Leukemia, Chronic Myeloid

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

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

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

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

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