Occurrence and current management of side effects in chronic myeloid leukemia patients treated frontline with tyrosine kinase inhibitors

Department of Cellular Biotechnology and Hematology, Sapienza University, Rome, Italy.

1. Introduction
Chronic myelogenous leukemia (CML) is a clonal disorder caused by the malignant transformation of a pluripotent stem cell. It is characterized by the Philadelphia chromosome (Ph), a genetic abnormality which arises from the reciprocal translocation t(9;22) (q34;q11) [1]. This translocation fuses the genes encoding BCR and ABL1, and results in expression of the constitutively active protein tyrosine kinase BCR-ABL1 [2]. The identification of the crucial role of BCR-ABL1 has allowed the design and development of imatinib mesylate, the first therapy to target the causal pathophysiology in CML [3]. Imatinib mesylate is now the first line therapy for CML: it acts by competitively binding the inactive form of BCR-ABL1, preventing a switch to the active form and partially blocking the enzyme ATP binding site. The phase III International Randomized Study of IFN versus STI571 (IRIS) trial compared imatinib and IFN plus cytarabine, in 1106 CML patients in early chronic phase [4]. The follow-up at 8 years showed that the cumulative complete cytogenetic response (CCyR) rate is 89%, the estimated survival rate is 85% and freedom from progression rate (FFP) is 92%, with an event-free survival of 81% [5]. Despite the beneficial effect of imatinib, some patients still develop resistance or intolerance to the drug: the estimated rate of resistance at 8-year follow-up of IRIS study is 16%, whereas a real life study showed that 31% of patients treated with imatinib should be considered as intolerant to the drug [6]. Second generation tyrosine kinase inhibitors are recommended by European LeuekemiaNet as possible therapeutic options for resistant, suboptimal response or intolerant patients to first-line imatinib [7]. Following the results of randomized phase III trials comparing standard dose imatinib to dasatinib or nilotinib front-line, these two latter drugs are approved as possible options for newly diagnosed chronic phase CML patients [8], [9]. Also with second-generation agents, some patients may experience intolerance and side effects are reported to differ between drugs [10]. In this review we detailed the reported incidence of hematologic and non-hematologic side effects in chronic phase CML patients treated with imatinib and second-generation agents and the current management of the adverse events.
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