Retrospective Single-Institution Review of Bosutinib Dose Optimization for Efficacy and Safety with Dose Ramp-up and Titration
Authors: Freydman Jessica , Sirignano David , Amrein Philip C. , Bergeron Meghan , Brunner Andrew M. , Foster Elsie , Fathi Amir T. , Graubert Timothy Aaron , Hock Hanno , Lee Michelle Hyunju , Moran Jenna , Narayan Rupa , Hobbs Gabriela S. 
Published: December 2024

Background
Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL have dramatically improved survival in chronic myeloid leukemia (CML), offering patients near normal life expectancy. Dose optimization balances achieving remission while mitigating adverse events which lead to decreased quality of life and treatment interruptions. Bosutinib causes dose dependent gastrointestinal (GI) toxicities in about 80% of patients. While previous data support feasible TKI dose reductions, there is a lack of real-world evidence assessing dose optimization with bosutinib in CML. At a large academic medical center, bosutinib optimization strategies include ramp-up dosing on initiation to mitigate toxicities and dose reduction throughout therapy for adverse effects.
Aims
Our objective was to characterize response and toxicity of bosutinib treated patients with ramp-up dosing at initiation and dose titration during therapy.
Methods
A retrospective chart analysis was performed for patients with bosutinib prescriptions serviced at Mass General Brigham Specialty Pharmacy between July 2013 and May 2023. 41 patients were identified; 31 evaluable for safety (4 excluded due to transfer of care/no documentation, 6 due to renal dose adjustment) and 23 evaluable for efficacy (an additional 6 excluded for &lt;3 months of treatment, 2 for disease not measurable by PCR).
Results
Median age was 73 years (range 29-88), median number of prior therapies was 1 (range 0-4), and 24/25 (96%) patients with prior therapy had intolerance to a previous TKI. Of the 23 patients in the efficacy analysis, 19 (83%) had ongoing therapy with bosutinib at data collection (median treatment duration 35 months, range 9-127). Of the 23 patients, 13 (57%) underwent bosutinib ramp-up with a median of 4 steps (range 2-4) titrated over a median of 3 weeks (range 1-16). Of patients who underwent ramp-up, the median start dose was 100mg (range 100-200mg) and the median final dose was 400mg (3 receiving therapy at &lt;300 mg and 10 at 400mg or 500mg at the end of ramp-up). The remaining 10 patients initiated therapy at a median of 300mg (range 100-500mg, 6 at &lt;300mg and 4 at 400mg or 500mg) with no further up-titration.
Safety: In the safety analysis of 31 patients, 12 (39%) had a dose reduction at a median of 6 months (range 0-70) after treatment initiation. Dose reduction was due to GI toxicity (n=6, 50%), fatigue (n=2, 17%), hepatotoxicity (n=2, 17%), other (n=4, 33%), and unknown (n=1, 8%). 7/31 (23%) additional patients discontinued therapy due to toxicity, including GI (n=5, 71%), fatigue (n=3, 43%), rash (n=3, 43%), and other (n=2, 29%), and 2 further patients did not receive ongoing therapy, 1 due to poor response and mild GI symptoms and 1 due to death unrelated to therapy. 25/31 (81%) patients experienced toxicity on bosutinib, with 16/25 (64%) at 400mg or 500mg. 19/31 (61%) of patients experienced diarrhea, with 15/19 (79%) reporting diarrhea at 400mg or 500mg.
Efficacy: Of 19/23 (83%) patients with ongoing therapy, 15/19 (79%) had MMR and 14/15 (93%) maintained MMR with 10 (71%) on &lt; 300mg and 4 (29%) on 400-500mg. One patient lost MMR after reduction to 100mg from 200mg for hepatoxicity; the dose was titrated to 400mg with improvement in BCR::ABL from 13.9% to 2.8% after one month. Of the remaining 4 patients who never achieved MMR, 2 maintained PCR &lt;1% on doses of 100mg and 300mg, 1 was initiated on bosutinib 100mg and increased to 200mg to maintain PCR &lt;1%, and 1 achieved PCR &lt;1% on 400mg but lost it due to suspected non-adherence. Of the 4 patients not on therapy at data collection, 1 achieved PCR &lt;1% on 400mg, 1 achieved PCR&lt;1% on 500mg and maintained it at 300mg, 1 did not achieve disease control despite increasing from 100mg to 400mg, and 1 underwent bone marrow transplant after dose increase from 100mg to 500mg without MMR.
Conclusion
Bosutinib ramp-up and titration may be safe and efficacious. Although most patients underwent dose reduction due to toxicity, the majority maintained MMR on lower than approved doses. Only 1 patient experienced loss of MMR with subsequent PCR improvement upon dose increase; another patient started bosutinib 100mg and increased to 200mg to maintain PCR&lt;1%. Like alternative TKIs, dose titration may be a strategy to maintain response and continue therapy while limiting toxicity. Moreover, due to bosutinib's toxicity profile, dose ramp-up at initiation is safe and may improve tolerability. Further data is needed to support bosutinib dose optimization.