Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia

Hagop Kantarjian and Jorge Cortes

Summary of Key Points

Incidence

• About 5000 cases of chronic myeloid leukemia (CML) occur per year in the United States; CML represents 15% of all leukemias.

• Median age is 55 to 60 years at diagnosis.

Clinical Findings

• Common findings include fatigue, anemia, abdominal discomfort, splenomegaly, and leukocytosis.

• At diagnosis 40% to 50% of patients are asymptomatic.

• White blood cell count is usually greater than 50 × 109 cells/L, with a left-shifted differential, basophilia, and thrombocytosis.

Differential Diagnosis

• Chronic myelomonocytic leukemia

• Other myeloproliferative disorders

• Leukemoid reactions

Evaluation

• History and physical examination, complete blood cell count with differential and platelet count, and chemistries

• Bone marrow aspiration and biopsy

• Testing for the presence of the Philadelphia (Ph) chromosome by cytogenetic analysis; testing for the presence of the BCR-ABL fusion gene by fluorescent in situ hybridization (FISH) and by quantitative polymerase chain reaction (qPCR) analysis

Therapy

• Hydroxyurea or a BCR-ABL tyrosine kinase inhibitor (TKI; e.g., imatinib mesylate, nilotinib, dasatinib) is given initially to control leukocytosis and thrombocytosis.

• Imatinib induces a complete hematologic and cytogenetic response in most patients; estimated 8- to 10-year survival rate is 85% (93% if only CML-related deaths considered).

• Randomized studies of frontline therapy with second-generation TKIs (e.g., nilotinib, dasatinib) show better results than those of imatinib.

• New TKIs (e.g., dasatinib, nilotinib, bosutinib, ponatinib) are active after imatinib failure.

• Allogeneic stem cell transplantation may be curative but is associated with considerable morbidity and mortality.

Introduction

Chronic myeloid (or myelogenous) leukemia (CML) is a clonal hematopoietic stem cell disorder. It is characterized by overproduction of myeloid cells, a result of excessive proliferation, and reduced apoptosis. Clinical findings include fatigue, splenomegaly, leukocytosis, and anemia. Basophilia and thrombocytosis are common.33 CML is defined by the presence of a characteristic cytogenetic abnormality, the Philadelphia (Ph) chromosome, a reciprocal balanced translocation between the long arms of chromosome 9 and 22, t(9;22)(q34;q11.2). This results in a BCR-ABL fusion gene, which is causally related to the disease pathophysiology.66

The typical course of untreated CML is biphasic or triphasic. Most patients are diagnosed in the indolent or chronic phase. If not treated appropriately, CML progresses into the accelerated and blastic phases, which are ominously fatal. Before the discovery of imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor (TKI), the median survival of patients with chronic-phase CML was 3 to 4 years with hydroxyurea and 6 to 7 years with interferon-α (IFN-α). Imatinib has resulted in a dramatic change in the prognosis of CML and is associated with an estimated 8- to 10-year survival rate of 85% (93% if only CML-related deaths are considered). Allogeneic stem cell transplantation (SCT) is curative in CML but is associated with mortality and with significant morbidity. As the long-term results with imatinib and other TKIs continue to mature positively, allogeneic SCT, previously a frontline therapy among eligible patients, is now considered as a second- or third-line strategy in CML after failure of TKI therapy.

Incidence, Epidemiology, and Etiology

CML accounts for 15% of cases of leukemia in the United States. There is a slight male preponderance (male-to-female ratio, 1.6 : 1). Its annual incidence is about 1.5 cases per 100,000 individuals. About 5,000 cases of CML are diagnosed annually. This incidence has not changed during the past few decades, and it increases with age. The median age at diagnosis is 55 to 65 years; it is uncommon in children and adolescents; only 2.7% of patients with CML are younger than 20 years.7

Before imatinib therapy, the prevalence of CML was about 25,000 cases in the United States. Now that the annual mortality after imatinib therapy has been reduced to 2% or less, the prevalence of CML will continue to rise, reaching a plateau (in the next 20 years) at about 180,000 cases (when the annual incidence will equal the annual mortality: based on a hazard risk of annual mortality of 1.5 for patients with CML compared with age-matched healthy individuals).8 This increase will change CML from an uncommon disorder to a prevalent one.

There are no known familial associations in CML. Its risk is not increased in monozygotic twins or in relatives of patients with CML. There are no known common etiologic agents identified in CML. Ionizing radiation (exposure to nuclear bombs or accidents; radiation treatment of ankylosing spondylitis and cervical cancer) has increased the risk of CML. Its peak incidence is 5 to 10 years after exposure and is dose related. The risk of CML is not increased in individuals working in the nuclear industry. Radiologists working without adequate protection (before 1940) had an increased risk of developing CML, but no such risk has been found in recent studies. Benzene exposure increases the risk of acute myelogenous leukemia but not of CML. CML is not a frequent secondary leukemia after treatment of other cancers with radiation and/or alkylating agents.9,10

Pathogenesis

Molecular Pathogenesis

The Ph chromosome abnormality is present in more than 90% of patients with typical CML (Fig. 101-1). It results from a balanced reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11.2). It is found in hematopoietic cells but not in other human cells. Its origin is close to the pluripotent stem cell, and it is present in erythroid, myeloid, monocytic, and megakaryocytic cells, less commonly in B lymphocytes, rarely in T lymphocytes, but not in marrow fibroblasts. The breakpoint of chromosome 9 results in translocation of the cellular oncogene ABL1 to a region on chromosome 22 coding for the major breakpoint cluster region (BCR). ABL1 is a homolog of V-ABL, the Abelson virus that causes leukemia in mice. This juxtaposes a 5′ portion of BCR to a 3′ position of ABL1 and produces a new hybrid oncogene, BCR-ABL. This codes for a novel BCR-ABL oncoprotein of molecular weight 210 kDa (p210BCR-ABL). The p210BCR-ABL oncoprotein results in uncontrolled kinase activity, which causes excessive proliferation and reduced apoptosis of CML cells,1313 leads to a growth advantage of CML cells to normal cells, and suppresses normal hematopoiesis. The normal stem cells, although suppressed, persist and reemerge after effective therapy of CML.

In Ph-positive acute lymphocytic leukemia, the breakpoint in BCR often occurs in a more centromeric region called the minor BCR region (mBCR). This produces a smaller BCR gene opposing ABL1, and therefore a fusion gene, messenger RNA, and BCR-ABL oncoprotein (p190BCR-ABL) of smaller sizes. A third rare breakpoint distal to the major BCR region, called µ-BCR, produces a p230BCR-ABL hybrid oncoprotein associated with a very indolent course of CML (see Fig. 101-1).14

The constitutive activation of BCR-ABL results in autophosphorylation and activation of downstream pathways that alter gene transcription, apoptosis, cytoskeletal organization, cytoadhesions, and degradation of inhibitory proteins. These signal transduction pathways involve RAS, mitogen-activated protein (MAP) kinases, signal transducers and activators of transcription (STAT), phosphatidylinositol-3-kinase (PI3K), MYC, and others. Many of these interactions are mediated through tyrosine phosphorylation and require binding of the BCR-ABL to adapter proteins such as GRB-2, CRK, CRK-like protein (CRKL), and Src homology–containing proteins (SHC). Understanding the pathophysiology of these events could result in the successful development of targeted therapies that may synergize with TKIs to improve further the prognosis in CML.

What causes the BCR-ABL molecular rearrangement is unknown. Molecular techniques that amplify detection of BCR-ABL to 1 in 108 detect it in marrow cells of 25% to 30% of normal adults, in 5% of infants, but not in cord blood.15 Because CML develops in only 1.5 of 100,000 individuals (i.e., 1 to 2 per 25,000 to 30,000 individuals who express BCR-ABL in their bone marrow), additional molecular events or lack of immune recognition of the clonal cells may contribute to the development of CML.

The fusion BCR-ABL gene and the p210 oncoprotein can be found in some patients with typical morphologic CML, in whom the t(9;22)(q34;q11.2) is not identified. These patients have a response to therapy and a survival rate similar to those with Ph-positive cases. Patients with Ph-negative and BCR-ABL-negative CML (see later discussion) constitute a different entity (atypical CML) and have a worse prognosis.16,17 The molecular pathophysiology of CML transformation is poorly understood. Several molecular events have been associated with CML transformation, including point mutations or deletions in the TP53 tumor suppression gene, MYC amplification, deletions in the CDKN2A tumor suppressor gene, alteration of the RB retinoblastoma gene, and others. The causal relation of these events to transformation is not clear.

Animal Models of Chronic Myeloid Leukemia

Experimental models have established a causal relationship between the BCR-ABL molecular events and the development of CML. Transgenic mice that express Bcr-Abl developed acute leukemia. A Bcr-Abl–expressing retrovirus used to infect murine bone marrow cells that later repopulate irradiated mice resulted in myeloproliferative disorders, including a CML-like syndrome.2020 Bcr-Abl, under the control of a tetracycline-repressible promoter, expressed in mice, resulted in a lymphoid leukemia that reversed in the presence of tetracycline,21 attesting to the leukemic potential of Bcr-Abl as a sole oncogenic abnormality. The recapitulation of CML-like disorders in animal models mediated by the Bcr-Abl molecular events established them as a root cause for CML and a legitimate molecular target for therapeutic interventions with TKIs.

Clinical Presentation

Chronic Phase

About 50% to 60% of patients with CML diagnosed in the United States are asymptomatic. The disease is found on routine physical examination or blood tests.

Common signs and symptoms of CML, when present, result from anemia and splenomegaly. These include fatigue, weight loss, malaise, early satiety, and left upper quadrant fullness or pain (Table 101-1). Rare manifestations include bleeding (associated with a low platelet count and/or platelet dysfunction), thrombosis (associated with thrombocytosis and/or marked leukocytosis), gouty arthritis (from elevated uric acid levels), priapism (usually with marked leukocytosis or thrombocytosis), retinal hemorrhages, and upper gastrointestinal ulceration and bleeding (from elevated histamine levels due to basophilia). Leukostatic symptoms (dyspnea, drowsiness, loss of coordination, confusion) caused by sludging in the pulmonary or cerebral vessels, are uncommon in chronic-phase CML despite white blood cell (WBC) counts exceeding 100 × 109 cells/L.

Table 101-1

Features of Patients with Newly Diagnosed Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia in Chronic Phase Referred to MD Anderson Cancer Center (1990–present; N = 1469)

Parameter Percentage
Age ≥ 60 years (median) 18 (46)
Female gender 41
Splenomegaly 32
Hepatomegaly 5
Lymphadenopathy 5
Other extramedullary disease 2
Hemoglobin < 10 g/dL 12
Platelets  
 >450 × 109 cells/L 31
 <100 × 109 cells/L 3
 WBC ≥ 50 × 109 cells/L 38
Marrow  
 ≥5% blasts 6
 ≥5% basophils 14
Peripheral blood  
 ≥3% blasts 9
 ≥7% basophils 10
Cytogenetic clonal evolution other than the Philadelphia chromosome 4
Sokal risk  
 Low 62
 Intermediate 27
 High 10

image

Splenomegaly is the most consistent physical sign in CML and is detected in 30% to 50% of cases. Hepatomegaly is less common (10% to 20%). Lymphadenopathy, infiltration of skin or other tissues, is uncommon. When present, these findings may suggest accelerated or blastic phases of CML or Ph-negative CML. Headaches, bone pain, arthralgias, pain from splenic infarction, and fever are more frequent with CML transformation.

Laboratory features of untreated CML include leukocytosis with predominance of neutrophils and a left shift extending to blast cells. Basophils and eosinophils might be increased. Thrombocytosis is common; thrombocytopenia is rare and, if present, suggests a worse prognosis. Anemia (hemoglobin < 11 g/dL) is present in one third of patients. Biochemical abnormalities include a low leukocyte alkaline phosphatase score, which also occurs in some patients with agnogenic myeloid metaplasia. Serum levels of vitamin B12, lactate dehydrogenase, uric acid, and lysozyme are often increased. Some patients demonstrate a cyclic oscillation of the WBC count.

The bone marrow is hypercellular with marked myeloid hyperplasia. The myeloid-to-erythroid ratio is usually 15 : 1 to 20 : 1. About 15% of patients have 5% or more blast cells in the peripheral blood or bone marrow at diagnosis. Increased reticulin fibrosis is common (30% to 40% grade 3/4 reticulin fibrosis by silver staining), but collagen fibrosis is rare at presentation.22 Interestingly, whereas the “spent phase” of myelofibrotic CML was commonly reported in the past (with busulfan therapy) as an end-stage CML event, it has become uncommon in the eras of IFN-α and imatinib therapy. Imatinib effectively reduces myelofibrosis in CML.23,24

Accelerated and Blastic Phases

The definitions of accelerated and blastic phases of CML are shown in Table 101-2. In most patients the transformation from chronic to advanced phase is insidious, with the disease becoming more difficult to control. This phase is referred to as the accelerated phase. The criteria of accelerated phase are variable. In one study, features that correlated with a median survival of 18 months or less included a blast percentage equal or greater than 15%, blasts plus promyelocytes equal or greater than 30%, basophils equal or greater than 20%, a platelet count less than 100 × 109 cells/L unrelated to therapy, and cytogenetic clonal evolution.25 Features of accelerated-phase CML should be revisited because some (e.g., clonal evolution more favorable, blasts >15% less favorable) have different prognostic implications from recent studies (Fig. 101-2).26 Five to 10 percent of patients are seen in the accelerated phase; these patients have an estimated 8-year survival rate of 75% when treated frontline with TKIs.27 The accelerated phase is also associated with worsening anemia and splenomegaly, organ infiltration (liver, lymph nodes, skin, bones, or other tissues), and constitutional symptoms (aches, fever, malaise, weight loss).

Table 101-2

Definitions of the Accelerated and Blastic Phases of Chronic Myelogenous Leukemia

Criteria MD Anderson Cancer Center* International Bone Marrow Transplant Registry World Health Organization
ACCELERATED PHASE    
Percent blasts 15-29 10-29 10-19
Percent blasts + promyelocytes ≥30 ≥20 NA
Percent basophils ≥20 ≥20% (basophils + eosinophils) ≥20
Platelets (×109/L) <100 Unresponsive ↑, persistent ↓ <100 or > 1000 unresponsive
Cytogenetics CE CE CE not at diagnosis
WBC NA Difficult to control, or doubling in < 5 days NA
Anemia NA Unresponsive NA
Splenomegaly NA Increasing NA
Other   Chloromas, myelofibrosis Megakaryocyte proliferation, fibrosis
BLASTIC PHASE      
30% or more blasts; or extramedullary blastic disease, except for the World Health Organization classification, which requires 20% or more.

image

CE, clonal evolution; NA, not applicable; WBC, white blood cells.

*These criteria were also used in all the IFN-α and tyrosine kinase inhibitors studies.

Blastic-phase CML is diagnosed by the presence of 30% or more blasts in the bone marrow and/or peripheral blood or by the presence of extramedullary blastic disease. Blastic-phase CML resembles acute leukemia. Patients may experience fever, bone aches, bleeding, infections, weight loss, and increasing splenomegaly. Approximately 70% of patients have a myeloid or undifferentiated blastic phase and 30% have a B-cell lymphoid blastic phase.

In most patients the CML evolves into the accelerated phase before the blastic phase, but in 20% of patients transformation to a blastic phase may occur without warning. Most patients in accelerated- or blastic-phase CML have additional chromosomal abnormalities, such as a double Ph, trisomy 8, or isochromosome 17. Extramedullary blastic-phase CML can occur in the lymph nodes, skin, meninges (especially in lymphoid blastic-phase CML), bone, and other sites.

Diagnosis

The diagnosis of typical CML is simple and consists of documenting, in the setting of persistent unexplained leukocytosis (or occasionally thrombocytosis), the presence of the Ph chromosome t(9;22)(q34;q11.2) by routine cytogenetics or of the corresponding BCR-ABL rearrangement by fluorescent in situ hybridization (FISH) analysis or molecular studies.

A FISH analysis relies on the colocalization of large genomic probes specific to the BCR and ABL1 genes. Comparison of simultaneous marrow and blood samples by FISH analysis shows high concordance. FISH studies may have a false-positive range of 1% to 5%, depending on the probes used.

Reverse-transcriptase polymerase chain reaction (RT-PCR) amplifies the region around the junction between BCR and ABL1. It is highly sensitive for the detection of minimal residual disease. PCR testing can either be qualitative, providing information about the presence of the BCR-ABL transcript, or quantitative, assessing the amount of BCR-ABL transcripts. Qualitative PCR may be useful for diagnosis of CML; quantitative PCR (qPCR) is ideal for monitoring response to therapy and is usually performed by real-time PCR. Simultaneous peripheral blood and marrow PCR studies show a high level of concordance. False-positive and false-negative results can happen with PCR. False-negative results may be from poor-quality RNA or failure of the reaction or from atypical transcripts (e.g., b3a3); false-positive results can be due to contamination. A 0.5- to 1-log coefficient of variability in some samples can occur depending on testing procedures, sample handling, and laboratory experience.28,29

Because of the increasing importance of monitoring patient response to TKI by various methods including qPCR and FISH studies, it is important to measure these at diagnosis to ensure their positivity and quantitation. In 5% of patients with CML, variant breakpoints result in a false-negative qPCR test because the traditional probes used do not detect these variants. If the test is not performed at diagnosis in these patients, subsequent qPCR studies will suggest a “false” complete molecular response.

The Ph chromosome is usually present at diagnosis in 100% of metaphases, often as the sole abnormality. Between 10% and 15% of patients have additional chromosomal changes (clonal evolution) involving trisomy 8, isochromosome 17, additional loss of material from the second chromosome 22 (double Ph), or others.

Eighty-five percent of patients have a typical t(9;22) translocation; 5% have variant translocations, which can be simple (involving chromosome 22 and a chromosome other than chromosome 9) or complex (involving one or more chromosomes in addition to chromosomes 9 and 22). With imatinib, patients with Ph variants have a response to therapy and prognosis similar to those with Ph-positive CML.

Diagnostic and Monitoring Procedures

The improved rates of complete cytogenetic response and of molecular response with imatinib now require new techniques that measure these responses more accurately (rather than relying on evaluation of only 20 metaphases by routine cytogenetic studies), with less painful procedures (peripheral blood rather than marrow samples), and with methods that measure minimal disease below the level of detection by routine karyotypic analysis (molecular studies). FISH studies can assess rapidly the disease status in 200 cells; this assessment may be done in cells in interphase and can be performed on blood specimens. Real-time PCR studies usually measure the ratio of the abnormal message, BCR-ABL, to a control gene (e.g., ABL). Because this is variable by laboratory and with time, efforts are ongoing to standardize the measurement of BCR-ABL transcripts in relation to an international standard (IS).30 Recent monitoring procedures in CML have emphasized replacing bone marrow studies (cytogenetics) with peripheral blood studies (FISH, qPCR) as more reliable and measuring deeper levels of response to TKIs. FISH studies are reliable in patients in complete cytogenetic response with a strong concordance between negative FISH studies and complete cytogenetic response. However, the concordance between the percent of Ph positivity by FISH and cytogenetic studies is not perfect. Recently, landmark studies have emphasized the importance of BCR-ABL transcripts of 10% or less as early indicators for response and long-term prognosis and that the finding of BCR-ABL transcripts of 1% or less (IS) (grossly equivalent to a complete cytogenetic response) is an important response criterion at 1 year or later. In general, BCR-ABL transcripts less than 10% (IS) are equivalent to a partial cytogenetic response with Ph-positive metaphases less than or equal to 35%; and BCR-ABL transcripts less than or equal to 1% (IS) are equivalent to a complete cytogenetic response.3134 A BCR-ABL transcript of less than or equal to 0.1% (IS) (approximately a 3-log reduction of disease from a standardized baseline) has been associated with a low risk of relapse and with favorable PFS. A negative qPCR analysis (undetectable BCR-ABL transcripts; 4.5-log reduction or more) may be technique dependent and is referred to as a complete molecular response.

Monitoring response to imatinib-based therapy may use different approaches depending on the investigators’ experience, whether changes of residual disease affect subsequent therapy, availability of methodologies, and other factors. In general, patients with newly diagnosed CML require an initial bone marrow analysis (to evaluate the percentage of blasts and basophils and whether clonal evolution is present) and then once a year (to detect cytogenetic abnormalities in both the Ph-positive and Ph-negative cell). Some experts recommend bone marrow studies every 3 to 6 months in the first year because of the prognostic significance of the Ph-positive status from routine marrow cytogenetic studies. Practically, peripheral blood FISH studies every 3 to 4 months provide a reasonable estimate of the response profile in the first year. Once Ph-positive cells are 0% by FISH, the complete cytogenetic response can be confirmed by a bone marrow analysis with routine cytogenetics and subsequent monitoring of minimal residual disease performed by peripheral FISH and qPCR studies. If BCR-ABL transcripts are less than 0.1% (IS), qPCR may be used as the single monitoring procedure. The simultaneous use of FISH and qPCR allows for verification of concordance of results in patients who are in complete cytogenetic response but not in major molecular response. In a patient in stable complete cytogenetic response, FISH and qPCR studies may be performed every 6 months. If concerns arise regarding changes in qPCR values, the study can be repeated more frequently (e.g., every 3 months). Some investigators suggest a twofold or 0.5-log increase in transcript levels may correlate with the development of mutations or with relapse.30,31 However, these analyses stem from individual laboratories with significant expertise and may not apply to routine practice. In general, in a patient in complete cytogenetic response, an increase of BCR-ABL transcripts should be confirmed before a change of therapy is considered, if at all. Significant fluctuations in BCR-ABL transcripts may also suggest poor treatment compliance and require discussions with the patient regarding compliance with TKI therapy.

Monitoring for mutations in the BCR-ABL kinase domain that are associated with resistance is important. Assessment of mutation status before therapy or in responding patients has no prognostic or therapeutic value. Mutation studies are important in patients who exhibit cytogenetic-hematologic relapse or resistance. In these patients, detection of a threonine-to-isoleucine mutation at codon 315 (T315I) will indicate the need to change therapy to allogeneic SCT, specific T315I inhibitors, or combinations of chemotherapy. Treatment of specific mutations may indicate the use of one TKI over others, based on preclinical studies and early clinical experience. For example, V299L and F317L mutations are less responsive to dasatinib, whereas some P-loop mutations or F359L may be less sensitive to nilotinib. Recent evidence suggests that testing for mutations among patients who exhibit a confirmed loss of major molecular response (increased BCR-ABL transcripts to > 0.1%) unrelated to poor treatment compliance may yield mutations in 10% to 20% of instances.

Important Landmarks for Response or Failure to TKI Therapy

Among patients receiving frontline imatinib therapy, an optimal response requires achievement at least a partial cytogenetic response (Ph-positive metaphases ≤ 35%) by 6 months of therapy and a complete cytogenetic response by 1 year of therapy. Recent studies have suggested that, with qPCR, an optimal response would be a reduction of the BCR-ABL transcripts to less than or equal to 10% (IS) at 3 to 6 months and to less than or equal to 1% (IS) after 1 year of therapy. Failure to achieve BCR-ABL transcripts of less than or equal to 10% (IS) or a partial cytogenetic response at 3 to 6 months, and failure to achieve and maintain a complete cytogenetic response beyond 1 year of imatinib therapy, indicate a worse prognosis. It has not been established yet whether a change of therapy at the early time points (3 to 6 months) improves outcome.3434 When second-generation TKIs (e.g., nilotinib, dasatinib) are used as frontline therapy, earlier responses are expected.35 An optimal response is considered to be achievement of complete cytogenetic response after 3 to 6 months of therapy. Patients not in complete cytogenetic response by that time have a worse event-free survival, but their survival is still excellent (estimated 3-year survival > 90%),35 therefore precluding the need to consider allogeneic SCT in this minority of patients (5% to 10% of total population) but advising closer observation to identify early patients who may require a change of therapy (e.g., to newer-generation TKIs such as ponatinib or allogeneic SCT).

Differential Diagnosis

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