Introduction: Older adults with B-cell acute lymphoblastic leukemia (B-ALL) have dismal outcomes due to adverse-risk disease biology and poor tolerability of curative therapy. Low disease burden pre-lymphodepletion (LD) prior to chimeric antigen receptor T-cell therapy (CAR-T) in patients (pts) with relapsed B-ALL is associated with lower CAR-T related toxicity and improved durability of remission. We hypothesized that treating older pts with B-ALL in first complete remission (CR1) with CAR-T would result in 1) low rates of toxicity and 2) durable CR without additional consolidative therapy.

Methods: This is a pilot single-center, one-arm study (NCT05707273) that enrolls pts ≥55 years with B-ALL who achieved CR1 with any frontline therapy and no upfront plan for transplant. Primary objectives are safety and tolerability. This study has a 6-pt safety lead-in (SLI) cohort at dose level 1 (200M CAR T cells) and an expansion cohort of an additional 12 pts. We used our naïve memory T cell-derived CD19-CAR-T (Aldoss I et al. Clin Cancer Res. 2022), administered following LD with fludarabine and cyclophosphamide. Pts are followed for toxicity and minimal residual disease (MRD) relapse by flow cytometry (FC) and clonoSEQ (if feasible) every 3 months for 2 years. Pts with Philadelphia chromosome (Ph)+ disease may receive post CAR-T tyrosine kinase inhibitor (TKI) maintenance starting after day 60 post CAR-T. Progression free survival (PFS) is defined as the time from the date of CAR T infusion to the date of progression/relapse or death, whichever came first. Patients with no event occurring by last contact will be censored.

Results: We treated 6 pts in the SLI, none of whom experienced dose-limiting toxicity, and subsequently we opened the expansion cohort. As of July 20, 2025, we enrolled 20 pts and the study was completed. Two pts were ineligible for LD due to relapse (isolated central nervous system, CD19- MRD) post leukapheresis. For infused pts (n=18), the median age was 64 years (range: 55-79). Six pts had Ph+, 5 had not otherwise specified (NOS), 2 had hypodiploidy/TP53m, 2 had CRLF2-rearranged Ph-like, 1 each had KMT2Ar, EP300::ZNF384, and TCF3::PBX1; 15 (83%) and 2 (11%) pts received blinatumomab and inotuzumab as part of initial therapy, respectively. All patients were in MRD- CR by FC pre-LD.

Thirteen (72%) pts developed transient grade (G) 1 cytokine release syndrome (CRS) that resolved with tocilizumab +/- steroid. No pt developed immune effector cell associated neurotoxicity syndrome (ICANS) or ≥G2 CRS. With a median follow up of 14.5 months (range: 3.4-26.9), the 1-yr PFS rate is 90% (95% C.I. 80-100%). Only 1 pt (Ph+) developed molecular relapse (negative FC) at 6 months while on TKI maintenance. This pt then received a different TKI and consolidation with allogeneic hematopoietic stem cell transplant and remains in remission. A second pt (75 yrs old; received induction with hyper CVAD + inotuzumab) developed therapy-related myelodysplastic syndrome 18 months post CAR-T. All other pts remain in MRD- CR as of last follow up. The first pt on the study who had Ph- ALL is >2 years post CAR-T and remains in MRD- CR by clonoSEQ without additional therapy. All six pts with Ph+ ALL began TKI maintenance post CAR-T. There have been no deaths thus far on study.

Despite the MRD- state pre-LD, CAR T cells expanded in vivo, peaking on days 7-14 (mean peak, 12.8%±2.7%; range, 0.9-36.5% in the CD3+ population). We observed CAR T cells in cerebrospinal fluid (CSF) in all 17 pts who had lumbar puncture evaluation on day 28 (median, 0.4x103/ml; range: 0.04–25.3x103/ml), which were detectable in the CSF up to 1 yr post therapy. For most patients, B-cell recovery was observed within 6 months post CAR-T. Walk speed and cognitive function were similar at baseline and day 100 [mean walk speed 1.02 vs 0.98 meter/second (p=0.46); median Montreal Cognitive Assessment of 26 vs 26 (0=0.17); median frailty scores 1 vs. 2 (p=0.17), respectively].

Conclusion: The use of CAR-T in older adults with B-ALL in MRD- CR1 is safe, with the only encountered toxicity of G1 CRS, which was manageable. CAR-T cells expanded in the blood and CSF despite the low antigen setting. We observed preliminary durable MRD- CR with preserved function and cognition on day 100 post CAR-T. Ongoing extensive correlative studies aim to better understand the features of CAR T cells that drive expansion in patients without active leukemia.

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2025
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