Author: Dr Frederick Appelbaum Fred Hutchinson Cancer Research Center Seattle 2008-07-28 Chronic myeloid (or myelogenous) leukemia developed in approximately 4500 Americans in 2006. Although it is sometimes seen in childhood, the incidence of the disease increases with age and the median age of diagnosis is around 60 years.
Biology and Classification
A specific chromosomal translocation, t(9;22), gives rise to CML. This translocation involves the movement of a small part of chromosome 9 to chromosome 22, and the reciprocal movement of a piece of chromosome 22 to chromosome 9 (See Figure 1). The abnormal chromosome 22 with the added piece of 9 is called the “Philadelphia chromosome”, based on the city where it was first described. The break in chromosome 9 occurs within a gene called “ABL”, while the break in chromosome 22 occurs in the gene called “BCR.” A result of the translocation is the creation of a new gene that is a fusion of BCR and ABL. The product of the fusion gene is what causes the abnormal cell growth. The exact site of the breaks within chromosome 9 and 22 can alter the function of the fusion gene; thus, t(9:22) is also associated with ALL, but the breakpoints in ALL and CML frequently differ.CML generally occurs in three phases: chronic phase, accelerated phase, and blast crisis. Chronic phase CML is characterized by a slow increase in the number of mature-appearing granulocytes in the bone marrow, peripheral blood, and often, the liver and the spleen. Even with no treatment patients may live for several years with chronic phase CML with few, if any, symptoms. However, if untreated, after some period of time the disease will enter an accelerated phase during which the rate of white cell increase accelerates, normal blood counts may start to drop and patients may develop systemic symptoms, including increased fatigue and night sweats. If patients receive no treatment, the accelerated phase usually lasts only a matter of months, after which patients enter blast crisis. Blast crisis resembles AML, with a rapid increase in abnormal myeloblasts and a rapid fall in normal counts. If untreated, blast crisis CML is usually fatal in a few weeks to months.
Causes
The only clearly identified risk factor for the development of CML is prior radiation exposure. CML is not hereditary nor is it contagious.Signs and Symptoms
At the time of diagnosis, most patients are in chronic phase, and as many as 50% of patients are diagnosed incidentally during routine screening or a blood evaluation for an unrelated problem. Symptoms, when present, may include fatigue, weight loss, bone aches and abdominal discomfort from the development of an enlarged spleen.Diagnosis of CML
The diagnosis of CML is almost always first suspected because of an increase in the number of granulocytes in the peripheral blood. Confirmation of the diagnosis requires the demonstration of the BCR/ABL translocation in the leukemic cells. This is often accomplished by cytogenetic analysis of the bone marrow, but FISH analysis or PCR testing may serve as a substitute. A bone marrow examination may be useful for documenting the stage of the disease.Treatment of CML
Chronic Phase
Therapy of chronic phase CML in the 1980s involved oral busulfan or oral hydroxyurea. Both are able to reduce abnormal blood count levels and control symptoms for, on average, about 4 years. Thereafter, the disease would progress into accelerated phase or blast crisis, and subsequent survival was measured in months. In the late 1980’s, interferon alfa was found to be a more effective therapy for CML, extending the average duration of chronic phase to slightly beyond 5 years. In the late 1990’s, imatinib mesylate was introduced and was compared to interferon in a large randomized trial. In that trial, after six months of therapy only 1% of patients being treated with imatinib had progressive disease compared to 10% of patients treated with interferon. [13] Based on this difference, the study was stopped and imatinib mesylate at a daily dose of 400 mg orally per day became the standard of care. After 5 years, 90% of patients with early chronic phase disease treated with imatinib were alive and 84% progression-free.Response to imatinib is determined by monitoring the peripheral blood counts (hematologic response), marrow cytogenetics (cytogenetic response), and PCR measurements of the BCR/ABL fusion product (molecular response). Hematologic response is the least sensitive test while molecular response is the most sensitive. The overall duration of response to imatinib appears to be longest in those patients who achieve a complete molecular response, and somewhat shorter in those who achieve a complete cytogenetic response without a complete molecular response. Response durations are considerably shorter in those who fail to achieve a cytogenetic response. It is uncertain if any patients can be cured with imatinib, and in those cases where the drug has been stopped, the disease has quickly reappeared.
Dasatinib and nilotinib are two newer agents that can induce responses in patients who have failed therapy with imatinib. Clinical trials are now underway comparing imatinib at the conventional dose of 400 mg versus imatinib at higher doses (600 mg or 800 mg), and also comparing imatinib with either dasatinib or nilotinib. Imatinib can cause nausea, headache, diarrhea, muscle cramps, rash, and peripheral edema, and these toxicities are more common are higher doses. Both nilotinib and dasatinib can have similar toxicities, but dasatinib is also sometimes associated with the development of a build up of fluid in the lungs (pleural effusions).
Bone marrow transplantation from a matched sibling or matched unrelated donor is able to cure approximately 70% of patients with early phase chronic CML, and was widely used as the initial therapy of choice before the development of imatinib. Because 10-15% of patients can die as a result of transplant-related toxicities, most patients and physicians prefer to treat with imatinib and only proceed to transplant once imatinib therapy fails. Although data are limited, it does not appear that prior therapy with imatinib makes transplantation any more risky; however, if transplantation is delayed until patients have progressed to accelerated phase, then outcomes are considerable worse. Thus, careful monitoring of patients with CML being treated with imatinib is warranted.
Accelerated Phase and Blast Crisis
Occasionally, patients are already in accelerated phase or blast crisis at the time of diagnosis. Such patients will frequently respond to imatinib, but the responses are less complete and of shorter duration than those seen in chronic phase.Patients who progress to accelerated phase or blast crisis while receiving imatinib can sometimes respond briefly to an increase in dose (from 400 to 800 mg/day, for example), but these responses are short lived. Dasatinib or nilotinib can induce responses in many patients who have failed therapy with imatinib. Bone marrow transplantation is the only therapy with curative potential in patients with advanced CML. The procedure has the best chance of working in patients with accelerated phase of blast crisis CML if it is carried out after patients have responded to therapy with dasatinib or nilotinib.