High-dose ponatinib in Korean CML and Ph+ ALL: real-world outcomes in early and heavily pretreated settings

Abstract Background: Ponatinib, a third-generation tyrosine kinase inhibitor (TKI), has shown effectiveness and safety in clinical trials; however, real-world data on its use in Asian populations remain limited. While a recent post-marketing surveillance (PMS) study from Japan provided insights into earlier-line use of ponatinib, evidence in heavily pretreated patients—particularly within the Korean population—remains scarce. Methods: We conducted a multicenter, prospective PMS study to evaluate the effectiveness and safety of ponatinib in Korean patients with chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) who were resistant or intolerant to prior TKIs or harbored the T315I mutation. Effectiveness was evaluated using hematologic, cytogenetic, and molecular responses assessed at baseline and at 3 or 6 months, when available. Safety was assessed based on adverse events (AEs). Results: A total of 148 patients—115 with CML (92 CP-CML, 12 AP-CML, 11 BP-CML) and 33 with Ph+ ALL—were enrolled across 24 sites, with the first patient enrolled in August 2018 and the last completing follow-up in November 2022. The median age was 56.0 years, with 59.5% (n=88) male and 40.5% (n=60) female. Among the 148 patients, ponatinib was administered as a first-line treatment in 0.7% (n=1), second-line treatment in 23.0% (n=34), third-line in 47.3% (n=70), and fourth-line or later in 29.1% (n=43), respectively. Regarding prior TKI treatments, 42.6% (n=63) of patients experienced both resistance and intolerance, 35.1% (n=52) showed resistance only, and 21.6% (n=32) experienced intolerance only. The majority of patients (85.8%, 127/148) initiated ponatinib at a dose of 45 mg/day. This dosing strategy reflects a dynamic dose-adjustment approach established in global clinical studies. The median treatment duration—representing patient exposure to ponatinib—was 169.5 days. In patients with CP-CML, the overall response rates were 92.5% (74/80) for complete hematologic response (CHR), 43.2% (35/81) for major molecular response (MMR, BCR::ABL1 IS ≤ 0.1%), and 60.7% (17/28) for complete cytogenetic response (CCyR). Among those without prior MMR, the cumulative incidence of MMR reached 23.9% by week 24 and 54.6% by week 30. In patients with Ph+ ALL, the overall MMR and CCyR rates were 82.4% (14/17) and 75.0% (3/4), respectively. CP-CML patients who received ponatinib as second-line therapy or earlier showed a higher overall MMR rate (57.9%, 11/19 vs. 38.7%, 24/62) compared to those treated in the third-line or later setting. Notably, CP-CML patients treated with ponatinib as second-line therapy or earlier demonstrated a significantly higher MR4.5 rate (47.4%, 9/19 vs. 16.1%, 10/62, p = 0.011) compared to those treated in the third-line or later setting. Among CML patients, those positive for the T315I mutation had an overall MMR rate of 50.0% (6/12), while those negative for T315I had an overall MMR rate of 40.6% (13/32); the difference between these groups was not statistically significant. Among all 148 patients, the most frequently reported adverse drug reactions (ADRs) were rash (21.6%, 32/148), hypertension (12.2%, 18/148), and pyrexia (10.1%, 15/148). Two vascular occlusive events (VOEs) were reported. Conclusion: Ponatinib showed favorable real-world effectiveness and manageable safety in Korean patients with CML and Ph+ ALL, particularly in those resistant or intolerant to prior TKIs or with the T315I mutation. High response rates were observed across both early- and later-line use; molecular responses were notably enhanced when ponatinib was initiated earlier and at higher doses. Despite higher dosing and greater drug exposure in an Asian population with a lower average BMI, ponatinib demonstrated a manageable safety profile under routine clinical monitoring. These findings support the clinical benefit of early high-dose ponatinib use in real-world settings.