Clinical impact of dose modification and dose intensity on response to ponatinib (PON) in patients (pts) with Philadelphia chromosome-positive (Ph+) leukemias.

7084 Background: PON is a potent oral pan–BCR-ABL tyrosine kinase inhibitor with clinical activity in pretreated pts with Ph+ leukemias. Dose modification of PON may be used to avoid or manage adverse events (AEs). This post hoc analysis assessed the clinical impact of dose modification and dose intensity on outcomes of pts in the phase 2 PACE trial. Methods: PON starting dose was 45 mg QD. Dose reduction: any reduction below 45 mg/d; dose interruption: treatment held for ≥3 consecutive days. Efficacy analyses were performed on CP-CML pts (N=267). Analysis of arterial thrombotic events (ATEs) included all pts (CP/BP/AP-CML, Ph+ ALL; N=449). Data are as of 3 Sept 2013; median follow-up was 24 (0.1-35) mo for all pts. Results: 78% of CP-CML pts had dose modification within the first 12 mo (82% at any time). Responses in pts with/without modification were comparable (Table). Of 149 responders, 87 (58%) achieved MCyR at 45 mg/d, 46 (31%) at 30 mg/d, 16 (11%) at 15 mg/d. Most pts who had a dose reduction after achieving a response maintained that response: MCyR (97%), complete cytogenetic response (CCyR; 96%), major molecular response (MMR; 92%). Among pts with a dose reduction lasting ≥6 mo after achieving response at a higher dose, 100% maintained MCyR (96%, CCyR; 93%, MMR). While dose intensity was the most significant predictor of MCyR by 12 mo (multivariate analysis MVA), substantial responses occurred at lower doses; estimated response rates were ~75% at 45 mg, ~60% at 30 mg, and ~30% at 15 mg. ATEs occurred in 17% of pts; each 15 mg/d reduction in avg daily dose is predicted to lead to ~40% reduction in risk of ATE (MVA). 2 yr overall survival was similar for CP-CML pts who had dose modifications (86%) v those who did not (86%) and for pts who had ATE (85%) v those who did not (87%). Of pts with ATEs, 46% had dose modifications. Conclusions: Pts on PON who undergo dose modification may still respond to treatment and dose modification may be an effective management tool. Careful consideration of the potential benefits and risks of PON should guide treatment decisions. Clinical trial information: NCT01207440. CP-CML n MCyRb % CCyRb % MMRa % Dose modificationa 218 58 47 38 No dose modification 49 47 45 35 a, anytime; b, by 12 mo.