Venetoclax and Blinatumomab for adult patients with relapsed/refractory or MRD positive Ph-negative B-cell precursor ALL: phase I part of the GMALL-BLIVEN trial.

Prognosis of adult patients with relapsed/refractory (r/r) or measurable residual disease (MRD)–positive B-precursor acute lymphoblastic leukemia (B-ALL) remains poor. Blinatumomab induces complete remissions (CR) and MRD negativity in a subset of patients, yet overall survival remains limited. As BCL2 overexpression contributes to leukemic cell survival and therapy resistance, combining Blinatumomab with the BCL2 inhibitor Venetoclax may enhance therapeutic efficacy. The GMALL-BLIVEN (NCT05182385) phase I multicenter trial evaluated the safety and feasibility of Venetoclax plus Blinatumomab in adults with CD19⁺, Philadelphia chromosome–negative r/r or MRD-positive B-ALL. Dose escalation followed a 3 + 3 design across three Venetoclax dose levels (DL-1: 400 mg; DL-2: 600 mg; DL-3: 800 mg) administered from day − 7 to day 42, with Blinatumomab given per label. The primary endpoint was determination of the maximum tolerated dose (MTD); key secondary endpoint was achievement of molecular complete remission (MOL-CR) by centralized IG/TR MRD assessment (sensitivity ≥ 10⁻⁴). Nine patients (median age 52 years, range 22–71) were enrolled across four German centers: four with r/r B-ALL and five with MRD-positive disease. Molecular subtypes included ZNF384-rearranged (n = 2), BCR::ABL1-like (n = 2), CEBP-rearranged (n = 1), hypodiploidy (n = 1), B-ALL NOS (n = 2), and KMT2A-rearranged (n = 1). No dose-limiting toxicities were observed, and the MTD was not reached. Treatment-emergent grade ≥ III toxicities included neutropenia, febrile neutropenia, cytokine release syndrome, and ICANS; no 30- or 60-day mortality occurred. Six patients completed two full cycles without treatment interruptions. The recommended phase II dose (RP2D) was established as Venetoclax 800 mg daily plus standard-dose Blinatumomab. All nine patients were evaluable for response. Among r/r B-ALL, responses included PR (n = 1), CR (n = 1), and PD (n = 2). Among MRD-positive patients, 4/5 achieved MOL-CR. Four patients were successfully bridged to allogeneic stem cell transplantation. After a median follow-up of 17.8 months, median overall survival was 15.0 months (r/r: 6.6 months; MRD-positive: 16.9 months). Non-responders were enriched for adverse molecular subtypes (BCR::ABL1-like and hypodiploid B-ALL). Venetoclax combined with Blinatumomab is safe and feasible in adults with r/r or MRD-positive B-ALL, without increased rates of CRS or neurotoxicity compared with Blinatumomab alone. High rates of MRD clearance were observed in MRD-positive patients. The phase II portion of GMALL-BLIVEN is ongoing at the RP2D of Venetoclax 800 mg daily.