The tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) has transformed the treatment of patients with chronic myeloid leukemia (CML). Based on positive findings from the International Randomized Study of Interferon Versus STI571 (IRIS) trial,1
published in 2003, imatinib quickly replaced interferon-α as the standard of care. Imatinib has prolonged survival in newly diagnosed patients with chronic-phase (CP) CML; patients from the IRIS study have been followed now for 8 years.2
Their survival rate is 85% overall and 93% when only patients with CML-related deaths and those who have not received stem cell transplant are considered. The more potent BCR–ABL1 TKIs, dasatinib (Sprycel, Bristol-Myers Squibb Company, Princeton, NJ, USA) and nilotinib (Tasigna, Novartis Pharmaceuticals Corporation), were approved by the US Food and Drug Administration (FDA) in 2006 and 2007, respectively, as second-line agents in patients with imatinib resistance or intolerance, and in 2010 both agents received FDA approval for treatment of patients with newly diagnosed CML.3, 4
FDA approval for use of nilotinib in newly diagnosed patients with CML-CP was based on data from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) Study comparing nilotinib with imatinib.5
Positive results comparing dasatinib with imatinib in newly diagnosed patients from the Dasatinib versus Imatinib in Patients With Newly Diagnosed Chronic Phase CML (DASISION) Study also have been reported.6
Imatinib, dasatinib and nilotinib together represent a formidable treatment approach for patients with CML. As with all medication, the effectiveness of TKIs relies on their proper use, including good adherence, which in turn depends partly on drug tolerability.
The importance of management of adverse events (AEs) in CML is underscored by the association between the occurrence of AEs and reduced treatment adherence.7, 8
High symptom burden, which can be exacerbated by treatment-related AEs, often leads to interruption of treatment or decreased dose or frequency of treatment.7, 8, 9
Consequently, lower levels of adherence are associated with suboptimal responses to imatinib,7, 10, 11
and several groups have shown the negative impact of reduced adherence on long-term achievement or maintenance of responses, and event-free survival.7, 12, 13
Patients with lower rates of adherence had significantly reduced likelihood of achieving major molecular response or complete molecular response at 6 years,7
higher probability of losing complete cytogenetic response at 2 years, and lower rates of event-free survival at 5 years, compared with more adherent patients. A proactive strategy to alleviate AEs before they become serious or affect adherence is therefore necessary.
For physicians who are incorporating TKIs into their treatment armamentarium, familiarity with the AE profiles associated with TKI therapy allows early identification and management of AEs or intolerance. Some of the AEs have been reported with all of these agents, including cardiac AEs, rash, nausea, fatigue, headache, myelosuppression and elevated liver enzymes. Other AEs are more prevalent with one TKI than another. In addition, the frequency and intensity of AEs differ when TKIs are used in first-line or second-line settings.1, 5, 6, 14
This review discusses the most common AEs associated with TKI therapy and outlines treatment strategies to help manage patients at risk for or experiencing these events.