Ponatinib 2-Year Efficacy, Safety and Health-Related Quality of Life in Patients with Philadelphia Chromosome-Positive Leukemia: An Open-Label, Multicenter, Phase 2 Clinical Trial in China
Authors: Yu Lu , Wang Huifang , Liu Xiaoli , Liu Bingcheng , Zhao Xielan , He Qun , Zeng Qingshu , Sun Zimin , Liu Ting , Zhu Huanling , Liu Zhuogang , Du Xin , Jin Jie , Meng Li , Hou Ming , Chen Suning , Yang Linhua , Xian Mingji , Kotobuki Yoshitaka , Zhang Shuang , Jiang Qian 
Published: December 2024

Background: Ponatinib is a potent BCR::ABL1 tyrosine kinase inhibitor (TKI) effective against all single-mutation variants of BCR::ABL1, including the T315I mutation. The phase 2 clinical trial (NCT04233346) evaluated the efficacy and safety of ponatinib in Chinese patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who were resistant or intolerant to dasatinib or nilotinib, or who had the BCR::ABL1 T315I mutation.
Objective: The objective of this study was to assess the efficacy, safety, and health-related quality of life (HRQoL) of ponatinib in patients with CML in chronic phase (CP), accelerated phase (AP), or blast phase (BP), and in those with Ph+ ALL who are resistant or intolerant to dasatinib or nilotinib, or who possesed the T315I mutation.
Methods: Ponatinib was initially received at 30 mg (n = 31) or 45 mg (n = 31) once daily for CP-CML patients, with eligibility to reduce to 15 mg upon achieving major cytogenetic response (MCyR), or at 45 mg once daily for patients with AP/BP-CML or Ph+ ALL (n = 31). The primary endpoint for CP-CML patients was the achievement of MCyR at 12 months, while for patients with AP/BP-CML and Ph+ ALL, it was the achievement of major hematologic response (MaHR) by 6 months. Secondary endpoints included molecular response rates and safety profiles particularly focusing on arterial occlusive events (AOEs). Progression-free survival (PFS) and overall survival (OS) probabilities at 60 months were estimated using Kaplan-Meier methods. The EORTC QLQ-C30 (version 3.0) was utilized to assess HRQoL in CP-CML patients. The cutoff date as of July 31, 2023 was reported.
Results: In this analysis of 93 patients (62 with CP-CML and 31 with AP/BP-CML or Ph+ ALL), the median age was 46 years (range: 34-57 years). The T315I mutation was present in 50% of the patients. Specifically, 40% of patients in the CP-CML subgroup and 68% of patients in the AP/BP-CML or Ph+ ALL subgroup harbored the T315I mutation. Most patients (90%) had received ≥ 2 prior TKIs, and 27% had at least one cardiovascular risk factor at baseline.The median follow-up time is 26 months (range: 12-31 months). Among 62 evaluable patients with CP-CML, cumulative MCyR and complete cytogenetic response (CCyR) were achieved in 62% and 59% of the 45-mg cohort and 41% and 38% of the 30-mg cohort. Among patients with the T315I mutation in the 45-mg cohort, 90%, 80%, 70%, and 30% achieved MCyR, CCyR, major molecular response (MMR), and MR4.5, respectively, while those with resistance or intolerance had rates of 70%, 70%, 45%, and 25% for the same responses. The cumulative MaHR rate among patients in AP/BP-CML or Ph+ALL subgroup was 53%. By the cutoff date, the median PFS and OS were not reached in patients with CP-CML. Grade ≥3 cumulative treatment-emergent AOEs were observed in 3 (10%), 4 (13%), and 5 (16%) patients in the 30-mg cohort, the 45-mg cohort of CP-CML patients, and patients with AP/BP-CML or Ph+ ALL, respectively, with no increase in exposure-adjusted incidence of new AOEs over time.
Significant differences in the summary score (p = 0.028) and global health status (p = 0.043) of HRQoL in 30-mg CP-CML patients were observed at 18 months compared to baseline. The 30-mg cohort showed a positive correlation between MMR response at 3 months and improvements in physical (p &lt; 0.001), role (p = 0.004), emotional (p &lt; 0.001), cognitive (p &lt; 0.001), social functioning (p &lt; 0.001), and global health status (p = 0.002). Conversely, the 30-mg cohort had a negative correlation with fatigue (p &lt; 0.001), dyspnea (p &lt; 0.001), and sleep disturbances (p = 0.001), while the 45-mg cohort showed a negative correlation with nausea and vomiting (p = 0.004) and constipation (p = 0.034) in CP-CML patients at 3 months.
Conclusion: Consistent with the previous PACE and OPTIC clinical trials, the initial analysis of the two-year results of the clinical trial in China demonstrated that ponatinib provides durable and clinically meaningful responses in a population of heavily pretreated CML and Ph+ ALL patients. In addition, ponatinib notably improved health-related quality of life in patients with CP-CML.
Disclosures: Mingji Xian: Current employment of Otsuka Beijing Research Institute Co., Ltd, Beijing, China. Shuang Zhang: Current employment of Zhejiang Otsuka Pharmaceutical Co., Ltd, Shanghai, China