommon at usual doses.7 , 8 , 9 , 10 , 11

TABLE 93.1 Agents Used in Chronic Myelogenous Leukemia

Summary of Suggested Dosing for Agents Used in CML

An unusual and infrequent complication of chronic hydroxyurea use is the development

TABLE 93.2 Recommendations for Interferon Administration

In general, the recommended dose of INF-α is 5 million units/m2/day, adjusted to the

INF-α, interferon alpha; WBC, white blood cell.

TABLE 93.3 Treatment Continuation/Discontinuation Algorithm for Interferon-α

3 mo Less than or equal to a partial hematologic Discontinue

6 mo Less than or equal to a partial hematologic Discontinue

12 mo Less than or equal to a partial hematologic Discontinue

Complete hematologic response, no cytogenetic

risk factors (splenomegaly or thrombocytosis). At 6 months, patients with a complete

have residual BCR-ABL transcript. The absence of the BCR-ABL transcript is a

The cost-effectiveness of INF-α has been determined by two investigators.32 , 33 For a

estimated 4-year survival of 86%.40

immunophenotyped to determine if the CML is transforming into a myeloid or lymphoid

Bone Marrow Transplant

Allogeneic Hematopoietic Cell Transplant

Unrelated Donor Hematopoietic Cell Transplant

nonmyeloablative HCT regimens may be considered (see below).

TABLE 93.4 Summary of Treatment Options: Chronic Myelogenous Leukemia

Treatment Options for CML Chronic Phase

Young (< 50)

HLA-matched sibling HSCT (Patients Imatiniba

HLA-matched sibling HSCT (Patients Imatiniba

Nonmyeloablative transplant Imatinib

Nonmyeloablative Hematopoietic Cell Transplant

An important change in the philosophy of preparative regimens for allogeneic transplant

Relapse After Hematopoietic Stem Cell Transplant

Relapse after HCT may be hematologic or cytogenetic. It is common for the Ph

Autologous Hematopoietic Stem Cell Transplant

It may be possible to obtain long-term survival in patients by using an infusion of Ph

Hematopoietic Stem Cell Versus Imatinib

Chronic Lymphocytic Leukemia

CLL is a malignancy of monoclonal small mature lymphocytes that have prolonged

Treatment Goals: Chronic Lymphocytic Leukemia

CD5-positive lymphocyte is transformed via multiple mutational steps into a monoclonal

Clinical Presentation and Diagnosis

Signs and Symptoms

TABLE 93.5 Staging Systems Used for Chronic Lymphocytic Leukemia

Rai staging system

Low 0 Lymphocytosis only 31 <10 59

Intermediate I Lymphocytosis and 35 9

High III Lymphocytosis and 6 2 10

Binet staging system

Low A Lymphocytosis, with 63 <10 51

A' Stage A with lymphocyte 49 <10 56

A′ Stage A with lymphocyte 14 7 38

Intermediate B Lymphocytosis, with 30 5