Olverembatinib (HQP1351) combined with blinatumomab in patients with lymphoid blast phase chronic myeloid leukemia (CML-LBP) or Philadelphia chromosome–positive B-cell precursor acute lymphoblastic leukemia (Ph ⁺ BCP-ALL).

6513 Background: Olverembatinib, a third-generation BCR::ABL1 TKI, has demonstrated clinical activity in TKI-resistant Ph + hematologic malignancies. This study evaluated olverembatinib combined with blinatumomab in patients with relapsed/refractory (R/R) Ph + B-cell precursor ALL (BCP-ALL) or CML-LBP outside China. Methods: In this phase 1b study (HQP1351CU101; NCT04260022), adults with R/R Ph + BCP-ALL or CML-LBP received olverembatinib from 30 mg QOD, with planned escalation to 40 mg QOD, combined with standard-dose blinatumomab in 6-week cycles. Using a 3+3 design, dose-limiting toxicities (DLTs) were assessed during cycle 1. Objectives included evaluation of safety and tolerability, complete response (CR) rate, and minimal residual disease (MRD) negativity rate. MRD was assessed by flow cytometry. Results: Between January 2023 and June 2025, 9 patients were enrolled (8 Ph + BCP-ALL, 1 CML-LBP). Median age was 47 years (range 32-60); 66.7% were male. Median time from diagnosis to olverembatinib treatment initiation was 2.46 (range 0.5-6.2) years; median leukocyte count 3.5×10⁹/L (range 2-171); median prior regimens 4 (range 2-10); and median TKIs 3 (range 1-6). BCR::ABL1 transcripts were P190 (n = 7), P210 (n = 2); one patient had the T315I mutation. Notably, 6 patients had received prior blinatumomab and relapsed during maintenance or subsequent therapy. The combination demonstrated a manageable safety profile, with most adverse events (AEs) being grade 1-2, consistent with the known toxicities of each agent. Four patients experienced grade 3 AEs related to olverembatinib, including increased lipase, neutropenia, thrombocytopenia, and pancreatitis. In the 30 mg QOD cohort (n = 3), no DLTs occurred. One patient in the 40 mg QOD cohort developed grade 3 pancreatitis (considered treatment related and a DLT) on day 4, which resolved with supportive care and dose reduction to 30 mg without recurrence; this patient achieved CR and MRD negativity by end of cycle 1. With median olverembatinib treatment duration of 15.7 weeks (range 1.4-37.1), 4 patients discontinued because of disease progression (n = 1) or bridge to CAR-T/transplantation (n = 3). Among 9 enrolled patients, 5 had positive MRD at study entry without CR. In this subgroup, 4 achieved CR and 2 achieved MRD negativity. One patient died due to disease progression, assessed as unrelated to study treatment. Conclusions: Olverembatinib combined with blinatumomab shows promising clinical activity in patients with R/R Ph + BCP-ALL or CML-LBP outside China, with encouraging response rates and MRD clearance. The regimen was generally well tolerated, with a safety profile consistent with individual agent toxicities. These findings support further investigation of this chemotherapy-free approach. Clinical trial information: NCT04260022 .