This retrospective study aimed to evaluate the impact of RMMs on AE reporting rates for ponatinib’s IIRs by analyzing real-world safety data collected globally over the 10-year period post approval. This analysis revealed a significant and sustained reduction in the reporting rates of all ten individual IIRs over time (Fig. 4). Initially, the reporting rates for these IIRs were the highest in the first year following commercialization, with the most frequently reported IIRs being myelosuppression, skin reactions, infections, and particularly VOEs. Following the introduction of various RMMs, including the product information update, the dissemination of DHPCs, and the distribution of educational materials to HCPs, the reporting rates of all IIRs declined markedly after 2 years of commercialization. The downward trend continued over the subsequent years to reach a reduction of approximately 90% in all IIRs after 10 years. The consistently stable and low reporting rates in recent years highlight the potential impact of the RMMs in improving clinicians’ awareness of AEs, patient monitoring, and patient care.

Timeline of postapproval risk-management measures and evolution of the IIRs aUpdated to include a warning risk of AOEs and VOEs associated with ponatinib and guidance to reduce the ponatinib dose for patients achieving a major cytogenic response [6, 7]. bTo inform HCPs about the risk of VOEs. AOE arterial occlusive event, DHPC Direct Healthcare Professional Communication, EU European Union, FDA US Food and Drug Administration, HCP healthcare professional, IIR important identified risk, LFT liver function test, MA marketing authorization, OPTIC Optimizing Ponatinib Treatment in CP-CML, PACE Ponatinib Ph+ ALL and CML Evaluation, REMS Risk Evaluation and Mitigation Strategy, Q quarter, SmPC Summary of Product Characteristics, US United States, USPI United States Prescribing Information, VOE vascular occlusive event, VTE venous thromboembolic event

During the period covered by this analysis, the effectiveness of the implemented RMMs was confirmed and some were stopped. Following the analysis of the survey results to assess the effectiveness of the DHPC and the HCP brochure in Europe, it was concluded that an appropriate level of awareness among HCPs had been achieved, and the information regarding treatment standards and risk of VOEs was well understood. The distribution of the HCP brochure and VOE follow-up questionnaire was discontinued in Europe on 5 September 2019 (Fig. 4). In the USA, the assessment of the REMS demonstrated that the REMS communication plan had met its goals to ensure that the benefits of ponatinib in the treatment of adults with CML or Ph+ ALL outweighed its risks. Therefore, on 29 May 2018, the US Food and Drug Administration (FDA) determined that a REMS was no longer required for ponatinib (Fig. 4) [12].

Notably, eight of the ten ponatinib-associated IIRs analyzed have been adequately characterized with appropriate management recommendations provided to the European Medicines Agency, and these IIRs have been removed from the ponatinib EU Risk Management Plan (Table 1; Fig. 4) [13]. Following the positive opinion of the Committee for Medicinal Products for Human Use in March 2022, ponatinib is no longer subject to additional monitoring, and the black triangle has been removed from the SmPC and package leaflet (Fig. 4) [7].

The two IIRs remaining on the ponatinib EU Risk Management Plan are serious infections and VOEs [13]. The VOEs associated with ponatinib are primarily driven by AOEs [14]. These IIRs have been well characterized, and relevant guidance has been provided within the EU SmPC and USPI since the emergence of the VOEs signal. Ponatinib should not be used in patients with a history of myocardial infarction, prior revascularization, or stroke unless the potential benefit of treatment outweighs the potential risk. Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed and then monitored, along with evidence of arterial occlusion [7]. Guidance to reduce the ponatinib dose for patients achieving a major cytogenetic response was also provided in the two labels.

Given that the occurrence of AOEs in patients treated with ponatinib had been found to be dose dependent [15] and that preliminary analyses of the PACE trial demonstrated that responses were maintained despite dose reductions as a result of AEs or after prospective dose reduction implemented in October 2013 to mitigate safety risks [16], the prospective OPTIC trial sought to evaluate a response-based ponatinib dosing strategy to optimize efficacy and improve safety of ponatinib in adults with CP-CML who were resistant to at least two TKIs or who harbored the T315I mutation [10]. Participants in the OPTIC trial were randomized to ponatinib starting doses of 45 mg, 30 mg, and 15 mg once daily. Upon achievement of ≤ 1% BCR::ABL1IS, doses were reduced to 15 mg in the 45 mg and 30 mg cohorts. The primary end point, achievement of ≤ 1% BCR::ABL1IS at 12 months, was met in 44.1% of patients in the 45 mg cohort, 29.0% in the 30 mg cohort, and 23.1% in the 15 mg cohort. The rates of grade ≥ 3 treatment-emergent AOEs were similar between the three cohorts, and the study demonstrated a manageable safety profile overall for ponatinib in patients with CP-CML. The study suggested a novel ponatinib treatment regimen (a 45 mg starting dose and reduction to 15 mg upon reaching ≤ 1% BCR::ABL1IS), which maximizes clinical response while minimizing toxicity. Consistently, the final 5-year analysis of the PACE trial in 2018 demonstrated that the prospective dose reductions of ponatinib implemented after October 2013 did not impact the durability of clinical responses [17]. The OPTIC dosing regimen was updated in the USPI in 2020 [6].

Recently, long-term results from the OPTIC trial further confirmed the clinical benefits of ponatinib in patients with CP-CML resistant to at least two TKIs or harboring the T315I mutation [18]. By 60 months, response rates of ≤ 1% BCR::ABL1IS were achieved by 60, 41, and 40% of patients in the 45 mg, 30 mg, and 15 mg cohorts, respectively. Importantly, exposure-adjusted AOE rates were similar across the three cohorts. These results were consistent with primary OPTIC analyses and reinforced the assertion that a ponatinib dosing regimen starting with a dose of 45 mg once daily and reducing to 15 mg once daily upon attainment of ≤ 1% BCR::ABL1IS offers an optimal benefit-risk ratio. In October 2025, the 5-year data from the OPTIC study were incorporated in the ponatinib USPI and SmPC [6, 7]. The current SmPC states that reducing the dose of ponatinib to 15 mg should be considered for CP-CML patients who have achieved molecular response (MR2, i.e., ≤ 1% BCR::ABL1IS), taking the following factors into account in the individual patient assessment: cardiovascular risk, side effects of ponatinib therapy, time to response, and BCR::ABL transcript levels. If dose reduction is undertaken, close monitoring of response is recommended. In patients with loss of response, the dose of ponatinib can be re-escalated to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Ponatinib should be continued until loss of response at the re-escalated dose or unacceptable toxicity [7].

A retrospective analysis of 5-year AOE data from the PACE trial was conducted by an independent cardiovascular adjudication committee using a charter-defined process and standardized event definitions to better understand the clinical relevance of the ponatinib-associated AOEs [11]. Results showed lower rates of adjudicated AOEs (17%) compared with non-adjudicated rates (25%), suggesting a prior overestimation of ponatinib-related AOE risk. The most common symptomatic events adjudicated as not being AOEs were angina pectoris, chest pain, and non-cardiac chest pain. Notably, the rate of adjudicated AOEs was higher for patients with multiple baseline cardiovascular risk factors: 29% in patients with at least three risk factors, 13% in those with one or two risk factors, and 3% in patients with no risk factors. This adjudication study provided a more accurate understanding and estimation of the ponatinib-associated AOE risk. Together, the findings from the OPTIC trial [10, 18,19,20] and the retrospective PACE AOE analysis [11] contribute to a more comprehensive characterization of ponatinib’s safety profile, helping guide decisions when treating patients with ponatinib.

The present study provides an in-depth evaluation of AE reporting rates for ponatinib’s IIRs; however, certain limitations linked to the use of postmarketing data should be acknowledged. Firstly, postmarketing case reports are often submitted voluntarily, which can lead to biases, such as the under-reporting of AEs. This includes the Weber effect, a reporting bias first reported in 1984 associated with less frequent reporting of AEs in the later years following a drug’s regulatory approval [21, 22]. However, more recent studies have found varied reporting patterns that do not match the Weber effect [23,24,25]. Of particular note, a study of AE reporting patterns in oncology drugs approved by the FDA from 2004 to 2007 found no single consistent pattern and no evidence of the Weber effect [23]. Therefore, one cannot assume that AE reporting for ponatinib should follow the Weber effect.

Other factors that can contribute to reporting bias include notoriety bias [26] and reliance on estimated patient exposure. Despite these limitations, our findings are a valuable resource for clinicians, demonstrating how AE reporting of ponatinib’s IIRs has evolved over time and suggesting a positive impact of RMMs on the management of ponatinib safety risks.