CML is a clonal malignancy usually characterized by splenomegaly and production of increased numbers of granulocytes; course is initially indolent but eventuates in leukemic phase (blast crisis) that has a poorer prognosis than de novo AML; rate of progression to blast crisis is variable; overall survival averages 4 years from diagnosis.
In the United States about 14,620 cases have occurred in 2015. More than 90% of cases have a reciprocal translocation between chromosomes 9 and 22, creating the Philadelphia (Ph) chromosome and a fusion gene product called BCR-ABL. (BCR is from 9, ABL from 22.) The chromosome abnormality appears in all bone marrow-derived cells except T cells. The protein made by the chimeric gene is 210 kDa in chronic phase and 190 kDa in acute blast transformation. In some pts, the chronic phase is clinically silent and pts present with acute leukemia with the Ph chromosome.
Clinical and Laboratory Features 
Symptoms develop gradually; easy fatigability, malaise, anorexia, abdominal discomfort and early satiety from the large spleen, excessive sweating. Occasional pts are found incidentally based on elevated leukocyte count. WBC is usually >25,000/µL with the increase accounted for by granulocytes and their precursors back to the myelocyte stage; bands and mature forms predominate. Basophils may account for 10-15% of the cells in the blood. Platelet count is normal or increased. Anemia is often present. Neutrophil alkaline phosphatase score is low. Marrow is hypercellular with granulocytic hyperplasia. Marrow blast cell count is normal or slightly elevated. Serum levels of vitamin B12, B12-binding proteins, and LDH are elevated in proportion to the WBC. With high blood counts, spurious hyperkalemia and hypoglycemia may be seen.
Chronic phase lasts for 2-4 years. Accelerated phase is marked by anemia disproportionate to the disease activity or treatment. Platelet counts fall. Additional cytogenetic abnormalities appear. Blast cell counts increase. Usually within 6-8 months, overt blast crisis develops in which maturation ceases and blasts predominate. The clinical picture is that of acute leukemia. Half of the cases become AML, one-third have morphologic features of acute lymphoid leukemia, 10% are erythroleukemia, and the rest are undifferentiated. Survival in blast crisis is often <4 months.
Treatment: Chronic Myeloid Leukemia Criteria for response are provided in Table 65-2. Allogeneic bone marrow transplantation has the potential to cure the disease in chronic phase. However, the first treatment is imatinib, a molecule that inhibits the chimeric gene product's tyrosine kinase activity. A daily oral dose of 400 mg produces complete hematologic remission of >90% and cytogenetic remission in 76%. If a matched donor is available, it is best to transplant pts in complete remission. Several mechanisms of resistance to imatinib have emerged, and it is unlikely that it leads to permanent remissions when used alone; however, follow-up is not sufficient to draw firm conclusions. Pts who no longer respond to imatinib may respond to other tyrosine kinase inhibitors such as dasatinib (100 mg PO qd) or nilotinib (400 mg PO bid). The T315I mutation in the BCR/ABL gene conveys resistance to all three kinase inhibitors. Ponatinib (45 mg/d) is effective in patients with the T315I mutation, but concerns have been raised about vascular toxicity. Allopurinol, 300 mg/d, prevents urate nephropathy. The only curative therapy for the disease is HLA-matched allogeneic bone marrow transplantation. The optimal timing of transplantation is unclear, but transplantation in chronic phase is more effective than transplantation in accelerated phase or blast crisis. Transplantation appears most effective in pts treated within a year of diagnosis. Long-term disease-free survival may be obtained in 50-60% of transplanted pts. Infusion of donor lymphocytes can restore remission in relapsing pts. In pts without a matched donor, autologous transplantation may be helpful using peripheral blood stem cells. Treatment of pts in blast crisis with imatinib can obtain responses, but they are not durable. |
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