Safety and efficacy of carniospinal irradiation (CSI) before CAR T cell therapy in patients with acute lymphoblastic leukemia (ALL) with central nervous system (CNS) disease: A potential role for CSI beyond cell killing and into immune priming

Abstract

Abstract Background: Outcomes of patients (pts) with B-cell acute lymphoblastic leukemia (B-ALL) have improved significantly with the introduction of targeted therapies such as blinatumomab, inotuzumab, and CD19-directed CAR T cell therapies. However, relapses are still common in adults with B-ALL, including isolated CNS relapse or CNS relapse with concomitant systemic relapse. Craniospinal Irradiation (CSI), a comprehensive treatment administered to patients with CNS disease before allogeneic transplant, has shown an improvement in relapse-free survival. There is emerging data on the role of radiation in immune priming, immunogenic cell death, particularly when administered before CAR T cell therapy. To that end, we have now introduced CSI before CAR T cell therapy in patients with B-ALL and CNS relapse. Methods We retrospectively reviewed patients with B-ALL who received CD19 CAR T cell therapy between February 2022 and March 2025. We identified patients with CNS disease (based on imaging and/or CSF positivity) who received CSI prior to CAR T cell therapy. A total of 12 patients were identified who received CSI, administered after pheresis and before the CAR T cell infusion. The CSI dose was 23.4 Gy in 13 fractions. In patients who received brexu-cel, CAR T expansion was measured by anti-FMC63-based flow cytometry in the peripheral blood. Results A total of 12 patients were identified who received CSI prior to CAR T cell infusion. The time from the completion of CSI to infusion of CAR T cells was a median of 20 days (range, 7-67). Eleven received Brexu-cel, and 1 received Obe-cel. Median age was 36 years (range, 23-71). Of the 12 patients, 8 (66%) were Ph-positive; 2 (16%) were Ph-like. Median number of prior therapies was 2 (range, 2-4); 11 (92%) had received prior blinatumomab, 6 (50%) received prior inotuzumab, and 2 (17%) had prior allo-SCT. Five (38%) patients had isolated CNS relapse, 6 had CNS + systemic relapse (5 with BM MRD positive by either flow/NGS and 1 with frank marrow relapse). One patient had CNS plus orbital disease. The median follow-up measured from CAR T cell infusion was 17.7 months (range, 3 - 41.8). Marrow evaluation before CAR T showed NGS MRD-negative disease in 9 (75%) patients, and NGS was unavailable in 3 (25%) patients. Among the 12 patients, CAR T expansion data were available for 10 patients, and the median peak CAR T expansion was 59 (range, 1-2222), with the peak observed on Day 9. Of these 10 patients, 7 (70%) exhibited a peak CAR T expansion of ≥15 cells/µL, which has previously been reported by our group to be associated with favorable post-CART outcomes in patients in marrow remission who receive Brexu-cel (Khaire, ASCO 2025). At the time of the day 28 assessment, all patients were negative by flow cytometry, and the nine patients with available NGS results were also NGS MRD negative in the bone marrow. One patient proceeded with an Allo SCT as post-CART consolidation. Eight of 12 patients had CRS of any grade, with one grade 3. Eight of 12 patients had ICANS of any grade, with 2 having grade 3, and one having grade 4. With a median follow-up of 17.7 months, 3 of the 12 patients relapsed, with one relapse in the CNS, one extramedullary relapse, and one systemic relapse. One-year PFS and OS were 83% and 100%, respectively. Conclusion MRD-negative patients with CNS disease treated with CSI is safe and show favorable outcomes with CD19 CAR T in terms of CAR T expansion, CNS clearance, and durable remission duration, which was comparable to those with no CNS disease based on our recently reported data.