Ramakrishnan, Aravind

Abstract Introduction: Brexucabtagene autoleucel (Brexu-cel) is a CD19-targeted chimeric antigen receptor (CAR-)T cell therapy approved for treatment of relapsed/refractory (r/r) B-ALL. Brexu-cel's approval was founded on data from the ZUMA-3 trial, in which 78 patients (pts) were treated at the pivotal dose of 1x10e6 CAR-T cells/kg, resulting in a complete remission (CR) rate of 73%. Three-year follow-up from ZUMA-3 demonstrated median relapse-free and overall survival (RFS/OS) of 11.6 and 25.6 months (mos) for all treated pts. Amongst responders, the median OS was 60.4 mos for those who did not receive a subsequent allogeneic hematopoietic cell transplant (HCT) (n=43), but only 36.3 months for those who did (n=14). This has led some to conclude that HCT may not be beneficial following brexu-cel therapy for r/r B-ALL; however, it must be noted that 29 (37%) of the pts treated on ZUMA-3 received brexu-cel for post-HCT relapse. T cells collected from individuals who relapse in the post-HCT setting are largely of donor origin, making the CAR-T product comparable to a genetically modified donor lymphocyte infusion (DLI). The immunology at play in this scenario may be different from that in which CAR-T cells are of truly autologous origin. Methods: The Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database includes pt characteristics and outcomes of brexu-cel therapy given as standard-of-care across 41 US institutions. We identified pts who achieved an MRD negative (neg) CR by either flow cytometry (minimum sensitivity 10e-4) or NGS following brexu-cel for r/r Ph neg B-ALL and categorized them into three groups with regard to use of HCT: Never HCT, Pre-CAR HCT, or Post-CAR HCT. Pts who received second HCT following brexu-cel for post-HCT relapse (n=9) were excluded. Pt/disease characteristics, RFS, and OS were assessed for each group, landmarked at 73 days after brexu-cel infusion (the median time to consolidative allogeneic HCT). Results: In the ROCCA database we identified 165 pts who achieved MRD neg CR following brexu-cel, amongst whom 69 never underwent HCT, 49 were transplanted pre-CAR (ie, brexu-cel served as a genetically modified DLI), and 47 underwent post-CAR consolidative HCT while in CR. The median follow-up is 373 days. The median age was higher in the Never HCT group (49, range 19-83) in comparison with the Pre-CAR HCT (40, 24-72) and Post-CAR HCT (34, 18-70) groups. Thirty-five percent were >60yo in the Never HCT group vs 20% in the Pre-CAR HCT and 9% in the Post-CAR HCT groups. Ph-like disease was present in 38%, 29%, and 43% of the Never HCT, Pre-CAR HCT, and Post-CAR HCT groups, respectively (p=0.35). No significant differences were observed in pre-apheresis bone marrow blasts, presence of CNS disease at apheresis, prior blinatumomab or inotuzumab treatment, or use of bridging therapy across the groups, though there was a higher prevalence of non-CNS extramedullary disease in the Pre- and Post-CAR HCT groups (32, 39%) vs the Never HCT group (13%) (p=0.004). A minority of pts in all groups were deemed to be in MRD neg CR prior to apheresis (6-20%). Median RFS was 260 days in the Never HCT group and not reached in the Pre- and Post-CAR HCT groups (p=0.002), with respective 1-yr RFS of 38%, 64%, and 67%. Median OS was not reached in any group and was similar for all at 1-yr at 68-79% (p=0.13). Characteristics of those in the Never HCT group who were least likely to relapse included age >60 (OR 0.22, CI 0.07-0.73 vs age 18-39, p=0.024) and those with non-Ph-like B-ALL (OR 0.33, CI 0.12-0.94, vs Ph-like, p=0.037) in univariate analyses. Conclusions: Real-world data regarding outcomes following brexu-cel therapy allow evaluation of the role for consolidative allogeneic HCT, which remains one of the most important unresolved questions in the use of CAR-T therapy for r/r B-ALL. This analysis demonstrates that a first consolidative HCT after achieving MRD neg CR with brexu-cel is associated with a significant decrease in relapse. Additionally, use of brexu-cel for post-HCT relapse is also associated with a significantly lower risk of relapse compared with those who never received an allogeneic HCT. With the current duration of followup, OS is not significantly different across the three groups. These data suggest there is a benefit for relapse-free survival in pts receiving an allogeneic HCT at some point in the course of treatment for r/r Ph neg B-ALL.

Abstract Introduction: Multiple myeloma (MM) accounts for nearly 20% of all hematologic cancers in the US and remains a substantial clinical burden, with patients (pts) requiring multiple lines of therapy (LOT). While advances such as BCMA-directed CAR T-cell therapy have improved outcomes, challenges persist, including disease relapse, treatment toxicities (CRS, ICANS, and non-ICANS neurotoxicities), and access. AZD0120 (formerly GC012F) is a first-in-class autologous BCMA/CD19 dual-targeting CAR T-cell therapy using the FasTCAR rapid manufacturing platform that preserves the naive and central memory T-cell phenotypes with marked in vivo proliferative capacity. Phase 1 investigator-initiated trials in China demonstrated deep, durable responses and a favorable safety profile following single-infusion AZD0120 in newly diagnosed and relapsed/refractory MM (RRMM) (Du J, et al. EHA 2024 and ASCO 2023). Here, we report for the first time preliminary phase 1b results from DURGA-1, an ongoing phase 1b/2 clinical trial evaluating the safety and efficacy of AZD0120 in pts with RRMM. Methods: This open-label, single-arm, US-based, multicenter study (NCT05850234) evaluated the safety/tolerability of 2 dose levels (DL) of AZD0120 in pts with RRMM along with preliminary efficacy. Eligible ptswere aged ≥18 y with RRMM (3+ prior LOT [pLOT] including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody), ECOG PS 0–1, and documented evidence of progressive disease. Exposure to BCMA-directed therapy ≥6 mo with best response of PR or better was permitted. Pts underwent lymphodepletion followed by a single infusion of AZD0120. Pts in DL1 received 1x105 cells/kg; DL2 received 3x105 cells/kg. Dose escalation and recommended phase 2 dose (RP2D) were determined by a safety review committee. Phase 1b primary objectives included safety/tolerability and RP2D determination; secondary objectives included efficacy, cellular kinetics (CK), and pharmacodynamics. Results: As of data cutoff (DCO) on 18 July 2025, a total of 25 pts received infusion of AZD0120 (n=12 DL1; n=13 DL2). The median age was 64 y (range 44–78), median pLOT was 4 (range 3–7), 72% were triple-class refractory, 20% had prior BCMA CAR T-cell therapy, 4% had prior teclistamab, 28% had high-risk cytogenetic features [del(13q), del(17p13), t(4;14), t(14;16), amp(1q)], and 8% had extramedullary plasmacytomas. The median time from apheresis to release was 14 d (range 10–30). Median time from apheresis to infusion was 28 d (range 19–44) with 5 pts receiving bridging therapy. Median follow-up was 1.4 mo (range 0–19.3). No dose-limiting toxicities were reported for either dose. The most common treatment-emergent AEs (TEAEs, any grade) were CRS (64%), neutrophil count decreased (56%), and anemia (32%). The most common grade ≥3 TEAEs were neutrophil count decreased (52%), lymphocyte count decreased (32%), and white blood cell count decreased (32%). CRS was reported in 75% of pts at DL1 (all grade 1) and 54% at DL2 (46% grade 1; 8% grade 2), with no cases of grade ≥3 CRS. Median time to CRS onset (DL1/DL2) was 9 d (range 2–11), with a median duration of 2 d (range 1–4); 12 pts (48%) received tocilizumab for CRS management and 12% received dexamethasone. No cases of ICANS, related non-ICANS neurotoxicity, IEC-colitis, or secondary primary malignancies have been reported. There have been no deaths. For efficacy-evaluable patients (n=15), ORR was 100% (33% sCR, 47% VGPR, 20% PR). CR rates in evaluable pts were 30% in DL1 (n=10) and 40% in DL2 (n=5); median time to response was 0.9 mo for both DLs (range 0.9–1.9 DL1; 0.6–1.8 DL2). All MRD-evaluable pts (n=5 DL1; n=3 DL2; DCO 01 July 2025) were MRD-negative by NGS at a sensitivity of 10-5. Three pts in DL1 with ≥12 mo follow-up maintained MRD negativity. Consistent with robust in vivo expansion, CK analysis from 16 evaluable pts (DCO 12 June 2025) demonstrated a median Tmax of 13 d post-infusion with a median Cmax of 85,266 copies/mg gDNA. Median persistence was 42 d (range 13–273). Updated clinical data with additional follow-up will be presented. Conclusion: Preliminary phase 1b results demonstrated AZD0120 was well tolerated, with a low incidence of serious AEs, no grade ≥3 CRS, and no ICANS. FasTCAR-manufactured AZD0120 had expectedin vivo expansion, which may have resulted in the predictable CRS profile. A single infusion of AZD0120 achieved early, deep responses with 100% MRD negativity from 4L+ triple-class‒exposed pts with RRMM.

Abstract Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

BACKGROUND ELRA is a humanized, BCMA/CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, SC ELRA given as 2 step-up priming doses (12 mg on day 1 and 32 mg on day 4 of cycle 1) followed by 76 mg QW in patients (pts) with RRMM naive to BCMA-directed therapy resulted in an ORR of 61.0%. With a median follow-up of 28.4 mos, the median DOR, PFS, and OS were not reached (NR; 2-year rate, 66.9%), 17.2, and 24.6 mos, respectively. Overall, 56.3% of pts had CRS (grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 pt) had CRS with doses ≥4. Recurrent CRS occurred in 15.1% of pts. The phase 1/2 MagnetisMM-9 (MM-9; NCT05014412) study is examining an alternative priming regimen and longer dosing intervals of ELRA. Here, we present updated MM-9 results. METHODS In MM-9, pts with RRMM and disease refractory to ≥1 IMiD drug, ≥1 PI, and ≥1 anti-CD38 antibody were given SC ELRA as step-up priming doses of 4 and 20 mg on Day 1 and Day 4 of Cycle 1, respectively. After the priming doses, ELRA 76 mg was given QW for the next 6 cycles (Part 1) or for 1 cycle followed by 116 (dose level 1 [DL1]) or 152 (dose level 2 [DL2]) mg Q2W for the next 5 cycles (Part 2A). After 6 cycles, the dosing frequency was decreased from QW to Q2W (Part 1) or from Q2W to Q4W (Part 2) in pts who achieved ≥PR lasting ≥2 months. The recommended phase 2 dose from Part 2A (152 mg, DL2) was evaluated in Part 2B (dose expansion). The primary endpoint for both parts is grade ≥2 CRS rate per ASTCT criteria during Cycle 1. Secondary endpoints include evaluation of efficacy and adverse events. Data cutoff: February 13, 2024. RESULTS Overall, 85 pts (median age, 64.0 y) were treated with ELRA. The majority (72.9%) of pts had R-ISS stage I/II disease (23.5% with R-ISS stage III); 31.8% had high-risk cytogenetics. Median number of prior lines of therapy was 5.0 (range, 1-12). The median treatment duration was 8.6, 2.9, 1.4, and 3.3 mos, in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B, respectively. Median follow-up for pts overall (n=85), in Part 1 (n=33), Part 2A DL1 (n=12), Part 2A DL2 (n=11), and Part 2B (n=29) was 10.4, 23.3, 16.5, 15.2, and 9.3 mos, respectively. Overall, the ORR was 58.8%. For pts in Part 1, Part 2A DL1, Part 2A DL2, or Part 2B, ORR was 66.7%, 58.3%, 36.4%, and 58.6%, respectively; median DOR was NR (9-mo rate: 86.4%), 10.8 mos (9-mo rate: 80.0%), NR (9-mo rate: 100.0%), and NR (9-mo rate: 84.8%); median PFS was 17.1 (9-mo rate: 62.8%), 11.6 (9-mo rate: 50.9%), 1.6 mos (9-mo rate: 40.0%), and NR (9-mo rate: 57.1%); median OS was NR (9-mo rate: 75.8%), 17.4 mos (9-mo rate: 66.7%), NR (9-mo rate: 60.0%), and NR (9-mo rate: 72.4%), respectively. For pts in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B, grade ≥2 CRS rates during Cycle 1 were 15.2%, 16.7%, 27.3%, and 6.9%, respectively. For pts in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B, CRS rates were 30.3%, 33.3%, 36.4%, and 24.1% after dose 1, 27.3%, 25.0%, 36.4%, and 24.1% after dose 2, 15.2%, 33.3%, 27.3%, and 20.7% after dose 3, 6.1%, 8.3%, 0%, and 3.4% after dose 4, and 6.1%, 16.7%, 9.1%, and 0% after doses ≥5. Recurrent CRS occurred in 18.2%, 33.3%, 18.2%, and 17.2% of pts in Part 1, Part 2A DL1, Part 2A DL2, and Part 2B. The most common (>60%) TEAEs (any grade/grade ≥3) were hematologic TEAEs (Part 1, 75.8%/75.8%; Part 2A DL1, 83.3%/83.3%; Part 2A DL2, 81.8%/81.8%; Part 2B, 79.3%/69.0%), infections (Part 1, 78.8%/48.5%; Part 2A DL1, 83.3%/66.7%; Part 2A DL2, 72.7%/63.6%; Part 2B, 62.1%/37.9%), and CRS (Part 1, 60.6%/0%; Part 2A DL1, 83.3%/0%; Part 2A DL2, 90.9%/9.1%; Part 2B, 48.3%/0%). Grade 5 TEAEs not including PD were infection (n=4), fall (n=1), subdural hematoma (n=1), and food poisoning (n=1). CONCLUSIONS The 4/20 mg step-up priming regimen and alternative dosing schedules in MM-9 resulted in similar efficacy vs the step-up regimen used in the registrational MM-3 study (12/32 mg). Responses were durable with encouraging PFS and OS with the alternative step up and longer dosing schedule. While the overall safety signals with the alternative step up regimen are similar to those seen with MM-3, the CRS profile differed with more CRS events after each subsequent dose and a higher prevalence of recurrent CRS. Thus, the optimal ELRA step-up regimen remains 12/32 mg from the original regimen in the MM-3 study. In addition, these early results suggest that reducing the dose frequency of ELRA may not compromise efficacy.

7522 Background: Elranatamab (ELRA) is a humanized BCMA-CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, SC ELRA was given as 2 step-up priming doses (12 mg on C1D1 and 32 mg on C1D4) followed by 76 mg QW in patients (pts) with RRMM. Overall, 56.3% of pts had CRS (grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 pt) had CRS with doses 4+. Recurrent CRS (>1 event) occurred in 15.1% of pts (Lesokhin Nat Med 2023). Methods: MagnetisMM-9 (MM-9; NCT05014412) is a phase 1/2, open-label, nonrandomized study of ELRA examining an alternative 2-dose step-up priming regimen (4 and 20 mg on C1D1 and C1D4, respectively). Eligible pts had RRMM and were refractory to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody. After the priming doses, ELRA 76 mg was given QW for 6 cycles (Part 1) or for 1 cycle followed by 116 or 152 mg Q2W for 5 cycles (Part 2A). The RP2D from Part 2A (152 mg) was evaluated in Part 2B (dose expansion). The rate of grade ≥2 CRS per ASTCT criteria during C1 is the primary endpoint for both parts. Secondary endpoints include evaluation of AEs and PK. Here, we report the overall safety and CRS profile associated with the 4/20 mg priming regimen. Results: For 85 treated pts, median age was 64.0 y; 49.4% were male; 23.5% had EMD; 31.8% had high-risk cytogenetics. Pts had a median of 5.0 (range, 1-12) prior LOTs; 85.9% had triple-class refractory disease. After a median follow-up of 7.4 mo, the most common (>50%) AEs were CRS (63.5%; grade ≥2, 15.3%) and neutropenia (54.1%; all grade ≥2). ICANS occurred in 4.7% of pts (all grade ≤2). The grade ≥2 CRS rate in C1 was 14.1% (90% CI, 8.4-21.9). CRS rates after the first 3 doses are in the the table. For doses 4+, any grade (grade ≥2) CRS was observed in 10.6% (3.5%) of pts overall, 12.1% (3.0%) of pts continuing to receive 76 mg (n=33), 25.0% (0%) of pts receiving 116 mg (n=12), and 5.0% (5.0%) of pts receiving 152 mg (RP2D; n=40). Overall, recurrent CRS was observed in 20.0% of pts. The geometric means (CV%) of free ELRA concentrations 24 h (Cmax-24h) after step-up doses 1 and 2 were 85.64 (48%) and 242.8 (55%). Conclusions: The 4/20 mg step-up priming regimen and alternative dosing schedules resulted in similar safety and incidence of overall and grade ≥2 CRS events vs the regimen used in MM-3 (12/32 mg), with no new safety signals identified. However, the CRS profile in this study differed, with more CRS after doses 2, 3, and 4+ and a higher prevalence of recurrent CRS. The Cmax-24h of free ELRA (CV%) after the priming doses were lower than those in MM-3 (107.4 [47%] and 405.1 [72%], respectively). Thus, the priming regimen used in MM-3 remains the optimal regimen for mitigating CRS. Future analyses of ongoing studies will be used to confirm these results. Clinical trial information: NCT05014412 . [Table: see text]