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The Biology and Treatment of Chronic Myelogenous Leukemia

The Biology and Treatment of Chronic Myelogenous Leukemia

ABSTRACT: Over the past 2 decades, our understanding of the pathobiological events underlying chronic myelogenous leukemia (CML) has grown. At the same time, effective transplant and nontransplant treatment approaches to CML have been developed that increase the options available to newly diagnosed patients, and that can cure or prolong survival in this formerly incurable disease. Newly diagnosed patients presenting with extreme leukocytosis or thrombocytosis may benefit from immediate therapy with hydroxyurea (Hydrea) and pheresis. After stabilization, eligible patients may elect to undergo immediate transplant. The majority, however, should begin therapy with either interferon-alpha and cytarabine, or they should be entered into the STI-571 trials. [ONCOLOGY 15(1):23-35, 2001]


Chronic myelogenous leukemia
(CML) is a malignancy of the
human hematopoietic stem cell. It is characterized clinically by the presence of
increased immature and mature granulocytes in the peripheral blood. Red blood
cell and platelet numbers may also be abnormal. Myeloid hyperplasia is the
dominant feature in the marrow. The characteristic cytogenetic abnormality is a
deletion of the short arm of chromosome 22 (22q-) known as the Philadelphia
chromosome (Ph) and is often found as a balanced translocation with chromosome
9, abbreviated t(9;22). This abnormal chromosome is present in all myeloid lineages, in some B lineage lymphoid cells, and
occasionally, in T lymphocytes. At the molecular level, this translocation is
recognized as a fusion between the breakpoint cluster region (BCR) on chromosome
22 and the Abelson gene (ABL) on chromosome 9, thus resulting in the BCR-ABL
oncogene and its protein product, p210BCR-ABL. [1,2]

The median age at onset is 50 years, although children may also
be affected by CML.[2] Asymptomatic patients may be discovered through
abnormalities in routine blood tests. Alternatively, patients may present with
leukocytosis, splenomegaly, fatigue, anorexia, weight loss, or other signs of
systemic disease.[2] As many as 50% of patients will have splenomegaly at
presentation. Clinical features at presentation may have prognostic importance (Table

The majority of newly presenting patients experience a
"chronic phase" during which signs and symptoms of leukemia can be
controlled with hyrodxyurea (Hydrea) or interferon-alpha. In many patients, CML
eventually progresses to an "accelerated phase" characterized by
cytogenetic evidence of clonal evolution, further blood count abnormalities,
increased drug dosage requirements, and/or worsening clinical symptoms.
Eventually, patients may enter a "blast crisis," defined by the
presence of 30% or more myeloblasts or lymphoblasts in the blood or marrow.[4,5]
Certain cytogenetic abnormalities involving chromosomes 7, 8, 9, 17, and 21 may
herald progression to the accelerated phase or blast crisis.[4,6]


The hybrid mRNA created by the fusion of the BCR and ABL genes
encodes the p210BCR-ABL. At least two other isoforms of the fusion protein may
be created. A breakpoint upstream of the one observed in the p210BCR-ABL results
in p190BCR-ABL, while a breakpoint downstream results in
p230BCR-ABL. The p190BCR-ABL is commonly found in acute lymphocytic leukemia (ALL),[7] while the
p230BCR-ABL is observed in chronic neutrophilic leukemia (CNL).[8]

The p210BCR-ABL is a cytoplasmic protein with tyrosine kinase
activity that stimulates transcription of several target genes. The net result
is abnormal adhesion, proliferation, differentiation, and apoptosis of malignant
cells containing the BCR-ABL gene. These abnormalities lead to an increase in
circulating immature myeloid progenitors. Prolonged survival of CML cells may
allow acquisition of additional cytogenetic mutations, resulting in resistance
to chemotherapy and evolution to blast crisis.[1,9-12]

Conventional Therapy With Busulfan or Hydroxyurea

Busulfan (Myleran) is an alkylating agent that was initially
used to treat CML in the early 1950s.[13] It is an effective therapeutic agent
in CML; however, fatal marrow suppression and lung fibrosis may result from
busulfan administration.[5]

Hydroxyurea is a cycle-specific inhibitor of DNA synthesis with
biological activity in CML. Hydroxyurea provides disease control rates similar
to or better than those achieved with busulfan but with less toxicity.[14,15]
Myelosuppression, a major problem with busulfan, is usually transient with
hydroxyurea.[5] Other side effects of hydroxyurea include nausea and anorexia,
skin atrophy, alopecia, macrocytosis, megaloblastic changes in the marrow, and
rarely, skin or mucosal ulcers.[5]

Complete cytogenetic responses seldom occur with either
hydroxyurea or busulfan. However, a randomized study demonstrated significantly
longer median survival and duration of chronic phase with hydroxyurea.[15]


Interferon-alpha is a naturally occurring cytokine introduced
into CML therapy in the early 1980s.[16] Many investigators now consider it to
be the treatment of choice for newly diagnosed chronic-phase patients ineligible
for allogeneic hematopoietic stem cell transplantation. Interferon-alpha used as
a single agent for initial therapy yields complete hematologic response rates in
up to 80% of cases, and major cytogenetic responses (> 66% Ph-negative
metaphases) in up to 38% of selected, newly diagnosed patients.[17] Results of
randomized trials comparing interferon-alpha to conventional therapy are
described in Table 2.[18-22]

Most investigators recommend subcutaneous administration of
interferon-alpha on a daily basis at a dose of 5 million U/m2/d. To avoid
toxicity, treatment should be initiated at 25% of the target dose, increased
gradually over 1 month, and adjusted according to blood counts. Use of an
intermittent treatment schedule or a lower target dose may not produce sustained
remissions as effectively. Prolonged administration of interferon (12 to 18
months) may be necessary to achieve a complete or major cytogenetic

Patients who attain a major cytogenetic response on
interferon-alpha therapy may experience long-term hematologic remissions and,
rarely, the disappearance of the BCR-ABL gene abnormality. It is not yet known
how long interferon-alpha therapy should be continued in responding patients to
avoid disease recurrence; however, administration for at least several years
after cytogenetic remission seems prudent.

Failure to achieve a major cytogenetic remission after treatment
with recommended doses of interferon-alpha for 1 to 2 years is considered a poor
prognostic indicator (Figure 1).[23] In such cases, patients may be eligible for
experimental therapy, or use of hydroxyurea may be warranted to reduce cost and

Several clinical trials suggest that interferon-alpha is
superior to busulfan and/or hydroxyurea therapy for the treatment of CML.[18-22]
A meta-analysis of trials found that CML patients treated with interferon-alpha
achieve a superior 5-year survival, when compared with busulfan and/or
hydroxyurea (57% vs 42%). The absolute improvement in the 5-year survival rate
was 20% in trials of interferon vs busulfan and 15% in trials of interferon vs

Combination Therapy

Combination therapy consisting of interferon-alpha and
cytarabine in newly diagnosed chronic-phase CML patients may be more effective
than therapy with interferon-alpha alone. Oral cytarabine is administered daily
at a dose of
10 mg/m2 (or according to other low-dose schedules) in combination with
daily subcutaneous interferon-alpha, 5 million U/m2. Combination therapy
has resulted in major cytogenetic response rates in up to 50% of patients as
well as significantly improved long-term survival rates, compared to
interferon-alpha alone. However, toxicity with the combined therapy regimen may
also be greater.[23,25]

Related-Donor Hematopoietic Stem Cell Transplantation

At present, allogeneic hematopoietic stem cell transplantation
is the only proven curative therapy for CML. Patients transplanted during
chronic phase and within 1 year of diagnosis (early chronic phase) report the
most favorable outcome. The reported incidence of long-term disease-free
survival for these patients ranges from 50% to more than 80%, whereas for
patients undergoing transplantation in accelerated phase or in blast crisis, the
survival rate is only approximately 40% and 15%, respectively.

The incidence of relapse among patients receiving transplants in
the chronic phase is approximately 10%; however, the relapse rate increases to
approximately 60% when transplantation is performed in blast crisis. Other
patient characteristics that contribute to an adverse effect on outcome include
older recipient age and a prolonged interval from the time of diagnosis to
transplant. Modifications to traditional transplantation approaches—eg, use of
blood rather than marrow as a source of donor stem cells, removal of total-body
irradiation from the preparative regimen, and use of hematopoietic growth factor
support—may improve outcome.[26,27]

Graft-vs-Host Disease

Graft-vs-host disease (GVHD) is the primary cause of death in
related-donor hematopoietic stem cell transplantation. Better GVHD prophylaxis
regimens using cyclosporine (Neoral, Sandimmune) and short-course methotrexate
have improved outcome, and preparative regimens that minimize inflammatory
damage to normal tissue may also reduce the clinical effects of GVHD.[28]

Although GVHD may be deleterious to the patient, an
immune-mediated antileukemia effect (graft-vs-leukemia) is important in
preventing relapse after human leukocyte antigen (HLA)-identical sibling
transplants for CML and possibly other malignancies. Graft-vs-leukemia effects
are mediated at least in part by T lymphocytes and, possibly, by other immune
effector cells. Consequently, relapse rates after T-cell-depleted allogeneic
hematopoietic stem cell transplantation may be higher than in the non-T-cell-depleted
transplant setting.

The efficacy of hydroxyurea or interferon-alpha therapy vs
related-donor hematopoietic stem cell transplantation has not been investigated
in randomized trials. However, retrospective analyses suggest an improved
long-term survival advantage for CML patients receiving related-donor
transplantation, compared to patients receiving hydroxyurea or interferon-alpha.
A lower early mortality rate has been observed in
interferon-alpha/hydroxyurea-treated patients, although long-term survival rates
fall because of continued late relapse.

In the hematopoietic stem cell transplantation group, there is a
high early mortality associated with transplant-related complications. However,
the survival curve then reaches a plateau because few late relapses or other
fatal complications occur. As a result, the survival curves cross at 2 to 6
years, depending on the risk categories studied, and long-term survival for
transplant recipients proves superior (Figure 2).[29] Of course, such analyses
do not take into account more elusive end points such as long-term side effects,
quality of life, and cost of therapy, which may differ with hematopoietic stem
cell transplantation and interferon-alpha therapy for CML.

One seemingly logical approach to the treatment of CML is a
trial of interferon-alpha followed by relatively early intervention with
allogeneic stem cell transplantation in patients who do not tolerate
interferon-alpha therapy or in whom such therapy fails. This approach has been
controversial because some investigators report an adverse effect from previous
interferon-alpha therapy on allogeneic transplant outcome,[30] while others find
no such effect.[31-33] A recent European report suggests that an adverse effect
on subsequent stem cell transplantation for CML can be avoided if
interferon-alpha therapy is curtailed at least 3 months before transplant
therapy is initiated.[34]


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