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C. Gambacorti-Passerini et al.
ble to those observed in studies of second-line nilotinib and dasatinib. With similar follow-up durations, CCyR rates of 37% and 49% were reported with nilotinib and dasatinib, respectively, compared with 47% with bosu- tinib in the present study.4,8,13 Estimated rates of on-treat- ment PD/death (19%) and transformation to AP/BP CML (5%) remain low with bosutinib; only 2 IM-R patients had on-treatment transformation to AP after year 2, although there is a potential bias from patients lost to follow up. Similar rates of transformation were observed with sec- ond-line dasatinib (5%).5,14 The estimated OS rate at 5 years is high, with a modest decrease from the 2-year OS rate (84% vs. 91%). This 5-year rate is also comparable to those reported for dasatinib (91%), nilotinib (87%), and ponatinib (81%) in CP CML patients after prior TKI fail- ure.8
Responses were observed in all but 2 (T315I and M244V) of the 26 patients with newly-emerging BCR- ABL1 mutations. All but one of 14 patients with newly- emerging mutations that are highly resistant to bosutinib15 had a best response of at least CHR; 5 (36%) had a best response of at least PCyR. Effects of dose reductions on response were limited as most patients who dose reduced dose attained/maintained an MCyR. Only 4% and 2% of patients who reduced dose to 400 mg/day and 300 mg/day, respectively, lost their previously achieved MCyR.
Gastrointestinal toxicities remained the most common- ly reported AEs overall at the 5-year follow up (diarrhea, 86%; nausea, 46%; vomiting, 37%). Initial events occurred early, with incidences through year 2 of 84% for diarrhea, 45% for nausea, and 37% for vomiting.11 Although diarrhea was common, grade 3 events occurred in only 10% of patients (no grade 4), and only 4 patients discontinued because of this AE, all within two years of initiating bosutinib. Grade 3/4 hematologic AEs, such as thrombocytopenia (25%) and neutropenia (10%), occurred at rates similar to or lower than those observed with second-line dasatinib (24% and 36%), nilotinib (30% and 31%), and ponatinib (35% and 23%).4,5,16 Rates of cross-intolerance between bosutinib and prior imatinib were low, suggesting that most patients intolerant to ima- tinib therapy may be successfully treated with bosutinib.
Given the long-term nature of TKI therapy, late-emerg- ing toxicities are of concern, particularly cardiac and vas- cular events. In a study of bosutinib versus imatinib as first- line treatment for CP CML, the incidence of cardiac and vascular AEs with bosutinib was low and similar to that of imatinib.17,18 In the present study, the incidence of newly-
occurring cardiac and vascular AEs with second-line bosu- tinib remained low after year 2. However, most (85%) dis- continuations due to AEs as the primary reason occurred within the first two years; thus, patients remaining on treatment after year 2 may have a lower risk of experienc- ing these events. The incidence of renal AEs, while low, remained similar in years 3-5. Bosutinib has been associat- ed with a decrease in glomerular filtration rate that is typ- ically modest and potentially reversible (similar to what has been reported with imatinib).19,20 Dose adjustments are recommended in patients with baseline and treatment- emergent renal impairment.6,19 Careful monitoring, sup- portive care, and prompt management of toxicities may allow patients to continue treatment long term.
Most baseline and on-treatment factors examined appeared not to be predictive of response duration, OS, or PFS. Baseline Ph+ ratio ≤35% (vs. ≥95) was associated with all 3 types of long-term outcomes (MCyR duration but not CCyR duration). Lower percentage of peripheral blood blasts at baseline and MCyR by week 12 were associated with both improved OS and PFS. Having a baseline BCR- ABL1 mutation, regardless of sensitivity to bosutinib, was predictive of decreased OS and, interestingly, having an abnormal LFT on-treatment was predictive of increased OS. This unexpected result may be due to increased bosu- tinib exposure levels resulting from the underlying cause of the abnormal LFT, leading to an increase in efficacy; however, population pharmacokinetics modeling from this study has found no relationship between baseline LFTs and bosutinib pharmacokinetics. Notably, prior response or resistance to IM did not predict any long-term outcomes. Because P-values were not adjusted for multi- ple comparisons, marginally significant P-values should be interpreted with caution.
The potent and durable activity and distinct toxicity profile of bosutinib confirm it is an important option for treating CML patients in the second-line setting, as demonstrated by its long-term efficacy and safety in these patients; a 10-year follow up is planned for patients enrolled in an ongoing extension study.
Acknowledgments
The authors would like to acknowledge Dr. H. Jean Khoury for his extraordinary contributions to the research and treatment of hematologic malignancies. This study was sponsored by Pfizer Inc. Medical writing support was provided by Johna Van Stelten, PhD, of Complete Healthcare Communications, LLC, and was funded by Pfizer Inc. Dr. Jorge Cortes’ participation in this study was sup- ported in part by NCI grants CA016672 and CA049639.
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