Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 13-27: Chronic Myeloid Leukemia + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Elevated white blood count (WBC) Left-shifted myeloid series but low percentage of promyelocytes and blasts Presence of bcr/abl gene (Philadelphia chromosome) +++ General Considerations ++ Myeloproliferative disorder characterized by overproduction of myeloid cells Associated with characteristic chromosomal abnormality, the Philadelphia chromosome, a reciprocal translocation between long arms of chromosomes 9 and 22 Translocated portion of 9q contains abl, a protooncogene, which is received on 22q, at the break point cluster (bcr) site The fusion gene bcr/abl produces a novel protein that possesses tyrosine kinase activity, leading to leukemia Disease may progress from chronic phase to accelerated phase and to blast crisis Progression is often associated with added chromosomal defects superimposed on the Philadelphia chromosome Blast crisis chronic myeloid leukemia (CML) is morphologically indistinguishable from acute leukemia +++ Demographics ++ CML occurs mainly in middle age; median age at presentation is 50 years + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Fatigue, night sweats, and low-grade fevers Abdominal fullness related to splenomegaly Leukostasis clinical syndrome (blurred vision, respiratory distress, and/or priapism) is rare Sternal tenderness Fever in absence of infection, bone pain, and splenomegaly may mark disease acceleration +++ Differential Diagnosis ++ Reactive leukocytosis resulting from infection, inflammation, or cancer Other myeloproliferative disorder: essential thrombocytosis, polycythemia vera, or myelofibrosis + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ Median WBC at diagnosis is 150,000/mcL, although some cases are discovered when WBC is only modestly increased In the rare cases of the leukostasis clinical syndrome, WBC usually > 500,000/mcL Hematocrit is usually normal at presentation Platelet count may be normal or elevated (sometimes strikingly elevated) Basophilia and eosinophilia may be present Peripheral blood smear Myeloid series left-shifted with mature forms dominating Blasts usually < 5% Red blood cell (RBC) morphology normal; nucleated RBCs rarely seen The diagnosis is confirmed by finding the Philadelphia chromosome (bcr/abl gene) in peripheral blood Progressive anemia and thrombocytopenia occur in accelerated and blast phases, and percentage of blasts in blood and bone marrow increases +++ Diagnostic Procedures ++ Bone marrow aspirate and biopsy: hypercellular, with left-shifted myelopoiesis is not diagnostic, but distinguishes chronic phase from more advanced disease Cytogenetics in bone marrow may show abnormalities in addition to the Philadelphia chromosome When blasts comprise > 20% of bone marrow cells, blast phase of CML is diagnosed + Treatment Download Section PDF Listen +++ +++ Medications ++ Imatinib mesylate, 400 mg orally once daily Results in nearly universal (98%) hematologic control of chronic phase disease Rate of a major molecular response is ~30% at 1 year Dasatinib and nilotinib Increase the rate of achievement of a major molecular response compared to imatinib 64% for dasatinib at 100 mg/day by 2 years 71% for nilotinib at 300–400 mg twice daily by 2 years Result in a lower rate of progression to advanced-stage disease Can also salvage 90% of patients who do not respond to imatinib and may therefore be reserved for use in that setting Bosutinib A dual Src/Abl tyrosine kinase inhibitor The complete cytogenetic response rate is 25% The T315I mutation in abl is specifically resistant to therapy with imatinib, dasatinib, nilotinib, and bosutinib but appears to be sensitive to the third-generation agent, ponatinib Asciminib Indicated for patients who have not responded to multiple tyrosine kinase inhibitors, including ponatinib, as well as for patients with the T315I mutation Has shown a 54% complete hematologic response rate and a 48% sustained major molecular response in heavily pretreated patients Dose-limiting toxic effects include asymptomatic elevations in the lipase level and clinical pancreatitis Omacetaxine Non–tyrosine kinase inhibitor Approved for patients with CML who are resistant to at least two tyrosine kinase inhibitors Can produce major cytogenetic responses in 18% of patients +++ Therapeutic Procedures ++ Treatment usually not emergent even with WBC > 200,000/mcL Emergent leukapheresis is performed in conjunction with myelosuppressive therapy in rare instances of extreme hyperleukocytosis Allogeneic stem cell transplantation should be considered for patients in whom Disease is not well controlled Disease progresses after initial control Accelerated or blast phase disease is present + Outcome Download Section PDF Listen +++ +++ Follow-Up ++ Patients receiving tyrosine kinase inhibitors should be monitored with a quantitative polymerase chain reaction (PCR) assay Patients with a consistent increase in bcr/abl transcript or those with a suboptimal molecular response should undergo abl mutation testing and then switched to an alternative tyrosine kinase inhibitor Response is assessed by Hematologic complete remission, with normalization of blood counts and splenomegaly, usually within several weeks to 3 months Cytogenetic responses within 3–6 months Quantitative assessment of the bcr/abl gene by polymerase chain reaction (PCR) assay Bone marrow cytogenetics after 6 months of imatinib treatment to assess hematologic and cytogenetic remission +++ Complications ++ Leukostasis clinical syndrome +++ Prognosis ++ With imatinib therapy and the development of molecular targeted agents, more than 80% of patients remain alive and without disease progression at 9 years Allogeneic stem cell transplantation is the only proven curative option However, some patients may be cured by well-tolerated oral agents Current studies suggest that tyrosine kinase inhibitor therapy may be safely discontinued after 2 years in patients who achieve a sustained major molecular response with 50–60% of patients remaining in molecular remission at least 1 year later +++ When to Refer ++ All patients with CML should be referred to a hematologist or oncologist +++ When to Admit ++ Hospitalization is rarely necessary Should be reserved for patients with symptoms of leukostasis at diagnosis or for those in whom CML transforms to acute leukemia + References Download Section PDF Listen +++ + +Craddock CF. We do still transplant CML, don't we? Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):177–84. [PubMed: 30504307] + +Molica M et al. Insights into the optimal use of ponatinib in patients with chronic phase chronic myeloid leukaemia. Ther Adv Hematol. 2019 Mar 1;10:2040620719826444. [PubMed: 30854182] + +Westerweel PE et al. New approaches and treatment combinations for the management of chronic myeloid leukemia. Front Oncol. 2019 Aug 6;9:665. [PubMed: 31448223]