AZD0486 is a novel, fully human IgG4 CD19xCD3 bispecific T-cell engager engineered with low-affinity CD3 binding to reduce cytokine release while preserving T-cell cytotoxic activity against malignant B cells. Initially studied in R/R B-cell non-Hodgkin lymphoma, AZD0486 is now being evaluated in the Phase I SYRUS trial (NCT06137118) for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). The study includes a dose-escalation phase (Part A) assessing intravenous AZD0486 in adults (16–80 years) with CD19+ B-ALL who received ≥2 prior lines of therapy or were ineligible for standard treatment after ≥1 prior line. Patients received AZD0486 using a step-up dosing strategy, with target doses administered every two weeks starting on Cycle 1 Day 15. Two dose levels—DL1 (2.4 mg) and DL2 (7.2 mg)—have been evaluated so far.

The study enrolled 24 patients (13 in DL1 and 11 in DL2) who were heavily pretreated (median of 3 prior therapies) and included high-risk subgroups such as those resistant to blinatumomab and/or CAR-T therapy (up to 69.2% in DL1), double-exposed patients, and those with ≥50% bone marrow blasts. In DL1, CR or CRi rate was 46% (6/13), with 83% (5/6) of responders achieving MRD negativity. DL2 showed higher activity, with 67% (6/9 evaluable patients) achieving CR/CRi—all of whom were MRD negative. Among patients with high disease burden (≥50% bone marrow blasts), 8 of 10 across both cohorts achieved CR at the end of Cycle 1. Notably, three patients proceeded to allogeneic stem cell transplant following response. Durable remissions were observed, with ten patients maintaining ongoing CRs ranging from 6 to 330 days.

The safety profile of AZD0486 was manageable with no new safety signals. Cytokine release syndrome (CRS) occurred more frequently at the higher dose level (73% in DL2 vs. 31% in DL1), though events were predominantly Grade 1–2 and managed with tocilizumab. One Grade 2 case of ICANS was reported in DL2. Single dose-limiting toxicity (DLT) was observed in DL1 (Grade 3 AST elevation and prolonged Grade 4 cytopenia), and no patients discontinued treatment due to AZD0486-related adverse events. Overall, these preliminary findings support AZD0486 as a promising and well-tolerated treatment in heavily pretreated R/R B-ALL, including in patients with prior bispecific or CAR-T exposure. 

KOL insights

“While a significant number of Acute Lymphoblastic Leukemia patients experience relapse, the demand for effective treatments in this population remains unmet. However, there has been rapid progress in the development of newer therapies.” – Expert Opinion

“In pediatric acute lymphoblastic leukemia, modern risk-directed treatments have achieved 5-year overall survival rates surpassing 90%. Efforts now concentrate on enhancing outcomes and reducing intensive therapy-related toxicity through expanded utilization of immunotherapy, identification of targetable genetic anomalies, and refinement of risk assessment accuracy.”– Expert Opinion

Conclusion

The ALL treatment landscape is advancing rapidly, shifting from traditional chemotherapy to targeted immunotherapies and cell-based approaches. ASPARLAS remains a key chemo component, while BLINCYTO’s June 2024 FDA expansion to frontline CD19+ Ph-negative B-ALL highlights its growing role. CAR-T therapies like TECARTUS (adults) and KYMRIAH (up to 25 years) offer deep remissions in R/R. For T cell-ALL, options remain limited with ARRANON. The pipeline is robust, led by Orca Bio’s Orca-T (positive Phase III data; BLA planned in 2025), Cellectis’ UCART22 (CD22 CAR-T with key data in Q3 2025), and AstraZeneca’s AZD0486 (CD19xCD3 bispecific, Phase I/II data expected in 2026). The early results position AZD0486 as a strong, differentiated candidate for further development in R/R B-ALL. Overall, innovation is focused on improving durability, reducing toxicity, and broadening access.