Long-Term Safety and Efficacy Outcomes of Varnimcabtagene Autoleucel in Relapsed Refractory B Cell Malignancies: India Phase 2 Imagine Study

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Introduction Varnimcabtagene autoleucel (IMN-003A) is an autologous CD19-targeted CAR T-cell product with 4-1BB co-stim domain and A3B1 murine scFv, manufactured in India. Here, we present long-term outcomes from IMAGINE, a Phase 2, multicenter, single-arm study in patients with relapsed/refractory B cell malignancies (RR BCM) (CTRI/2022/03/041162). Varnim-cel is approved in India for RR B-NHL above age 18 years. Methods Eligible patients (pts) were aged 3 to 45 years (B-ALL) and ≥ 18 years (B-NHL) with RR BCM and measurable disease, as assessed by lymphoid blasts (B-ALL) or metabolic tumour bulk (B-NHL), received ≥1 prior regimen, refractory to the last line of treatment with good performance status (ECOG 0 to 1). Target dose was 1 × 10 6 /kg CAR+ cells (B-ALL) and 5 × 10 6 /kg CAR+ cells (B-NHL) (overall range 0.1 × 10 6 to 5 × 10 6 ) administered in a 3-day fractionated schedule (10%/30%/60%), with at least 24h between infusions. Primary objectives were overall response rate (ORR: CR + CRi in B-ALL and CR + PR in B-NHL) at day +90 after first infusion, and safety. Response was assessed as per NCCN (B-ALL) and IWG (B-NHL) criteria; bone marrow minimal residual disease (MRD) for B-ALL by flow cytometry at 10 -4 sensitivity and B-NHL by PET-CT. Adverse events grading was by CTCAE v5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) criteria for CRS and ICANS. Results As of data cut-off, of 25 pts enrolled (median age 31 yrs, range 3 - 66) with RR BCM [n=13 B-ALL, median blasts 0.34% (range 0.01 - 27.2); n=12 B-NHL, median TMTV 67.9 ml (range 27.1 - 1177), median SPD 3846 mm 2 (range 1001 to 35849], 24 pts received varnim-cel (1 withdrawal) majority of infusions on Days 0, +3, +7. Median CAR-T cell manufacturing time was 14 days (range 10 - 27) with 100% manufacturing success. At data cutoff, median follow-up post infusion was 368 days (range 12 – 731). ORR was 92% (22/24) at D+28 (B-ALL 92%, MRDneg 91%; B-NHL 92%, CR 64%); 83% (20/24) at D+90 (B-ALL 83%, MRDneg 90%; B-NHL 83%, CR 70%); and 42% (B-NHL 50%, CR 83%) at D+365. AESIs reported were CRS (Grade [G] 1 63%; G3+ 4%; overall 67%); ICANS (G1 4%; G3+ 0%; overall 4%); neutropenia (G3+ 92%; overall 100%); anemia (G3+ 29%; overall 96%); and thrombocytopenia (G3+ 21%; overall 92%). CRS median onset was D+6 and duration 3 days. No G3+ ICANS was reported. Tocilizumab , steroids and anakinra usage was in 37.5% (n=9/24, majority for persistent G1 CRS), 8% and 4% respectively. One pt died due to treatment related mortality (CRS, B-ALL). Median duration of B cell aplasia was 299d (range 41 to NR), hypogammaglobulinemia seen in 58% pts and post discharge hospitalization events, pre-relapse, were 8 (4 viral; 3 bacterial; 1 fungal). At data cutoff, median PFS and OS was 272d and not reached (range 12 – NR for both). Conclusion Varnimcabtagene autoleucel offers a favourable safety profile achieving long-term efficacy without severe neurotoxicity enhancing patient outcomes.

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