UCD19 CAR-T cell therapy for adults with B-cell acute lymphoblastic leukemia in first complete remission with MRD positivity: Preliminary Results of A phase I/ib clincal trial

Abstract Introduction For adults with newly diagnosed B-ALL who achieve complete remission after induction therapy, detectable minimal residual disease (MRD) at end of induction is a significant risk factor for relapse. CD19 CAR-T cell therapy results in durable remissions for approximately ~20-40% of adult patients with relapsed/refractory B-ALL without additional consolidative therapy. Durability of response after CD19 CAR-T might be improved if delivered earlier in the treatment course due to better T-cell fitness, lower disease burden, and less resistant disease. UCD19 is an investigational 4-1BB-based CD19-directed CAR-T cell product with a unique TNFSF19-derived transmembrane domain. We hypothesized that UCD19 CAR-T cell therapy could be safely administered to adults with B-ALL in MRD+ CR1 who are at high risk for relapse. Methods We designed a phase I/Ib clinical trial with UCD19 CAR-T cell therapy for adults with B-ALL in CR1 after induction with MRD positivity by either flow cytometry or NGS (ClonoSeq). Ph-negative patients are eligible if MRD+ after day 28 of induction, and Ph+ patients are eligible if MRD+ after day 56. Two dose levels of CAR-T cells (DL1=0.5x108, DL2=1.5x108) were explored in the phase I portion. All patients receive Flu/Cy lymphodepletion prior to CAR-T. Relapse is defined as ≥5% marrow blasts or new extramedullary disease, or emergence of MRD by flow cytometry or NGS after having previously been MRD-negative. Results Thus far, 12 patients (median age 47, range 18-72) have been enrolled and treated with UCD19 at a median of 106 days from diagnosis (range 71-169 days). Induction therapy for all patients consisted of multi-agent chemotherapy or TKI/steroids. Nine of 12 patients remained MRD+ after bridging, prior to UCD19. The first two patients were treated at DL1, and all subsequent patients have been treated at DL2. Two patients were Ph+, three were Ph-like (one each IGH::CRLF2, IGH::EPOR, PDGFRB::EBF1), two were KMT2A rearranged, and two were TP53 mutated. Two DLTs were observed at DL2 (Grade 4 neutropenia beyond D+42). After CAR T cell infusion, one patient experienced grade 1 CRS, and no patients have had ICANS. All 12 patients were MRD-negative by flow and NGS at day 30 and were B-cell aplastic in peripheral blood post-UCD19. 5 patients (42%, 95% CI: 15-72%) remain with B-cell aplasia at a median of 147 days (range 42-485) from infusion, and 7 patients (58%, 95% CI 27-85%) have lost B-cell aplasia at a median of 97 days (range 63-243). No patients with ongoing B-cell aplasia have relapsed, while three of 7 patients (43%, 95% CI: 10 – 82%) who lost B-cell aplasia (time to BCA loss 63-140 days) developed NGS-MRD recurrence at a median of 196 days (range 156-365) from infusion. A second infusion of UCD19 was administered to four patients who had loss of B-cell aplasia within the first 6 months of infusion, none of whom regained B-cell aplasia after reinfusion. All three patients with NGS-MRD recurrence became NGS-MRD negative after one cycle of blinatumomab and were subsequently consolidated with allogeneic stem cell transplant. All 12 patients are alive and in NGS-MRD negative CR at time of last follow up. Comparing patients who maintained B-cell aplasia beyond 6 months versus those who did not, there was no significant difference in CAR expansion/persistence as measured by median Cmax (15.58 vs 37.08 cells/µL, p=0.26) or median AUC (300.4 vs 322.35, p=0.428). ConclusionFor adult B-ALL patients in MRD+ CR1 after induction, UCD19 CAR-T has been relatively well tolerated and has converted patients to MRD-negative CR to date. Low disease burden relapses (detected by NGS-MRD) occurred in some patients who had loss of BCA within 6 months of infusion. Enrollment in the phase 1b dose expansion at DL2 is ongoing.