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 (p210^BCR-ABL). The p210^BCR-ABL oncoprotein results in uncontrolled kinase activity, which causes excessive proliferation and reduced apoptosis of CML cells,^13–13 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.

Figure 101-1 The Philadelphia (Ph) chromosome, initially described as a minute chromosome, was later identified as a balanced reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22) (q34;q11.2). This results in the translocation of the *ABL1* gene from chromosome 9 in proximity to the breakpoint cluster region (*BCR*) on chromosome 22. Depending on the breakpoint site on chromosome 22, three resultant BCR-ABL oncoproteins are generated: (1) P210^BCR-ABL, which occurs in the large majority of patients with Ph-positive chronic myeloid leukemia (CML); (2) P190^BCR-ABL, present in two thirds of patients with Ph-positive acute lymphocytic leukemia (the other one third have the P210^BCR-ABL product); and (3) P230^BCR-ABL, which is found rarely (1% to 2%) in patients with an indolent course of Ph-positive CML. The three breakpoints on chromosome 22, M-Bcr (P210), m-bcr (P190), µ-bcr (P230), which correspond to the three resultant BCR-ABL oncoproteins, are shown.

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 (p190^BCR-ABL) of smaller sizes. A third rare breakpoint distal to the major BCR region, called µ-BCR, produces a p230^BCR-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.20–20 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

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.

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.

Figure 101-2 Progression-free survival (PFS) in CML by different characteristics, highlighting that clonal evolution (CE) at diagnosis is not associated with adverse prognosis. CE during the course of CML has a slight adverse prognostic impact but cannot be considered an accelerated phase feature because the associated estimated 4-year PFS rate is 68%, similar to that of chronic phase. Similarly, thrombocytosis (>1000 × 10⁹ cells/L) is associated with an estimated 4-year PFS rate of 84%. The estimated 4-year PFS rate in accelerated phase (classic standard criteria) is 45%. The figure also highlights that although a blast percentage of 20% to 29% is associated with an adverse accelerated phase like prognosis, it cannot be considered a blastic-phase feature (as proposed by the World Health Organization) because it seems to be closer in outcome to accelerated than to blastic phase. Patients who are seen with 10% to 14% blasts have an adverse prognosis similar to those with accelerated-phase disease. Therefore, the proposed new criteria of accelerated phase may exclude clonal evolution but include patients with blast percentages greater than 10%.

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.^31–34 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.34–34 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

CML can be confused with leukemoid reactions. These reactions are usually transient and have a temporal cause (severe infection, corticosteroids, stress). Patients show modest rises of WBC counts as high as 50 × 10⁹ cells/L with toxic granulocytic vacuolation and Döhle bodies in the granulocytes and have a normal or increased leukocyte alkaline phosphatase level. Corticosteroids can rarely cause self-limiting extreme neutrophilia with a left shift.

CML should be differentiated from other myeloproliferative disorders or myelodysplastic syndromes such as chronic myelomonocytic leukemia, proliferative myelodysplastic syndrome, agnogenic myeloid metaplasia, polycythemia rubra vera, and essential thrombocytosis. Although the clinical syndromes may overlap, cytogenetic and molecular studies demonstrating the presence of Ph or the BCR-ABL rearrangement clarify the diagnosis.

A difficult diagnostic situation may arise in patients with a typical morphologic picture of CML (splenomegaly, leukocytosis) but who do not have the Ph chromosome. In some, the BCR-ABL hybrid gene can be demonstrated by molecular studies. Patients who are Ph chromosome negative and BCR-ABL negative often have chronic myelomonocytic leukemia. Patients may rarely have myeloid hyperplasia, with selective involvement of the neutrophil, eosinophil, or basophilic cell lineages. These patients are described as having chronic neutrophilic, eosinophilic, or basophilic leukemia and do not have the Ph chromosome or BCR-ABL fusion gene. Occasionally, patients with Ph-positive CML may have essential thrombocytosis (marked thrombocytosis without leukocytosis). Cytogenetic studies are required in all patients with essential thrombocytosis to identify the occasional patient with Ph-positive CML and essential thrombocytosis–like presentation.

Prognosis

Prognosis in CML has changed drastically over the past 10 years. Before the availability of TKIs, the median survival of patients with CML in chronic phase (85% to 90% of newly diagnosed patients) was 6 to 7 years with IFN-α with or without cytarabine. For candidates for allogeneic SCT, the expected 20-year survival rate was 40% to 50% in younger patients with a matched related donor. With TKI therapy the estimated 10-year survival rate in chronic phase is more than 80%.27,36 With an annual mortality of 1% to 2% in the first 10 years, the estimated median survival may exceed 25 years (Fig. 101-3).^27,36 Thus, chronic-phase CML may have now changed to an indolent disorder in which most patients may survive normally with continued oral TKI therapy. Therapy with TKIs has also changed the prognosis in accelerated phase.²⁷ Patients with clonal evolution as the only sign of accelerated disease have an estimated 5-year survival rate of 80%.³⁷ Survival in blastic phase is also better with imatinib therapy, but only modestly so (median survival improved from 3 to 6 months to 12 to 15 months).²⁷ Prognosis of lymphoid blastic-phase disease is slightly more favorable, with a response rate to anti–acute lymphocytic leukemia chemotherapy with TKIs of 60% and a median survival of 12 to 18 months.

Figure 101-3 Survival of all patients with newly diagnosed Ph-positive chronic myeloid leukemia in chronic phase referred to MD Anderson Cancer Center since 1970 (N = 2035). The estimated 10-year survival rate with recent tyrosine kinase inhibitor therapy is 82%. Patients treated between 1970 and 1980 received mostly hydroxyurea-based therapy; their median survival was about 4 years. Patients treated between 1981 and 2000 received mostly interferon-α–based therapy The median survival of patients treated with interferon therapy from 1981 to 1990 is about 6.5 years; it is about 10 years for patients treated between 1991 and 2000 because of the added benefit of sequential therapy with imatinib late in their course.

Before imatinib, several prognostic models (Sokal, Hasford) divided patients in chronic phase into low-, intermediate-, and high-risk groups based on pretreatment adverse prognostic factors, including older age, splenomegaly, thrombocytosis, higher percentage of blasts and basophils, and presence of cytogenetic clonal evolution.38,39 Therapy with imatinib and other TKIs has now altered the prognostic significance of several of these factors, including deletion of derivative chromosome 9, age, and myelofibrosis.^23,24,40 Myelofibrosis, in fact, resolves quite effectively with imatinib therapy.²⁴ Currently, the most relevant prognostic factor of imatinib therapy is the degree of cytogenetic and molecular response to initial imatinib therapy (in the first 3 to 12 months).^32–35 Thus, the introduction of TKI therapy in CML will require new definitions of the accelerated phase and understanding of the adverse factors and risk models in CML. Recent prognostic factor analyses of patients on TKI therapy suggest that the three persistent independent adverse factors include severe basophilia, high peripheral blast percent, and massive splenomegaly. A recently proposed European risk score (EUTOS score) categorizes patients into two prognostic groups based on the percent of peripheral basophils and spleen size (in centimeters below the costal margin). This model has not been consistently reproduced.⁴¹

Management

Chronic-Phase CML

In the 1980s to 1990s, the two frontline therapies in CML were IFN-α–based regimens and allogeneic SCT.⁴² The positive results with imatinib therapy led to its establishment as standard frontline therapy. Allogeneic SCT is now delayed as a second- or third-line strategy after failure of imatinib and/or other TKIs. Two recent randomized trials of standard imatinib (400 mg orally daily) versus second-generation TKIs using nilotinib in two different dose schedules (300 or 400 mg orally twice daily) or dasatinib (100 mg in a single dose daily) showed nilotinib and dasatinib to be associated with better rates of early surrogate end points for long-term survival, including higher rates of complete cytogenetic response, major molecular response, and complete molecular response. The newer TKIs were associated with lower rates of transformation to accelerated or blastic phases and with lower rates of events and progression. With the current follow-up, the survival rates with imatinib versus second-generation TKIs are not different. Based on these results, the U.S. Food and Drug Administration (FDA) granted approval in 2009 for nilotinib and dasatinib to be used as frontline therapies in newly diagnosed chronic CML.^43,44

Imatinib, Nilotinib, and Dasatinib

The role of imatinib therapy in CML was established in a series of pivotal trials of imatinib after IFN-α failure in chronic, accelerated, and blastic phases of CML and later in a frontline international randomized study of interferon plus cytarabine versus STI571 (the IRIS trial).45,46

Imatinib mesylate, a 2-phenylaminopyrimidine derivative, binds to the canonical adenosine triphosphate (ATP)-binding site of the ABL kinase domain. It blocks phosphorylation of tyrosine residues on substrate protein. Blocking ATP binding inactivates the ABL kinase, because it cannot transfer phosphate to its substrate. Inhibiting phosphorylation prevents activation of signal transduction pathways that cause CML (Fig. 101-4). Imatinib inhibits several tyrosine kinases, including p210^BCR-ABL, p190^BCR-ABL, v-ABL, c-ABL, c-Kit, and platelet-derived growth factor receptor (PDGF-R).

Figure 101-4 The BCR-ABL oncoprotein has constitutive tyrosine kinase activity compared with the tightly regulated tyrosine kinase activity of the normal ABL product. The BCR-ABL kinase activates multiple substrates and binding partners, resulting in activation of downstream signaling pathways. This results in increased proliferation and reduced apoptosis of chronic myeloid leukemia (CML) cells. By binding to the Abl kinase domain, imatinib prevents the phosphorylation of BCR-ABL, thus interrupting the activation of the CML pathways.

In the IRIS study, 1106 patients with newly diagnosed CML were randomized to imatinib 400 mg orally daily versus IFN-α plus cytarabine. Imatinib was associated with significantly higher rates of major (Ph-positive metaphases ≤ 35%; 85% vs. 22%) and complete cytogenetic responses (74% vs. 8%), and lower rates of progression (3% vs. 20%) and transformation (1.5% vs. 7%) after 12 months of therapy.⁴⁵ An update of the 8-year follow-up in the 553 patients treated with imatinib continued to show excellent results: projected complete cytogenetic response rate (single-time response) of 83%; annual rate of progression to accelerated-blastic phase of 4% in the first 2 to 3 years and 1% or less later on imatinib therapy; and annual mortality rate of 1% to 2%. At the 8-year follow-up, 304 patients (55%) were still on imatinib. Rates of transformation and mortality seem to have been reduced in years 4 through 8 (≤2%) compared with the first 3 years (5% to 8%). The estimated 8-year survival rate was 85%. The estimated 8-year survival rate excluding non-CML–related deaths was 93%.⁴⁷ Survival was also better with imatinib versus IFN-α plus cytarabine (survival rates 89% vs. 86%), but the difference was not drastic, because of the crossover design of the IRIS study and the commercial availability of imatinib, both resulting in a change from IFN-α plus cytarabine to imatinib in about 90% of patients within a median of 9 months from start of therapy. Comparison of imatinib results to historical experiences demonstrates more significant survival differences.^27,36

Among patients in late chronic-phase CML after IFN-α failure receiving imatinib, the long-term results show a complete cytogenetic response rate of 41% and estimated 6- and 10-year survival rates of 76% and 68%, respectively.48,49 In accelerated-phase CML the complete cytogenetic response rate was 40% and the estimated 4-year survival rate was 60%.⁵⁰ In blastic-phase CML, response rates were lower and more transient and the median survival duration only 6 to 12 months (Table 101-3).⁵¹

Table 101-3

Results of Imatinib Therapy in Chronic Myelogenous Leukemia

Phase	% Cytogenetic Response		% Molecular Response		% Estimated Survival (at X year)
Phase	Major	Complete	Major	Complete	% Estimated Survival (at X year)
Chronic—newly diagnosed	90	87	70	20-40	82-90 (8-10)
Chronic—after interferon failure	57-67	57	63	30	68 (10)
Accelerated	40	30	NA	NA	60 (4)
Blastic	30	10	NA	NA	10-20 (2)

In the IRIS study, the cumulative incidence of major molecular response was 70% and of disappearance of BCR-ABL transcripts 30% to 50%.⁴⁷ Achieving a major molecular response in complete cytogenetic response at 12 months was associated with estimated 5-year rates of transformation-free survival and survival rates of 100%.⁴⁷ Disappearance of BCR-ABL transcripts was initially observed in a minority of patients (5%) but is now reported with longer-term follow-ups in 30% to 50% of patients.⁵² This rate depends on the sensitivity of the qPCR. In general, a reduction of BCR-ABL transcripts by 4.5 log or more (or BCR-ABL transcripts ≤ 0.0032 [IS]) may reach levels below detection in most molecular laboratories.

Higher doses of imatinib of 600 to 800 mg daily may overcome resistance to standard-dose imatinib in some patients.⁵² In patients with accelerated-phase CML, high-dose imatinib was associated with higher response rates and longer survival.⁵⁰

Imatinib is associated with mild-to-moderate side effects, including nausea, vomiting, diarrhea, rashes, muscle cramps, bone aches, periorbital or leg edema, and weight gain. Serious but uncommon side effects (1% to 2%) include hepatic, renal, or cardiopulmonary dysfunction. These are manageable with dose reductions or treatment interruptions.⁵³ Drug-related myelosuppression occurs in 10% to 30% of patients in newly diagnosed CML. This is managed with brief treatment interruptions and/or dose modifications or with growth factors (e.g., erythropoietin for anemia, filgrastim for neutropenia). Chromosomal abnormalities may appear in the Ph-negative cells in 5% to 10% of responding patients. These include abnormalities observed in myelodysplastic syndrome and acute myeloid leukemia, such as chromosome 5 or 7 abnormalities, trisomy 8, 20q−, and others. These chromosomal abnormalities are probably the result of unmasking of a fragile stem cell prone to development of CML or to genetic instability. Such changes disappear spontaneously in up to 70% of cases. Evolution to a Ph-negative myelodysplastic syndrome or acute myeloid leukemia is rare and probably part of the new natural course of CML.⁵⁴

A phase III frontline study in newly diagnosed CML (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients [ENESTnd]) compared the standard dose of imatinib of 400 mg orally daily with two schedules of nilotinib 400 mg orally twice daily (original approved dose schedule) and a lower-dose schedule of 300 mg orally twice daily. This study demonstrated a significant improvement in the primary end point of the study, achievement of major molecular response by 12 months of therapy, favoring nilotinib, resulting in the FDA approval of nilotinib 300 mg orally twice daily as a standard of care for patients with newly diagnosed chronic-phase CML.⁴⁴ With a minimum follow-up of 3 years, the updated results continue to show better results with nilotinib in relation to achievement of major molecular response (70% to 73% with nilotinib vs. 53% with imatinib; P < .0001), deeper molecular responses, defined as MR^4.0 (BCR-ABL transcript levels < 0.01%) (IS) and MR^4.5 (BCR-ABL transcript levels < 0.0032%) (IS). Importantly, the incidence of disease transformation to accelerated or blastic phase was lower with nilotinib (3.2% with nilotinib 300 mg twice a day, 2.1% with nilotinib 400 mg twice a day) compared with imatinib (6.7%). Survival rates were not significantly different with nilotinib versus imatinib. A similar phase III frontline study comparing imatinib 400 mg orally daily to dasatinib 100 mg orally daily (DASISION trial) also showed a significant difference in the primary study end point, confirmed complete cytogenetic response by 12 month of therapy, favoring dasatinib, and thus resulting in the FDA approval of dasatinib 100 mg daily as a standard of care for newly diagnosed CML. The longer follow-up in the study continues to confirm the benefit of dasatinib in relation to early surrogate end points of long-term outcome, including rates of major molecular response and transformation to accelerated- and blastic-phase disease.⁴³

Nilotinib is given orally twice daily on an empty stomach (2 hours before or after meals). On average, the chronic mild-to-moderate side effects affecting quality of life are lower with nilotinib compared with imatinib (fluid retention, periorbital edema, bone aches, muscle cramps, weight gain), but headaches, hyperglycemia, elevation of lipase or amylase, and rashes are more frequent with nilotinib. With dasatinib, chronic mild-to-moderate side effects are also less frequent. Dasatinib is associated with pleural effusions in 10% to 15% of the patients, which are severe, requiring thoracocentesis in 2% to 3%. Most resolve with dasatinib treatment interruptions, diuretics, and short courses of corticosteroids and with resumption of lower doses of dasatinib (20 to 70 mg orally daily). Myelosuppression is also significantly more common with dasatinib compared with imatinib.

Therapy with imatinib 400 mg daily, nilotinib 300 mg orally twice daily (on an empty stomach), or dasatinib 100 mg single daily dose is started as soon as the diagnosis of CML is established. Allopurinol is recommended until the WBC count is less than 10 × 10⁹ cells/L. Tumor lysis syndrome is rare, except in occasional patients in advanced-phase disease who require hydration and closer monitoring. With TKIs, the WBC and platelet counts decrease in the first 2 to 4 weeks and normalize within 1 to 2 months. Complete blood cell counts are recommended weekly during the first month of therapy and then every 1 to 2 months. For patients with accelerated- or blastic-phase CML, complete blood cell counts should be performed more frequently and as indicated clinically. Therapy with TKIs should be continued indefinitely. Discontinuation of imatinib treatment even among patients with durable complete molecular responses (>2 years) has been associated with molecular relapse in about half.⁵⁵ High-dose imatinib (i.e., 600 to 800 mg daily) may be considered in CML transformation or Ph-positive acute lymphocytic leukemia (in combination with chemotherapy) or in patients with cytogenetic relapse while undergoing therapy with imatinib.

Allogeneic Stem Cell Transplantation

Allogeneic SCT is curative in selected patients with CML. It is most effective during the chronic phase. Among patients in first chronic phase who receive a transplant from a matched sibling, the estimated 20-year survival rate is 40% to 50% (Fig. 101-5). The report from the International Bone Marrow Transplant Registry (IBMTR), compiling data from more than 6000 patients undergoing transplants, showed a 5-year survival rate of 60% for first chronic-phase/sibling donor patients but a 20-year survival rate of 40% to 45%.⁵⁶ Most of the 10% to 15% additional deaths between years 5 and 20 were due to transplant-associated complications rather than CML relapse. Chronic morbidities for SCT include graft-versus-host disease (GVHD), infertility, cataracts, hip necrosis, second cancers, and GVHD-associated organ damage (pulmonary, hepatic) or immune-mediated complications. Transplant-related mortality ranges from 5% to 50%, depending on several factors, including patient age, whether the donor is related or unrelated, the degree of matching, and other factors, such as positivity for cytomegalovirus (CMV), preparative and post-transplant regimens, and institutional expertise.^56–61 Disease-free survival rates with related allogeneic SCT are 40% to 80% in chronic-phase CML. The disease-free survival rates are 60% to 80% among patients younger than 30 to 40 years of age and 30% to 40% in patients older than age 50 years. Disease-free survival rates range from 30% to 60% in accelerated-phase CML and from 5% to 30% in blastic-phase CML. Patients with clonal evolution as the only accelerated-phase criterion have disease-free survival rates of 60%. Patients receiving a transplant in second chronic-phase CML have favorable disease-free survival rates of about 40%.

Figure 101-5 Probability of survival of patients undergoing allogeneic stem cell transplant according to the International Bone Marrow Transplant Registry (N = 6548). Patients transplanted in first chronic phase (CP1) with a human leukocyte antigen-matched sibling (Sib) had the best outcome. Those transplanted with unrelated donors or not in CP1 had a worse outcome. The estimated 20-year survival rate of patients transplanted from a sibling donor in CP1 was 45%.

A major limitation of allogeneic SCT is the availability of related donors. Human leukocyte antigen (HLA)–compatible unrelated donors can be found in 50% of patients; the median time from donor search to transplant is 3 to 6 months. Complications and outcome with unrelated donor SCT are becoming similar to those with related donor SCT but still associated with higher rates of GVHD and transplant-related complications and mortality and with lower rates of disease-free survival and survival.

Nonmyeloablative preparative regimens have expanded the use of allogeneic SCT to older patients and have reduced transplant-associated complications, organ damage, and mortality. Results, in general, show high degrees of engraftment, less morbidity and mortality, but perhaps higher incidences of persistent residual disease and similar degrees of chronic GVHD.

Relapse can be managed effectively with withdrawal of immune suppressive therapy, imatinib or another TKI, donor lymphocyte infusions, IFN-α, or a second SCT. Imatinib results in remission rates of 40% to 60% if the relapse is molecular or cytogenetic in chronic phase.⁶² Imatinib or other TKIs are currently preferred as a first salvage option after allogeneic SCT relapse to donor lymphocyte infusions, because these infusions may exacerbate GVHD. TKIs are less effective if CML relapse is hematologic or in transformation. Donor lymphocyte infusions induce durable remission rates of 60% with molecular or cytogenetic relapse but may exacerbate GVHD (which can be fatal) and result in intense myelosuppression in 20% of patients.

Imatinib Resistance

“Resistance” to imatinib therapy can be defined as failure to achieve the following end points: (1) complete hematologic response (CHR) and BCR-ABL transcript levels less than or equal to 10% (IS) after 3 to 6 months of therapy or partial cytogenetic response by cytogenetics after 3 to 6 months of therapy; and (2) complete cytogenetic response or BCR-ABL transcripts less than or equal to 1% (IS) after 1 year or longer of therapy. Additionally, patients experiencing cytogenetic or hematologic relapse at any time on treatment are considered to have secondary resistance to imatinib.

The annual resistance rate to imatinib is 3% to 4% in the first 5 years. Resistance can be primary (mostly caused by BCR-ABL–independent mechanisms; i.e., with persistent inhibition of the BCR-ABL kinase), or secondary (after an initial response, most often due to BCR-ABL–dependent mechanisms, i.e., with reactivation of the BCR-ABL kinase). Several BCR-ABL–dependent mechanisms of imatinib resistance have been proposed, including amplification of BCR-ABL oncogene or transcript levels, multidrug resistance–dependent pumping of imatinib out of the cell, shifts of BCR-ABL localization in the CML cells, and mutations. BCR-ABL point mutations (>80 described so far) account for 40% to 50% of resistance. Mutations that can occur at the BCR-ABL kinase domain ATP-binding site (P-loop), at contact points with imatinib, or at other BCR-ABL sites (catalytic domain, activating loop) can produce relative or absolute resistance to imatinib; some mutations are not relevant to resistance. Mutations with relative resistance to imatinib can be overcome with higher doses of imatinib; others do not respond to increasing the imatinib dose but respond to treatment with the more potent second-generation TKIs. A particular mutation, T315I, confers absolute resistance to imatinib and to the second-generation TKIs (i.e., dasatinib, nilotinib, bosutinib) but may be responsive to ponatinib.

Patients who become resistant to imatinib have several treatment options, including allogeneic SCT and treatment with the new-generation TKIs and other agents. Imatinib resistance in chronic-phase CML is associated with an estimated 4-year survival rate of 60%. However, if progression is in accelerated or blastic phases, the prognosis is poor.⁶³ For patients in accelerated or blastic phase after imatinib resistance, every attempt should be made to refer them to allogeneic SCT. If patients become resistant to imatinib in chronic phase, a trial of one of the new-generation TKIs is reasonable. Subsequent therapy (i.e., allogeneic SCT) may depend on the presence of clonal evolution, presence and type of mutation, early response to TKI therapy, patient age, and donor availability and degree matching. In all cases of imatinib resistance, mutational analysis is recommended to identify patients with T315I or other mutations that can be selectively nonresponsive to one of the new-generation TKIs. If a T315I mutation is identified, second-generation TKIs are not effective and the patient should be referred for allogeneic SCT as soon as possible and in the interim the disease should be controlled with hydroxyurea, cytarabine, combinations of standard older therapies, or investigational agents (ponatinib, omacetaxime) that might be effective against T315I mutations. A treatment algorithm for CML is proposed in Figure 101-6.

Figure 101-6 Proposed treatment algorithm for patients with newly diagnosed chronic myeloid leukemia. Patients achieving major cytogenetic response after 3 to 6 months, and a complete cytogenetic response after 12 months of therapy should continue on imatinib until there is evidence of resistance. In case of resistance, allogeneic stem cell transplantation can be considered as the next option if the transplant-related mortality is acceptable to the patient. The patient can also consider treatment with the new-generation tyrosine kinase inhibitors (TKIs) (i.e., dasatinib, nilotinib, bosutinib, ponatinib), or with other investigational therapies, before proceeding to allogeneic stem cell transplant (SCT).

Dasatinib

Dasatinib (Sprycel) is a potent, oral, multitargeted kinase inhibitor of critical oncogenic kinases including BCR-ABL, Src, C-kit, and PDGF-R. This dual Abl/Src inhibitor is 300 times more potent than imatinib in preclinical models and is effective against all imatinib-resistant kinase domain mutations except T315I. Pivotal phase II studies, referred to as START (Src/abl Tyrosine kinase inhibition Activity Research Trials of dasatinib), demonstrated high efficacy of dasatinib in all phases of CML after imatinib failure and in Ph-positive acute lymphocytic leukemia. This led to its approval for this indication in 2006. In 387 patients with chronic-phase CML after imatinib failure, dasatinib 70 mg orally twice daily produced a CHR rate of 90%, a major cytogenetic response rate of 52%, a complete cytogenetic response rate of 39%, and an estimated 10-month PFS rate of 92%.⁶⁴ Response rates were higher in patients with imatinib intolerance versus resistance but were similar by whether mutations were present or absent. Results were similarly encouraging in accelerated blastic phases and in Ph-positive acute lymphocytic leukemia (Table 101-4).^64,65 A randomized study of dasatinib 70 mg orally twice daily versus high-dose imatinib (400 mg orally twice daily) in patients with chronic-phase CML after failure on imatinib 400 to 600 mg daily showed dasatinib to be associated with higher rates of major cytogenetic response (53% vs. 33%; P = .017), complete cytogenetic response (44% vs. 18%, P = .025), and PFS (estimated 24-month rate 86% vs. 65%; P = .0012).⁶⁶ Cytopenias were more common with dasatinib; pleural effusions occurred in 17% of patients on dasatinib. Pleural effusions were often exudates and were managed with treatment interruptions, diuretics and short courses of corticosteroids, and resumption of dasatinib at lower dose schedules. Myelosuppression was also managed with dose interruptions and reductions. A four-arm randomization study of different dasatinib dose schedules (50 mg twice daily, 100 mg single-dose daily, 70 mg twice daily, 140 mg single-dose daily) in 670 patients with chronic-phase CML after imatinib failure showed that a single daily dasatinib dose of 100 mg produced equivalent treatment results with fewer side effects.⁶⁷ This dasatinib dose is now standard for chronic-phase CML. At the 6-year follow up, dasatinib 100 mg therapy resulted in a cumulative complete cytogenetic response rate of 50%, a major molecular response rate of 42%, and an estimated 6-year survival rate of 71%.⁶⁸

Table 101-4

Results of Dasatinib Phase II Studies in Chronic Myeloid Leukemia (CML) After Imatinib Failure

CML Phase	No. of Patients	% CHR	% Cytogenetic Response		Estimated Survival (at X Year)%
CML Phase	No. of Patients	% CHR	Major	Complete	Estimated Survival (at X Year)%
Chronic	662	80	63	50	85 (6)
Accelerated	317	47-52	39-43	24	63-72 (2)
Blastic	116	30-40	38	33	20-30 (1-2)

CHR, complete hematologic response.

Data extrapolated from references 64 through 68 and 81.

Nilotinib

Nilotinib (Tasigna, AMN107) was rationally designed by replacement of the N-methylpiperazine binding group of imatinib to optimize the binding affinity and selectivity for the Abl kinase. Nilotinib, a selective BCR-ABL kinase inhibitor, is 30 times more potent than imatinib in preclinical models and was active against all imatinib-resistant mutations except T315I. The pivotal phase II studies with nilotinib 400 mg orally twice daily showed activity after imatinib failure. In the phase II pivotal trial of nilotinib in 321 patients in chronic phase after imatinib failure, the major cytogenetic response rate was 59%, the complete cytogenetic response rate was 44%, and the estimated 2-year survival rate was 87%. Side effects were modest, including grade 3/4 myelosuppression in 20% to 30%; no pleural effusions were observed.⁶⁹

The activity of nilotinib in accelerated- and blastic-phase CML after imatinib failure was also encouraging, although response rates were lower and response durations shorter (Table 101-5).^70,71 Nilotinib has been approved by the FDA (October 2007) for the treatment of CML in chronic or accelerated phases after imatinib failure.

Table 101-5

Results of Nilotinib Phase II Studies in Chronic Myeloid Leukemia (CML) after Imatinib Failure

CML Phase	No. of Patients	% CHR	% Cytogenetic Response		Estimated Survival (at X Year)%
CML Phase	No. of Patients	% CHR	Major	Complete	Estimated Survival (at X Year)%
Chronic	321	74	59	44	87 (2)
Accelerated	137	31	32	21	70 (2)
Blastic	136	21-24	38-52	30-32	27 (2)

CHR, complete hematologic response.

Data extrapolated from references 69 through 71.

Bosutinib

Bosutinib is an orally available dual Src/Abl inhibitor that is 30 to 200 times more potent than imatinib. It has minimal inhibitory activity against c-Kit and PDGF-R and therefore is expected to produce less myelosuppression and fewer pleural effusions. In studies of 288 patients with chronic-phase CML after imatinib failure treated with bosutinib 500 mg orally daily, the major cytogenetic response rate was 53%, the complete cytogenetic response rate was 41%, and the estimated 2-year survival rate was 92%.⁷² Grade 3/4 toxicities included diarrhea (8%), rashes (9%), and thrombocytopenia (5% to 10%).⁷³

Ponatinib

Ponatinib is an orally administered pan–BCR-ABL TKI with potent activity against native and mutated Bcr-ABL kinases, including T315I. In a large phase II study of 449 patients with CML (270 chronic, 85 accelerated, 94 blastic or Ph-positive acute lymphocytic leukemia) resistant or intolerant to several TKIs, ponatinib showed high activity. In chronic-phase CML the major cytogenetic response rate was 54%, the complete cytogenetic response rate was 44%, and the major molecular response rate was 30%. In the subset of 64 patients with T315I mutation the major cytogenetic response rate was 70%, the complete cytogenetic response rate was 66%, and the major molecular response rate was 50%. With a median follow-up of 10 months, 93% of patients in chronic-phase CML achieving major cytogenetic response have maintained it. Significant side effects included grade 3/4 pancreatitis in 6% and severe thrombocytopenia in 31%. In accelerated-phase CML, the major cytogenetic response rate was 34% (complete in 20%); in blastic phase it was 27% (complete in 23%). The activity of this agent overall and in the subset of T315I mutations, together with its reasonable safety profile, should make it an important addition to CML treatment options.

Other Agents

Other classes of agents that have shown reasonable activity against CML after imatinib failure include decitabine and omacetaxine (previously known as homoharringtonine).74,75

Selection of Sequential Therapies

The longer-term follow-up results of imatinib, nilotinib, and dasatinib in newly diagnosed CML are reassuring, with their acceptable toxicity profiles and absence of treatment-related mortality. Imatinib, nilotinib, and dasatinib are now frontline CML therapeutic agents in all patients regardless of age. Patients whose disease progresses while on TKI therapy may consider allogeneic SCT. This is associated with mortality rates of 5% to 50% in the first year and with significant chronic morbidities, including GVHD-related complications, cataracts, infertility, second cancers, and a 15% mortality between years 5 and 20 of follow-up that may be related to subtle but continuous transplant-related organ damage and some late relapses. Patients with TKI resistance may be treated with other TKIs depending on resistance status (chronic vs. transformation) and mutational studies. Allogeneic SCT can be implemented as second- or third-line therapy based on the considerations discussed earlier.

Old Traditional Standards of Care Revisited

Busulfan (1,4-dimethane-sulfonyl-oxybutane) is the first alkylating agent that demonstrated activity in CML. Busulfan therapy was associated with significant toxicities, including severe and prolonged myelosuppression. Busulfan should be used today only as part of conditioning regimens in allogeneic SCT and must be avoided in any patients awaiting allogeneic SCT because of the associated adverse outcome.

Hydroxyurea, a ribonucleotide reductase inhibitor, is a well-tolerated oral cytotoxic agent that can control blood cell counts rapidly in most patients with CML. Rare side effects include nausea, rashes, mouth ulcers, and hand or leg ulcers. Hydroxyurea is usually given at a daily dose of 1 to 10 g, depending on the degree of leukocytosis, and the dose adjusted to keep the WBC count between 2 × 10⁹ and 10 × 10⁹ cells/L. Hydroxyurea may be used for initial cytoreduction, as a temporary measure to control counts between definitive therapies, or as part of a combination approach with imatinib or other TKIs. It should not be used alone as a definitive treatment in CML because it rarely suppresses Ph-positive cells.

IFN-α showed anti-CML activity in the 1980s and was a standard of care in CML until the discovery of imatinib. IFN-α induced CHR rates of 50% to 80% in untreated chronic-phase CML and cytogenetic response rates of 40% to 60% (major in 10% to 40%; complete in 5% to 30%).⁷⁶ A meta-analysis of randomized studies of IFN-α versus hydroxyurea or busulfan showed that IFN-α therapy was associated with better survival than hydroxyurea or busulfan (5-year survival rates 57% vs. 42%, P < .00001).⁷⁷ IFN-α has minimal activity in accelerated or blastic phases of CML. It is associated with significant side effects including flulike symptoms, fever, chills, myalgias, fatigue, depression, neuropathy, diarrhea, memory problems, immune-mediated complications, myelosuppression, and others.⁷⁸ Achievement of a major or complete cytogenetic response with IFN-α is associated with significantly better long-term survival.⁷⁶ Combinations of IFN-α and low-dose cytarabine may improve results over IFN-α alone.⁷⁹ New formulations of IFN-α attached to polyethylene glycol (PEG) prolong its half-life, allow weekly administration, reduce toxicities, and may also improve results (at least with a particular pegylated IFN-α2a formulation, Pegasys).⁸⁰