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 4,830 new cases of CML will be diagnosed in 2008, and it is estimated that 450 patients will die of CML this year. The incidence is 1.7 per 100,000 population. With imatinib (Gleevec) therapy, the annual mortality may be reduced significantly (less than 2%–3% per year).
Epidemiology
Gender The male-to-female ratio is 1.1–1.4:1.
Age According to SEER (Surveillance, Epidemiology, and End Results) and MRC (Medical Research Council, UK) data, the median age of patients with CML is 66 years. However, most patients who are admitted to medical therapy studies are 50–60 years old, with a median age of ~53 years. Patients in bone marrow transplantation (BMT) studies are even younger, with a median age of ~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 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%–80% of patients.
Chronic phase If untreated, chronic-phase CML is associated with a median survival of 3.5–5.0 years. During the chronic phase, CML is asymptomatic in 25%–60% of all cases and, in these cases, 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%–70% of patients. The liver is enlarged in 10%–20% of cases.
Accelerated phase This is an ill-defined transitional phase. The criteria (M. D. Anderson Cancer Center [MDACC]) used recently in all the studies with tyrosine kinase inhibitors include the presence of 15%–29% blasts, ≥ 30% blasts and promyelocytes, or ≥ 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%. Thus, a new definition of accelerated phase (ie, predictive for short survival) needs to be developed.
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 World Health Organization has proposed to consider blast phase with ≥ 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 those with ≥ 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 3–6 months. Approximately 70% of patients in blastic phase have a myeloid phenotype; 25%, lymphoid; and 5%, undifferentiated. Prognosis is slightly better for a lymphoid blastic phase than for myeloid or undifferentiated cases (median survival 9 vs 3 months).
Patients in 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 > 25 × 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 work-up for CML.
The WBC differential usually shows granulocytes in all stages of maturation, from blasts to mature, morphologically normal granulocytes. Basophils are elevated, but only 10%–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 lymphocytes.
The platelet count is elevated in 30%–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. Platelet function is frequently abnormal but usually has no clinical significance.
Bone marrow The bone marrow is hypercellular, with cellularity of 75%–90%. The myeloid-to-erythroid ratio is usually 10–30:1. 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 increases with disease progression and is usually an adverse prognostic finding.
Other laboratory findings Leukocyte alkaline phosphatase activity is reduced at diagnosis. Serum levels of vitamin B12 and transcobalamin are increased, sometimes up to 10 times normal values. Serum levels of uric acid and lactic dehydrogenase (LDH) are also frequently elevated.
