Paper Details

ABSTRACT

Introduction: Ponatinib is a third-generation tyrosine kinase inhibitor approved for patients (pts) with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). While effective, ponatinib is associated with a risk of vascular adverse events, such as stroke, myocardial infarction (MI), and venous thromboembolism (VTE). The PACE trial reported a 25% incidence of serious arterial events and 6% for VTEs after 56.8 month-median follow-up on ponatinib therapy. The PhALLCON trial demonstrated that response-adapted ponatinib dosing reduced vascular adverse events while maintaining efficacy, with arterial thrombotic events occurring in 2.5% and VTEs in 11.7% of pts with the median duration of follow-up of 20.1 months. Neither PACE nor PhALLCON mandated a prophylaxis strategy. No clear recommendations for vascular thromboprophylaxis with ponatinib currently exist. There is a need to further clarify whether thromboprophylaxis can decrease the risk of vascular events in pts taking ponatinib. 

Methods: We performed a retrospective chart review of pts treated with ponatinib for Ph+ ALL from 01/01/2021 to 07/01/2026 at Banner MD Anderson Cancer Center. Pts with prior thrombotic history were not excluded from the cohort. Data extraction was performed in parallel by two investigators with resolution of disagreements. The primary endpoint was to determine the incidence of vascular events among ponatinib treated-treated pts receiving thromboprophylaxis. The secondary endpoint was to evaluate associations between vascular events and baseline vascular risk factors, ponatinib dosing and duration, and choice of thromboprophylaxis agent. Outcomes were descriptively compared with published historical ponatinib studies. 

Results: Forty-eight pts with Ph+ ALL were treated with ponatinib at our center between 2021 and 2026. Median follow-up was 25.3 months (IQR, 14.4–57.9 months). Pts were started at 45 mg during induction then dose-reduced to 30mg until achieving negative minimal residual disease and then maintained at 15 mg. Dose reduction occurred in 36/48 (75%) of pts during their treatment course. All pts received thromboprophylaxis at the time of ponatinib initiation consisting of prophylactic enoxaparin initially with transition for some pts to aspirin (20/48, 41.7%) or apixaban (14/48, 29.2%) during their course according to physician preference. Five pts (10.4%) developed arterial thrombotic events including 2 transient ischemic attacks (TIA), 2 strokes, and one celiac artery occlusion.  Two strokes and one TIA occurred during treatment with 15 mg ponatinib (one on apixaban and the other two on aspirin) and two during treatment with 30 mg (one on apixaban and the other on enoxaparin). No arterial events occurred at 45 mg. Four of these five pts had hypertension and hyperlipidemia, and one was an active smoker. One patient had no cardiovascular risk factors. Arterial events occurred substantially later than VTEs (range: 4.49 to 5.03 years). Three pts (6.3%) developed VTEs, all of whom were on enoxaparin prophylaxis. All VTEs were PICC-associated and occurred within the first 30 days of ponatinib therapy. Only one grade 1 bleeding event occurred for a patient on enoxaparin.    

Conclusions: In this real-world cohort managed with a response-adapted ponatinib dose optimization strategy and thromboprophylaxis, the incidence of arterial thrombotic events was numerically lower than the PACE trial yet more frequent than the PhALLCON trial. VTEs were confined to early PICC-associated thrombosis and occurred at a lower rate than PhALLCON suggesting that prophylaxis may be beneficial for VTE events. With the current frontline preference for ponatinib use in Ph+ ALL, it is vital to further clarify the real-world risk of ongoing vascular events with ponatinib over time with response guided ponatinib dosing and prophylaxis as well as to identify which pts may be more predisposed to these risks. This is particularly important in the context of ongoing studies with asciminib in this population (NCT06308588, NCT06773936, and NCT03595917), which may have a lower cardiovascular risk [Pérez-Lamas et al. Cancers 2023; Khadadah et al. Leukemia Research 2023; Alwadi et al., Blood 2024].