The efficacy and safety of switching to olverembatinib or continuing original TKI therapy in CML-CP patients treated with at least two prior TKIs: A prospective, multicenter, controll trial

Abstract Introduction: Olverembatinib (HQP1351) is a novel third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) in chronic myeloid leukemia-chronic phase (CML-CP). However, patients with CML-CP who failed to achieve MMR were aproved with shortened PFS and overall survival (OS). This study evaluated the efficacy and safety of switching to olverembatinib in patients with CML-CP whofailed to achieve MMR for more than 18 months and were treated at least two prior TKIs. Methods In this multicenter, prospective controlled trial (CTR2300072680), patients with CML-CP who had failed for treatment with ≥2 prior TKIs for ≥18 months were enrolled. Patients were assigned at 1:2 ratio to receive either olverembatinib (40 mg orally every other day) or continue their most recent TKI therapy (control group). The primary endpoint was the major molecular response (MMR) rate at 6 months. Secondary endpoints included deep molecular responses (DMR), cumulative response rates, OS, and safety. Results Between April 1, 2021 and April 1, 2025, 72 patients were assessed for eligibility, 63 patients were screened and enrolled in this prospective, multicenter, controlled trial, with 21 patients assigned to olverembatinib group and 42 patients to control group. The median age was 46 years (rang, 11-81 years), and males comprised 43/63 (68.3%) totally. The median disease duration at baseline was 9 years (rang, 2-20 years). All patients expressed P210 transcript type. 47.6% (10/21) of patients in the olverembatinib group and 28.5%(12/42) in the control group were recorded with 3/4 lines of prior TKI therapy. After 6 months switching to olverembatinib treatment, the 6 months-MMR rate in olverembatinib group was significantly higher than those in control group (olverembatinib group, 8/21(38.1%) versus control group 3/42 (7.1%); 95% CI: 8.8-53.2%; P=0.0042). At 12 months, the cumulative incidence of MMR was 42.86% (9/21) in the olverembatinib group compared to 16.67% (7/42) in the control group (P=0.0178). Similarly, the cumulative incidence of MR4.0 was 28.57% (6/21) in the olverembatinib group, higher than those in control group with 11.9% (5/42) (P = 0.0037). The cumulative incidence of MR4.5 was 28.57% (6/21) in the olverembatinib group, compared to those in control group with 2.38% (1/42) (P=0.0009). The most common treatment-emergent adverse events (TEAEs) of olverembatinib were primarily grade 1-2 and manageable. The most common grade 3/4 hematological TEAEs included thrombocytopenia (10/21, 47.61%) and anemia (4/21, 19.05%), followed by leukopenia (3/21, 14.29%) and neutropenia (2/21, 9.52%). Grade 3/4 non-hematological events were rare. Interestingly, 76.91% of AEs relatived to prior TKI therapy in CML-CP patients has been improved after patients switched to olverembatinib treatment. Conclusion A higher proportion of efficacy in patients switching to olverembatinib treatment than those remained on treatment and continued to derive benefit over time, supporting olverembatinib may as a standard of care for patients with CML-CP previously treated with ≥2 TKIs. Olverembatinib also can improve the AEs relatived to prior TKI therapy and maybe a valuable therapeutic option for CML-CP patients. Keyword Olverembatinib; chronic myeloid leukemia; tyrosine kinase inhibitor resistance; major molecular response; deep molecular response. This research was funded by Shenzhen Second People's Hospital Clinical Research Fund of Shenzhen High-level Hospital Construction Project (No.2023yjlcyj020). *Correspondence to: Xin Du, M.D., Ph.D., Department of Hematology, The Second People's Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen,Shenzhen 518000, Guangdong, China. E-mail: [email protected].