26 Progression-free survival was also improved, although the difference failed to reach statistical significance. Regulatory approval of dasatinib for newly diagnosed CPCML patients was granted in October 2010. Side Effects of Currently Approved TKIs A comprehensive appreciation of TKI-related TKI258 Dovitinib toxicities is beyond the scope of this review. Hematologic toxicity is common and correlates with disease state, being more frequent in patients with advanced disease compared to newly diagnosed patients. It is generally believed that this reflects the more limited reserve of normal hematopoiesis in patients with long-standing or more aggressive CML. Non-hematologic toxicity is diverse and dependent on the specific TKI. The good news is that these toxicities are largely non-overlapping, which implies that cross-intolerance to all three approved TKIs is rare.
For a comprehensive and detailed review of toxicity the reader is referred to a recent review.73 Importantly, annual updates of the IRIS study, as well as independent studies Woessner et al. Page 5 Cancer J. Author manuscript, available in PMC 2012 May 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Estrogen Receptor cancer confirmed the safety of long-term imatinib therapy in the sense that grade 3-4 toxicities are rare and no new and unexpected side effects became apparent with longer follow-up.41,74 The body of data available for dasatinib and nilotinib is more limited, and it will be important to remain vigilant as therapeutic time increases for these drugs.
Novel Agents ATP-Competitive ABL Inhibitors Without Activity Against T315I Several TKIs have been developed that exhibit a target spectrum similar to the approved drugs, although they are distinct in terms of off-target effects. The most advanced of these drugs is bosutinib , originally developed as a Src kinase inhibitor.75 Bosutinib has shown inhibitory activity in CML cell lines and primary cells, and has demonstrated tumor regression in CML xenograft models. Unlike approved TKIs, bosutinib does not inhibit c-Kit or PDGFR.76 Phase I and II studies revealed drug activity in patients who failed imatinib. However, as expected, efficacy in patients who failed a 2nd-generation TKI was lacking. A phase III study did not meet the primary endpoint.
Current speculation attributes lack of efficacy to insufficient dose intensity triggered by dose interruptions due to diarrhea, a common, but transient side effect that should have been managed with supportive care. Bosutinib could possibly add to the therapeutic armamentarium as another drug with a unique side effect profile. However, it does not address the problems of the T315I mutant and BCR-ABL independent resistance. Overall, the future of bosutinib is unclear.77 T315I Active Inhibitors The most advanced third-generation inhibitor of BCR-ABL is ponatinib.78 Unlike all approved TKIs, ponatinib is effective against the T315I mutant as well as a large sample of other mutants previously detected in patients with clinical TKI resistance.68 In vitro screens revealed no mutational vulnerabilities in BCR-ABL, suggesting that ponatinib may be the first true pan-BCR-ABL TKI.
This drug also inhibits other kinases including FLT3, FGFR, VEGFR, c-Kit, and PDGFR 79,80 Ponatinib showed significant activity in a phase I study of patients with Ph+ leukemia, mostly CML, who had failed other TKIs. Interestingly, responses were most impressive in patients with the T315I mutation, turning a poor prognostic factor into a favorable one.81 Ponatinib is currently in phase II clinical trials. PACE is a global, single-arm clinical study including patients in all disease phases of CML and Ph+ ALL. Given its activity against the T315I mutant, ponatinib may well replace nilotinib and dasatinib in salvage thera