A recent retrospective study presented at the 2024 ASH Annual Meeting & Exposition highlights the improved safety profile of ponatinib (Iclusig) in patients with acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) over a 10-year period, thanks to proactive risk management measures. The research, led by Elias Jabbour, MD, from The University of Texas MD Anderson Cancer Center, demonstrates a significant reduction in adverse events (AEs) associated with the drug since its initial approval.
Decline in Adverse Event Reporting
The study, which analyzed real-world safety data collected globally, revealed a substantial decrease in the total reporting rate of all important identified risks (IIRs). By the end of 2022, the reporting rate was 0.219, a marked improvement from 2.369 in 2013. Similar declines were observed in AEs of concern, such as arterial occlusive events (AOEs) and venous thromboembolic events (VTEs).
Post-Approval Risk Management
Ponatinib, a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI), received approval for CML and Philadelphia chromosome–positive ALL based on the phase 2 PACE trial. However, concerns regarding vascular occlusive events (VOEs) prompted the implementation of risk management measures following its approval.
These measures included:
- Updates to product information with warnings for AOE and VTE risk.
- Recommendations for dose reduction in patients achieving a major cytogenetic response.
- Distribution of a Dear Health Care Provider letter in the United States and Europe.
- Initiation of a Risk Evaluation and Mitigation Strategy (REMS) in the United States.
- Launch of a follow-up questionnaire to gather detailed information on VOEs.
Dose Optimization and Monitoring
The phase 2 OPTIC trial, initiated in 2015, aimed to optimize the dose of ponatinib and assess the rates of AOEs, VTEs, and other serious AEs at different dose levels in chronic-phase CML patients resistant to prior TKIs or with a T315I mutation. Furthermore, a retrospective analysis of the PACE trial was conducted to reassess safety outcomes.
Impact on Reporting Rates
Analysis of Incyte’s Global Safety Database showed that the most frequently reported AEs in the first year of ponatinib's commercialization were myelosuppression, skin reactions, infections, and AOEs, with rates of 0.505, 0.362, 0.330, and 0.291, respectively. Over the subsequent two years, these rates decreased, attributed to the postmarketing measures. After ten years, the rates significantly dropped to 0.043, 0.030, 0.045, and 0.038, respectively. Other IIRs also exhibited reduced reporting rates over the decade.
Evolution of Risk Management Strategies
As the safety profile of ponatinib became better understood, several risk management interventions were adjusted or discontinued. For instance, the brochure and questionnaire for healthcare providers in Europe were discontinued in 2019, and the FDA determined that the REMS program was no longer necessary in 2018. Additionally, eight of the ten IIRs were removed from the European risk management plan after sufficient characterization and implementation of management measures. As of March 2022, ponatinib is no longer subject to additional monitoring in Europe.
The OPTIC trial's findings led to a dose reduction strategy, decreasing the dosage from 45 mg to 15 mg in patients achieving a BCR::ABL1 level of 1% or lower. This change was incorporated into prescribing information in 2020. A retrospective analysis of the PACE trial also indicated a prior overestimation of AOE risk, with adjudicated AOE risk being higher in patients with multiple baseline cardiovascular risk factors.
Study Limitations and Conclusions
Investigators acknowledged limitations such as the Weber effect, which may have led to increased AE reporting immediately after approval, and the use of estimated patient exposure. Despite these limitations, Dr. Jabbour concluded, “Despite the potential limitations of this analysis such as underreporting of AEs and the use of estimated patient exposure, our results show that the introduction of measures designed to minimize the risk related to ponatinib use was associated with improved safety among patients receiving ponatinib.”
