Introduction Ponatinib, the only BCR::ABL1 TKI with no contraindicated mutations, has been evaluated in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) in two large, global, phase 2 studies. The PACE study (NCT01207440) evaluated ponatinib at a 45-mg QD flat dose in pts with heavily pretreated CP-CML, showing a 56% major cytogenetic response within the first 12 months, but at the cost of a 17% grade 3/4 arterial occlusive event (AOE) rate, resulting in United States (US) Food and Drug Administration (FDA) approval with a boxed warning. The OPTIC study (NCT02467270) was conducted to optimize ponatinib dosage to maximize efficacy while reducing safety concerns. In pts with heavily pretreated CML, OPTIC showed that ponatinib 45 mg QD administered until achievement of BCR::ABL1 ≤1% and then reduced to 15 mg QD resulted in a 52% BCR::ABL1 ≤1% rate by 12 months, with a 5% grade 3/4 AOE rate. By 5 years, 60% of pts had achieved BCR::ABL1 ≤1%, with a 60-month 6% grade 3/4 AOE rate. This efficacy and safety was achieved through appropriate down-dosing from 45 mg QD to 15 mg QD upon clinical benefit, which is the FDA-recommended dosage. The current study hypothesized that ponatinib's past safety challenges may cause healthcare professionals to administer ponatinib suboptimally; thus, we aimed to explore how ponatinib is being used in standard practice across the US. By utilizing supply chain analytics, we analyzed ponatinib treatment patterns and the implications thereof.

MethodsPonatinib prescription information from specialty pharmacy shipment data was analyzed. Pts with CML starting ponatinib as any line of therapy between January 2021 and March 2024 were included in the study. Dosage patterns for deidentified pts were determined by establishing a window of first and final dosage strength. New pt starts and restarts with >3 shipments were included to ensure sufficient length of pt journey. Pts were grouped into cohorts by starting year and month. A pt was said to have discontinued treatment if the patients did not receive any subsequent shipment beyond 90 days of the last expected refill, or if there was a >90-day gap either between the current refill and next shipment or between the last expected refill and the end of the data observation period. Last expected refill date was the last shipment date plus days of supply in the last shipment. Mean duration of therapy by starting dose and titration type was calculated using cohort-based persistency method. Metrics were evaluated 12 months post–new pt start month.

Results A total of 648 pts with CML were included in the analysis. Of the 313 (48%) pts who started treatment with ponatinib 45 mg QD, 84 (27%) dose-reduced to 15 mg QD; thus, only 13% of pts were treated with the FDA-recommended ponatinib dosage regimen. A total of 149 (48%) pts remained on 45 mg QD, 73 (23%) pts down-dosed to 30 mg QD, and 7 (2%) down-dosed to 10 mg QD. Of 213 (33%) pts who started ponatinib at 30 mg QD, most (132 pts; 62%) remained on 30 mg QD, while 60 (28%) and 5 (2%) pts down-dosed to 15 mg or 10 mg QD, respectively, and 16 (8%) titrated up to 45 mg QD. Most of the 108 pts who started treatment on 15 mg QD (91; 84%) remained on that dose; 11 (10%) and 3 (3%) pts titrated up to 30 mg and 45 mg QD, respectively, and 3 (3%) down-dosed to 10 mg QD. Of the 14 pts who started treatment on ponatinib 10 mg QD, 11 (79%) pts remained on 10 mg QD, and 3 (21%) pts titrated up to 15 mg QD. Mean duration of ponatinib therapy for all pts who down-dosed was 8 months longer than that of pts who did not (19 vs 11 months), regardless of the starting dose.

Conclusion The FDA-recommended regimen of 45 mg QD reduced to 15 mg QD upon achievement of BCR::ABL1 ≤1% is the optimal dosage regimen to maximize efficacy and minimize AOE risk. However, per this analysis, only 13% of pts in the US are being treated with the recommended dosage regimen. The anonymized nature of this analysis does not allow further investigation into the timing or reason for dose reduction (eg, safety or reaching a response). Importantly, starting ponatinib at 45 mg or 30 mg QD and subsequently reducing the dose resulted in 8 more months of therapy, possibly because of greater benefit; however, pts with safety considerations may have discontinued. Still, the importance of adequate ponatinib dosing should be emphasized to achieve the greatest benefit:risk ratio.

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2025
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