Background: Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) is associated with poor outcomes, with low complete remission (CR) rates (40% after first relapse, <20% after ≥2 relapses) and median overall survival (OS) of 2–6 months. CD22 is highly expressed in >90% of B-ALL cells, making it an ideal therapeutic target. Inotuzumab ozogamicin (InO), an anti-CD22 antibody-drug conjugate, combined with venetoclax (VEN) and dexamethasone (DEX), has shown promise in preclinical and early clinical studies. This prospective, multicenter, single-arm trial evaluated the efficacy and safety of this novel combination in R/R B-ALL patients.

Objectives: The primary objectives were to assess CR rate and minimal residual disease (MRD) negativity rate after one cycle. Secondary objectives included OS, relapse-free survival (RFS), non-relapse mortality, and adverse events (AEs).

Methods: This was a single-arm, prospective, multi-center clinical study (ChiCTR2400093987). Adults with R/R Ph-negative B-ALL were enrolled across multiple centers. Patients received InO (1mg on days 1, 8, 15), DEX (10mg/m² on days 1–4), and VEN (dose-escalated to 200mg/day from day 2, days 1–21) per 21-day cycle, for up to two cycles. CR was defined as <5% blasts, hematologic recovery, and no extramedullary disease; MRD negativity was assessed using 10-color flow cytometry (<10⁻⁴). Efficacy and safety were evaluated after cycle 1.

Results: Among 13 enrolled patients with R/R B-ALL (8 male, 5 female), a single cycle of InO-VEN-DEX therapy achieved complete remission (CR) in 91.7% (11/12) with 75.0% (9/12) attaining MRD negativity (<10⁻⁴ via 10-color flow cytometry). With a median follow-up of 8 months, all surviving patients who achieved CR (n=10) maintained remission without recurrence. The median overall survival (OS) and progression-free survival (PFS) were not reached. Hematologic toxicities included grade 3/4 neutropenia (82%), thrombocytopenia (73%), and anemia (64%), all managed supportively. Two significant adverse events occurred: (1) one patient (7.7%) developed grade 3 tumor lysis syndrome, controlled with allopurinol/hydration; (2) one patient (7.7%) experienced grade 4 neutropenia after CR complicated by fatal sepsis. No instances of venous occlusive disease (VOD), cytokine release syndrome (CRS), or direct treatment-related mortality were documented.

Conclusions: This pioneering triplet regimen of Inotuzumab Ozogamicin, Venetoclax, and Dexamethasone demonstrates compelling efficacy in R/R B-ALL, achieving rapid and durable complete remissions (91.7% CR) with deep molecular responses (75.0% MRD negativity) after a single cycle—outcomes surpassing historical salvage chemotherapy benchmarks. Critically, all patients attaining CR who survived beyond the observation period (n=10/11, 91%) maintained ongoing remission without relapse at 8-month follow-up, underscoring the regimens' potential to induce biologically stable disease control. While hematologic toxicities were universal but manageable, the sepsis-related death (7.7%) linked to grade 4 neutropenia highlights the imperative for aggressive infection prophylaxis during therapy. The absence of VOD, CRS, or direct treatment mortality reinforces the manageable safety profile when using risk-adapted supportive strategies. Collectively, these findings position InO-VEN-DEX as a high-efficacy, clinically feasible bridge to curative intent therapies (e.g., allogeneic HSCT) in R/R B-ALL, warranting validation in expanded cohorts.

Disclosures No relevant conflicts of interest to declare.

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2025
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