Chronic Myeloid Leukemia
Summary of Key Points
Evaluation
• History and physical examination, complete blood cell count with differential and platelet count, and chemistries
• Bone marrow aspiration and biopsy
• Testing for the presence of the Philadelphia (Ph) chromosome by cytogenetic analysis; testing for the presence of the BCR-ABL fusion gene by fluorescent in situ hybridization (FISH) and by quantitative polymerase chain reaction (qPCR) analysis
Therapy
• Hydroxyurea or a BCR-ABL tyrosine kinase inhibitor (TKI; e.g., imatinib mesylate, nilotinib, dasatinib) is given initially to control leukocytosis and thrombocytosis.
• Imatinib induces a complete hematologic and cytogenetic response in most patients; estimated 8- to 10-year survival rate is 85% (93% if only CML-related deaths considered).
• Randomized studies of frontline therapy with second-generation TKIs (e.g., nilotinib, dasatinib) show better results than those of imatinib.
• New TKIs (e.g., dasatinib, nilotinib, bosutinib, ponatinib) are active after imatinib failure.
• Allogeneic stem cell transplantation may be curative but is associated with considerable morbidity and mortality.
1. A 50-year-old man is seen with left upper quadrant pain, splenomegaly 6 cm below the costal margin, hemoglobin value of 12 g/dL, white blood cell count of 52 × 109/L, and a platelet count of 450 × 109/L. Bone marrow is hypercellular with 4% blasts and 2% basophils. Cytogenetic studies show the Philadelphia chromosome abnormality. His brother is a perfect human leukocyte antigen (HLA) match. The next step in his immediate treatment may include any of the following except:
2. In Philadelphia (Ph) chromosome–positive chronic myeloid leukemia (CML), the most frequent molecular BCR-ABL oncoprotein abnormality is:
3. A 65-year-old woman is seen with leukocytosis, a white blood cell count of 110 × 109/L, a platelet count of 510 × 109/L, and a hemoglobin value of 12.5 g/dL. Bone marrow studies show a hypercellular marrow with 5% blasts. Cytogenetic studies show a diploid karyotype. Her brother is a full HLA match. The next step in this patient’s management is:
A Start hydroxyurea (Hydrea) and refer immediately for allogeneic stem cell transplantation
C Start intensive chemotherapy for acute myelogenous leukemia
D Order fluorescent in situ hybridization analysis and molecular studies for BCR-ABL
4. A 62-year-old man with Ph-positive CML has been on imatinib therapy 400 mg daily for the past 3 years. Recent studies show loss of response with a white blood cell count of 25 × 109/L. Bone marrow studies show 100% Ph-positive metaphases. Mutation studies show T315I mutations. His sister is a full HLA match. The next step is:
1. Answer: D. Frontline therapy with tyrosine kinase inhibitors offers estimated 5- to 10-year survival rates of 85% to 90%, with minimal morbidity and mortality. Frontline allogeneic stem cell transplantation is associated with 5% to 30% mortality depending on patient age, HLA matching, and other factors.
2. Answer: B. In Ph-positive CML, the large majority of patients, 99%, have the P210 abnormality. P190 chronic-phase CML is rare and is thought to be associated with a worse prognosis. P230 chronic-phase CML is also very rare and is associated with favorable prognosis. A double message is usually degradation of the P210 into P190 and is related to technique rather than a true event.
3. Answer: D. About 5% of patients with a morphologic picture of CML do not show the Ph chromosome abnormality. In half of them, the BCR-ABL molecular abnormality is detectable, and these patients should be treated with tyrosine kinase inhibitors (e.g., imatinib). They have a similar response to tyrosine kinase inhibitors and a similar favorable prognosis on such therapy as those with Ph-positive CML.
4. Answer: D. The only BCR-ABL tyrosine kinase inhibitor that is known today to suppress T315I CML clones is ponatinib. This mutation is resistant to the second-generation tyrosine kinase inhibitors (i.e., nilotinib, dasatinib, bosutinib). The patient also should be referred for consideration of allogeneic stem cell transplantation.
