A 51 year old male is found to have splenomegaly on physical examination. His blood work shows a haemoglobin of 110g/L, white blood cell count of 122 with a left shift and platelet count of 900,000. He is immediately referred to a haematologist, who suspects chronic myelogenous leukemia.
What is the abnormality in CML and what therapies exist to treat it?
Points for discussion:
- CML is a myeloproliferative neoplasm due to the deregulated activation of the BCR-ABL tyrosine kinase resulting from the c-ABL oncogene from chromosome 9 justaposed to the BCR gene on chromosome 22. This is known as the t(9;22) translocation resulting in persistent granulocytic cell proliferation. A bone marrow biopsy is required to ensure there is no progression to accelerative or blast phase CML.
- A landmark trial by O’Brien et al published in 2003 comparing Imatinib to INF + Cytarabine confirmed a complete cytogenetic response in 69% of patients by 12 months of use.
- Imatinib binds to the site of tyrosine kinase activity, thereby preventing its ability to be phophorylated. Second line TKIs have recently been approved for use in first line CP-CML, and include Dasatinib and Nilotinib with the advantage of faster achievement of cytogenetic and molecular response times. Despite this, there is no evidence that there newer agents in fact improve overall survival.
O’Brien et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. New England Journal of Medicine 2003 March 13, 348 (11): 994-1004