Chronic Myeloid Leukemia

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Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of the primitive hematopoietic stem cell.

Overview

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of the primitive hematopoietic stem cell. The disease is monoclonal in origin, affecting myeloid, monocytic, erythroid, megakaryocytic, B-cell, and, sometimes, T-cell lineages. Bone marrow stromal cells are not involved.

CML accounts for 15% of all leukemias in adults. Approximately 8,220 new cases of CML will be diagnosed in 2016, with an estimated 1,070 deaths. The age-adjusted incidence is 1.6 per 100,000 population. With imatinib therapy, the annual mortality has been reduced significantly (to less than 2% to 3% per year, with further mortality reductions after the first 2 to 3 years). This has resulted in an increase in prevalence from approximately 70,000 patients in the US in 2010 to a projected 144,000 in 2030.

Epidemiology

Gender

The male-to-female ratio is 1.1:1 to 1.4:1.

Age

According to Surveillance, Epidemiology, and End Results (SEER) program and Medical Research Council (MRC) data, the median age of patients with CML is 66 years. However, most patients who are admitted to medical therapy studies are 50 to 60 years old (median: approximately 53 years). Patients in bone marrow transplantation (BMT) studies are usually younger (median age: approximately 40 years).

Etiology and Risk Factors

The cause of CML is unclear. Some associations with genetic and environmental factors have been reported, but in most cases no causative factors can be identified.

Genetic Factors

There is little evidence linking genetic factors to CML. Offspring of parents with CML do not have a higher incidence of CML than does the general population.

Environmental Factors

Nuclear and radiation exposures, including therapeutic radiation, have been associated with the development of CML. Exposure to chemicals has not been consistently associated with greater risk.

Signs and Symptoms

CML usually runs a biphasic or triphasic course. This process includes an initial chronic phase and a terminal blastic phase, which is preceded by an accelerated phase in 60% to 80% of patients.

Chronic Phase

If untreated or treated with drugs that do not significantly affect the Philadelphia-chromosome cells in the marrow, chronic-phase CML is associated with a median survival of 4 to 5 years. During the chronic phase, CML is asymptomatic in 25% to 60% of all cases; in such instances, the disease is usually discovered on a routine blood examination.

In symptomatic patients, the most common presenting signs and symptoms are fatigue, left upper quadrant pain or mass, weight loss, and palpable splenomegaly in 30% to 70% of patients. The liver is enlarged in 10% to 20% of cases. Occasionally, patients with very high white blood cell (WBC) counts especially in the advanced phases of the disease may have manifestations of hyperviscosity, including priapism, tinnitus, stupor, visual changes from retinal hemorrhage, and cerebrovascular accidents.

Patients in chronic-phase CML do not have an increased risk for infection.

TABLE 1

Criteria for accelerated-phase CML according to MDACC, IBMTR, and WHO

Accelerated Phase

This is an ill-defined transitional phase. The criteria used to define accelerated phase in all the studies with interferon and tyrosine kinase inhibitors include the presence of any one of the following factors: blasts > 15%, blasts plus promyelocytes > 30%, basophils > 20%, platelets < 100 × 109/L unrelated to therapy or cytogenetic clonal evolution. Other classifications include more subjective criteria (Table 1) and have not been clinically validated. The classification used may affect the expected outcome for a group of patients defined as being in the accelerated phase. With imatinib therapy, the estimated 4-year survival rate exceeds 50%. The accelerated phase is more frequently symptomatic, and it includes the development of fever, night sweats, weight loss, and progressive splenomegaly.

Blastic Phase

The blastic phase morphologically resembles acute leukemia. Its diagnosis requires the presence of at least 30% blasts in the bone marrow or peripheral blood. The World Health Organization (WHO) has proposed the diagnosis of blast phase if there are at least 20% blasts, but this classification has not been validated, and recent evidence suggests that patients with 20% to 29% blasts have a significantly better prognosis than do those having at least 30% blasts. In some patients, the blastic phase is characterized by extramedullary deposits of leukemic cells, most frequently in the central nervous system (CNS), lymph nodes, skin, or bones.

Historically, patients in the blastic phase usually die within 3 to 6 months. Approximately 70% of blastic phase patients have a myeloid phenotype, 25% have a lymphoid phenotype, and 5% have an undifferentiated phenotype. Prognosis is slightly better for a lymphoid blastic phase than for myeloid or undifferentiated cases (median survival: 9 vs 3 months).

Patients in the blastic phase are more likely to experience symptoms, including weight loss, fever, night sweats, and bone pain. Symptoms of anemia, infectious complications, and bleeding are common. Subcutaneous nodules or hemorrhagic tender skin lesions, lymphadenopathy, and signs of CNS leukemia may also occur.

Laboratory Features

Peripheral Blood

The most common feature of CML is an elevated WBC count, usually exceeding 25 × 109/L and frequently exceeding 100 × 109/L, occasionally with cyclic variations. The finding of unexplained, persistent leukocytosis (eg, > 12–15 × 109/L) in the absence of infections or other causes of WBC count elevation should prompt a workup for CML.

The WBC differential usually shows granulocytes in all stages of maturation, from blasts to mature, morphologically normal granulocytes. Basophils are frequently elevated, but only 10% to 15% of patients have ≥ 7% basophils in the peripheral blood. Frequently, eosinophils are also mildly increased. The absolute lymphocyte count is elevated at the expense of T-cell lymphocytes.

The platelet count is elevated in 30% to 50% of patients and is higher than 1,000 × 109/L in a small percentage of patients with CML. When thrombocytopenia occurs, it usually signals disease acceleration.

Some patients have mild anemia at diagnosis.

Neutrophil function is usually normal or only mildly impaired, but natural killer (NK) cell activity is impaired. Clonal expansion of T-cell lymphocytes is detected in some patients at the time of diagnosis and may increase during therapy with dasatinib. Platelet function is frequently abnormal but usually has no clinical significance.

Bone Marrow

The bone marrow is hypercellular, with a cellularity of 75% to 90%. The myeloid-to-erythroid ratio is usually 10:1 to 30:1. All stages of maturation of the WBC series are usually seen, but the myelocyte predominates.

Megakaryocytes are increased in number early in the disease and may show dysplastic features. They are usually smaller than the typical normal megakaryocytes. Fibrosis may be evident at diagnosis, but it is more common with disease progression and is usually an adverse prognostic finding. A bone marrow aspiration at the time of diagnosis is a must and is always required to properly stage the disease and to plan therapy.

Other Laboratory Findings

Leukocyte alkaline phosphatase activity is reduced at diagnosis. Serum levels of vitamin B12and transcobalamin are increased, sometimes up to 10 times normal values. Serum levels of uric acid and lactate dehydrogenase (LDH) are also frequently elevated.

Cytogenetic and Molecular Findings

Philadelphia Chromosome

CML is characterized by the Philadelphia (Ph) chromosome, which represents a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11.2). The ABL1 proto-oncogene, the human homologue of the v-ABL oncogene that induces murine leukemia, is located in chromosome 9q34 and encodes for a nonreceptor protein tyrosine kinase expressed in most mammalian cells. BCR is a gene involved in cell signaling and transduction and is located on chromosome 22. Interestingly, both ABL1 and BCR null mice are viable and have normal hematopoiesis. Breakpoints occur within the BCR gene and usually involve an area known as the major breakpoint cluster region (M-BCR), located either between exons 14 (b3) and 15 (b4) or between exons 13 (b2) and 14 (b3). Therefore, two different fusion genes can be formed, both of them joining exon 2 of ABL1 with either exon 13, e13a2 (b2a2) or exon 14, e14a2 of BCR (b3a2). Among the 5% to 10% of patients who do not have the Ph chromosome detected by karyotyping, 30% to 40% have the molecular rearrangement identified by fluorescence in situ hybridization (FISH) and/or polymerase chain reaction (PCR). Patients without this rearrangement are considered to have “atypical CML,” a unique entity having a different natural history, prognosis, and treatment.

Upon translation, a new protein with a molecular weight of 210 kd (p210BCR-ABL) is synthesized, which, when compared with the normal ABL1, has markedly increased kinase activity and can transform transfected cells and induce leukemia in transgenic mice. Occasionally, the breakpoint can occur in other areas (m-BCR and μ-BCR), leading to different transcripts (eg, p190BCR-ABL and p230BCR-ABL, respectively). The mechanism of oncogenesis of p210BCR-ABL is unclear, but upon phosphorylation it can activate several intracellular pathways, including the Ras and the mitogen-activated protein kinase pathway, the Jak-STAT pathway, the PI3 kinase pathway, and the MYC pathway. Ultimately, this process leads to altered adhesion to extracellular matrix and stroma, constitutive activation of mitogenic signals, and inhibition of apoptosis.

Staging and Prognosis

Staging Systems

Several characteristics of CML affect the prognosis, including age; spleen size; WBC and platelet counts; and percentage of blasts, eosinophils, and basophils in the peripheral blood. Deletions of the derivative chromosome 9 [del der(9)] are identified in 10% to 15% of patients and have been associated with an adverse prognosis in patients managed with older treatment modalities. Tyrosine kinase inhibitors, however, overcome the adverse prognosis associated with del der(9). Recent data from the German CML study group suggest that for newly diagnosed and interferon-resistant chronic-phase patients the presence of a second Philadelphia chromosome, trisomy 8, isochrome 17q, or trisomy 19 is associated with delayed time to response to imatinib and shorter disease-free and overall survival times. These factors have been incorporated into several staging systems.

Sokal’s Classification

A frequently used risk classification is Sokal’s prognostic risk system. In this system, the hazard ratio function is derived from the following formula: λi(+)/λo(t) = Exp 0.0116 (age − 43.4) + 0.0345 (spleen − 7.51) + 0.188 [(platelets/700)2 − 0.563] + 0.0887 (blasts − 2.10). From a practical standpoint, the score can be derived from connecting to an easily found site on Google and entering the various parameters.

This risk classification defines three prognostic groups with hazard ratios of < 0.8, 0.8–1.2, and > 1.2 (ie, low-, intermediate-, and high-risk groups).

The Hasford classification has been suggested to separate more clearly and without overlap risk groups among patients treated with interferon therapy. The Hasford score is derived from the formula (0.6666 × age [0 when age < 50 years; 1, otherwise] + 0.0420 × spleen size [cm below costal margin] + 0.0584 × blasts [%] + 0.0413 × eosinophils [%] + 0.2039 × basophils [0 when basophils < 3%; 1, otherwise] + 1.0956 × platelet count [0 when platelet count < 1,500 × 109/L; 1, otherwise]) × 1,000. Based on the score, patients can be classified into three risk groups: low (score ≥ 780), intermediate (score > 780 and ≥ 1,480), and high (score ≥ 1,480). This classification may be less predictive in the imatinib era. Both the Sokal and Hasford classifications predict the probability of achieving a response to tyrosine kinase inhibitors. Recently, a new simplified prognostic score, the European Treatment and Outcome Study (EUTOS) score, has been proposed. This score is simple and classifies patients into only two categories. The EUTOS score is defined by the formula (7 × percent basophils) + (4 × spleen size in cm below costal margin). A score of > 87 identifies patients with high risk and a score of ≤87 identifies those with low risk. However, two independent series have not confirmed the ability of the EUTOS score to properly discriminate between risk groups.

Sidebar: The expected survival of patients with CML has improved significantly since the introduction of tyrosine kinase inhibitors. Recent analyses have now shown that the life expectancy of patients with CML is nearly equivalent to that of the general population. A European series including 2,290 patients treated with imatinib in clinical trials in several countries in Europe reported an 8-year overall survival of 89%. This represented a relative survival of 96% compared with individuals who did not have CML (Pfirrmann et al. ASH 2014; abstract 153). Another series analyzed the outcome of 483 patients treated at a single institution in the United States with different tyrosine kinase inhibitors as initial therapy for CML. The 5-year relative survival was 94.8%. This improved to 96.7% for patients who achieved a complete cytogenetic response at any time during their treatment and 100% for those with an MR4.5 (Sasaki K et al: Lancet Haematol 2:e186–e193, 2015). Thus, patients with CML who have access to tyrosine kinase inhibitors and who are adequately managed and properly monitored can enjoy a near normal life expectancy.

Treatment

Chronic Phase

Conventional chemotherapy

Busulfan and hydroxyurea. Busulfan and hydroxyurea were the chemotherapeutic agents used most frequently in CML until the development of interferon and, more recently, tyrosine kinase inhibitors. Busulfan is now rarely used.

Hydroxyurea is most frequently used to control the WBC count while confirming the diagnosis of CML. The dose can be adjusted individually to control the WBC count. In some instances, a dose of 10 g/d to 12 g/d may be needed.

Neither busulfan nor hydroxyurea significantly reduces the percentage of cells bearing the Ph chromosome, and, therefore, the risk of transformation to the blastic phase is unchanged. Their use should be limited to temporary control of hematologic manifestations, while the diagnostic workup is in progress and before definitive therapy with a tyrosine kinase inhibitor is instituted. Once the diagnosis of CML is confirmed, a tyrosine kinase inhibitor should be initiated immediately. There is usually no need for or benefit from initially “debulking” with hydroxyurea.

TABLE 2

Response definitions in CML

Interferon

Interferon-α can induce a complete hematologic response (Table 2) in 70% to 80% of patients with CML, as well as some degree of suppression of Ph chromosome–positive cells (ie, cytogenetic response) in 40% to 60% of patients, which is complete in up to 20% to 25% of patients. Randomized studies have documented a survival advantage for patients treated with interferon-α who achieved a major, and particularly a complete, cytogenetic response.

Patients who achieve a complete cytogenetic response (CCyR) have a 10-year survival rate of 75% or more, compared with less than 40% for those having a partial response and less than 30% for individuals having a lesser response or no response.

Interferon and cytarabine (Ara-C). The combination of interferon-α and low-dose Ara-C induced a higher (ie, 40% to 50%) response rate, and possibly a survival advantage.

Approximately 30% of those achieving complete cytogenetic remission with interferon-α may achieve a sustained molecular remission and are probably cured. Among the others, 40% to 60% remain free of disease after more than 10 years despite the presence of minimal residual disease. This has been called “operational cure.”

Formulations of interferon-α attached to polyethylene glycol (PEG) have a longer half-life that allows for weekly administration and may have decreased toxicity.

FIGURE 1

Treatment algorithm for chronic-phase CML. Options marked with a question mark define investigational approaches that cannot be considered standard at this time.

Imatinib

Imatinib is a potent inhibitor of the tyrosine kinase activity of BCR-ABL and a few other tyrosine kinases, such as PDGF-R (platelet-derived growth factor receptor) and c-KIT. It has demonstrated significant activity in patients with CML in all phases of the disease, whether they have received prior therapy (with interferon) or receive imatinib as their initial therapy. Among patients with chronic-phase CML who failed to respond to prior interferon-α therapy, 55% to 85% achieved a major cytogenetic remission, including 45% to 80% with a complete cytogenetic remission. Patients who were deemed to be at high risk on the basis of Sokal scores had a lower rate of CCyR (69%) than did patients who were at low risk or intermediate risk (89% and 82%, respectively). Among patients treated in early chronic-phase CML who had not received prior therapy, the rate of CCyR is 83%, with an overall survival rate at 8 years of 85%, and an event-free survival of 81%.

Overall and event-free survival rates with imatinib therapy are significantly better than those seen with interferon. Thus, imatinib replaced interferon as the standard therapy for CML (Figure 1). The proper management of patients receiving imatinib is important to optimize long-term outcome.

Results of a randomized phase III study comparing 400 mg and 800 mg of imatinib daily as initial therapy for patients in chronic phase suggested a higher rate of response at earlier time points for patients treated with 800 mg, with a lower rate of transformation by 18 months of follow-up (3.2% vs 1.9%). An update of this same study after 24 months of follow-up showed no difference in the rate of CCyR, major molecular response (MMR), event-free survival, or progression-free survival between the two cohorts. This result may have been explained in part by the high rate of dose reductions and treatment discontinuation, particularly in the high-dose group. Patients who maintained a dose intensity throughout the study of at least 600 mg had a significantly higher rate of MMR. Another randomized study exploring 400 mg and 800 mg of imatinib or imatinib combined with interferon as initial therapy for patients with CML in chronic phase showed an improvement in the time to CCyR and MMR for patients treated with 800 mg, compared with the other two arms. This result translated into a trend for an improved 5-year progression-free survival (94%), compared with patients treated with standard-dose imatinib (87%) or with imatinib plus interferon (91%). The long-term benefit observed in this study might be due to the fact that dose intensity was maintained at a higher level.

Dose. The standard dose of imatinib is 400 mg/day for the chronic phase and 600 mg/day for the accelerated and blastic phases. Dose reductions may be needed in some patients because of toxicity, but doses less than 300 mg/day are usually not recommended. Available data from the phase I study show a decrease in the probability of response with doses lower than 300 mg/day.

Toxicity. Imatinib is generally well tolerated. However, some patients may experience grade 1/2 adverse events, including nausea, peripheral or periorbital edema, muscle cramps, diarrhea, rashes, weight gain, and fatigue. These events are frequently minor and either do not require therapy or respond to adequate early intervention. Fluid retention responds to diuretics when indicated; diarrhea can be managed with loperamide or other agents; nausea usually responds to prochlorperazine, promethazine, or other agents; muscle cramps can be managed with tonic water or quinine; and rash may be managed with antihistamines and/or corticosteroids (topical and/or systemic).

Myelosuppression is the most common grade 3/4 adverse event. Neutropenia can be seen in up to 45% of patients, thrombocytopenia in up to 25% of patients, and anemia in 10% of patients. Treatment is held for grade ≥ 3 neutropenia (neutrophil count < 109/L) or thrombocytopenia (platelet count < 50 × 109/L) and restarted when counts recover above these levels. If the recovery takes longer than 2 weeks, the dose may be reduced. Treatment interruptions and dose reductions are usually not recommended for anemia, neutropenia, or grade 1 or 2 thrombocytopenia. Myelosuppression is much more likely to occur during the first 2 to 3 months of therapy and is best managed with treatment interruption and close monitoring. Hematopoietic growth factors (granulocyte colony-stimulating factor [G-CSF, filgrastim], oprelvekin, and erythropoietin) have been used successfully to manage prolonged or recurrent myelosuppression, but the long-term safety of this approach needs to be assessed.

Several studies have investigated the use of interferon combined with imatinib. A French study suggested that the combination resulted in an improved rate of complete molecular response compared with imatinib alone. Two other studies (by Hehlmann et al and by Cortes et al) did not find such improved response with this combination. Importantly, none of the three studies showed an improvement in event-free survival, rate of transformation, or overall survival. Thus, the combination of interferon with imatinib remains, at best, investigational.

Imatinib failure. The most frequently identified mechanism of resistance to imatinib is the development of mutations at the ABL kinase domain. Mutations are identified in 40% to 60% of patients with imatinib resistance, with the most frequent occurring in the P-loop. Not all mutations confer the same level of resistance to imatinib, and some may be overcome by increased concentrations of imatinib. The mutation most resistant to imatinib is T315I. Other mutations may have variable sensitivity to different tyrosine kinase inhibitors, and this information may be used when selecting an inhibitor to use on individual patients. Thus, assessing the presence of mutations is always indicated when changing therapy, particularly for resistance to therapy. Mutations are more frequently found in instances of secondary resistance (ie, loss of response) than in primary resistance (ie, not achieving a given response at a given time). Mutations are much less frequently found in patients with suboptimal response or warning categories per the European LeukemiaNet criteria, and assessing for mutations is not indicated at the start of therapy for patients in chronic phase. Among patients in blast phase (and rarely in accelerated phase), mutations may be found before the start of any tyrosine kinase inhibitor therapy.

A prognostic model has been developed to predict the probability of response and event-free survival after treatment with second-generation tyrosine kinase inhibitors (dasatinib and nilotinib) after imatinib failure. Among 123 patients treated with these agents, a multivariate analysis identified two factors as being significantly and independently associated with long-term outcome: performance status (≥ 1 adverse feature) and cytogenetic response in patients with prior imatinib therapy (adverse feature, no prior cytogenetic response). Patients with zero adverse features, one adverse feature, or two adverse features had event-free survival rates at 24 months of 78%, 49%, and 20%, respectively.

TABLE 3

European LeukemiaNet criteria for failure and suboptimal response

Changing therapy based on failure to achieve a molecular response or losing such a response cannot be justified in most instances at the present time. Even when patients who have not achieved an MMR after 18 months of therapy have an inferior event-free survival compared with those achieving at least a MMR, the rate of event-free survival is still 86% at 7 years (provided they have a CCyR), and in most instances the event represents only a loss of cytogenetic response. If the proposed alternative treatment option carries any significant risk of mortality or morbidity, the risk may be unnecessary. The clinical significance of the presence of mutations only in patients with an adequate response is still unclear. Thus, mutations should be investigated in patients with clinical evidence of failure. In this setting, a change of therapy is indicated regardless of whether a mutation is found, but in some instances specific mutations may guide the selection of therapy.

The criteria for failure and suboptimal response established by the European LeukemiaNet have become standard (Table 3). These criteria emphasize the response achieved and the time to such response. Patients who meet criteria for failure should be offered therapy with a second-generation tyrosine kinase inhibitor. For patients with suboptimal responses, there are no available data indicating what the optimal management may be, although imatinib dose escalation is usually recommended. There are no available data on the benefit of changing to a second-generation tyrosine kinase inhibitor for patients with suboptimal response.

Second-generation tyrosine kinase inhibitors

A second generation of tyrosine kinase inhibitors has been developed to overcome resistance to imatinib. Three of these agents have gained regulatory approval (dasatinib, nilotinib, and bosutinib). These agents have been shown to inhibit both the wild type BCR-ABL and nearly all of the clinically significant mutants of BCR-ABL, except for the T315I mutation, as well as tumor cells with a few other selected mutations that vary from agent to agent. The results from the initial clinical trials have demonstrated significant clinical activity with both agents.

Dasatinib. Dasatinib is structurally unrelated to imatinib and can bind both the inactive and active configurations of BCR-ABL. In addition, dasatinib is a dual inhibitor that blocks Src and ABL. It is two orders of magnitude more potent than imatinib.

The initial phase II trials of dasatinib used a dose of 70 mg twice daily. Significant clinical activity was seen in patients at all stages of the disease after imatinib resistance or intolerance, with complete CCyRs in 53% in chronic phase, 33% in accelerated phase, 27% in myeloid blast phase, and 46% in lymphoid blast phase. Duration of response correlates with the stage of disease, with progression-free survival of 57% at 5 years for those in chronic phase and 46% at 2 years in accelerated phase. In contrast, the median progression-free survival time was 5.6 months and 3.1 months, respectively, for those in the myeloid and lymphoid blast phases. Myelosuppression is the most comonly observed adverse event, with grade 3 or 4 neutropenia occurring in 35% of patients and thrombocytopenia in 23%. Grade 3/4 pleural effusion occurred in only 4% of patients (compared with 10% treated at a dose of 70 mg twice daily). Recent reports suggest that some patients may experience pulmonary hypertension.

Some of the most significant adverse events include myelosuppression (grade 3/4 neutropenia and thrombocytopenia in nearly 50% each), pleural effusion, and gastrointestinal hemorrhage (particularly in patients at advanced stages of disease). Alternative schedules improve the toxicity profile. In a randomized study, dasatinib administered at 100 mg once daily was associated with significantly less myelosuppression and pleural effusion when compared with dosing at 70 mg twice daily (and compared with 50 mg twice daily or 140 mg once daily). The response to therapy was similar, with a CCyR rate of 50% and MMR rates of 43%, compared with rates of 54% and 40%, respectively, at a dosage of 70 mg twice daily. Progression-free survival estimates at 6 years were 49% (in patients treated at 100 mg once daily), 51% (at 50 mg twice daily), 40% (at 140 mg once daily), and 47% (at 70 mg twice daily). Corresponding overall survival rates were 71%, 74%, 77%, and 70%, respectively, and transformation-free survival rates were 76%, 80%, 83%, and 74%, respectively. The most common nonhematologic adverse events were musculoskeletal pain (49%), headache (47%), infection (47%), and diarrhea (41%), and the most common grade 3 or 4 adverse events were infection (6%) and pleural effusion (5%). By 6 years, 7% of patients treated at 100 mg once daily discontinued treatment because of pleural effusion.

Dasatinib has also been investigated and approved as initial therapy for chronic-phase CML. A randomized phase III trial of dasatinib (at 100 mg daily) vs imatinib (at 400 mg daily) demonstrated a higher rate for dasatinib of sustained CCyR by 12 months (77% vs 66%, P = .007). With a minimum of 24 months follow-up, cumulative rates of MMR are 64% and 46%, respectively, and MR4.5 (a 4.5 log reduction in molecular response) rates of 17% and 8%, respectively. This has resulted in a lower rate of transformation to accelerated or blast phase with dasatinib (2.3%) than with imatinib (5%). A recent report of the 5-year follow-up continued to show superiority of dasatinib, with the cumulative rate of MR4.5 of 42% for dasatinib-treated patients vs 33% for those randomized to imatinib. Responses occur earlier in patients treated with dasatinib, with 84% of patients reaching BCR-ABL levels of < 10% at 3 months compared with 64% of those receiving imatinib. Pleural effusions have occurred in 28% of patients treated with dasatinib and in 1% of those treated with imatinib. There was also a trend for more cardiovascular and cerebrovascular events with dasatinib, while the incidence of other nonhematologic adverse events was similar or lower with dasatinib.

Dasatinib is approved for the treatment of patents with CML in all phases of the disease who have experienced resistance to or intolerance of imatinib, and as initial therapy for patients in chronic phase. The standard dose for patients in chronic phase is 100 mg once daily; a dosage of 140 mg once daily is recommended for patients in advanced stages. Recently, dasatinib has also been approved for use as initial therapy for patients in chronic phase, with the standard dose also being 100 mg once daily.

Nilotinib. Nilotinib was designed based on the imatinib structure and modified to improve its binding to BCR-ABL and to increase its selectivity. These modifications result in an agent at least one order of magnitude more potent than imatinib against BCR-ABL.

In phase II studies, significant activity has been documented in patients treated with nilotinib (400 mg twice daily) after treatment with imatinib fails. The rate of CCyR for patients treated in chronic phase after imatinib resistance or intolerance was 44%, and for those treated in accelerated phase was 19%. Responses have been durable, with a sustained CCyR at 24 months in 84% of patients treated in the chronic phase. In the accelerated phase, progression-free survival is 64% at 24 months. The most significant toxicities reported have been myelosuppression (grade 3/4 neutropenia or thrombocytopenia in approximately 30% of patients with each treatment), and biochemical abnormalities (elevation of indirect bilirubin, lipase, and glucose) that have been usually transient and asymptomatic. There is also the potential for QTc prolongation (a class effect for all tyrosine kinase inhibitors), although less than 3% of patients have had significant prolongation, most frequently asymptomatic.

A randomized phase III trial investigated the used of nilotinib as initial therapy for CML in chronic phase with two different dose schedules, 300 mg twice daily and 400 mg twice daily, compared with imatinib. The rate of CCyR at 12 months was significantly superior for patients treated with nilotinib (78% with 400 mg and 80% with 300 mg) compared with those treated with imatinib (65%; P < .001). A similar advantage in MMR was seen (rates at 12 months, 43%, 44%, and 22%, respectively; P < .001). Most important, the rate of transformation after 36 months of minimum follow-up was significantly lower for patients treated with nilotinib (2.1% to 3.2%) than for those treated with imatinib (6%). In a recent update with 6 years of follow-up, the cumulative rate of MR4.5 by 6 years is 56% with nilotinib administered at 300 mg twice daily, 55% with nilotinib at 400 mg twice daily, and 33% with imatinib. The rates of transformation to the accelerated and blast phases were 11%, 6% and 21%, respectively. Responses occurred earlier with 3-month rates of BCR-ABL/ABL < 10% of 83%, 82% and 62%, respectively. More patients treated with nilotinib had cardiovascular, cerebrovascular, or peripheral arterial events as well as rash and headaches, with other events mostly balanced or less frequent with nilotinib.

Nilotinib is currently approved for treatment of patients in the chronic or accelerated phase of CML who have experienced resistance or intolerance to imatinib, and the standard dose for patients treated after imatinib failure is 400 mg twice daily. Nilotinib is also approved as initial therapy for CML in chronic phase, with the standard dose for this indication being 300 mg twice daily. Nilotinib should be taken on an empty stomach, because food may significantly increase its absorption.

Bosutinib. Bosutinib is another Src and ABL inhibitor with activity against most mutants of BCR-ABL but with no activity against PDGF-R and KIT. Among 288 patients who received bosutinib after imatinib resistance or intolerance, 46% achieved a CCyR (49% for imatinib-intolerant and 44% for imatinib-resistant patients) with MMR in 35% of all patients (35% and 34%, respectively). The 2-year progression-free survival was 81% and overall survival 91%. Responses have been durable and are observed across a wide range of mutations, except T315I. The main adverse events are diarrhea (84%; 10% grade 3/4), rash (34%; grade 3/4 9%) and elevation of transaminases (22%; grade 3/4 7%). These adverse events usuallly occur in the first few months of therapy and with proper management rarely lead to treatment discontinuation, leading to treatment discontinuation in 2%, 1% and 2%, respectively). A randomized trial of bosutinib vs imatinib as initial therapy for patients with CML in chronic phase failed to show an improvement in CCyR at 12 months (primary endpoint) and thus did not gain regulatory approval. However, rate of response (BCR-ABL/ABL < 10%) at 3 months and molecular response were significantly better with bosutinib leading to fewer transformations to accelerated or blast phase.

Bostuinib is currently approved for patients with CML in all stages who have resistance or intolerance to prior therapy. The standard starting dose is 500 mg daily.

Ponatinib. Ponatinib is an orally bioavailable tyrosine kinase inhibitor that has in vitro efficacy against all known mutations against which it has been tested, including T315I. No resistant clones have emerged in vitro to this agent. In a phase II study of patients with resistance or intolerance to prior therapy, 449 patients (270 in chronic phase) were treated of whom 92% had previously received at least two approved tyrosine kinase inhibitor and 56% three approved tyrosine kinase inhibitor. A major cytogenetic response was achieved in 56%, including 51% of patients with resistance or intolerance to dasatinib or nilotinib and 70% of those with T315I mutation, and CCyR in 46% (40% and 66%, respectively). At 36 months, 83% were projected to maintain their major cytogenetic response , resulting in a progression-free survival of 61% and overall survival of 82%. The most common non-hematologic adverse events included abdominal pain, rash, constipation, headache, and dry skin (approximately 40% each, mostly grade 1/2). Grade 3/4 adverse events included hypertension (12%), elevated lipase (12%), and abdominal pain (10%). Arterial thrombotic events occurred in 22% of patients, including cardiovascular in 10%, cerebrovascular in 9% and peripheral arterial in 7%. Ponatinib is currently approved for CML in all stages of the disease in whom no other tyrosine kinase inhibitor is indicated or who have the T315I mutation. The standard starting dose is 45 mg daily. Ongoing studies are exploring whether lower starting doses may maintain efficacy and ameliorate risk.

Omacetaxine. Omacetaxine is a semisynthetic formulation of homoharringtonine, which was used as an experimental agent to treat patients with CML before the advent of tyrosine kinase inhibitors. Omacetaxine has been used to treat patients who have experienced failure of at least two prior tyrosine kinase inhibitor. Among 81 such patients in chronic phase, 18% achieved a major cytogenetic response with a median duration of 12.5 months. The most common grade 3/4 toxicties were hematologicl, with myelosuppression occurring in 79% of patients.Omacetaxine is currently approved for patients with CML in chronic or accelerated phasewho have experienced resistance or intolerance to at least two prior tyrosine kinase inhibitors.

Sidebar: ABL-001 is a new tyrosine kinase inhibitor that binds BCR-ABL in the myristoyl site, in contrast to currently available tyrosine kinase inhibitor who bind in the ATP-binding site. Binding of ABL-001 to BC-ABL is thus not affected by the presence of T315I mutation. It also has no QTc-prolonging effect. ABL-001 potently inhibits un-mutated BCR-ABL. Resistance may develop through emergence of a new A337V mutant that does not affect the binding or inhibitory efficacy of nilotinib. When used in combination with nilotinib in animal models prevents the emergence of resistance and leads to sustained disease control even after treatment discontinuation. Studies with ABL-001 are underway to investigate the safety and efficacy in humans. (Wylie A et al: ASH 2014; abstract 398).

Allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) is potentially curative in CML, although relapses and mortality from complications such as chronic graft-vs-host disease (GVHD) may occur many years after transplantation. Results are better for patients in the chronic phase than for those in either the accelerated or blastic phase. Long-term survival rates of 60% to 90% and disease-free survival rates of 40% to 80% can be achieved in the chronic phase. The role of BMT is now changing in view of the results obtained with imatinib.

Predictors of response. Early BMT within the first 1 to 3 years after diagnosis may be associated with a better outcome than BMT performed later in the course of disease. Younger patients also have a better outcome than do older patients, with those younger than 20 to 30 years of age having the best prognosis. The use of the European Group for Bone and Marrow Transplantation (EBMT) score helps to separate patients who may have a better outcome from those who may not.

Conditioning regimens. Conditioning regimens, including total-body irradiation (TBI), have been traditionally used, but non–TBI-containing regimens (eg, with busulfan and cyclophosphamide) have produced similar results. More recently, conditioning regimens using pharmacologic targeting of busulfan have been associated with decreased regimen-related toxicity while preserving efficacy. Also, nonmyeloablative conditioning regimens frequently containing purine analogs (mini-BMT) have been tested recently to expand the use of transplants to older patients or to those with medical conditions that preclude conventional BMT.

GVHD. The major morbidity from BMT is GVHD. T-cell depletion of the graft can reduce the incidence of this complication, but at the expense of higher relapse and graft failure rates. (For a full discussion of GVHD, see the “Hematopoietic Cell Transplantation” chapter.)

Alternatives to matched-related donors. For patients who do not have a matched-related donor, matched-unrelated donor transplants are reasonable alternatives. The 9-year experience from the National Marrow Donor Program in 1,432 patients reported a 3-year survival rate of 37.5%. Early transplantation results in better outcome, with patients transplanted in the chronic phase having a 3-year disease-free survival of 63%. The outcome of patients transplanted during the accelerated, blastic, or second chronic phase is inferior. More recently, cord blood transplants and haploidentical transplants have become more feasible with decreasing mortality, thus increasing the access to transplant to more patients for whom donor availability was the limiting factor. Still, the success of tyrosine kinase inhibitors has limited the use of SCT to the advanced phases of the disease or patients with resistance to three or more tyrosine kinase inhibitors.

Relapse after BMT. Donor leukocyte infusions are the most effective strategy to treat patients who relapse after BMT. With this strategy, 70% to 80% of patients can achieve a cytogenetic complete response; the best results are achieved when patients are treated during cytogenetic or molecular relapse. Imatinib has also been effective for patients who relapse after BMT. A complete hematologic response in more than 70% of patients, and a cytogenetic response in 58%, have been reported, with the best responses obtained in patients relapsing in chronic phase.

Monitoring. In the tyrosine kinase inhibitor era, the treatment objective has evolved from achieving hematologic responses (hydroxyurea), to cytogenetic responses (interferon-α), to molecular responses. All patients have to be evaluated with cytogenetic analysis before the start of therapy. A baseline RT-PCR analysis is useful as it can inform whether transcripts can be detected. PCR negativity in the presence of the Philadelphia chromosome suggests the presence of atypical transcripts that cannot be detected by routine RT-PCR, thus this technique would be uninformative for follow-up in these uncommon circumstances. Conventional cytogenetic analysis is important at baseline and for follow-up because it provides valuable information about the entire karyotype (ie, clonal evolution, cytogenetic abnormalities in Ph chromosome–negative cells) that cannot be obtained with FISH or RT-PCR and has prognostic implications. A cytogenetic analysis every 3 to 6 months during the first year and every 12 to 24 months thereafter is recommended until a stable, deep molecular response is achieved. Thereafter, it could be used to monitor patients with chromosomal abnormalities in Ph-negative metaphases. RT-PCR is recommended every 3 months for the first 12 months (or until achievement of MMR) and then every 6 months indefinitely. Achievement of CCyR is associated with an improved probability of survival. Patients who achieve CCyR have a relative survival that is nearly equivalent to that of the general population. MMR is associated with an improved event-free survival and duration of CCyR. The response target of deeper responses (MR4.5; BCR-ABL/ABL ≤ 0.0032%) has become increasingly relevant because, when sustained, deeper responses may offer the possibility of treatment discontinuation. Growing evidence shows that early responses are important to predict the long-term outcome of patients. Patients who achieve BCR-ABL transcripts of < 10% by 3 months (or its approximate equivalent in cytogenetic response terms, major cytogenetic response) have the best outcomes. Patients who do not achieve these landmarks have a significantly inferior event-free survival and a trend to a lower overall survival.

Duration of therapy and treatment discontinuation. At this time, treatment is planned to be continued indefinitely. A growing minority of patients have reached MR4.5 or undetectable levels of disease by PCR (with at least 4.5-log sensitivity). Several studies (Ross et al, Mahon et al) have offered treatment discontinuation to patients with sustained PCR negativity for at least 2 years while on therapy with imatinib. Approximately 60% of patients relapsed after treatment discontinuation. Most relapses occur within the first 6 months and patients have been reported to respond to re-initiation of imatinib. These results suggest that a subset of patients may maintain a molecular remission after discontinuation of imatinib therapy, but the risk of relapse is still high and the long-term risks and outcomes are still unknown. Thus, unless patients are included in clinical trials investigating treatment discontinuation, patients should continue therapy indefinitely.When offered treatment discontinuation, patients must be monitored with RT-PCR at least every month for the first 6 months, then every 2 months for the next 6 to 12 months, then every 3 months for another 6 to 12 months, then every 6 months indefinitely.

Sidebar: Most available data on treatment discontinuation come from patients treated with imatinib. The STOP2G-TKI study has enrolled 52 of the planned 100 patients treated with dasatinib or nilotinib used either as initial therapy (n = 5) or after resistance or intolerance to imatinib. Patients with undetectable transcripts with PCR sensitivity of at least 4.5 logs sustained for at least 2 years are eligible to enroll, with the primary objective being the rate of treatment-free survival in MMR. After a median follow-up of 3.7 months, 46% of patients lost MMR, for a projected treatment-free survival in MMR of 57.4% at 2 years. Patients who received dasatinib or nilotinib as initial therapy or for intolerance to imatinib had a 12-month treatment-free survival in MMR of 65.6% compared with 41.6% for those with prior suboptimal response or failure to respond to imatinib (Rea D et al: ASH 2014; abstract 811). Further follow-up and larger series are needed to better understand the role of treatment discontinuation of second-generation tyrosine kinase inhibitors in these settings.

Treatment recommendations

The long-term results of imatinib are excellent, with an overall survival of nearly 90% at 8 years. However, at least 35% of patients do not achieve an optimal outcome (ie, do not achieve and maintain at least a CCyR or are intolerant). It is recommended that all patients in chronic phase should be offered standard-dose imatinib (400 mg daily) or second-generation tyrosine kinase inhibitors nilotinib (300 mg twice daily) or dasatinib (100 mg once daily) as initial therapy. The results from recent randomized trials suggest better early results with dasatinib or nilotinib compared with imatinib. Although these results suggest that dasatinib and nilotinib should be the preferred options for patients with CML, it is not known yet whether the long-term outcome will be better for patients treated with these agents than for those treated with imatinib, with a change to a second-generation tyrosine kinase inhibitor only for those who experience treatment failure. A recent analysis suggested that when one accounts for effective salvage therapy by use of a second-generation tyrosine kinase inhibitor in patients who fail to respond to imatinib, the event-free survival rate improves to at least 88% at 7 years. Patients should be followed closely to determine that the expected results are met at the specified times and treatment is changed as soon as a lag in response is identified, particularly in those treated with imatinib (with failure probably defined as lack of CCyR at 6 months) (Table 3). Patients showing an optimal response should continue uninterrupted treatment indefinitely. For patients having a suboptimal response, dose escalation is recommended. Despite the prognostic implications of not achieving BCR-ABL/ABL levels of < 10% at 3 months, change of therapy is not indicated at this stage as there are no studies that demonstrate benefit in long-term outcome with a change of therapy. However, more than 80% of these patients will still enjoy a favorable long-term outcome. Thus, a change of therapy is indicated only when criteria for failure are met as defined by the European LeukemiaNet. In such instances, change in therapy to one of the second-generation tyrosine kinase inhibitors (bosutinib, dasatinib, or nilotinib) is indicated. For patients with resistance to at least two prior tyrosine kinase inhibitors or to one second-generation tyrosine kinase inhibitor, ponatinib is also indicated. Omacetaxine should also be considered for patients who have not responded to at least two and perhaps three tyrosine kinase inhibitors.

The role of allogeneic stem cell transplantation in CML has changed, and it is now considered mostly a third-line treatment option. For patients who fail to respond to treatment with two tyrosine kinase inhibitors, transplantation may be considered and discussed with the patient. Adequate response at early time points is important, particularly for young patients with a transplant option. If there is no cytogenetic response at 6 months or no major cytogenetic response by 12 months, transplant should be considered. Patients with a T315I mutation who have failed to respond to ponatinib or in whom ponatinib is contraindicated (eg, because of arterio-thrombotic events) should be considered for SCT if they are adequate candidates. Results with SCT are much better when these patients are transplanted in chronic phase; thus, patients with known T315I mutation should be considered for SCT in chronic phase if they are optimal candidates for this procedure. Otherwise, they should be included in clinical trials.

Accelerated and Blastic Phases

Tyrosine kinase inhibitor

Imatinib is also effective for patients with CML in transformation. Seventy-one percent of patients in accelerated phase treated with 600 mg/d of imatinib had a hematologic response. The major cytogenetic response rate was 24%, with 67% having a time to disease progression of 12 months. These results are significantly superior to those achieved using a dose of 400 mg per day, making 600 mg daily the standard treatment for patients in accelerated phase. In blast phase, 52% of patients achieved a hematologic remission, and 31% achieved a sustained remission lasting at least 4 weeks with imatinib. However, the median response duration is only 10 months, even when considering only patients with sustained remission (ie, lasting at least 4 weeks). Patients with clonal evolution have a lower probability of response and a shorter survival time than patients without clonal evolution when treated with imatinib.

Second-generation (nilotinib, dasatinib, and bosutinib) and third-generation (ponatinib) tyrosine kinase inhibitors also have significant clinical activity in patients with advanced-stage disease who failed to respond to prior tyrosine kinase inhibitor treatment. With nilotinib, 55% of patients in accelerated phase achieved hematologic response, and 32% achieved a major cytogenetic response, for a 2-year progression-free survival rate of 33% and overall survival of 70%. Responses have been observed also in blast phase but nilotinib is not approved for this indication. Dasatinib induced a major hematologic response in 66% and major cytogenetic response in 39% of patients in accelerated phase at a dose of 140 mg once daily. In blast phase 28% of patients with myeloid phenotype and 42% of those with lymphoid phenotype achieved a major hematologic response with dasatinib at 140 mg once daily; corresponding rates of major cytogenetic response were 25% and 50%, respectively. Median progression-free survival time was 3.8 and 4.7 months, respectively. Results are similar with a 70 mg twice-daily regimen but with a trend for improved tolerability with the once-daily schedule. Dasatinib is approved for both accelerated and blast phase CML. Bosutinib is also approved for patients with accelerated and blast phase disease. At a dose of 500 mg once daily, overall hematologic responses have been achieved in 57% and 28% of patients in accelerated or blast phase, respectively, and 40% and 37% achieved major cytogenetic response. Ponatinib has induced high rates of response in advanced-phase CML at the standard dose of 45 mg daily. In accelerated-phase CML, 55% of patients achieved a major hematologic response and 39% had a major cytogenetic response, with 12-month progression-free survival of 55%. In blast phase, corresponding rates were 31% for major hematologic response and 23% for major cytogenetic response, with a progression-free survival rate of 19%. Omacetaxine is also approved for patients with accelerated-phase CML, with a reported 14% rate of major hematologic response but no major cytogenetic response; median survival time was 14.3 months. Occasionally, patients may present with features of accelerated-phase disease at the time of diagnosis of CML. When treated with tyrosine kinase inhibitors as initial therapy, particularly second-generation tyrosine kinase inhibitors, these patients have a favorable outcome similar to that of patients with chronic-phase features, and thus may not require SCT.

BMT

Compared with results in patients in the chronic phase, results with allogeneic BMT are worse in patients in the accelerated or blast phase, with 4-year survival rates of only 10% to 30%. Patients in the accelerated phase (determined on the basis of clonal evolution only) who undergo BMT less than 1 year after diagnosis have a 4-year probability of survival of 74%. Patients in the blast phase who respond to therapy with a second-generation tyrosine kinase inhibitor should be offered a BMT in the second chronic phase if an adequate donor is available.

Suggested Reading

Al-Kali A, Kantarjian H, Shan J, et al: Current event-free survival after sequential tyrosine kinase inhibitor therapy for chronic myeloid leukemia. Cancer 117:327–335, 2011.

Baccarani M, Deininger MW, Rosti G, et al: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122:872–884, 2013.

Branford S, Yeung DT, Parker WT, et al: Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 124:511–518, 2014.

Cortes JE, Kim DW, Pinilla-Ibarz J, et al: A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369:1783–1796, 2013.

Brümmendorf TH, Cortes JE, de Souza CA, et al: Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol 168:69–81, 2015.

Cortes J, Hochhaus A, Hughes T, et al: Front-line and salvage therapies with tyrosine kinase inhibitors and other treatments in chronic myeloid leukemia. J Clin Oncol 29:524–531, 2011.

Cortes J, Quintas-Cardama A, Jones D, et al: Immune modulation of minimal residual disease in early chronic phase chronic myelogenous leukemia: A randomized trial of frontline high-dose imatinib mesylate with or without pegylated interferon alpha-2b and granulocyte-macrophage colony-stimulating factor. Cancer 117:572–580, 2011.

Cortes JE, Kim DW, Kantarjian HM, et al: Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: Results from the BELA trial. J Clin Oncol 30:3486–3492, 2012.

Cortes JE, Wetzler M, Lipton J, et al: Subcutaneous omacetaxine (OM) treatment of chronic phase (cp) chronic myeloid leukemia (CML) patients following multiple tyrosine kinase inhibitor (TKI) failure. Blood 116:abstract 2290, 2010.

Cortes JE, Kantarjian HM, Rea D, et al: Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer 121:1637–1644, 2015.

Fabarius A, Leitner A, Hochaus A, et al: Impact of additional cytogenetic aberrations on prognosis of CML: long-term observation of 1151 patients from the randomized CML study IV. Blood 118:6760–6768, 2011.

Gambacorti-Passerini C, Kantarjian HM, Kim DW, et al: Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol 2015 Jun 1. [Epub ahead of print]

Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al: Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 27:107–112, 2013.

Hehlmann R, Lauseker M, Jung-Munkwitz S, et al: Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29:1634–1642, 2011.

Hughes TP, Saglio G, Kantarjian HM, et al: Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood 123:1353–1360, 2014.

Jain P, Kantarjian H, Nazha A, et al: Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: Results with four tyrosine kinase inhibitor modalities. Blood 121:4867–4874, 2013.

Jabbour E, Kantarjian H, O’Brien S, et al: Predictive factors for outcome and response in patients treated with second-generation tyrosine kinase inhibitors for chronic myeloid leukemia in chronic phase after imatinib failure. Blood 117:1822–1827, 2011.

Kantarjian H, Cortes J, Kim DW, et al: Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-Month median follow-up. Blood 113:6322–6329, 2009.

Kantarjian H, Pasquini R, Lévy V, et al: Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: Two-year follow-up of a randomized phase 2 study (START-R). Cancer 115:4136–4147, 2009.

Kantarjian H, Shah NP, Hochhaus A, et al: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260–2270, 2010.

Khoury HJ, Cortes JE, Kantarjian HM, et al: Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 119:3403–3412, 2012.

Mahon FX, Rea D, Guilhot J, et al: Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11:1029–1035, 2010.

Marin D, Bazeos A, Mahon FX, et al: Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28:2381–2388, 2010.

Ohanian M, Kantarjian HM, Quintas-Cardama A, et al: Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk 14:155–162, 2014.

Ross DM, Branford S, Seymour JF, et al: Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 24:1719–1724, 2010.

Saglio G, Kim DW, Issaragrisil S, et al: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251–2259, 2010.

Sasaki K, Strom SS, O’Brien S, et al: Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: Analysis of patient data from six prospective clinical trials. Lancet Hematol 2:e186–e193, 2015.

Shah NP, Guilhot F, Cortes JE, et al: Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: Follow-up of a phase 3 study. Blood 123:2317–2324, 2014.

Velev N, Cortes J, Champlin R, et al: Stem cell transplantation for patients with chronic myeloid leukemia resistant to tyrosine kinase inhibitors with BCR-ABL kinase domain mutation T315I. Cancer 116:3631–3637, 2010.

White DL, Dang P, Engler J, et al: Functional activity of the OCT-1 protein is predictive of long-term outcome in patients with chronic-phase chronic myeloid leukemia treated with imatinib. J Clin Oncol 28:2761–2767, 2010.

Yeung DT, Osborn MP, White DL, et al: TIDEL-II: First-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 125:915–923, 2015.

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