The t(9;22) (q34;q11) translocation, commonly known as the Philadelphia chromosome (Ph), results in the formation of the BCR-ABL1 fusion gene, which plays a pivotal role in the pathogenesis of two leukemias: chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) (Onida et al., n.d, Bernt and Hunger, 2014). In CML, the Philadelphia chromosome is found in approximately 95 % of cases and is more frequently associated with the p210 fusion transcript (Onida et al., n.d, Braun et al., 2020). In contrast, in ALL, it is present in 3–5 % of pediatric cases and roughly 25 % of adult cases, with the p190 fusion transcript being more prevalent (Bernt and Hunger, 2014, Braun et al., 2020). Although the prevalence of Ph+ ALL is comparatively low, its clinical significance is due to the fact that Ph+ ALL is associated with a significantly worse prognosis compared to Ph- ALL, characterized by lower rates of achieving complete remission, shorter durations of disease-free survival, higher relapse rates, and an increased likelihood of central nervous system involvement (Gleißner et al., 2002).

The poor prognosis associated with Ph+ ALL has been mitigated to some extent by the introduction of tyrosine kinase inhibitors (TKIs) (Byun et al., 2017). These include first-generation imatinib and second-generation agents such as bosutinib, nilotinib, and dasatinib (Oehler, 2020). TKIs work by binding to the ATP-binding site of the ABL kinase domain (KD) (An et al., 2010). Imatinib and nilotinib target the inactive configuration, while dasatinib and bosutinib bind to the active configuration (An et al., 2010, Aguilera and Tsimberidou, 2009). By disrupting the ATPase activity of the kinase, which is crucial for activating downstream signaling pathways, TKIs effectively inhibit the proliferative activity of leukemic cells (An et al., 2010, Aguilera and Tsimberidou, 2009).

However, the growing use of TKIs for treating Ph+ leukemias has led to increasing concerns about resistance (Braun et al., 2020). Most cases of acquired resistance during therapy have been attributed to mutations in the ABL1 KD, with mutations in the ATP-binding site being particularly significant (Braun et al., 2020). One critical mutation is the “gatekeeper” mutation, T315I (Braun et al., 2020). This mutation involves a C→T nucleotide substitution, resulting in the replacement of threonine with isoleucine at position 315 (Braun et al., 2020, Gao et al., 2023). The threonine hydroxyl group at this site is essential for forming a hydrogen bond required for binding first- and second-generation TKIs (Gao et al., 2023). The substitution with isoleucine, which has a bulkier and more hydrophobic side chain, introduces steric hindrance and disrupts hydrogen bond formation (Gao et al., 2023). As a result, the T315I mutation confers resistance to all first- and second-generation TKIs (Braun et al., 2020, Gao et al., 2023).

A third-generation TKI, ponatinib, was specifically designed to overcome resistance caused by the T315I mutation (O’Hare et al., 2009). Ponatinib features an optimized binding interaction with the ABL1 KD, incorporating the bulky hydrophobic side chain of isoleucine into its structure through a carbon-carbon triple bond or phosphate group, effectively eliminating steric hindrance (Gao et al., 2023, O’Hare et al., 2009, Smith et al., 2013). Additionally, its binding sites span a wide range of protein residues, enabling it to bind efficiently to ABL1 KD in other single-mutation resistance variants and even the wild-type BCR-ABL1 kinase (Gao et al., 2023, O’Hare et al., 2009).

Numerous studies have demonstrated ponatinib's robust efficacy and tolerable safety profile as a frontline treatment for Ph+ ALL when combined with chemotherapy or immunotherapy (Nicolini et al., n.d, Pavlovsky et al., 2018). This has been observed in single-group studies involving both resistant and non-resistant cases (Nicolini et al., n.d, Pavlovsky et al., 2018). Indirect comparisons with the first-generation TKI imatinib have shown that ponatinib, when combined with the HyperCVAD regimen, is associated with higher rates of complete molecular remission (CMR) and overall survival (OS) in patients with Ph+ ALL (Ribera et al., 2023). Furthermore, a meta-analysis of indirect comparisons has demonstrated ponatinib's superior efficacy compared to other TKIs, based on data from single-arm studies (Jabbour et al., 2018a). However, no meta-analysis to date has provided direct comparisons of ponatinib with other TKIs for the treatment of Ph+ ALL.

The aim of this study is to systematically analyze data from both randomized controlled trials (RCTs) and real-world cohorts to evaluate the efficacy of ponatinib compared to other TKIs, specifically in achieving CMR and in providing a survival benefit.