Gupta, Vishal

Abstract In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

Abstract The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO exposed). InO-exposed patients were more heavily pretreated (P = .02) and frequently had active marrow disease before apheresis (P = .03). Response rate and toxicity profile after brexu-cel were comparable for InO-exposed and InO-naïve patients; however, consolidation therapy after brexu-cel response was used at a higher rate in InO-naïve patients (P = .005). With a median follow-up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS; P = .013) and overall survival (OS; P = .006) in univariate analyses; however, prior InO exposure did not influence PFS (hazard ratio, 1.20; 95% confidence interval, 0.71-2.03) in multivariate models. Within InO-exposed patients, InO responders had superior PFS (P = .002) and OS (P < .0001) relative to InO-refractory patients. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (P = .51) and OS (P = .86) for patients receiving InO as bridging therapy or before apheresis. In conclusion, although InO exposure was associated with inferior survival outcomes after brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively affects brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.

Introduction: In October 2021, the FDA approved brexu-cel for the treatment of adults ≥ 18 years old with R/R B-ALL. Following this approval, a consortium of cancer centers was formed across the US to investigate outcomes following commercial brexu-cel use for adults with R/R B-ALL. One area of interest is the toxicity profile of brexu-cel when given in the real-world context, including the respective incidences and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS). Methods: Eligible pts included adults ≥ 18 years old who received commercial brexu-cel starting in October 2021 onward at a participating center in the US (N = 25). Retrospective patient data were collected across participating institutions, with the most recent data lock occurring on June 30, 2023. Criteria from the ASTCT were used to grade CRS and ICANS severity. Statistical methods included the use of medians and simple ratios for descriptive outcomes; univariate logistic regression models were used to assess the association of various factors with the probability of CRS and ICANS, and Cox regression was used to examine the association of each with the hazards of mortality and failure for event-free survival (EFS; earliest of progression, relapse, or death). Results: Key demographics and toxicities are described in Tables 1 and 2 (respectively). Of the 152 pts infused with brexu-cel, 82% (N = 125) developed CRS and 56% (N = 85) developed ICANS. CRS and ICANS did NOT develop in 12% (N = 19). Twenty percent of all pts (N = 31) required ICU-level care for management of CAR-related toxicities, with a median LOS in ICU of 4 days (range 1-79). In univariate models, grade 3+ ICANS was most likely to occur in pts with active disease (≥ 5% marrow blasts and/or EMD) at the time of apheresis (OR 2.63, 1.28-5.38, p = 0.008); a numerical increase for grade 3+ CRS (OR 2.35, 0.69-8, p = 0.17) was seen in pts with active disease at apheresis. Therapies received for these CAR-related toxicities included steroids, tocilizumab (toci), and anakinra (Table 2). Among pts who received steroids (N = 94), 37% (N = 34) achieved a sufficient response to the first steroid trial and did not require subsequent therapies; otherwise, toxicities improved with the first steroid course but later worsened in 16% (N = 15); the first trial of steroids was not effective but improved when further steroids were given in 31% (N = 29); there were no responses to any doses of steroids in 10% (N = 9). In pts receiving toci (N = 103), 31% (N = 32) achieved a sufficient response to the first dose and did not require any further therapy; toxicities improved with the first dose but later worsened in 31% (N = 32); the first dose was ineffective but improvement was seen with subsequent doses in 21% (N = 22); 9% (N = 9) did not respond at all to toci. The rate of death within day +28 was 6% (N = 9), and the respective causes were typically multifactorial: CRS was implicated in 3 cases, ICANS in 3, infection in 5, disease relapse/progression in 2, and HLH in 1 case. In total, uncontrolled ICANS was implicated in the death of 6 pts (between day +9 to day +106). HLH was reported in 6 pts: in most cases, this was a biochemical diagnosis, and it either overlapped with concurrent CRS or infection or occurred following CRS/ICANS. The most common infections between day 0 and day +28 included bacteremia in 8% of pts (N = 12), fungal infections in 4% (N = 6), pneumonia in 3% (N = 5), and CMV infections in 3% (N = 4). The fungal infections included 4 instances of invasive sinopulmonary infections (2 due to aspergillus; 2 due to mucormycosis) and 2 cases of candidemia. With both CRS and ICANS treated as a time-varying covariate, the development of grade 3+ CRS was associated with a higher hazard of death (HR 2.38, 1.00-5.66, p = 0.05); grade 3+ ICANS was not associated with a demonstrably higher risk of death (HR 1.11, 0.60-2.05, p = 0.74). The HR of EFS failure for Grade 3+ CRS was 1.81 (0.87-3.79, p = 0.12) and for grade 3+ ICANS HR = 0.93 (0.56-1.53, p = 0.77). Conclusions: In this real-world study of toxicities from brexu-cel use for adults with R/R B-ALL, we observed CRS and ICANS in the majority of pts, and no new safety signals were observed. Rates of severe CRS and ICANS were more common with active disease. Interestingly, though CRS-related mortality was rare, grade 3+ CRS was associated with a higher risk of death. Efforts to identify mechanisms and mitigable risk factors for these toxicities are warranted.