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Chronic Myeloid Leukemia

Chronic Myeloid Leukemia


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 5,430 new cases of CML were diagnosed in 2012, with an estimated 610 deaths. The age-adjusted incidence is 1.6 per 100,000 population. With imatinib (Gleevec) therapy, the annual mortality has been reduced significantly (less than 2% to 3% per year, and less 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.

FDA Approvals

In December 2012, the US Food and Drug Administration (FDA) approved ponatinib (Iclusig) to treat CML. The trial that led to the approval, the PACE trial, was a phase II clinical trial that included patients with various phases of CML. All were treated with ponatinib. The data show that 54% of chronic-phase CML patients in the trial (including 70% percent of patients who have a T315I mutation) achieved a major cytogenetic response. In accelerated- and blast-phase CML, ponatinib’s effectiveness was determined by the number of patients who experienced a major hematologic response. The data show that major hematologic response was observed in 58% of patients with accelerated-phase CML (57% of resistant/intolerant patients and 50% with T315I mutation), and 34% of those with blast-phase CML (35% of resistant/intolerant patients and 33% with T315I mutation). Other results show that 52% of patients with accelerated-phase CML experienced major hematologic response for a median duration of 9.5 months and 31% of patients with blast-phase CML achieved major hematologic response for a median duration of 4.7 months.

In October 2012, the FDA approved omacetaxine mepesuccinate (Synribo) for the treatment of adults with CML whose cancer has progressed following treatment with at least two tyrosine kinase inhibitors. The effectiveness of omacetaxine was evaluated from the combined data subsets of two phase II, open-label, multicenter studies that included patients with chronic- and accelerated-phase CML. In chronic-phase CML, a major cytogenetic response was seen in 18.4% of patients (14 out of 76), with a mean time of onset of 3.5 months. The median duration of response was 12.5 months (Kaplan-Meier estimate). In accelerated-phase CML, 14.3% of patients achieved major hematologic response (5 out of 35), with a mean time of onset of 2.3 months. The median duration of response was 4.7 months (Kaplan-Meier estimate).

In September 2012, the FDA approved the tyrosine kinase inhibitor bosutinib (Bosulif) to treat Philadelphia chromosome–positive CML. The drug is intended for patients with chronic-, accelerated-, or blast-phase CML who cannot tolerate or are resistant to other therapies (including imatinib). The trial that led to the approval of bosutinib was a single-arm clinical study that enrolled 546 adult patients. All participants were treated with bosutinib. Patients included in the trial had disease that progressed after treatment (with imatinib, dasatinib, or nilotinib) or were unable to tolerate the side effects of these therapies. Results showed 34% of patients with chronic-phase CML who had been previously treated with imatinib achieved a major cytogenetic response (MCyR) after 24 weeks; in all, 52.8% of patients who achieved MCyR at some point had their response last at least 18 months. In patients previously treated with imatinib followed by dasatinib and/or nilotinib, about 27% achieved MCyR within the first 24 weeks of treatment; of those, 51.4% had their MCyR last at least 9 months. In patients with accelerated-phase CML previously treated with at least imatinib, 33% had complete hematologic response and 55% achieved overall hematologic response within the first 48 weeks of treatment. Meanwhile, 15% and 28% of patients with blast-phase CML achieved complete hematologic response and overall hematologic response, respectively.



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


According to Surveillance, Epidemiology and End Results (SEER) 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.


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