Updated efficacy and safety of olverembatinib (HQP1351) as second-line therapy in patients with chronic-phase chronic myeloid leukemia (CP-CML).

6510 Background: Olverembatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) approved in China for chronic myeloid leukemia (CML) resistant/intolerant to ≥ 2 TKIs or with the T315I mutation. This study assessed olverembatinib as second-line treatment in patients with CP-CML resistant/intolerant to first-line TKIs without the T315I mutation. Methods: This single-arm, multicenter, open-label study enrolled patients (ECOG PS 0-2, adequate hepatic/renal function) who receive olverembatinib 40 mg orally every other day in 28-day cycles. Efficacy and safety were assessed every 3 cycles. The primary endpoint was complete cytogenetic response (CCyR) rate. Results: From August 4, 2022, through January 14, 2026, 47 patients were enrolled (91.5% first-line TKI resistant, 8.5% intolerant). The median age was 42.0 (19-70) years; 66.0% were male. Twelve (25.5%) received first-line imatinib, and 35 (74.5%) received first-line second-generation TKIs. Thirty-six (76.6%) had no baseline BCR::ABL1 kinase domain mutations, and 11 (23.4%) had non-T315I mutations. At data cutoff, 33 (70.2%) continued treatment, while 14 (29.8%) discontinued because of adverse events (n = 3), treatment failure (n = 4), progression (n = 2), or other reasons (n = 5). Among 42 evaluable patients, 76.2% achieved CCyR and 47.6% major molecular response (MMR). CCyR/MMR rates increased progressively: cycle 6 (57.5%/25.0%), cycle 9 (60.4%/33.3%), cycle 12 (75.0%/37.5%), cycle 15 (83.3%/46.7%), cycle 18 (89.3%/50.0%), cycle 21 (92.0%/64.0%), and cycle 24 (91.3%/60.9%). Complete hematologic response was achieved in 83.3% (15/18) and major cytogenetic response in 83.3% (35/42). Among 32 patients pretreated with first-line second-generation TKIs, 81.3% achieved CCyR and 50% MMR. The median treatment duration was 16.0 (6-38) cycles. Any-grade treatment-related adverse events (TRAEs) occurred in 42 (89.4%) patients; 21 (44.7%) had grade ≥ 3 TRAEs; and 6 (12.8%) had serious adverse events (SAEs). Nonhematologic TRAEs (mainly grade 1-2) included skin hyperpigmentation (51.1%), hyperuricemia (31.9%), and creatine phosphokinase increased (27.7%). Grade ≥ 3 hematologic toxicities included platelet count decreased (42.6%), neutropenia (25.5%), and anemia (8.5%). Olverembatinib-related SAEs included platelet count decreased (6.4%), anemia, myelosuppression, and pyrexia (2.1% each). Most hematologic TRAEs were manageable with supportive care. Two cardiovascular events (grade 1 hypertension) were possibly treatment-related. No deaths occurred. Conclusions: Olverembatinib shows good tolerability and leads to high MMR and CCyR in patients with CP-CML without T315I mutation that is resistant/intolerant to first-line TKIs. Clinical trial information: ChiCTR2200061655.