Use of CD19 CAR-T Cells in Adult B-Cell Acute Lymphoblastic Leukemia (B-ALL) with Minimal Residual Disease (MRD) Positivity at First Complete Remission: Preliminary Outcomes from a Phase I Clinical Trial

Introduction: While >90% of adults with B-ALL will achieve morphological remission with frontline chemotherapy/TKI-based approaches, long-term survival of patients with minimal residual disease (MRD+) is ~30%, with poor outcomes driven by high rates of relapse. Incorporation of blinatumomab and/or inotuzumab in CR1 may mitigate the negative prognostic significance of MRD, however it is unclear if intensity of standard post-remission therapy can be safely reduced without compromising outcomes. CD19 CAR-T cell therapy results in durable remissions for approximately 20-30% of adult and 40-50% of pediatric patients with relapsed/refractory B-ALL, without additional consolidative therapy. We hypothesized that durability of response might be improved if CAR-T is 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 designed a phase I clinical trial to determine safety and tolerability of UCD19 CAR-T cell therapy for adults with B-ALL in MRD+ CR1 who are at high risk for relapse.

Methods: Eligible patients include adults (≥18yo) with B-ALL in CR1 after induction therapy, with MRD positivity by either flow cytometry or NGS (Clonoseq). Ph- ALL patients are eligible if MRD+ after day 28 of induction, and Ph+ patients are eligible if MRD+ after day 84. Two dose levels of CAR-T cells (DL1=0.5x10⁸, DL2=1.5x10⁸) are being explored per a BOIN design. Bridging therapy is allowed prior to lymphodepleting chemotherapy (Flu/Cy) and CAR-T infusion. Bone marrow assessments are performed at 1, 3, 6, and 12 months post infusion, and peripheral blood NGS-MRD is measured monthly through at least month 6.

Results: Seven patients (median age 48 years, range 18-69) have been enrolled and treated with UCD19 (2 at DL1, 5 at DL2) at a median of 115 days from diagnosis (range 74-168 days). 1 patient was MRD+ by flow and NGS, and 6 patients were MRD+ by NGS only at screening. 1 DLT was observed at DL2 (Grade 4 neutropenia, thrombocytopenia beyond D+42). This patient also developed grade 4 sepsis related to UCD19. No CRS or ICANS has been observed. Of the 6 patients with >1 month of follow-up, all are MRD-negative by NGS at a median of 3 months (range 1-5 months) post UCD19. B-cell recovery has occurred in 2 patients (median 2.5 months post infusion), while 4 patients have ongoing B-cell aplasia (1-4 months post UCD19). CAR-T expansion kinetics and cytokine profiles were compared to adults with relapsed/refractory non-hodgkin lymphoma (NHL) who received UCD19 on a separate study. While there were no significant differences between the groups, there was a trend toward lower peak expansion by dPCR (mean 48.7 vs. 117 cells/mL, p=0.48), longer time to peak expansion (mean 10.8 vs 14.4 days, p=0.255), lower AUC (mean 593.5 vs. 1184, p=0.55), as well as less median IFNg (18.6 vs. 135.6 pg/ml, p=0.19), IL-6 (1.8 vs 135.6 pg/ml, p=0.29), IL-8 (32.2 vs 129.5 pg/ml, p=0.34), and TNFa (0.77 vs 129.5 pg/ml, p=0.14) in ALL vs NHL patients.

Conclusions: Thus far, UCD19 has been safely administered to 7 adult patients with B-ALL in MRD+ CR1. Early outcomes are promising with high rate of conversion to MRD-negativity post treatment. Longer follow-up is needed to determine if remissions remain durable, and to determine the relationship between functional persistence (as measured by B-cell aplasia) and remission durability. Enrollment is ongoing at DL2.

Schneider:Lentigen Technology, a Miltenyi Biotec Company: Current Employment. Fry:United States Patent and Trademark Office: Patents & Royalties: WO2017205747A1; United States Patent and Trademark Office: Patents & Royalties: WO2015084513A1; United States Patent and Trademark Office: Patents & Royalties: WO2019178382A1; Sana Biotechnology: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months.