Matched donor allogeneic CAR-T for adult B-ALL: toxicity, efficacy, repeat dosing, and the importance of lymphodepletion.

Autologous CD19-targeting CAR-T has transformed management of relapsed/refractory adult B-cell acute lymphoblastic leukaemia(B-ALL) but relapse post-allogeneic stem cell transplant(allo-SCT) is frequently accompanied by profound lymphopenia, impaired T-cell fitness and aggressive disease requiring urgent treatment, making autologous CAR-T challenging to deliver. We developed an allogeneic matched-donor CD19CAR product (CAR-DLI) for adult B-ALL following allo-SCT failure. Here we evaluate the risks/benefits of pre-CAR-DLI lymphodepleting chemotherapy (LD), and the efficacy of repeat CAR-DLI dosing as per conventional DLI scheduling/protocols. Patients aged 16-70y with r/r B-ALL post-allo-SCT were eligible. Primary outcomes were toxicity and feasibility of CAR-DLI manufacture; secondary outcomes included CAR-DLI engraftment/ expansion/ persistence. 17 allo-SCT donors were leukapheresed and 14 patients (median age,43y) were infused. Median disease burden at registration was 63.5% bone marrow blasts (range, MRD-100%). Patients 1-7 received CAR-DLI-alone; patients 8-14 received CAR-DLI+LD with fludarabine/cyclophosphamide. CAR-DLI+LD vs CAR-DLI-alone was associated with superior peak CAR-DLI engraftment (93,134 vs. 8010 copies/ug gDNA), expansion (858,101 vs. 39,038 copies/ug gDNA/28d) and persistence (median 197 days vs. 32 days). CAR-DLI+LD was not associated with more immunotoxicity than CAR-DLI-alone, and GvHD (grade-1/skin) affected only 2/14(14%) patients. CAR-DLI+LD vs CAR-DLI-alone conferred superior event-free-survival (EFS) and overall-survival (OS) at 12m (57% vs 29%; 83% vs 29%). Repeat CAR-DLI dosing was administered to 8/14(57%) patients with morphological/MRD+ relapse, but with minimal engraftment/expansion or toxicity/efficacy. CAR-DLI+LD has a tolerable safety profile without significant GvHD and is associated with significantly better outcomes than CAR-DLI-alone. Repeat CAR-DLI dosing beyond dose 1 was not found to be effective in this analysis. NCT02893189.