Discussion
ELN recommendations, diarrhea, CML, toxicity, toxicities, GI toxicity
ADVERSE EVENTS, CML, RECRUITMENT, EVENT
Overall and despite its premature termination, the results of the BODO trial using step-in dosing of bosutinib confirms the efficacy findings from other later-line bosutinib trials such as the phase I/II trial or the BYOND trial [The run-in dosing strategy evaluated here with bosutinib was successful in less than 60% of our pts, whereas > 40% did not arrive at the 500 mg dose level due to toxicity during the first 3 months of treatment. This led to a median daily dose of bosutinib of 403 mg/day during the first 6 months of treatment which is still higher than in other trials starting with full dose bosutinib. For comparison, median (range) dose intensity in the Ph + CP CML cohort in the BYOND trial amounted to 313.1 (79.7–560.6) mg/day overall; 320.1 (98.4–560.6), 309.4 (79.7–500.0), and 308.0 (125.0–500.0) in the second-, third-, and fourth-line cohorts, respectively [Overall, and at least in part due to the limited sample size related to the premature study termination, the trial failed to achieve its primary goal, i.e., to prove that a step-in dosing concept indeed significantly reduces the incidence of early-occurring higher grade GI toxicities. Instead and to our surprise, the rate of adverse events overall was comparable to other trials performed in similar scenarios but without the use of step-in dosing. This questions the hypothesis that bosutinib-induced, particularly early-occurring GI toxicities can be mitigated by reduced dosing concepts at least once a starting does of 300 mg is being used. We rather hypothesize that optimized patient management by experienced CML experts may help to optimize bosutinib therapy as ultimately, the AEs only rarely led to permanent treatment discontinuation. Interestingly, median time to first AE of diarrhea in the BODO trial was 23 days, and the median duration of any grade diarrhea was 14 days (range: 1–960). For comparison in study 200, the median time to onset of diarrhea was 2.0 days and grade 3 diarrhea had a median event duration of 3.0 days [Dose optimization regimens have already been studied in various bosutinib treatment settings. Kota et al. [Altogether, the following reasons could be suspected to explain why the dose-increasing regimen investigated here was not able to significantly reduce GI side effects within this study apart from the reduced sample size: 1. The relatively high starting does of bosutinib (i.e., 300 mg QD) which was selected on the basis of available phase 1 data in Caucasians; 2. The relatively short intervals of dose increases (2 weeks) which however was consistent with the approach taken in the Japanese study mentioned above; 3. The study design (one-armed as opposed to a randomized study with a fixed-dose comparator arm) with reduction of toxicity compared to historic controls as primary endpoint; and 4. the relatively high target dose of bosutinib (500 mg QD) reflecting the approved dose in later-line treatment whereas (similar to other TKIs such as nilotinib) the lower dose of (here 400 mg QD) reflects the approved dose in first line.In summary, this is one of the (if not the) largest cohorts published on the efficacy and safety of a second-generation TKI after intolerance/failure to another 2G-TKI administered in first line. Given the limitations of a single-arm study with premature study closure due to incomplete recruitment, we could not demonstrate an advantage of the step-in dosing concept chosen here to reduce the frequency of grade 2–4 GI toxicity overall. However, using this regimen, bosutinib was able to induce optimal responses according to ELN recommendations [