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 5,050 new cases of CML will be diagnosed in 2009, and it is estimated that 470 patients will die of CML this year. The incidence is 1.7 per 100,000 population. With imatinib (Gleevec) therapy, the annual mortality has been reduced significantly (less than 2%-3% per year).

Epidemiology

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

Age
According to SEER and 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 even younger, (median age: approximately 40 years). Age differences must be considered in all studies, because this variable may affect results.

Etiology and risk factors

The etiology of CML is unclear. Some associations with genetic and environmental factors have been reported, but, in most cases, no such 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, chronic-phase CML is associated with a median survival of 3.5 to 5.0 years. During the chronic phase, CML is asymptomatic in 25% to 60% of all cases; in these cases, the disease is 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. Occasionally, patients with very high WBC counts may have manifestations of hyperviscosity, including priapism, tinnitus, stupor, visual changes from retinal hemorrhages, and cerebrovascular accidents.

Patients in chronic-phase CML do not have an increased risk for infection. Splenomegaly is documented in 30% to 70% of patients. The liver is enlarged in 10% to 20% of cases.

Accelerated phase
This is an ill-defined transitional phase. The criteria used recently in all the studies with tyrosine kinase inhibitors include the presence of 15% to 29% blasts, at least 30% blasts and promyelocytes, or at least 20% basophils in the peripheral blood or a platelet count < 100 × 10⁹/L unrelated to therapy. Cytogenetic clonal evolution is also a criterion for acceleration. Other classifications include more subjective criteria (Table 1). The classification used may affect the expected outcome for a group of patients defined as accelerated phase. With imatinib therapy, the estimated 4-year survival rate exceeds 50%.

The accelerated phase is frequently symptomatic, including 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% of blasts in the bone marrow or peripheral blood. The WHO has proposed to consider blast phase with 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 CNS, lymph nodes, skin, or bones.

Patients in blastic phase usually die within 3 to 6 months. Approximately 70% of patients in blastic phase 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.