In PACE, a phase 2 trial of ponatinib that included patients with chronic phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit:risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel response-based dose-reduction strategy for a TKI in CP-CML. Adults with CP-CML resistant/intolerant to at least 2 prior BCR-ABL1 TKIs, or with a BCR-ABL1 T315I mutation, were randomized 1:1:1 to ponatinib 45mg (45mg cohort), 30mg (30mg cohort), or 15mg (15mg cohort) once daily. Patients who received 45 or 30mg daily reduced their dose to 15mg upon achievement of response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. Between August 2015 and May 2019, 283 patients were randomized; 282 (94/group) received treatment (data cutoff, 5/31/20). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45mg cohort, 29.0% (18.4-41.6) in the 30mg cohort, and 23.1% (13.4-35.3) in the 15mg cohort. Independently confirmed grade 3/4 treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45, 30, and 15mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit:risk outcomes occurred with the 45mg starting dose reducing to 15mg upon achievement of response (ClinicalTrials.gov number, NCT02467270).
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