Chronic Myeloid Leukemia
Epidemiology and Etiology
Chronic myeloid leukemia (CML) accounts for 14% of leukemias diagnosed in the US, with an estimated 8450 new cases in 2020 and a median age at diagnosis of 65 years1
Pathology
The characteristic peripheral blood smear of patients with CML demonstrates basophilia and granulocytosis with neutrophils and immature granulocytes, while the bone marrow aspirate commonly reveals hyperplasia of the granulocytic series (promyelocytes, myelocytes, metamyelocytes, band forms, and mature granulocytes).
The hallmark of CML is the fusion of two genes, BCR on chromosome 22 and ABLl on chromosome 9, resulting in the BCR-ABLl fusion gene t(9;22) also known as the Philadelphia chromosome.Clinical Presentation
The natural history of CML is a triphasic process with a chronic phase, an accelerated phase, and a blast phase. Chronic phase is associated with an asymptomatic accumulation of differentiated myeloid cells in the marrow, spleen, and peripheral circulation. CML patients will invariably progress to accelerated and blast phases without treatment. The majority of patients present in chronic phase CML identified incidentally by routine CBC. Symptoms may be related to splenomegaly (left-sided abdominal pain, early satiety) or anemia. Peripheral blood counts show increased white blood cells with all levels of granulocytic differentiation, from myeloblasts to segmented neutrophils. Transformation from chronic to blast phase may be insidious or abrupt.
Diagnostic Testing
The presence of the BCR-ABLl rearrangement by cytogenetics, FISH, or polymerase chain reaction (PCR) along with the characteristic blood or bone marrow findings confirms the diagnosis of CML.
TREATMENT
• Patients in chronic and accelerated phase are treated with oral TKIs such as imatinib, dasatinib, nilotinib, bosutinib, or ponatinib. The choice of agent typically depends on treatment-related adverse effects and patient preference.
Ponatinib is typically reserved for those who have failed two prior TKIs or who develop tyrosine kinase domain resistance mutations, such as T315I.36 Quantitative PCR (qPCR) for BCR-ABLl is performed every 3 months to monitor response to treatment. Complete hematologic remission (CHR) is defined as normalization of peripheral blood counts and absence of splenomegaly, whereas complete cytogenetic response (CCyR) is defined by the absence of Philadelphia chromosome metaphases on bone marrow cytogenetic analysis; major molecular remission is defined by qPCR when BCR-ABLl transcripts in the peripheral blood are #8804;0.1% on the International Scale (IS). Treatment milestones: CHR and/or BCR-ABLl transcripts in the marrow #8804;10% (IS) by 3 months, CCyR and/or BCR-ABLl transcripts in the marrow #8804;1% (IS) by 6 months, and BCR-ABLl transcripts in the marrow #8804;0.1% (IS) by 12 months after starting a TKI constitute an optimal response to therapy. Failure to achieve treatment milestones may warrant switching TKIs and assessment for acquired mutations within the tyrosine kinase domain which confer resistance to TKIs. For patients who develop TKI resistance, ponatinib, asciminib (STAMP [specifically targeting ABL myristoyl pocket] inhibitor), and omacetaxine may be considered.36• Blast crises are more challenging to manage and the treatment often involves TKIs, chemotherapy, and stem cell transplantation. In addition, stem cell transplantation can be considered in patients who relapse after initial response to TKIs and/or who develop resistance to TKIs.