Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial

Abstract

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).

Real‐life incidence of thrombotic events in leukemia patients treated with ponatinib

“…Results of the PACE trial showed a 14% cumulative incidence of grade 3-4 AOE in CML and Ph-ALL patients on ponatinib with a starting dose of 45 mg. 4 The OPTIC trial, in which CML patients were evenly assigned to starting doses of 45, 30, and 15 mg, reports a 5% incidence of grade 3-4 AOE. 5 Like the OPTIC trial, we found an increased incidence of AOE at higher starting doses of ponatinib. Our lower incidence of AOE may be related to a larger portion of patients starting on lower doses, with a median starting dose of 30 mg (Table 1).…”

“…4 Furthermore, the recent phase II OPTIC trial has demonstrated an optimal risk-benefit in CML patients who started ponatinib at 45 mg daily and reduced to 15 mg upon achievement of response. 5 Available literature on ponatinib-associated CV events has limited generalizability due to heterogeneous patient populations, and reporting in real-life patient cohorts is rare. We, therefore, aimed to determine the incidence of AOE and VTE in a real-life CML and Ph-ALL population receiving ponatinib-based therapy.…”

Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring

“…In this study, 283 patients with CML-CP who failed prior TKIs (55% received ≥3 prior TKIs) or who had a T315I mutation (24%), were randomly assigned in a 1:1:1 ratio to receive a once-daily dose of ponatinib 45 mg (45 mg cohort), 30 mg (30 mg cohort), or 15 mg (15 mg cohort). 112 Upon achievement of BCR::ABL1…”

“…Based on the results from the phase II OPTIC trial, an updated label was issued in December 2020 including an optimized, response‐based dosing regimen of ponatinib, aiming to maximize efficacy while decreasing the risk of adverse events. In this study, 283 patients with CML‐CP who failed prior TKIs (55% received ≥3 prior TKIs) or who had a T315I mutation (24%), were randomly assigned in a 1:1:1 ratio to receive a once‐daily dose of ponatinib 45 mg (45 mg cohort), 30 mg (30 mg cohort), or 15 mg (15 mg cohort) 112 . Upon achievement of BCR::ABL1 [IS] ≤1%, the dose of ponatinib was reduced to 15 mg daily.…”

A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase

“…Although not a new agent, an adapted schedule of administration (response-directed dose reduction) has been used for ponatinib in the OPTIC trial [ 94 ], which may decrease the risk of AOEs. This response-adapted approach can be considered for overall treatment with TKIs in the future.…”