CD19-CAR T Cells As Definitive Consolidation for Older Adults with B-Cell Acute Lymphoblastic Leukemia in First Complete Remission: A Pilot Study

Introduction: Older adults (>55 years) with B-cell acute lymphoblastic leukemia (B-ALL) have dismal outcomes due to adverse-risk disease biology and poor tolerability of curative therapeutic modalities. While most older adults treated with frontline low-intensity chemotherapy with or without targeted immunotherapies achieve complete remission (CR), they commonly experience subsequent relapse or treatment-related death. CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T) is promising in advanced B-ALL, inducing high rates of durable CR. However, high pre-lymphodepletion (LD) disease burden is associated with significant CAR-T related toxicity and low durability of post-infusion CR and may limit its application in older patients (pts) with relapsed B-ALL. We hypothesized that administering CAR-T to older pts with B-ALL in first CR (CR1) would result in 1) low rates of toxicity and 2) durable CR without additional cycles of therapy. Methods: This is a pilot single-center, one-arm, non-randomized study (NCT05707273) that enrolls pts ≥55 years with B-cell ALL who achieved CR1 with any frontline therapy regardless of minimal residual disease (MRD) status and with no intention to proceed to allogeneic hematopoietic cell transplantation (alloHCT). Eligible pts undergo autologous leukapheresis. Pts receive low intensity bridging consolidation therapy, followed by standard LD and CAR-T infusion. The primary objective is safety and tolerability. This study has a 6-pt safety lead-in (SLI) cohort on dose level (DL) 1 (200M CAR T cells). A DL -1 is implemented if dose limiting toxicity (DLT)/unacceptable toxicity (UT) occurs in >33% pts in the SLI. We use our memory-enriched CAR-T (Aldoss I et al. Clin Cancer Res. 2022). Once the recommended phase 2 dosing (RP2D) is identified, an additional 9 pts are enrolled on an expansion cohort. Pts are followed for toxicity and MRD relapse by flow cytometry (FC) and clonoSEQ (if feasible) every 3 months. Pts with Ph+ disease are eligible to receive tyrosine kinase inhibitors (TKI) as maintenance therapy after day 60 post CAR-T infusion. Results: We treated 6 pts in the SLI, none of whom experienced DLT/UT. DL1 was declared the RP2D and the expansion cohort was opened. To date (July 18, 2024), we have enrolled 16 pts, 2 of whom were ineligible either due to toxicity pre-leukapheresis or CD19- relapse pre-LD, 13 of whom received CAR-T (11 completed the 28-day DLT period, 2 actively in the DLT period) and 1of whom will undergo leukapheresis by the time of submission. For the infused pts (n=13), the median age was 66 yrs (range: 55-79); 7 were male. Five pts had Ph+, 2 had TP53m, 1 each had CRLF2r Ph-like, KMT2Ar, EP300::ZNF384, TCF3::PBX1, CDKN2A deletion and trisomy 5. Ten (77%) pts received blinatumomab as part of initial therapy. All patients were in MRD- CR by FC pre-LD. Among pts who completed the DLT period (n=11), 7 (64%) experienced transient grade (G) 1 cytokine release syndrome (CRS) that resolved with tocilizumab +/- corticosteroid. No pt developed immune effector cell associated neurotoxicity syndrome (ICANS) or ≥G2 CRS. The first pt with Ph- ALL is >14 months follow up post CAR-T and remains in MRD- CR by clonoSEQ without additional therapy. Four Ph+ ALL pts began TKI maintenance therapy 60 days post CAR-T. With a median follow up of 175 days (range: 44-443) for pts who completed the DLT period, only 1 pt with Ph+ ALL has developed molecular relapse (negative flow) at 6 months while on TKI maintenance. This pt remains alive and in CR after changing TKI and receiving alloHCT. All other pts are in MRD- CR. There have been no deaths thus far on this study. Despite the low antigen setting (MRD- CR) pre-LD, CAR T cells expanded in vivo, peaking on days 7-14 (mean peak, 14%±3.6%; range, 0.88-36.5%) in the CD3+ population; CAR T cells were observed in the cerebrospinal fluid (CSF) in all 10 pts who had a lumbar puncture evaluation on day 28 (median, 0.28x103/ml; range: 0.04-25.3x103/ml). Among evaluable patients, baseline and day 100 walk speed and cognitive function were similar (mean walk speed 0.71 vs 0.72 meter/second; mean Montreal cognitive assessments of 25 vs 27, respectively). Conclusion: The use of CAR-T in older adults with B-ALL in CR1 appears safe with no observed ICANS or ≥G2 CRS. CAR T cells had a robust expansion in the blood and CSF despite the low antigen setting. We have observed preliminary durable remissions and pts maintained function and cognition on day 100 post CAR-T.

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