Sengupta, Sanhita

Patients in the liso-cel plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50×106 [dose level (DL)1] or 100×106 [DL2] chimeric antigen receptor-positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n=5; DL2, n=51), median (range) age was 64.5 years (44‒77), 98% had high-risk cytogenetics, 55% had progression on Bruton tyrosine kinase inhibitor and venetoclax failure, and median (range) number of prior therapies was 5 (1‒13). Median (range) follow-up was 24.8 months (3.1‒51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31‒60) and overall response rate was 86% (95% CI, 74‒94). Median (95% CI) duration of response was not reached (NR; 28.7‒NR) for patients with CR/CRi and 41.4 months (23.3‒NR) for all responders. Median (95% CI) progression-free survival was 31.4 months (20.1‒NR). In DL1+DL2, most common grade ≥3 treatment-emergent adverse events (TEAE) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of patients (grade 3, 4%; no grade 4/5), and neurological events in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with relapsed/refractory CLL/SLL with predictable and manageable safety. Clinicaltrials.gov: NCT03331198; NCT03435796.

7037 Background: TRANSCEND CLL 004 (NCT03331198) is a phase 1/2, open-label, nonrandomized, multicohort study in adult patients (pt) with R/R chronic lymphocytic leukemia/small lymphocytic lymphoma with liso-cel mono and liso-cel + ibrutinib combo cohorts. Given the study design, we performed PS matching/weighting to adjust for differences in key covariates between cohorts to compare efficacy and safety. Methods: Here, PS is the probability of receiving combo given the covariates and estimated by logistic regression. Covariates were hemoglobin, LDH, number of prior therapies, platelets, prior BTKi + venetoclax exposure, R/R on prior BTKi, and bulky disease for efficacy; and ALC, bulky disease, CRP, ferritin, and number of prior therapies for safety. PS balancing methods were optimal 1:1 matching, average treatment effect for treated pts (ATT) full matching, and ATT inverse probability of treatment weighting (IPTW). Efficacy endpoints were response (CR rate, ORR) and time to event endpoints (DOR, PFS, OS). Safety endpoints were proportions of pts with any-grade (gr)/gr ≥ 3 cytokine release syndrome (CRS) and investigator-identified neurological events (NE). Results: Fifty-one and 88 efficacy-evaluable pts were treated at dose level 2 (100 × 10 6 CAR + T cells) in the combo and mono cohorts, respectively. Before matching/weighting on PS, odds of achieving CR and overall response were statistically significantly higher for combo (Table). DOR did not differ between cohorts. For PFS and OS, HRs were lower with combo vs mono (not statistically significant [NS]). Odds of gr ≥ 3 CRS/NE were lower with combo vs mono (NS). After matching/weighting, odds of CR (except IPTW ATT) and overall response remained statistically significantly higher in combo. HRs for PFS and OS and ORs for gr ≥ 3 CRS/NE were numerically lower with combo vs mono (NS, except IPTW ATT for PFS). HRs for DOR were less but close to HR of 1. Conclusions: The liso-cel + ibrutinib combo demonstrated a trend for better efficacy and safety vs liso-cel mono, with statistically significant differences for CR rate and ORR. Clinical trial information: NCT03331198 . Efficacy and safety outcomes: combo vs mono. No adjustment ATT optimal 1:1 IPTW - ATT CR rate, OR (95% CI) 2.07* (1.01–4.28) 2.40* (1.05–5.66) 2.00(0.89–4.61) ORR, OR (95% CI) 3.96* (1.68–10.51) 3.43* (1.33–9.71) 4.18* (1.63–11.78) DOR, HR (95% CI) 0.98(0.51–1.87) 0.88(0.43–1.78) 0.96(0.50–1.85) PFS, HR (95% CI) 0.62(0.37–1.02) 0.61(0.35–1.05) 0.59* (0.35–0.98) OS, HR (95% CI) 0.70(0.38–1.28) 0.73(0.37–1.43) 0.66(0.36–1.22) CRS, OR (95% CI) 0.63(0.26–1.56) 0.67(0.24–1.84) 0.69(0.24–1.88) Gr ≥ 3 CRS, OR (95% CI) 0.23(0.01–1.35) 0.49(0.02–5.28) 0.26(0.01–1.94) NE, OR (95% CI) 0.84(0.41–1.68) 0.92(0.40–2.08) 1.10(0.48–2.52) Gr ≥ 3 NE, OR (95% CI) 0.56(0.19–1.45) 0.58(0.16–1.89) 0.68(0.19–2.30) *Statistically significant difference at 5% level.

7529 Background: iAEs, such as cytokine release syndrome (CRS) and macrophage activation syndrome (MAS), can occur after infusion of chimeric antigen receptor T cell therapies such as ide-cel, but are typically low-grade and manageable with tocilizumab and corticosteroids. Although high-grade iAEs are rare with ide-cel, identification of patients at increased risk may improve management and remains an unmet need. Three composite biomarkers (multivariate models) of iAE risk were previously developed in a discovery cohort from the KarMMa and KarMMa-2 studies of ide-cel in RRMM (Mashadi-Hossein A, et al. J Clin Oncol 2023;41(16_suppl):e20005). Here, we validate these 3 prototype models for risk of developing high-grade iAEs after ide-cel infusion. Methods: Two models used pretreatment patient and routine clinical laboratory parameters; the third model also included change in 6 exploratory cytokines from baseline to 1 day following ide-cel infusion. To validate, each model was retrospectively applied to KarMMa-3 (NCT03651128) data in a blinded fashion, and sensitivity and specificity to identify grade ≥3 CRS and any-grade MAS were determined. Model performance thresholds used for sensitivity and specificity were 90% and 50%, respectively. Performance for identifying grade 2 CRS was also analyzed post hoc. Results: The first and simplest model comprised a manual algorithm with 7 features; it identified patients with grade ≥3 CRS or MAS with 85% sensitivity and 60% specificity. The second model comprised 19 routinely measured pretreatment features; it identified grade ≥3 CRS with 91% sensitivity and 59% specificity, and any-grade MAS with 60% sensitivity and 88% specificity. The third and most complex model comprised 7 pretreatment clinical features and 6 exploratory cytokines; it identified grade ≥3 CRS with 100% sensitivity and 51% specificity, and any-grade MAS with 100% sensitivity and 81% specificity. None of the models identified grade ≥2 CRS with passable sensitivity or specificity. Clustering analyses across all features showed that only a subset of grade 2 CRS cases was within the previously identified high-risk iAE cluster while the remaining grade 2 CRS cases were spread across other clusters. Conclusions: Two of the 3 composite biomarkers met validation criteria for grade ≥3 CRS risk. Criteria were not met for grade 2 CRS, suggesting these models are specific to higher-grade events and that grade 2 CRS represents a more heterogeneous group of patients. While high-grade iAEs are rare with ide-cel, these models may further optimize the robust benefit–risk profile that ide-cel has demonstrated by helping identify, prior to or shortly after infusion, patients most at risk for severe events. Clinical trial information: NCT03651128 .