C Chronic Myelogenous Leukemia: A Review and Update of Therapeutic Strategies Guillermo Garcia-Manero,

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437
Chronic Myelogenous Leukemia: A Review and
Update of Therapeutic Strategies
Guillermo Garcia-Manero, M.D.1
Stefan Faderl, M.D.1
Susan O’Brien, M.D.1
Jorge Cortes, M.D.1
Moshe Talpaz, M.D.2
Hagop M. Kantarjian, M.D.1
1
Department of Leukemia, The University of Texas
M. D. Anderson Cancer Center, Houston, Texas.
2
Department of Bioimmunotherapy, The University
of Texas M. D. Anderson Cancer Center, Houston,
Texas.
Address for reprints: Hagop M. Kantarjian, M.D., Department of Leukemia, The University of Texas M. D.
Anderson Cancer Center, 1515 Holcombe Boulevard,
Box 428, Houston, TX 77030; Fax: (713) 792-2031;
E-mail: [email protected]
Received February 13, 2003; revision received
March 28, 2003; accepted April 9, 2003
© 2003 American Cancer Society
DOI 10.1002/cncr.11520
C
hronic myelogenous leukemia (CML) is a myeloproliferative disorder of pluripotent hematopoietic stem cells.1 The growth advantage of the leukemic cells over normal hematopoietic cells is due
to both excessive proliferation and failure of programmed cell death
(apoptosis) of the CML cells.2– 6 Patients with CML may present with
signs or symptoms related to leukocytosis, splenomegaly, or anemia.
However, the presenting features of CML have changed over time,
and in 30 – 40% of cases it often is diagnosed accidentally by a routine
blood test or physical examination (Table 1).
The Philadelphia chromosome (Ph), the hallmark cytogenetic
abnormality of CML, is identified in the bone marrow cells of
⬎ 90% of patients with the clinical and laboratory features of CML
(Fig. 1).7,8 The Ph abnormality, which represents a balanced translocation involving the long arms of chromosomes 9 and 22, t(9;
22)(q34;q11), produces the BCR-ABL fusion gene. BCR-ABL gives rise to
a chimeric protein, p210BCR-ABL, which is characterized by constitutive
activation of its tyrosine kinase activity. Increased autophosphorylation
and abnormal phosphorylation of various cytosolic protein targets then
induces activation of multiple downstream signaling pathways that are
responsible for the phenotype of CML.9 –13
The course of CML follows a biphasic or triphasic course with
a chronic, accelerated, and blastic phase. Survival from the time of
diagnosis of each phase is shown in Figure 2. The majority of
patients (85%) present in chronic phase but, if left untreated, the
disease will progress into the accelerated and blastic phases. The
median survival of patients with CML has improved from 3– 4 years
when treated with busulfan or hydroxyurea to 6 – 8 years in the era
of interferon-␣ (IFN-␣) therapy. The introduction of newer therapies such as imatinib mesylate (Gleevec™ [STI571]; Novartis Pharmaceutical Corporation, East Hanover, NJ), a BCR-ABL-specific
tyrosine kinase inhibitor, may further improve the outcome of
patients with CML (Fig. 3). Allogeneic stem cell transplantation
(SCT) can produce long-term event-free survival rates of 40 – 80%,
depending on several factors such as disease stage, patient age,
and degree of host-donor matching.
CML provides a prime example of a disease characterized by a
well defined cytogenetic-molecular abnormality that is capable of
transforming hematopoietic progenitor cells, thus inducing the clinical manifestations of the disease. Therefore, CML has become a
paradigm for our understanding of leukemogenesis, for targeted drug
development in recent years (of which imatinib mesylate is one
example), and for the significance of the evaluation of minimal residual disease in the setting of SCT and other treatment approaches.
438
CANCER August 1, 2003 / Volume 98 / Number 3
TABLE 1
Presentation of Chronic Myelogenous Leukemia in Newly Diagnosed Patients by Time Period
Percent of patients
Parameter
No. referred
Age (yrs)
Splenomegaly
Hepatomegaly
Lymphadenopathy
Symptoms at presentation
Hemoglobin (g/dL)
Platelets (⫻ 109/L)
Leukocytes (⫻ 109/L)
Peripheral blasts
% bone marrow blasts
% peripheral basophils
% bone marrow basophils
Prognostic group
(Hasford score69)
Category
1965–1980
1981–1989
1990–2000
2001 Onward
ⱖ 60
Yes
Yes
Yes
Yes
⬍ 12
⬎ 700
⬎ 100
Yes
ⱖ5
ⱖ7
ⱖ4
Good
Intermediate
Poor
215
19
75
44
22
16
61
27
71
66
11
15
25
40
38
22
409
12
57
23
9
40
50
20
56
55
7
12
21
59
34
7
1073
17
46
8
4
40
46
14
51
57
7
14
19
55
37
8
230
26
36
6
3
32
34
16
43
54
7
11
29
49
45
7
P value
⬍ 0.001
⬍ 0.001
⬍ 0.001
⬍ 0.001
⬍ 0.001
⬍ 0.001
⬍ 0.001
⬍ 0.001
0.03
0.16
0.54
0.01
⬍ 0.001
FIGURE 1.
The Philadelphia chromo-
some.
ETIOLOGY
The cause of CML is unknown. Leukemogenesis is a
multistep phenomenon that is divided into initiation,
promotion, and progression phases. The initiation
phase involves acquisition of a genetic defect that
confers cell survival advantage. What triggers the generation of the initiation step in CML is unknown. In
experiments in which leukemic cell lines were exposed to gamma irradiation, fusion genes characteristic of different forms of leukemias were induced,
although these defects were also detected at a low
level in untreated cells.14 The generation of the BCRABL gene is now recognized as the key molecular
event leading to CML. What induces this molecular
rearrangement is unknown. Using highly sensitive
polymerase chain reaction (PCR) techniques, BCR-
ABL transcripts could be detected in the bone marrow cells of 25–30% of healthy volunteers and in 5%
of infants, but not in cord blood cells.15,16 Because
clinical CML is reported to develop in only 1–2 of
100,000 individuals, it follows that in most of these
individuals, those cells expressing BCR-ABL do not
produce overt CML disease. This observation suggests that immune regulatory processes or additional molecular events contribute to the development of CML. There is no evidence supporting
hereditary or genetic factors. BCR-ABL is found only
in hematopoietic cells, and there is no increased
incidence of CML in monozygotic twins or in the
relatives of patients with CML. No chemical or infectious exposures have been linked to CML. The
incidence of CML is reported to be higher in survi-
Chronic Myelogenous Leukemia/Garcia-Manero et al.
439
FIGURE 2. Survival of patients in the
chronic, accelerated, or blastic phases
of chronic myelogenous leukemia.
FIGURE 3.
Survival of patients with
chronic myelogenous leukemia who
were referred in early chronic phase by
year of therapy (M. D. Anderson patient
data obtained between 1965–2002).
vors of the atomic bomb or nuclear exposures, as
well as after ionizing radiation.
INCIDENCE
Every year, approximately 5000 –7000 individuals are
diagnosed with CML in the U.S. The annual incidence
is 1–2 cases per 100,000 individuals. CML accounts for
approximately 15% of all leukemias and 7–20% of
adult leukemias. The incidence has not changed over
the last 50 years. CML affects males more often than
females (ratio of 1.3–2.2 to 1). The incidence of CML
increases with age. The median age at presentation
reported from large cohort studies is 45–55 years.17–19
The median age reported in the Surveillance, Epide-
440
miology, and End Results (SEER) program data is 67
years, suggesting either a referral bias of younger patients to investigational studies and tertiary centers, or
a different coding reporting of the SEER data.20,21 In
the trials of imatinib mesylate, 30% of patients were
age ⬎ 60 years,22 although this incidence was only 12%
in studies of IFN-␣ regimens, perhaps reflecting a
referral bias because older patients tend not to tolerate IFN as well as their younger counterparts.23 CML
comprises ⬍ 5% of pediatric leukemia cases.
BIOLOGY
CML is defined by the Ph chromosome or the presence of the BCR-ABL transcript in the leukemic
cells.24 –27 The Ph chromosome is detectable in 90% of
patients with a clinical and laboratory picture of CML
(Ph-positive CML). In the remaining 10% of Ph-negative patients, BCR-ABL transcripts can be found in
approximately 30 –50%. These Ph-negative, BCR-ABLpositive CML cases have clinicopathologic features
and prognosis identical to Ph-positive CML patients,
and respond similarly to therapy.28 –30 The truly Phnegative and BCR-ABL-negative patients are a heterogeneous group with an inferior prognosis that is variably referred to as Ph-negative CML, atypical CML,
proliferative variants of myelodysplastic syndromes,
or chronic myelomonocytic leukemia (CMML).31,32
The Ph chromosome was first described in 1960 as
a shortened chromosome 22.7 It was later characterized as a balanced translocation between the long
arms of chromosomes 9 and 22, t(9;22)(q34;q11).8 The
Ph has been identified in myeloid, erythroid,
megakaryocytic, and B-lymphoid precursor cells;
rarely in T-lymphoid precursor cells; and not at all in
bone marrow fibroblasts, indicating that CML originates in a pluripotent hematopoietic stem cell. Variant
chromosomal abnormalities have been described in
CML, including simple and complex Ph translocations
and “masked” Ph (translocations between chromosomes 9;22 and other chromosomes), depending on
the number and particular chromosomes involved.
C-ABL has 11 exons and expands over 230 kilobases (kb). It is located on chromosome 9q34 and
encodes a 140-kilodalton (kD) protein with weak tyrosine kinase activity. C-ABL has two alternate exon I
sequences that are transcribed differentially from two
different promoters (Fig. 1). These exons are designated Ib and Ia and their respective promoters are Pb
and Pa. Exon Ib is located at the 5⬘ end of the gene and
is 150 –200 kb upstream of exon Ia. The first common
exon of C-ABL is exon 2. The proximal promoter (Pa)
and the distal promoter (Pb) are separated by 175 kb.
They direct the synthesis of 2 different mRNA species
of 6 kb and 7 kb, respectively. In approximately 90% of
Ph translocations, the proximal promoter, Pa, is
nested within the BCR-ABL transcriptional unit. In the
majority of cases of CML, the translocation breakpoint
occurs between exons Ib and Ia; therefore, the Ph
chromosome contains the entire coding sequence of
C-ABL (exons 2-11) and an intact exon Ia and its
promoter. It should be noted that the C-ABL promoter
is usually silenced and has no regulatory effect on
BCR-ABL transcription.33 In t(9;22), this 3⬘ end of CABL is transposed from chromosome 9 into the major
breakpoint cluster region of BCR (M-BCR) on chromosome 22. This region is located between exons 12 and
16 (also known as b1– b5) of BCR on chromosome 22
and extends over 5.8 kb. Usually, the breakpoints in
BCR are located between introns b2 and b3 or b3 and
b4. As a consequence, a BCR-ABL fusion gene is generated with either a b2a2 or b3a2 junction (denoting
the exons in BCR and ABL involved). This hybrid gene
is transcribed into an 8.5-kb mRNA that is translated
into a chimeric protein of 210 kD, p210BCR-ABL.24
A second breakpoint cluster region of BCR is referred to as the minor breakpoint cluster region or
m-BCR, and is located 5⬘ of M-BCR. It reportedly is
involved in 50 – 80% of Ph-positive acute lymphoblastic leukemia (ALL) cases,34 but only rarely occurs in
CML.35 Although several investigators have reported
low levels of this transcript in patients with CML,36,37
the m-BCR breakpoint is within a long intron separating alternative exon e2⬘ from exon 2. Secondary splicing of alternative exons e1⬘ and e2⬘ generates an e1a2
junction between BCR (e1) and ABL (a2). Because of
the proximal location of m-BCR, the BCR-ABL fusion
gene generated is smaller, resulting in a fusion protein
of only 190 kD, p190BCR-ABL. A third breakpoint cluster
region, ␮-BCR, located more distally at the 3⬘ end of
M-BCR, has recently been described. It is located between exons e19 and e20, creating an e19a2 junction.
The fusion protein generated has a molecular weight
of 230 kD and is known as p230BCR-ABL. p230BCR-ABL
has been described in cases of chronic neutrophilic
leukemia, a rare disorder marked by sustained mature
neutrophilic expansion, thrombocytosis, and a more
indolent clinical behavior with a lower likelihood to
transform than p210BCR-ABL-positive CML. The
p230ABL-BCR oncoprotein is usually expressed at low
levels in the leukemic cells, which may explain the less
aggressive course of this disease variant.38
Transfection of bone marrow-derived cell lines
with a retroviral vector-encoding BCR-ABL resulted in
growth factor independency and malignant transformation. The N-terminus of ABL contains three Srchomology (SH) domains (SH1–SH3 domains), a catalytic domain, and a myristorylation sequence that
allows the binding of BCR-ABL to plasma membrane
proteins. The C-terminus is comprised of a DNA-binding domain, nuclear localization signals, and an actinbinding site. Interactions of BCR with functional domains of ABL are believed to be responsible for the
leukemogenic activity of BCR-ABL. The coiled-coil
dimerization motif of the N-terminal segment of BCR
influences the activity of ABL domains so that the
tyrosine kinase activity of the fusion protein is increased. BCR also interferes with the SH3 domain of
ABL. Because the SH3 domain has a negative regulatory effect on the tyrosine kinase activity of ABL, this
interference constitutively activates the phosphotyrosine kinase activity of ABL. The C-ABL sequences
deleted in p210BCR-ABL share homology with several
nonreceptor tyrosine kinases including SRC. Deletion
of these sequences activates the transforming capacity
of C-ABL. The transforming activity of BCR-ABL is also
regulated by the first exon of BCR. This first exon of
BCR binds to the SRC Homology 2 (SH2) domain of
ABL. This binding is essential for the transforming
capacity of BCR-ABL.9,10
Signal Transduction Cascades of CML
BCR-ABL oncoproteins are constitutively active tyrosine kinases. They exert their leukemogenic effect
via autophosphorylation and phosphorylation of several signal transduction pathways including RAS, RAF,
ERK, JNK, MYC, JAK/STAT, PI3Kinase-AKT, and NF-␬B
pathways.39 – 48 Multiple adapter proteins such as
CRKL, p62Dok, paxillin, CBL, RIN, SHC, and GRB2 link
BCR-ABL to its downstream targets. GRB2 is fundamental in connecting p210BCR-ABL with RAS. GRB2 is a
26-kD protein comprised of 1 SH2 domain and 2 SH3
domains. It couples BCR-ABL to SOS, a RAS activator.
GRB2 performs its docking function by binding with
its SH2 domain to phosphorylated tyrosine kinases
such as BCR-ABL, and with its SH3 domains to SOS.
GRB2 cannot bind to either BCR or ABL alone. It
specifically binds to the amino acid residue Y177F in
the first exon of BCR. This interaction is essential for
RAS signaling. Mutation of Y177F inhibits the transforming capacity of BCR-ABL, implicating the RAS
pathway at the core of the transforming signals generated by BCR-ABL. BCR-ABL also activates ubiquitindependent degradation of targeted proteins. BCR-ABL
may also induce the proteasomal degradation of cyclin-dependent kinase inhibitors, such as p27, and
thus may promote cell cycle progression. BCR-ABL
has also been reported to have antiapoptotic activity.
Expression of BCR-ABL protects growth factor-dependent cells from apoptotic cell death after cytokine
withdrawal, and up-regulates bcl-2 and bcl-XL.
The causal association between the BCR-ABL molecular abnormalities and the development of CML
441
has been proven in several animal models.11–13 Transfection of BCR-ABL into hematopoietic stem cells,
which were then reinfused into irradiated mice, mirrored the pathophysiology of a CML-like disease in
humans; a CML-like proliferative disease was noted in
50% of engrafted mice, whereas others developed lymphoblastic-like disease or monocytic tumors. The
finding that expression of BCR-ABL itself can imitate
the clinical manifestations of CML, including progression from chronic to blastic phase, has encouraged the
development of BCR-ABL-specific tyrosine kinase inhibitors such as imatinib mesylate.
Molecular Events in Transformed CML
Additional nonrandom cytogenetic abnormalities are
found in 50 – 80% of patients with advanced stage
CML. These include the presence of a double Ph,
trisomy 8, isochromosome 17 or other chromosome
17 abnormalities, additional chromosomes 19 and 21,
monosomies of chromosome 7, and t(3;21)(q26;q22).
Isochromosome 17 is typically associated with myeloid blastic phase.49 –51 Molecular abnormalities include clonal immunoglobulin and T-cell receptor rearrangements in patients with lymphoid transformation;
mutations of RAS; and abnormalities of p53, RB1, CMYC, p16INK4, and AML-EVI-1. The majority of these
abnormalities have a cytogenetic counterpart and are
associated with particular phenotypic characteristics.
p53 abnormalities are frequently associated with myeloid blastic phase and at times are linked to isochromosome 17, whereas RB1 abnormalities are usually
found in lymphoid blastic phase. Mutations in p53
have been observed in transformed phases but not in
chronic-phase CML, suggesting that functional loss of
p53 may be involved in disease evolution.
SYMPTOMS AND SIGNS: NATURAL HISTORY
CML typically evolves along three clinical phases. The
initial chronic phase is followed by an accelerated
phase that eventually transforms into the blastic
phase. Approximately 85% of patients present in
chronic phase and nearly 80% of cases progress into
the accelerated phase before development of the blastic phase. Presenting features are changing in time
because of earlier diagnosis, a result of routine physical examinations and blood testing (Table 1). The
incidence of asymptomatic presentation in the
chronic phase has increased from 15% to approximately 40 –50%. Features of increased tumor burden
or aggressive disease (splenomegaly, basophilia, highrisk presentation) are also reportedly decreasing.
Symptoms at the time of presentation are often the
result of anemia or splenomegaly, and include fatigue
and left upper abdominal pain or mass.52 Less com-
442
mon presentations are related to a hypermetabolic
state with fever, anorexia, weight loss, or gout, or to
consequences of platelet dysfunction such as hemorrhage, ecchymosis, hematomas, or thromboembolic
events. Findings of hyperleukocytosis and hyperviscosity include priapism, tinnitus, stupor, retinal hemorrhages, and cerebrovascular accidents. On physical
examination, splenomegaly is reported in 40 – 60%, of
cases and hepatomegaly in 10 –20%. Manifestations of
extramedullary hematopoiesis such as subcutaneous
lesions or lymphadenopathy are rare, and identify a
subgroup of patients with poor prognosis. Features of
accelerated phase are evidence of progressive maturation arrest with increased blasts and basophils, resistance to therapy, increased constitutional symptoms, progressive splenomegaly, cytogenetic clonal
evolution, leukocytosis, and thrombocytosis or thrombocytopenia.52,53 Approximately 10 –20% of patients
die in accelerated phase, which is reported to have a
median survival time of 1– 1.5 years. Patients who
develop blastic phase often are symptomatic with
weight loss, fever, night sweats, and bone pain, as well
as infections and bleeding.54 – 61 Extramedullary hematopoiesis is also frequent and involves the lymph
nodes, skin, subcutaneous tissues, bone, and central
nervous system (30% of lymphoid blastic-phase disease).62,63 Lymphoid blastic phase is more frequent in
younger patients (40% in patients age ⬍ 40 years).61,62
Definitions of accelerated and blastic-phase CML are
summarized in Table 2.53,55
LABORATORY FINDINGS
The most common feature in chronic-phase CML is
leukocytosis; approximately 50 –70% of patients
present with a leukocyte count ⬎ 100 ⫻ 109/L. Cyclic
variations in the leukocyte count have been described
in 10 –20% of patients. Thrombocytosis is observed in
30 –50% of patients and may exceed 1000 ⫻ 109 /L.
Platelet aggregation abnormalities are frequent. Anemia (hemoglobin level ⬍ 10 g/dL) is observed in 20%
of patients. The peripheral blood differential shows
myeloid cells in all stages of maturation. Basophils
and eosinophils may be increased. The leukocyte alkaline phosphatase (LAP) score, although rarely used
now, is low and may help to differentiate CML from
other myeloproliferative disorders or secondary leukemoid reactions. The bone marrow is hypercellular
with an elevated myeloid to erythroid ratio of 10:1 to
30:1. Megakaryocytes are frequently increased, and
Gaucher-like cells and sea-blue histiocytes are observed in 10% of cases. Grade 3-4 reticulin stain-measured myelofibrosis is reported in 40% of cases and
has been associated with a worse prognosis.64
More stringent accelerated phase criteria derived
TABLE 2
Features and Definitions of Accelerated and Blastic-Phase CML
Accelerated phase CML
A. Multivariate analysis-derived criteria:
Peripheral blasts ⱖ 15%
Peripheral blasts ⫹ promyelocytes ⱖ 30%
Peripheral basophils ⱖ 20%
Platelets ⬍ 100 ⫻ 109/L unrelated to therapy
Cytogenetic clonal evolution
B. Criteria used in common practice:
Bone marrow or peripheral blasts ⱖ 10%
Bone marrow or peripheral basophils and eosinophils ⱖ 20%
Frequent Peger-Huët-like neutrophils, nucleated red cells, or megakaryocytic
nuclear fragments
Increased bone marrow reticulin or collagen fibrosis
Leukocytosis (⬎ 50 ⫻ 109/L), anemia (hematocrit ⬍ 25%), and thrombocytopenia
(⬎ 100 ⫻ 109/L) not responsive to antileukemic therapy
Marked thrombocytosis (⬎ 1000 ⫻ 109/L)
Progressive splenomegaly unresponsive to therapy
Unexplained fever or bone pain
Requirement of increased doses of medication
Blastic-phase CML
– ⱖ 30% bone marrow or peripheral blasts
– Extramedullary hematopoiesis with immature blasts
CML: chronic myelogenous leukemia.
from a multivariate analysis are shown in Table 2.
Increased number of blasts (ⱖ 15%) or blasts and
promyelocytes (ⱖ 30%), basophilia (ⱖ 20%) in the
blood or bone marrow, thrombocytopenia ⬍ 100
⫻ 109/L is unrelated to therapy, and clonal evolution
have been defined by multivariate analysis to be predictive of a survival of ⱕ 1.5 years.53
The blastic phase of CML is defined by the presence of ⱖ 30% blasts, or extramedullary blastic infiltrates.55 Approximately 50% of patients have the myeloid phenotype, 25% have the lymphoid phenotype,
and 25% of patients have undifferentiated or other
rare blastic phenotypes (megakaryocytic, erythroid,
promyelocytic, or basophilic).55–59 Lymphoid blastic
origin is defined by a negative peroxidase (MPO) stain;
positive terminal deoxynucleotidyl transferase (TdT);
and the expression of pre-B cell markers including
CD19, CD20, and the common acute lymphoid leukemia antigen (CALLA, CD10).60,61 Myeloid marker coexpression in lymphoid blastic phase is common. Few
patients with lymphoid blast-phase CML express low
levels of peroxidase positivity (⬍ 5%).60
PROGNOSTIC FACTORS
The clinical course of CML is heterogeneous. With
hydroxyurea or busulfan therapy, the median survival
is reported to be 3– 4 years. The expected annual mortality rate is 5–10% in the first 2 years and 15–25%
subsequently. Pretreatment poor prognostic factors
for survival include the presence of splenomegaly,
older age, leukocytosis, increased blast or basophil
counts, thrombocytosis or thrombocytopenia, and cytogenetic clonal evolution.65 Several multivariate-derived prognostic models and staging systems have
been proposed.65–70 These models are helpful in defining individual prognosis, assigning patients to different strategies based on risk, evaluating the effects of
newer therapies, and comparing the relative benefits
of existing therapies within risk groups. The percentages of patients in good (30 –50%), intermediate (30 –
40%), and poor (10 –20%) risk categories have varied in
different studies. Median survival times with chemotherapy ranged from 50 – 60 months, 36 – 40 months,
and 24 –30 months, respectively. With IFN-␣ the median survival times were reported to be 102 months,
80 –95 months, and 45– 60 months, respectively, in the
3 risk groups. The European Collaborative CML Prognostic Factors Project Group developed a prognostic
score (also known as the Euro score or Hasford score)
that included age, spleen size, percent of blasts, percent of eosinophils plus basophils, and platelet counts
as variables. Using this model, 42% of patients were
found to have low-risk, 45% to have intermediate-risk,
and 13% to have high-risk disease. The 10-year survival rates were 42%, 18%, and 5%, respectively.69 Response to treatment with IFN-␣ and imatinib mesylate
were also powerful treatment-associated prognostic
factors. The 10-year survival rates of patients achieving a complete cytogenetic response with IFN-␣ were
reported to be between 70 – 80%.71–74
Cytogenetic clonal evolution remains a poor prognostic factor in CML65,66,70 in the era of IFN-␣, as well
as with imatinib mesylate therapy.22,75,76 However, its
prognostic significance depends on several factors including the specific abnormality, its prevalence, onset
time, association with other variables, and therapy.65,77
Clonal evolution as the only sign of disease acceleration is associated with favorable prognosis after allogeneic SCT.78
Several molecular markers have been investigated
for their prognostic significance. Large deletions of
derivative chromosome 9 were observed in a subgroup of patients (15%) and were associated with poor
prognosis (median survival of 38 months vs. 88
months; P ⬍ 0.01).79 DNA methylation of the Pa promoter of C-ABL was associated with late chronic phase
and with transformation.80,81 Telomere shortening in
chronic-phase disease was associated with faster progression to accelerated phase and with increased risk
of blastic transformation within 2 years.82 Expression
443
of proteins of the IFN regulatory family (IRF), in particular IRF 4, were down-regulated in T cells from
patients with CML, and were found to predict for
response to IFN-␣ treatment.83,84
DIAGNOSTIC EVALUATION
The diagnostic workup includes a complete blood
count with differential and platelet count to evaluate
blastosis, basophilia, thrombocytosis, and thrombocytopenia; and bone marrow aspiration and biopsy to
quantify the percentage of blasts and basophils, degree of fibrosis, and for cytogenetic analysis. Cytogenetic analysis remains the gold standard in the diagnosis of CML. The major advantage of conventional
chromosome studies is the detection of other cytogenetic abnormalities (i.e., clonal evolution as a marker
of disease progression). Conventional cytogenetic
analysis is limited by the number of metaphases analyzed (approximately 20 –25 with a good harvest), and
is time-consuming. Patients occasionally may present
with thrombocytosis alone and are erroneously labeled as having essential thrombocytosis. Thus, all
patients with the clinical and laboratory picture of
essential thrombocytosis should also undergo cytogenetic analysis to identify the rare Ph-positive cases.
Genomic polymerase chain reaction (PCR) and Southern blot analysis can delineate the exact BCR breakpoints. Reverse transcriptase (RT)-PCR and Northern
blot analysis are able to detect BCR-ABL transcripts,
and antibodies against BCR or ABL detect the BCRABL protein. Occasionally, patients present with
p190BCR-ABL-positive disease that can be detected by
PCR but not by Southern blot analysis.35 Another rare
entity, p230BCR-ABL CML, may manifest as Ph-positive,
BCR-ABL-negative CML. Specific PCR studies and protein analysis will confirm the diagnosis of p230BCR-ABL
CML.38
The differential diagnosis in CML includes leukemoid reactions (typical leukocyte counts of ⬍ 50
⫻ 109/L and the presence of toxic granulation and
vacuolation, as well as Döhle bodies in the granulocytes, the absence of basophilia, and a normal or
increased LAP score), use of corticosteroids (which
rarely cause extreme neutrophilia and left shift, selflimited), and other myelodysplastic or myeloproliferative syndromes. Patients with agnogenic myeloid
metaplasia with or without myelofibrosis often have
splenomegaly and may present with neutrophilia and
thrombocytosis. Patients with polycythemia rubra
vera associated with iron deficiency may present with
a normal hemoglobin and hematocrit values and elevated neutrophil and platelet counts. Documentation
of the Ph abnormality is virtually diagnostic for CML
and helps to exclude other conditions.
444
Laboratory Monitoring of Response and Evaluation of
Minimal Residual Disease
Response to therapy is evaluated by the disappearance
of the Ph chromosome or the BCR-ABL transcripts.
Cytogenetic analysis has a limited role in the detection
and follow-up of minimal residual disease, which is
better evaluated with other techniques.85–100 Fluorescent in situ hybridization (FISH) is typically performed
by cohybridization of a BCR and ABL probe to denatured metaphase chromosomes or interphase nuclei.
FISH techniques allow rapid evaluation of several
hundred cells in a time-efficient manner. Several molecular techniques are used to detect the BCR-ABL
gene. Southern blot analysis is limited by the amount
of DNA required. False-positive or false-negative results with Southern blot analysis are rare, but can
occur due to changes in the size of the rearranged
band. Southern blot analysis measures the level of
BCR-ABL and these results usually correspond with
cytogenetic results. Southern blot analysis has a low
sensitivity and cannot be used to assess minimal residual disease. It is best used in patients who are Ph
negative to detect Ph-negative, BCR-ABL-positive
CML. BCR-ABL protein detection and quantification
can be performed by Western blot analysis, through
probing protein lysates, from blood or bone marrow
with an antibody against ABL, thus allowing the detection of the three BCR-ABL protein isoforms.96
PCR, the most sensitive molecular technique, is
particularly well suited for the evaluation of minimal
residual disease.90 –100 It can detect 1 Ph-positive cell
among 104 to 108 normal cells. Qualitative RT-PCR
studies are useful in monitoring residual disease in
cytogenetic complete responders. Original studies involved patients after allogeneic SCT.98 Positivity as
detected by nested PCR at 6 months and 12 months
after transplantation was found to correlate significantly with disease recurrence.98 RT-PCR negativity in
patients who achieved a complete cytogenetic response in the nontransplantation setting also has
been found to be predictive of long-term event-free
survival.74,93 Quantitative real-time RT-PCR and competitive RT-PCR studies are currently being evaluated
for their predictive value for achieving rapid response
in patients with active disease, and for long-term
event-free survival in patients achieving a complete
cytogenetic response while receiving imatinib mesylate therapy.99 –102 A practical approach to monitoring
patients is shown in Table 3. The occurrence of additional chromosomal abnormalities has been described
in Ph-positive as well as Ph-negative cells of patients
treated with imatinib mesylate.103,104 This finding also
had been reported previously with IFN-␣ therapy.105
TABLE 3
Monitoring of Patients with Ph-Positive CML Receiving Imatinib
Time receiving therapy
Tests
Pretherapy
On therapy
Cytogenetics; FISH-PB; QPCR-PB
FISH every 2–3 months; cytogenetics every
6–12 months; once FISH ⬍ 10%,
confirm CR by cytogenetic studies
QPCR every 2–3 months
Cytogenetics every 6–12 months
In CR
Ph: Philadelphia chromosome; Cml: chronic myelogenous Leukemia, FISH: fluorescent in situ hybridization; PB: peripheral blood; QPCR: quantitative polymerase chain reaction; CR: complete response.
These abnormalities have included trisomy 8 and
chromosome 5 or 7 abnormalities. Because the prognostic significance of these abnormalities is unknown,
it would be appropriate to continue monitoring patients with additional bone marrow cytogenetic studies at least once a year.
TREATMENT
Treatment decisions in patients with CML are based
on the patient’s age and phase of the disease.106 –108
Busulfan was the first agent shown to provide effective
hematologic control in patients with CML,109 but its
use should be discouraged outside the setting of preparative regimens for allogeneic SCT.110 The use of
busulfan outside the setting of preparative allogeneic
SCT regimens has been associated with significantly
worse survival, with worse outcome after allogeneic
SCT, and with potentially serious side effects including
delayed myelosuppression and organ damage.111,112
Hydroxyurea is an excellent debulking agent and allows for the rapid control of the blood count, inducing
hematological responses in 50 – 80% of patients.113 Cytogenetic responses are rare, and hydroxyurea does
not appear to change the natural history of CML.
Hydroxyurea is very effective in initial cytoreduction
as an adjunct to other more definitive therapies, and
to control disease in preparation for allogeneic SCT.
However, it should not be considered definitive therapy for CML. Other palliative strategies include 6-mercaptopurine, 6-thioguanine, cytarabine, melphalan,
other chemotherapies, and anagrelide (for thrombocytosis).
Definitive Therapy for Patients with CML is Divided into
Transplant and NonTransplant Alternatives.
Allogeneic SCT
Allogeneic SCT is curative in selected patients with
CML, and is most effective when performed during the
chronic phase of disease. In chronic-phase CML, allogeneic SCT is associated with 3–5-year survival rates of
40 – 80%, and 10-year survival rates of 30 – 60%. Transplantation-related mortality (TRM) ranges from
5–50%, depending on patient age, donor origin (related vs. unrelated) and degree of matching, patient
and host cytomegalovirus status, adequate use of antiinfective prophylaxis, preparative regimens, and institutional expertise, among other factors.114 –122 Recurrence rates are 20% and the risk of disease
recurrence is reported to plateau at 5 –7 years after
transplantation. The two most significant factors reported to influence transplantation outcome are patient age and phase of disease. Disease-free survival
(DFS) rates with matched-related allogeneic SCT are
40 – 80% in chronic phase, 15– 40% in accelerated
phase, and 5–20% in blastic phase. In chronic phase
CML, patients age ⬍ 30 – 40 years are reported to have
DFS rates of 60 – 80%, 1-year TRM rates of ⬍ 5% to
20%, and recurrence rates of 20%. Outcome worsens
with older age. Large series have reported 5-year survival rates of 30 – 40% in patients age ⬎ 50 years. The
European Bone Marrow Transplantation Registry
(EBMTR) reported a TRM of 47% and a 5-year DFS of
25% in patients age ⬎ 45 years.115
The optimal timing of transplantation is controversial; the majority of transplantation centers recommend transplantation in early chronic-phase CML
within 1 year from diagnosis. Several recent updates
have shown little difference in long-term outcome
among patients transplanted in the first 12 months
after diagnosis compared with those transplanted during the first 24 months.123 The use of IFN-␣ prior to
transplantation has not been shown to negatively influence the outcome of matched related allogeneic
SCT nor the outcome of unrelated allogeneic SCT,
provided IFN-␣ is discontinued at least 3 months prior
to the transplant procedure.106,124 –126 Toxicity from
preparative regimens is observed in 100% of patients.
Acute graft-versus-host disease (GVHD) occurs in 10 –
60% of patients and is the cause of death in 10 –15%.
Chronic GVHD occurs in 75% of patients and its associated mortality is 10%. Strategies to minimize
GVHD include the use of T-cell depletion, which improves TRM but increases recurrence rates and the
occurrence of secondary lymphoproliferative disorders. The most common causes of death after transplantation are acute GVHD (2–13%), chronic GVHD
(8 –10%), interstitial pneumonitis (4 –32%), opportunistic infections (3–24%), venoocclusive disease (1–
4%), and resistant disease recurrence (5–10%). Longterm complications of allogeneic SCT include sterility,
cataracts, hip necrosis, secondary tumors (5–10%),
chronic GVHD complications, and worse quality of
life. One limitation of allogeneic SCT is the availability
of related donors. Human leukocyte antigen (HLA)-
445
compatible unrelated donors are found in 50% of patients. Patients of white origin have an 85% chance of
identification of a perfect match. The median time
from donor search to transplantation is approximately
3– 6 months.120,121,127 The use of unrelated donors is
associated with higher morbidity and mortality rates.
Recent single institutional studies have reported similar outcomes with unrelated SCT compared with related SCT when the transplant is provided by a molecularly perfectly matched donor.122 Greater than
50% of the mortality associated with unrelated allogeneic SCT is secondary to acute and chronic GVHD.
Nonablative preparative regimens (mini-transplants, reduced intensity transplants) have attempted
to expand the indications of allogeneic SCT to older
patients, and to reduce transplant mortality and complications. Preparative regimens rely on immunosuppressive (rather than ablative) therapy to allow for
donor cell engraftment. Early results of nonablative
regimens in patients not considered to be eligible for
standard transplantation demonstrate acceptable degrees of engraftment, less mortality, more persistent
residual disease, and perhaps similar degrees of
GVHD.128 The improved results from reduced morbidity and mortality may be offset by the higher incidence
of persistent or recurrent disease, which could be approached with post-SCT maneuvers such as donor
lymphocyte infusions (DLI), IFN-␣, or imatinib mesylate. Patients who develop disease recurrence after
allogeneic SCT may be reinduced into a second longterm DFS with multiple modalities including DLI,
imatinib mesylate, IFN-␣, or second allogeneic
SCT.129 –135 RT-PCR studies predict for the probability
of disease recurrence occurring after allogeneic SCT;
patients who remain RT-PCR-positive 12 months after
allogeneic SCT are reported to have a 30 – 40% recurrence probability compared with a probability of ⬍ 5%
among RT-PCR-negative patients.98 DLI induce longterm DFS in 60% of patients who develop disease
recurrence during the chronic phase of disease, but in
only 10 –30% of those who develop disease recurrence
during the accelerated or blastic phase.133 It also is
associated with recurrent GVHD (20 –30%), severe myelosuppression (20 –30%), and mortality (10 –20%).
Imatinib is effective in inducing complete cytogenetic
and molecular disease remissions in patients whose
disease recurs molecularly, cytogenetically, or in
chronic phase after allogeneic SCT.135 Imatinib may
soon precede DLI as the treatment of choice for this
condition, particularly in patients with GVHD. Its results in patients who develop a disease recurrence
during the accelerated or blastic phase of disease are
poor. In such patients, combinations of imatinib with
chemotherapy and DLIs should be considered, al-
446
though patients should be monitored for the development of GVHD. IFN-␣ achieves responses in 30 – 40%
of patients who develop disease recurrence in the
chronic phase after allogeneic SCT.131,132 A second
allogeneic SCT can be considered in patients who are
⬎ 12 months from a previous transplantation (to reduce complications and mortality), most likely after
failure to respond to some of the above measures.134
Patients with a high predicted risk of disease recurrence (e.g., transplantation in accelerated-blastic
phase) after allogeneic SCT may benefit from preventive postallogeneic SCT maintenance measures such
as imatinib or IFN-␣.
Nontransplantation Therapies
Interferon-␣-based therapies
Single-agent IFN-␣ is active in CML. IFN-␣ doses used
have ranged from 3–5 MU 3 times a week to 5 MU/m2
daily or the maximally tolerated daily dose.17–19 There
is a dose-response effect, but side effects appear to
increase with higher doses. Response rates with single-agent IFN-␣ include a complete hematologic response (CHR) of 40 – 80%, a cytogenetic response of
15–58%, a major cytogenetic response (Ph ⬍ 35%) of
30 –50%, and a complete cytogenetic response (Ph of
0%) of 5–25%. The median survivals ranged from
60 –90 months.136 –143 Achieving a complete cytogenetic response was associated with 10-year survival
rates of 70 – 80%.71–74 Several randomized studies have
compared IFN-␣ therapy with hydroxyurea or busulfan. In the majority of studies, IFN-␣ was associated
with significantly higher response rates and longer
survivals.138 –143 A meta-analysis confirmed the benefit
of IFN-␣ on survival, mainly in a low-risk group of
patients.142 IFN-␣ has been combined with low doses
of cytosine arabinoside (Ara-C). Several single-arm
and randomized studies of IFN-␣ plus Ara-C compared with IFN-␣ alone have been conducted to
date.144 –149 When IFN-␣ was given at a dose of 5
MU/m2 daily and Ara-C was given at a dose of 10 mg
subcutaneously daily, a CHR was achieved in 92% of
patients and a cytogenetic response was noted in 74%.
The rates of major cytogenetic response were higher
with IFN-␣ and daily Ara-C compared with IFN-␣ and
intermittent Ara-C or IFN-␣ alone.147 Two randomized
trials comparing IFN-␣ plus Ara-C with IFN-␣ have
been reported to date.148,149 In a French multicenter
trial conducted in patients with CML, IFN-␣ plus AraC was associated with a significantly higher CHR rate
at 6 months (66% vs. 55%; P ⬍ 0.01), a higher cytogenetic response rate at 12 months (61%vs. 50%; major
in 38%vs. 26% [P ⬍ 0.01]), and significantly better
survival (5-year survival rate of 70% vs. 60%; P ⫽ 0.02).
A landmark analysis at 2 years demonstrated an asso-
ciation between cytogenetic response and survival;
the 7-year survival rate was 85% with a complete or
partial cytogenetic response, 62% with a minor cytogenetic response, and 25% for others.148 In the experience of the Italian Cooperative Study Group on CML
(ICSG-CML), the combination of IFN-␣ plus Ara-C
demonstrated better major cytogenetic response rates
than IFN-␣ alone, but not better survival. However,
the median duration of Ara-C therapy was only 7
months, and the drug was often discontinued because
of side effects.149
Imatinib Mesylate
Imatinib has revolutionized the treatment and prognosis of CML.150 –163 Several studies in patients with
chronic-phase CML have shown high rates of complete cytogenetic responses. The impact of such therapy on long-term prognosis awaits further maturation
of the data. However, if the early results continue to
persist with long-term follow-up in relation to high
rates of complete and durable cytogenetic responses,
as well as low transformation and mortality rates and
no new unexpected frequent long-term imatinib toxicities, then imatinib will soon be established as the
most effective treatment for CML.
Imatinib was identified as a lead compound in a
high-throughput in vitro screen for tyrosine kinase
inhibitors, and then was optimized for its activity for
specific kinases.152 After the preclinical studies, and
after overcoming several hurdles related to animal
toxicities, oral formulation, and market economic
considerations, imatinib entered Phase I trials in
1998155,156 and was approved by the Food and Drug
Administration (FDA) in 2001 for the treatment of
patients with chronic-phase CML after IFN-␣ failure,
those with accelerated phase, and those with blastic
phase.157,158 Imatinib is a small molecule 2-phenylaminopyrimidine that acts as an ATP mimic thus
occupying the binding site for ATP within BCR-ABL,
which then leads to inhibition of the phosphorylation
of tyrosine residues on substrate proteins and BCRABL itself.152 Consequently, imatinib prevents activation of signal transduction pathways that are crucial
for CML leukemogenesis. In addition to p210BCR-ABL,
imatinib inhibits several other tyrosine kinases including p190BCR-ABL, v-ABL, c-ABL, c-Kit, and platelet-derived growth factor-receptor (PDGF-R).
Phase I studies. In a Phase I study of patients with late
chronic-phase and blastic-phase CML, including Phpositive ALL, the dose of imatinib was escalated from
25 mg to 1000 mg orally daily.155,156 Common but
rarely serious side effects included nausea and emesis,
diarrhea, skin rash, muscle cramps, bone or joint
aches, myelosuppression, and weight gain. Less common side effects reported to occur at higher doses
were fluid retention, periorbital and peripheral
edema, fever, occasional liver dysfunction, and decreased skin pigmentation. No maximum tolerated
dose or dose-limiting toxicities were defined, but toxicities were more significant at doses of ⱖ 800 mg
daily. In the Phase I chronic-phase study, 83 patients
were treated. Among 54 patients who received imatinib at doses of ⱖ 300 mg, the CHR rate was 98% and
the cytogenetic response rate was 31% (complete in
13%).155 In blastic-phase CML, the bone marrow complete remission rate (bone marrow blasts ⬍ 5% with or
without peripheral count recovery) was 32% in myeloid blastic phase and 55% in lymphoid blastic phase;
responses were transient.156
Phase II studies. Three multiinstitutional, multinational pivotal studies of imatinib in late chronic phase
after IFN-␣ failure, accelerated phase, and blastic
phase were completed. The Phase II study in 532 patients in chronic phase CML and IFN-␣ failure utilized
a dose of 400 mg of imatinib orally daily. Major cytogenetic responses were observed in 65% of patients
and were complete in 48%. The estimated 24-month
transformation rate was 13%; the estimated 24-month
survival rate was 92%.22,164 A lower incidence of major
cytogenetic response was observed in patients with
splenomegaly, thrombocytopenia, anemia, a longer
duration of the chronic phase, active disease, clonal
evolution, and 100% Ph positivity at the initiation of
therapy.159 The updated results of this trial164 and of
the M. D. Anderson experience159 in patients treated
on this study and on the expanded access study are
summarized in Table 4.
The Phase II study of imatinib in patients with
accelerated phase disease accrued 235 patients (181
with a confirmed diagnosis of accelerated phase disease). Patients received imatinib 400 mg or 600 mg
daily. Overall, 82% of patients achieved a hematologic
response, which lasted for at least 4 weeks in 69%
(CHR in 34%). A major cytogenetic response was observed in 33% of patients (complete in 24%). The estimated 24-month progression-free survival and survival rates were 49% and 63%, respectively.157,165
Compared with 400 mg, imatinib 600 mg orally daily
was associated with better cytogenetic responses and
a longer median time to transformation and survival.157 The updated results of the FDA pivotal trial165
and the M. D. Anderson experience of patients treated
on this study and the expanded access study160 are
shown in Table 5.
In the Phase II study in patients with blastic phase
disease, the imatinib daily doses were 400 – 600 mg.
447
TABLE 4
Updated Results of Imatinib Therapy in Patients with Chronic Phase
CML after Interferon-␣ Failure
Parameter
No. treated
CHR (%)
Cytogenetic response (%)
Major
Complete
Progression-free survival (mos) (%)
Survival (mos) (%)
FDA pivotal
trial
M. D. Anderson
experience
532
95
261
98
65
48
87 (24)
92 (24)
62
45
98 (18)
96 (18)
CML: Chronic myelogenous leukemia; FDA: Food and Drug Administration; CHR: Complete hematologic response.
TABLE 5
Updated Results of Imatinib Therapy in Patients with Accelerated
Phase CML
Parameter
No. evaluable
CHR (%)
Major
Complete
Progression-free survival (mos) (%)
Survival (mos) (%)
FDA pivotal
trial
M. D. Anderson
experience
181
37
237
80
33
24
49 (24)
63 (24)
35
24
68 (18)
73 (18)
CML: Chronic myelogenous leukemia; FDA: Food and Drug Administration; CHR: complete hematologic response.
The overall response rates were 40 –50% (CHR in
7–20%), but the complete cytogenetic response rate
was only 7%.158 The median survival was 7 months.
Compared with Ara-C-based chemotherapy, imatinib
produced similar response rates in patients with nonlymphoid blastic phase, and was associated with lower
toxicity and induction mortality rates, and with better
survival.161 However, the results still were poor, and
combinations of imatinib and chemotherapy should
be investigated further. The results of imatinib in cases
of blastic phase have been updated and compared
with intensive chemotherapy in Table 6.
Phase III studies. A multinational study (IRIS) randomized 1106 patients to received either imatinib at a dose
of 400 mg orally daily (n ⫽ 553) or a combination of
IFN-␣ at a dose of 5 MU/m2 daily with Ara-C at a dose
of 20 mg/m2 subcutaneously daily for 10 days every
month (n ⫽ 553).163 The median follow-up time was
19 months. After 18 months of therapy, imatinib was
associated with significantly higher rates of major cytogenetic responses (87% vs. 35%) and complete cyto-
448
TABLE 6
Results of Imatinib Therapy in Patients with blastic phase CML and Comparison of Results with Ara-C-Based
Chemotherapy Combinations
Parameter
No. treated
CHR plus other objective
response (%)
Major
Complete
Survival
Median (mos)
12-mos. (%)
4-week mortality (%)
Imatinib; FDA
pivotal trial
Imatinib;
M. D. Anderson
Intensive
chemotherapy,
M.D. Anderson
229
75
133
8 ⫹ 22 (31%)
23 ⫹ 29 (52%)
29
16
7
12
7
Not available
7
28
7
23
4
4
15
15
P value
0.001
0.04
0.07
CML: chronic myelogenous leukemia; Ara-C: Cytosine arabinoside; FDA: Food and Drug Administration; CHR: Complete hematologic response.
TABLE 7
Comparison of Imatinib Versus Interferon-␣ plus Low-Dose Ara-C in
Newly Diagnosed Patients with Ph-Positive CML
18-month response
parameter
CHR (%)
Major
Complete
18-mos progression-free
survival (%)
18-mos transformation (%)
18-mos survival (%)
Imatinib
Interferon ⴙ Ara-C
P value
97
69
0.001
87
76
35
14
0.001
0.001
92
3
97
73
9
95
0.001
0.001
0.16
Ara-C: cytosine arabinoside; Ph: Philadelphia Chromosome; CML: chronic myelogenous leukemia;
CHR: Chronic hematologic response.
genetic responses (76% vs. 14%) and with lower rates
of disease progression (8% vs. 27%), transformation
(3% vs. 9%), and intolerance (1% vs. 19%) (Table 7).
These results illustrate that, whereas at the time of
diagnosis, practically 100% of the bone marrow cells in
patients with CML contain the Ph chromosome, a
healthy but suppressed normal stem cell pool must
exist in nearly all patients in the early chronic phase of
the disease that can be reactivated by the suppression
or elimination of Ph-containing leukemic bone marrow cells. Survival rates were 97% versus 95% (p
⫽ 0.16). However, the median duration of IFN-␣ plus
Ara-C therapy was only 8 months and at the time of
last follow-up, 89% of patients had either crossed over
to imatinib therapy (58%) or elected to be taken off
therapy and treated with commercially available imatinib. Thus, although a survival advantage for imatinib
may not be detectable in this randomized trial, it
could be inferred from comparisons with historical
data (Fig. 1). Based on these results, imatinib should
be considered the new frontline standard of care for
CML patients with early chronic-phase disease.
The incidence of qualitative or quantitative RT-PCR
negativity is currently approximately 10% in patients
with chronic-phase disease after IFN-␣ failure (median
follow-up of 3 years), 10% in newly diagnosed patients
after 12 months of imatinib at a dose of 400 mg daily,
and about 30% in similar patients treated with imatinib
at a dose of 800 mg daily.162,166 Recently, the emergence
of resistance to imatinib has become the focus of intense
research, especially in patients with acute leukemia and
those previously treated with IFN. Several mechanisms
have been identified, including mutations in the catalytic domain of the protein and, less frequently, amplification of BCR-ABL.167 At the current time, this is a rare
event in patients treated with imatinib initially. A practical approach to the management of the side effects
occurring with imatinib is shown in Table 8.
Special therapeutic considerations
Patients with severe signs and symptoms related to
hyperleukocytosis should undergo leukapheresis.
These symptoms include evidence of cardiopulmonary compromise, alterations to the central nervous
system, and priapism. Severe thrombocytosis may respond to anagrelide, thiotepa, IFN-␣, or pheresis.
Pregnant women with CML may have their disease
controlled with pheresis during the first trimester, and
later with hydroxyurea until delivery, although the
long-term sequelae of this intervention are unknown.
The use of IFN-␣ during pregnancy has been reported
to be safe anecdotally in patients with essential thrombocytosis and in those with CML. However, little experience exists regarding the use of imatinib during
TABLE 8
Management of Side Effects from Imatinib
Side effect
Management
Nausea and/or
emesis
Avoid taking imatinib on an empty stomach
Diarrhea
Skin rashes
Muscle cramps
Bone aches
Liver function
abnormalities
Antiemetics (e.g., ondansetron at a dose of 8 mg orally or
prochlorperazine at a dose of 10 mg orally 30 minutes
prior to intake of imatinib)
Adequate fluid intake
Loperamide at a dose of 2 mg orally after each loose bowel
movement (up to 16 mg daily) or diphenoxylate
atropine at a dose of 20 mg orally daily in 3–4 divided
doses
avoid sun exposure
topical steroids (e.g., 0.1% triamcinolone cream topically as
needed)
Systemic steroids (e.g., prednisone at a dose of 20 mg
orally daily for 3–5 days)
Electrolyte substitution
Tonic water (quinine)
Ca2⫹ replacements
Cox-2 inhibitors (e.g. celecoxib at a dose of 200 mg orally
daily or rofecoxib at a dose of 25 mg orally daily)
Hold imatinib
Resume within 1–2 weeks
Consider decreasing the dose (no less than 300 mg orally
daily)
Myelosuppression
Anemia
Neutropenia
Thrombocytopenia
Erythropoietin as needed
G-CSF as needed
Hold for platelets ⱕ 40 ⫻ 109/L
High-dose folic acid
Interleukin-11 as needed
Resume at lower dose level (no less than 300 mg orally
daily)
G-CSF: granulocyte–colony-stimulating factor.
pregnancy. Splenectomy may provide palliation in patients with CML in transformation.
Experimental therapies for CML
Other agents currently are being developed that may
have enhanced activity in combination with imatinib.
Polyethylene glycol (PEG) IFNs are a modified formulation of IFN-␣ attached to polyethylene glycol. This
prolongs the half-life of IFN-␣ from minutes to days,
allowing once-a-week administration, and may reduce
toxicity and improve efficacy.168 In a randomized
study in patients with early chronic-phase CML, 144
patients received either PEG-IFN-␣-2a (PEG Roferon
[Hoffman-La Roche, Nutley, NJ]; Pegasys) or IFN-␣2a.169 After 12 months of therapy, PEG-IFN-␣-2a was
associated with significantly higher CHR rates (69% vs.
41%; P ⫽ 0.0008), major cytogenetic response rates
(35% vs. 18%; P ⫽ 0.016), and a lower incidence of
449
withdrawal for side effects (8.5% vs. 22%). When combined with Ara-C, PEG-IFN-␣-2b (PEG Intron; Schering-Plough, Kenilworth, NJ) demonstrated encouraging results.170
YNK01 is an oral Ara-C precursor metabolized to
Ara-C in the liver. YNK01 combined with IFN-␣ in
patients with newly diagnosed CML resulted in a CHR
rate of 78%, a major cytogenetic response of 39%, and
a toxicity rate of 30%.171,172
Homoharringtonine (HHT) is a semisynthetic
plant alkaloid. In late chronic-phase CML, a low-dose
continuous infusion schedule of HHT (2.5 mg/m2 intravenously daily every 7–14 days) induced a CHR in
65% of patients and cytogenetic responses in approximately 30%.173 Survival was longer with the combination of HHT plus Ara-C versus HHT alone (4-year
survival rate of 58% vs. 38%; P ⫽ 0.02).174 Favorable
results have been observed in patients with early
chronic-phase CML treated with HHT alone and in
combinations.175,176 Current investigations include
combinations of HHT, IFN-␣, and Ara-C; subcutaneous routes of HHT delivery; and possible future combination with imatinib mesylate.177
5-aza-2⬘-deoxycytidine (decitabine) is a cytidine
analogue that inhibits DNA methyltransferase. Decitabine therapy produced response rates of 28% in patients with blastic phase CML and of 50 – 60% in patients with accelerated phase CML.178 –180 Decitabine
is currently under investigation in imatinib-resistant
CML phases.
Activation of the RAS signal transduction pathway
is a central event in BCR-ABL-induced malignant
transformation. Farnesyl transferase inhibitors (FTI)
inhibit the enzyme farnesyl protein transferase, disrupt RAS prenylation, alter proper subcellular localization, and result in inhibition of RAS-dependent cellular transformation. FTIs have demonstrated anti-CML
activity in preclinical murine animal models injected
with STI-resistant CML lines.181 FTIs have also been
evaluated with some success in patients with acute
myeloid leukemia and those with CML.182,183
Immunotherapy to treat CML has been tested in
the context of minimal residual disease after transplantation. One patient with accelerated phase CML
achieved a complete disease remission after therapy
with in vitro selected, expanded, leukemia-reactive,
cytotoxic T-lymphocytes.184 Vaccination of CML patients with BCR-ABL fusion peptides has been demonstrated to be safe and to elicit specific immune
responses.185,186 Other strategies include T-cell-depleted allogeneic SCT to reduce transplant toxicity,
followed by infusions of incremental doses of T-cells
to eradicate minimal residual disease.
The addition of granulocyte-macrophage colony-
450
stimulating factor (GM-CSF) therapy to IFN-␣-sensitive patients was reported to induce significant cytogenetic responses.187 Smith et al. reported that the
combination of GM-CSF and IFN-␣ induced rapid cytogenetic responses in 78% of 38 patients with CML.188
The rationale for this approach was that both GM-CSF
and IFN-␣ induced cell differentiation of CML progenitors in vitro. GM-CSF also induced increased expression of HLA-DR, facilitating recognition of CML cells
by natural killer lymphocytes.
Current and future studies of interest include combinations of imatinib (regular or high-dose)166,189,190
with IFNs, hematopoietic growth factors, Ara-C, HHT,
decitabine, FTIs, SRC inhibitors, and others.191 The use
of imatinib in the setting of allogeneic or autologous SCT
is being actively explored.135
Choice of Initial Therapy for Patients with Chronic-Phase
CML
Ongoing studies of imatinib as frontline therapy in
patients with newly diagnosed chronic phase CML,
and as salvage therapy, are maturing with continued
positive results. Patients with newly diagnosed
chronic phase CML who are treated outside the setting
of a clinical trial may be offered therapy either with
imatinib or allogeneic SCT. The choice of therapy is
based on 1) the benefit:risk ratio of allogeneic SCT
versus imatinib, 2) patient risk group, and 3) patient
preference. Although the standard of care remains
controversial and is updated continuously, treatment
algorithms are based on the following principles: 1)
Postponing allogeneic SCT for up to 24 months and
the pretransplantation use of imatinib do not appear
to influence transplantation outcome adversely123; 2)
The 1-year TRM is age-related and may define what is
a reasonably acceptable risk of transplantation in exchange for long-term outcome; 3) The median survival
with IFN-␣-based regimens is reported to be 6 –7
years, for good risk patients the median survival is 9
years, and for patients who achieve a complete cytogenetic response the 10- year survival rate is between
70 – 80%71–74; and 4) Because imatinib induces complete cytogenetic response rates of ⱖ 60%,162,163 the
median survival in CML patients may exceed 10 years
if the significance of a complete cytogenetic response
is similar when achieved with imatinib as when
achieved with IFN-␣ therapy.
Arguments favoring upfront allogeneic SCT include: 1) it is the only proven curative modality; and 2)
delaying allogeneic SCT may worsen patient outcome.
Long-term follow-up results with imatinib are not currently available. Therefore: A) it could have a transient
benefit, B) it may not have the same association of
cytogenetic response with survival, C) it may have
unexpected long-term toxicities, and D) it may adversely affect allogeneic SCT results.
Arguments in favor of imatinib as frontline CML
therapy include: 1) the potential of long-term eventfree survival outside the setting of allogeneic SCT (10%
at 10 years with IFN-␣); 2) comparing imatinib with
IFN-␣, the complete cytogenetic response rates (76%
vs. 14%) and major cytogenetics response rates (87%
vs. 35%) (surrogate endpoints for better survival) appear to be much higher with imatinib; 3) in addition to
allogeneic SCT mortality (approximately 5–20% in
some series and 10 –50% in others), there are considerable toxicities associated with allogeneic SCT (e.g.,
cataracts, sterility, second tumors, hip necrosis, decreased quality of life, and GVHD); and 4) the followup studies with imatinib have not demonstrated significant unusual or unexpected side effects, or high
rates of resistance in patients with chronic phase
disease.
Thus, with currently available knowledge, and until data further mature for imatinib and for allogeneicrelated and unrelated transplantation, patients may
be offered the options of allogeneic SCT or imatinib as
initial therapies, after a detailed discussion of updated
results has taken place.
Treatment of Accelerated and Blastic-Phase Disease
Response rates to chemotherapy combinations are reported to be 20% in patients with nonlymphoid blastic
phase and 60% in patients with lymphoid blastic
phase (with anti-ALL therapy). The median survivals
are 3– 6 months and 9 –12 months, respectively.
Allogeneic SCT is the only proven curative therapy
for accelerated and blastic phase disease. Cure rates
are in the range of 15– 40%, and 5–20%, respectively.
Patients with cytogenetic clonal evolution as the only
accelerated phase criterion appear to fare better, with
long-term event-free survival rates of 60% after allogeneic SCT. However, reinduction of a second chronic
phase or a disease remission before allogeneic SCT
may improve the outcome of allogeneic SCT in patients who achieve such remissions. Outside the context of allogeneic SCT, imatinib is the only approved
treatment for accelerated or blastic phase CML. Although single-agent imatinib is the most active agent
in accelerated phase, and still has activity in the blastic
phase, results are far less favorable than in chronic
phase CML, and it appears the majority of patients will
develop a disease recurrence (Table 6). Thus, combinations of imatinib with IFN-␣, Ara-C, other chemotherapy, or investigational agents (e.g., HHT, decitabine, or FTIs) are indicated in patients with advanced
phases of CML. In those patients with lymphoid
blastic phase and Ph-positive ALL, combinations of
imatinib with anti-ALL therapy (e.g., hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, and dexamethasone]) currently are being investigated. Similarly, patients with nonlymphoid blastic-phase disease
should be treated with combinations of imatinib and
anti-acute myeloid leukemia (AML) chemotherapy
(e.g., Ara-C plus anthracyclines) or investigational regimens (e.g., decitabine or FTIs). In general, patients
with disease in the accelerated or blastic phases
should be encouraged to participate in clinical trials to
attempt to determine the optimal treatment strategy.
Splenectomy is useful as a palliative measure in patients with massive painful splenomegaly and/or hypersplenism or thrombocytopenia, and should be favored over splenic irradiation.
CONCLUSIONS
The prognosis for patients with CML has significantly
improved over the last 20 years. Whereas the median
survival rates were 4 –5 years in the era of hydroxyurea,
the introduction of IFN-␣, both alone and in combination with Ara-C, has nearly doubled these numbers.
However, the development of imatinib has represented one of the biggest leaps forward in the treatment of CML. As a small molecule targeting a protein
specific for the leukemic cells, it helped to irreversibly
shift the focus to an understanding of the molecular
processes that underlie the malignant phenotype as a
basis for successful therapy. In addition to the impressive clinical results achieved with imatinib itself, the
possibility of being able to interfere with specific signaling pathways of tumor cells has spurred a flurry of
activity in the development of other targeted therapies
such as FTIs, SRC inhibitors, inhibitors of PI-3-kinase,
and proteasome inhibitors. Therefore, a true paradigm
shift has occurred in changing our therapeutic thinking and approach, not only in CML, but in other
malignancies as well.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
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C Chronic Myelogenous Leukemia: A Review and Update of Therapeutic Strategies Guillermo Garcia-Manero,

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