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Cellular Immunotherapies: Late Phase and Commercially Available Therapies The Impact of Inotuzumab Ozogamicin (InO) Treatment on Brexucabtagene Autoleucel (Brexu-cel) Outcomes in Adults with Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia (B-ALL) Introduction: Brexu-cel is the first approved CD19-directed chimeric antigen receptor (CAR) T-cell therapy for adult patients (pts) with relapsed/refractory (r/r) B-ALL. InO, an anti-CD22 antibody drug conjugate, is also approved for the same indication. With the accessibility to several targeted therapies in r/r B-ALL, the optimal sequence remains uncertain. The effect of prior treatment with InO on brexu-cel outcomes remains underreported, especially as a bridging therapy, as well as the effect of previous response to InO on post brexu-cel outcomes. Methods: This is a retrospective multicenter analysis from 25 U.S. institutions of adults (≥18 years) with r/r B-ALL treated with commercial brexu-cel from 2021 to 2023 post FDA approval. Methodologies for assessing minimal residual disease (MRD) (minimal threshold of 10 -4) included flow cytometry, NGS, or qPCR depending on institutional practice. Progression-free survival (PFS) and overall survival (OS) were calculated from day of brexu-cel infusion and were not censored for hematopoietic cell transplant (HCT) or maintenance. All living patients were censored at the time of last follow-up prior to data lock, which occurred on June 30, 2023. Results: Among 152 infused, 83 (54.6%) had pre-CAR InO therapy (InO-exposed), with a median of 3 administered doses (range: 1-22). Within the InO-exposed cohort, 23 (28%) pts received InO as a CAR T-cell bridging therapy (ie, between apheresis and lymphodepletion) with or without pre-apheresis and 60 (72%) pts received InO only during pre-apheresis. Baseline characteristics for InO exposed and InO-naïve pts are shown in Table 1. InO-exposed pts had higher median prior lines of therapies (4 vs. 3; p= 0.05), more frequently had active disease (≥5% marrow blasts) at the time of apheresis (67% vs. 44%, p= 0.02), and had lower incidence of Ph+ disease (19% vs. 45%, p=0.003), compared to InO-naïve pts, respectively. The incidences of cytokine release syndrome (CRS) (85% vs. 85%, p= 0.26) and ICANS (58% vs. 57%, p= 0.36) post infusion were similar, and post-infusion death in remission occurred in 17% and 12% among InO-exposed and InO-naïve pts, respectively. Morphological complete remission (CR) and MRD- rates following brexu-cel infusion were 89% and 77% for InO-exposed pts, and 92% and 70% for InO-naive pts, respectively. Post CAR therapy, more InO-naïve pts underwent consolidation/maintenance therapy (transplant, chemotherapy, or TKIs) compared to InO-exposed pts (41% vs. 19%, p= 0.004). The median follow-up after brexu-cel was 8.4 (range) months. Median OS (not reached (NR) vs. 12 months; p= 0.033) and median PFS (NR vs. 7 months; p= 0.029) were superior in InO-naïve pts compared to InO-exposed pts, respectively. However, after adjusting for pre-apheresis disease burden and post-CAR maintenance therapy, there were no longer significant differences in OS (HR= 1.25;95%CI: 0.62-2.53; p= 0.53) or PFS (HR= 1.24;95%CI:0.71-2.16, p=0.45) based on pre-CAR InO exposure. When InO-exposed pts were stratified based on prior InO-response (CR vs. no response), InO-responsive pts had superior estimated 12-month OS (64%) and PFS (38%) relative to InO-refractory pts (OS: 33%; PFS: 34%), but inferior to InO-naïve pts (OS: 75%; PFS 56%), with p-values of 0.0001 and 0.021 for OS and PFS, respectively (Figure 1). The timing of pre-CAR InO therapy did not impact brexu-cel survival outcomes, with comparable estimated 12-month OS (43% vs. 58%, p= 0.35) and PFS (46% vs. 38%, p= 0.57) for InO-exposed pts during bridging therapy and patients who received InO as a therapy prior to apheresis. Conclusion: After adjusting for pre-CAR disease burden and post-CAR consolidation/maintenance, we found that prior InO exposure does not significantly associate with PFS or OS following brexu-cel. However, relative to InO-responsive patients, patients who were InO-refractory appear to have worse post-CAR survival outcomes. Finally, timing of InO administration (ie as a prior line of therapy or as CAR bridging) did not influence outcomes brexu-cel outcomes.

Background and Significance: The rare nature and diagnostic difficulty associated with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has limited the inclusion of patients (pts) with these diseases, other than chronic myelomonocytic leukemia (CMML), in relevant clinical trials. This has resulted in the complete lack of approved agents for the treatment of pts with non-CMML MDS/MPN. Moreover, ASTX727 (oral decitabine-cedazuridine) was approved for CMML based on a study of only 16 pts with CMML. A larger study of CMML and non-CMML MDS/MPN is needed. MDS/MPNs appear to be BCL2-dependent (Bogenberger et al., 2015; Jilg et al., 2016), but data for venetoclax combination therapy are derived from retrospective analyses of relapsed/refractory disease (Cortes et al. 2019; Hammond et al., 2020) or single-arm studies not dedicated to MDS/MPN (NCT04655755, Venugopal et al. 2021). Venetoclax exposures are not affected by coadministration of ASTX727 and predict responses similar to historical data (Mannis et al. 2021). Based on these promising early data and the critical need, we proposed a randomized study of ASTX727 alone or in combination with venetoclax for pts with MDS/MPN and >5% blasts. Study Design and Methods: This is a National Cancer Institute-sponsored, multi-center, international, randomized phase 2 study (NCT05600894, NCI 10538) designed to evaluate the efficacy of ASTX727 alone or in combination with venetoclax in pts with newly diagnosed MDS/MPN with >5% marrow blasts. Key eligibility criteria include allowing hydroxyurea cytoreduction to a WBC <10,000/mm 3 for proliferative disease and excluding pts with need for emergent disease-directed therapy as well as prior therapy for myeloid malignancy other than hydroxyurea or thrombopoietic/erythropoietin stimulating agents. Pts will be randomized 1:1 to receive either ASTX727 alone (Days 1-5) or in combination with venetoclax, initially administered with a 3-day dosing ramp-up and given for 14 days per 28-day cycle (Figure 1). Pts are stratified by disease subtype, specifically CMML and non-CMML MDS/MPN. The primary endpoint is the rate of complete remission (adapted from the MDS/MPN-specific response criteria developed by Savona et al. 2015). Secondary endpoints include the overall response rate, overall survival, progression-free survival, allogeneic hematopoietic stem cell transplantation rate, clonality at time of hematologic remission, number of red cell and platelet transfusions required and toxicity of ASTX727 versus ASTX727 + venetoclax. Pts randomized to the ASTX727 monotherapy arm and without response after 4 cycles of therapy, or with progressive disease after an initial response, cross over to the ASTX727 + venetoclax arm. A futility analysis is planned for each cohort (first 18 and 13 pts in each treatment arm for the CMML and non-CMML cohorts, respectively). We assume that 85% and 90% of pts in the CMML and non-CMML MDS/MPN cohorts, respectively, randomized to the ASTX727 monotherapy arm will not achieve the primary endpoint and will cross over to the ASTX727 + venetoclax combination arm. The estimated accrual time of a total of 70 pts with CMML and 50 pts with non-CMML MDS/MPN will require about 2.9 and 2.1 years, respectively. Planned integrated studies include the use of an apoptosis multiplex immunoassay to evaluate how the addition of a BCL-2 inhibitor will influence the ability of ASTX727 to induce apoptosis and if particular thresholds of apoptosis are predictive of clinical response. Planned exploratory studies include the use of: 1) RNA-seq to evaluate if differences in baseline transcriptional programs appear to be predictive of response to ASTX727 and ASTX727+venetoclax, 2) next generation (Oncomine Comprehensive Assay (OCAv3)/whole exome sequencing to uncover biomarkers predictive of response/outcome, validate risk modeling to stratify these pts and detect/monitor measurable residual disease (MRD) on serial marrow samples that can predict depth of response with translation in improvement in event-based endpoints, and 3) circulating tumor DNA as a non-invasive means (i.e., without need for a marrow evaluation) of prospective MRD detection for prognostic use. This ongoing, randomized study may inform frontline therapeutic options, provide prospective data for venetoclax combination after HMA failure, and generate striking correlative science for pts with “high risk” MDS/MPN.

Introduction: Sickle cell disease (SCD) is the most common inherited hemoglobinopathy affecting populations across the United States. Several well-established patient-centered comprehensive care models have been in practice for preventive care and pain management. However, access to hematopoietic stem cell transplant (HSCT) and clinical trials for sickle cell gene therapies are limited, especially in pediatric and adult centers with limited HSCT-related resources. We describe a patient-centered collaborative model in the Upper Midwest United States to improve patient education and engagement as well as access to HSCT and gene therapy trials for patients with SCD. Collaborative Care Model: Since August 2021, centers across the Midwest meet monthly to improve access for HSCT and gene therapy as well as education about these therapies for individuals with SCD. The teams include: hematology and transplant teams from University of Minnesota, Comprehensive Sickle Cell Care team from Children's Hospital of Minneapolis, hematology and transplant team from Mayo Children's Hospital, hematology team from Essential Health, Duluth, Minnesota, hematology team from Sanford Children's Hospital Fargo and Sioux Falls and hematology team from Blank Children's Hospital, Des Moines, Iowa. This collaborative approach involves several stakeholders including an SCD community advocacy organization, hematology care providers across several rural as well as community/university hospitals, social workers, nurse coordinators, HSCT/gene therapy providers, as well as representatives from National Marrow Donor Program. Individual patient needs and available community support as well as institutional resources are discussed at length during monthly virtual meetings and a pre-intervention plan is established to ensure smooth transition of care to and from primary centers (Figure 1). Ongoing communication with the primary team helps with efficient transition of care after transplant as patients continue ongoing monitoring and care closer to home. Community partners help with early education of the families and provide necessary resources and support. Institutional partners like NMDP provide support with immune typing and discuss ongoing support and other resources available for providers and families. Results/Impact: Since the implementation of this collaborative model, there has been a steady increase in early referrals for education regarding HSCT and potential gene therapies trials for patients with SCD. There has been about 100% increase in new patient referrals since the implementation of this collaborative model compared to the average new referrals in the previous years (2021-22 vs 2018-19; Figure 2). Enrollment in HSCT as well as gene therapy clinical trials also has increased 2-3 folds since the implementation of the collaborative care model. It has helped established early discussion and longitudinal care and has also led to ongoing evaluation and discussions for availability of optimal donors, determining eligibility for HSCT and gene therapy trials as well as providing ongoing support and education to the sickle cell community and providers regarding the available therapies for SCD. This has also facilitated the transplant team establish earlier and better rapport with patients and their families and provide necessary education with an in-depth discussion regarding the potential benefits and risks of therapies such as HSCT and gene therapy. These discussions often occur over multiple visits and helps address psychological as well social barriers with a prospective evaluation. Additionally, the ongoing discussion among the providers helps with longitudinal monitoring of the patients and provide an assessment of the risks and benefits of therapies as the patient's disease course continues to evolve. This multi-stake holder collaborative approach continues to provide a well-established platform for discussion of newer therapies and access to open clinical trials, available resources for patients and families, and improve patient care and experience. The impact of this collaboration is noted in significant increase in early referrals and educational consults for HSCT and gene therapies, improved patient engagement as well as the acceptability and participation in clinical trials.

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.

Introduction In October 2021, brexucabtagene autoleucel (brexu-cel) received U.S. FDA approval as the first CAR T-cell therapy for adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) based on the 55-patient ZUMA-3 Phase II study. We subsequently established ROCCA and now report on the largest cohort of patients treated with commercial brexu-cel for r/r B-ALL to date. Methods Adults (18+) with r/r B-ALL infused with commercial brexu-cel across 25 U.S. institutions were included. ASTCT consensus criteria were used to score CRS and ICANS. Methodologies for assessing MRD (minimal threshold of 10 -4) included flow cytometry, NGS, or qPCR depending on institution practice. Duration of remission (DOR) was calculated from time of complete response (CR); progression-free survival (PFS) and overall survival (OS) were calculated from day of brexu-cel infusion and were not censored for hematopoietic cell transplant (HCT) or maintenance. All living patients were censored at the time of last follow-up prior to data lock, which occurred on June 30, 2023. Results Among 152 infused, the median age was 46 (range, 18-81), 57% were male, and 34% were Hispanic. Most (67%) had Ph- ALL, were heavily pre-treated (median 4 prior lines), and entered apheresis with high disease burden (57%). At time of apheresis, 23% of patients only had MRD+ disease and 15% were in complete molecular remission. While 82% developed CRS, the majority was grade 1-2, with 9% of the overall cohort experiencing grade 3-4 CRS. In contrast, 55% developed ICANS, with 32% of the entire cohort experiencing grade 3-4 ICANS. Eight patients (5%) died of toxicity/infection prior to D+28 response assessment. Among 133 patients with response assessment, 120 (90%) achieved morphologic CR, of whom 82% were MRD-, 15% were MRD+, and 3% MRD unknown. The median follow-up for survivors was 8.4 months; 45 patients have relapsed and 42 patients died. Median DOR was not reached. Median PFS and OS were 8.6 months and 15.6 months, respectively. Estimated PFS and OS of the entire cohort at 6-months were 61% (95% CI, 52-68) and 81% (95% CI, 73-87) and at 12-months were 47% (95% CI, 37-56) and 63% (95% CI, 53-72), respectively. We found no association between pre-CAR disease burden and post-CAR PFS/OS. However, patients with MRD- response to CAR had superior PFS relative to patients with MRD+ CR (median 14 months vs. 5 months, P=0.002). Forty-four patients received post-CAR consolidation/maintenance therapy while in CR: 25 allogeneic HCT, 15 TKI, 2 POMP, and 3 other/unknown. To examine the effect of consolidation/maintenance following brexu-cel, we performed a landmark analysis of PFS limited to patients alive and in CR at 2-months post-CAR infusion (N=113) and suggests superior PFS in patients receiving either HCT or other forms maintenance, relative to those receiving no further therapy following brexu-cel ( P=0.055). We then investigated post-CAR MRD-response in combination with receipt of post-CAR consolidation/maintenance and found that even among patients achieving MRD-negative response, post-CAR consolidation/maintenance led to superior PFS (Figure 1). Conclusions Among 152 adults treated with commercial brexu-cel for r/r B-ALL across 25 U.S. institutions, we found very high response rates (CR/CRi: 90%; 82% MRD-) consistent with the Zuma-3 data. While rates of severe CRS are low, grade 3-4 ICANS was observed in 32% of patients and warrants further investigation We demonstrate the prognostic impact of achieving an MRD-negative CR and an emerging role for consolidation/maintenance therapies to enhance the durability of response following brexu-cel in adults r/r B-ALL.

Introduction: Corticosteroids (CS) are the standard first-line treatment for patients (pts) with chronic graft-versus-host disease (cGvHD), but pts can be unresponsive or become refractory to or dependent on CS (SR/D).Ruxolitinib (RUX), a JAK1/2 inhibitor, is approved for the treatment of pts ≥12 years of age with SR/D-cGVHD, based on the primary outcomes from the randomized, phase III REACH3 (NCT03112603) study, which demonstrated the superior efficacy of RUX vs best available treatment (BAT) in pts with SR/D-cGVHD. Here, we present the final, long-term efficacy and safety outcomes from REACH3. Methods: Pts ≥12 years of age with moderate or severe SR/D-cGVHD were randomized 1:1 to receive either RUX 10 mg twice daily (BID) or investigator-selected BAT and followed for 3 years, till discontinuation or death. The primary analysis was conducted at week 24 (Cycle 7 Day 1 [C7D1]) in randomized pts, then pts entered the extension period (C7-39) in which they continued treatment, switched from BAT to RUX (crossover cohort), or discontinued treatment and entered long-term survival follow-up (FU). Failure-free survival (FFS; key secondary endpoint), duration of response (DOR), overall survival (OS), non-relapse mortality (NRM), malignancy relapse (MR), and safety were analyzed at 3 years (week 156; final data cut off 15 Dec 2022). Overall response rate (ORR) and best overall response (BOR) during the crossover treatment period were analyzed for pts who switched from BAT to RUX on or after C7D1. Results: Of 329 pts randomized, 53 completed the treatment period and 276 discontinued, 115 entered survival FU (RUX: 73/165; BAT:42/164); 70 pts crossed over from BAT to RUX of which 16 completed the crossover treatment period and 24 entered survival FU. Median FFS was longer in the RUX vs BAT arms (38.4 vs 5.7 months; hazard ratio [HR]=0.361, 95% confidence interval [CI]: 0.268, 0.485) with 12-month FFS probabilities of 64.0% (95% CI: 56.1, 70.8) and 28.8% (95% CI: 21.8, 36.1), respectively. Median OS was not reached and there was no difference in risk of death between the arms (HR=0.851, 95% CI: 0.544, 1.331) [Table 1]. Median DOR was 6.4 months (95% CI: 4.9, 11.4) in the BAT arm but was not reached for the RUX arm; notably, the probability of maintaining DOR at 3 years was higher in RUX (59.6%; 95% CI: 50.4, 67.6) vs BAT (26.7%; 95% CI: 18.5, 35.5). NRM event rates were similar between the arms (RUX: 29/165; BAT 34/164), and MR events were similar and low in both arms (13/156 and 11/160, RUX and BAT respectively) up to 3 years. The ORR at week 24 after crossover from BAT to RUX was 50.0% (95% CI: 37.8, 62.2), including complete response (CR) in 4 (5.7%) pts and partial response (PR) in 31 (44.3%) pts. The BOR during crossover was 81.4% (95% CI: 70.3, 89.7), including CR of 7.1% and PR of 74.3%; disease progression only occurred in 1 pt. Almost all pts treated during the main treatment period (RUX: 100%; BAT: 93.7%) experienced ≥1 adverse event (AE) and, in general, AE rates were higher in the RUX vs BAT arms [Table 2], likely due to prolonged FU and exposure to RUX (median exposure to treatment of 52.9 weeks vs. 24.1 weeks for RUX and BAT, respectively).Anemia was the most common AE (RUX: 33.9%; BAT: 15.8%) and grade ≥3 AE for RUX (17.6% vs BAT 9.5%, respectively); grade ≥3 neutropenia, thrombocytopenia, alanine aminotransferase increase, and gamma-glutamyltransferase increase were also ≥5% higher for RUX than BAT. Anemia (24.2%; grade ≥3, 10.3%) and thrombocytopenia (3.8%) were the most common RUX and BAT treatment-related AEs, respectively. Infections, excluding tuberculosis, were the most common AE of special interest (77.6% vs. 68.4%; grade ≥3, 31.5% and 26.6%, for RUX and BAT, respectively). On-treatment deaths were mainly due to cGvHD (n/N, RUX: 10/18; BAT 6/12). Conclusions: After 3 years of treatment in REACH3, the longer FFS and higher DOR with RUX vs BAT indicated that cGVHD was more in control with RUX treatment. Notably, efficacy was demonstrated in pts who switched from BAT to RUX with an ORR similar to that in pts randomized to RUX. RUX was well tolerated with no unexpected toxicities and safety that was consistent with earlier studies. Overall, the long-term control of cGVHD and tolerability of RUX was demonstrated for pts ≥12 years of age with SR/D-cGvHD.

Background Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR-T) cell therapy that recently received U.S. FDA approval as the first CAR-T cell therapy for adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Social determinants of health (SDoH) are shown to significantly influence outcomes in B-ALL. However, how SDoH relate to and affect outcomes in patients with B-ALL receiving CAR-T therapy has not been well established. We studied the impact of SDoH on outcomes of adults with B-ALL receiving brexu-cel as part of the Real-world Outcomes Collaborative of CAR-T in Adult ALL (ROCCA). Methods This retrospective multicenter analysis spanning 25 U.S centers included adults (≥18 years) with r/r B-ALL treated with commercial brexu-cel between 2021-2023. Progression-free survival (PFS) and overall survival (OS) were calculated from the day of brexu-cel infusion and were not censored for hematopoietic cell transplant (HCT) or maintenance. Univariate and multivariate Cox proportional hazards models were used to evaluate the association of age, sex, pre-apheresis disease burden, and SDoH (referral source, insurance, distance from home to CAR-T site, marital status, and the social deprivation index) with progression-free survival (PFS) and overall survival (OS). The social deprivation index (SDI), a composite measure (including income, education, employment, housing, household characteristics, and transportation) used to quantify socio-economic variation in health outcomes, with higher SDI indicating greater social disadvantage, was estimated at the zip code level. (Butler et al., 2013) Results Of the 152 patients who received brexu-cel (Table 1), 57% were male. 51% identified as non-Hispanic White, with the remainder identifying as Hispanic (34%), Asian/Pacific Islander (7%), Black (6%), American Indian/Alaskan Native (1%), or mixed race (1%). A majority (46%) were referred for brexu-cel from private/community-based practices and 62% lived within 50 miles of the CAR-T center (36% lived >50 miles and 2% were unknown). Health insurance coverage included primarily public (49%) and private (42%); no patients were uninsured. High SDI (76-100% percentile) was present in 26%, while 14% had a low SDI (0-25 th percentile). In unadjusted analyses, there was no difference in PFS or OS between patients with high versus low SDI; closer distance to the CAR-T site (<50 miles versus >50 miles)) was associated with worse OS (HR 1.96; 95% CI 1.00, 3.84; p=0.05). Multivariate analysis (Table 2) revealed that male sex was associated with inferior PFS (HR 1.98; 95% CI 1.02, 3.85; p=0.04) and OS (HR 2.52; 95% CI 1.09, 5.84; p=0.03). There was no difference in PFS (HR 0.95, 95% CI 0.48-1.88, p=0.88) or OS (HR 0.80; 95% CI 0.33,1.92; p=0.62) when comparing Hispanic and non-Hispanic White patients. Additionally, there was no difference in PFS or OS based on any SDoH, including insurance type, marital status, referral source, caregiver type, and distance to transplant center. Conclusions In patients receiving brexu-cel, survival outcomes appear independent of SDoH. Contrary to previous reports suggesting inferior outcomes for Hispanic patients with B-ALL after receiving traditional systemic therapies, we observed comparable outcomes to non-Hispanic patients treated with brexu-cel. Distance from the CAR-T site and referrals from the community did not affect outcomes. Additionally, those with higher SDI had similar outcomes to those with a lower SDI, although this analysis was limited by sample size and the selection bias that exists in being referred for brexu-cel in the first place. The relatively lower logistical burden of CAR-T compared to allogeneic stem cell transplant or non-fixed duration systemic therapies may have mitigated the impact of SDoH on outcomes. These real-world data suggest that continuing to improve access to and treatment with brexu-cel may improve overall outcomes for disadvantaged populations with r/r B-ALL.

Introduction: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is a CD19-directed bispecific T-cell engager that is also approved for r/r B-ALL, and often used as early salvage therapy. Data in the pediatric/AYA population suggest that patients who did not respond to blinatumomab may have inferior outcomes to CD19-directed CAR-T products compared to those who have achieved a response to blinatumomab or were blinatumomab-naïve (Myers et al. J Clin Oncol 2022). In this study, we evaluate the response to blinatumomab and subsequent response to brexu-cel in adults with r/r B-ALL. Methods: Retrospective data were collected from 25 centers across the U.S. as part of the real-world outcomes collaborative study of CAR-T in B-ALL (ROCCA). Consecutive patients treated with brexu-cel from 2021 to 2023 were categorized by blinatumomab exposure status. Those exposed were separated into “blinatumomab responders” (B-R), defined as patients achieving a CR/CRi in response to any number of cycles of blinatumomab, and “non-responders” (B-NR). Each cohort was compared for outcomes of interest. The primary outcome was CR/CRi rate at day 28 following brexu-cel administration. Secondary outcomes were duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Survival outcomes were calculated from day of brexu-cel infusion and were not censored for allogeneic hematopoietic cell transplantation or maintenance therapy. All living patients were censored at data cutoff on June 30, 2023. Survival comparisons were made by log rank test. Results: Among 152 patients who received brexu-cel, the median follow-up time was 8.4 months. Eighty-eight (57%) of 152 r/r B-ALL brexu-cel recipients had received blinatumomab prior to apheresis. The median number of pre-apheresis blinatumomab cycles was 2 (range 1-12). The baseline characteristics of B-R, B-NR, and blinatumomab-naïve (B-NV) patients were similar, including pre-apheresis disease burden and receipt of maintenance therapy following brexu-cel infusion (Table 1). Seventy percent (N= 62) of the blinatumomab-exposed patients were B-R, while 30% (N=26) were B-NR. Rates of CR/CRi at day 28 following brexu-cel infusion were similar between B-R, B-NR, and B-NV patients (79% vs 84% vs 78%, respectively). Most of these remissions were negative for measurable residual disease (MRD), with similar MRD negativity rates in the three groups (table 2). 1-year DOR and PFS were significantly higher in the B-NV group compared to B-R or B-NR (77% vs 49% vs 50%, p<.0001; 60% vs 37% vs 30%, p<.0001). B-NV and B-R had better 1-year survival compared to B-NR (71% vs 65% vs 32%, p<.0001). There were more CD19-negative relapses following brexu-cel in B-NR (29%) and B-R (18%) compared to B-NV patients (8%), although this was not statistically significant. Conclusions: Brexu-cel induced deep responses in a majority of adults with r/r B-ALL, irrespective of prior exposure or response to blinatumomab. Similar to data published by the pediatric CAR-T cell groups, our data draw speculation that adult patients who did not respond to blinatumomab experience shorter overall survival following brexu-cel compared to those who responded to or did not receive blinatumomab. This should be confirmed in a larger, prospective clinical trial. Because this analysis could not account for patients who achieved durable remission after blinatumomab, these differences may not reflect superiority of sequencing brexu-cel before blinatumomab. The higher number of CD19-negative relapses in the blinatumomab-exposed cohort add to the interest in pursuing strategies to address antigen escape following CAR-T cell therapy directed against a previously targeted antigen.

High dose chemotherapy followed by autologous hematopoietic cell transplantation (auto HCT) is a standard therapy for patients with plasma cell disorders (PCD). A barrier to improving candidate selection for auto HCT is appraisal of risk for transplant related complications. Electrocardiography (ECG) is a standard pre-HCT test to evaluate the potential for arrhythmia and structural heart disease. We hypothesized that an artificial intelligence (AI) based interpretation of ECG waveform data (AI-ECG) could enhance risk prediction for cardiac-specific and other outcomes following auto HCT for patients with PCD. To test this hypothesis, we used several AI-ECG tools developed using a deep-learning based approach that were trained to predict comorbidity (Attia et al, Lancet 2019 & Grogan et al, Mayo Clin Proc 2021). Model outputs include a scaled prediction value indicating increasing risk for atrial fibrillation/flutter (AF), reduced ejection fraction (EF), or cardiac amyloidosis. We evaluated this tool in 9,225 ECGs obtained from 849 patients (median 6 ECGs/patient, inter-quartile range: 3-12) who underwent first or subsequent auto HCT at Memorial Sloan Kettering Cancer Center between 2016-2022 and who had a diagnosis of multiple myeloma (N = 810), amyloidosis (N = 37), or other PCD (N = 2). The endpoints were to determine whether baseline AI-ECG prediction of AF risk correlated with peri-transplant AF events, and to explore whether model outputs correlated with survival and other cardiac clinical outcomes. The mean age of patients was 61.0 years (range 23.7 - 81.2) and median follow up was 2.7 years post auto HCT. Contributing cardiovascular risk factors included a prior history of AF (N = 101, 11.9%), coronary or cerebrovascular disease (N = 95, 11.2%), and diabetes mellitus (N = 98, 11.5%). Reduced dose melphalan (< 200 mg/m 2) was administered in 26%. The HCT-comorbidity index (HCT-CI) was high risk (≥3) in 52.7%. The one-year overall survival and progression-free survival in the whole cohort was 94% (95% confidence interval (95% CI): 92 - 95%) and 86% (84 - 89%), respectively. Among patients not in AF at pre HCT evaluation, the 90-day cumulative incidence of AF was 5.6% (4.2 - 7.3%). In univariable competing risk regression, baseline pre HCT AI-ECG appraisal of AF risk was strongly correlated with incidence AF in patients who were in sinus rhythm before HCT (hazard ratio (HR): 25.1, 95% CI: 11.7 - 53.7, p < 0.001). In a multivariable model adjusting for patient age and HCT-CI, AI-ECG AF predicted risk remained associated with incidence of post HCT AF (HR: 13.4, 95% CI: 5.9 - 30.4, p < 0.001). Considering a decision threshold identified during original model training, AI-ECG predicted AF events with an accuracy of 75% (Mcnemar's p < 2 x 10 -16). The precision, recall, and F1-score were 0.94, 0.77, and 0.85, respectively. AI-ECG predicted age correlated highly with actual patient age (Spearman rho = 0.59, p < 2 x 10 -16). Amyloid risk scores were highly correlated with a known clinical history of amyloidosis (median 0.45 versus 0.05, Wilcoxon rank-sum p < 0.001). Patients with EF < 50% had greater prediction scores for cardiomyopathy compared to patients with normal EF (median 0.23 versus 0.01, Wilcoxon rank-sum p <0.001). In univariable analysis, increasing AI-ECG predicted age (HR 1.02, CI: 1.003 - 1.04, p = 0.02) and predicted AF risk score (HR: 3.2, CI: 1.4 - 7.2, p = 0.006) were associated with risk for death, whereas predicted amyloid score and predicted low EF were not associated with decreased survival. In multivariable analysis of all patients that considered patient age, hematopoietic comorbidity index, and remission status at HCT, increasing predicted AF score trended towards association with increased risk for death (HR: 2.3, 95%CI: 1.0 - 5.5, p = 0.059). Predicted AF score correlated highly with the HCT-CI and patient age. Finally, we examined whether risk prediction for low EF correlated with peri-HCT fluid overload (FO) defined by absolute weight gain. The incidence of ≥ 10% weight gain (grade 2 FO) and ≥ 20% weight gain (grade 3 FO) at 180 days post HCT was 7.4% (95% CI: 5.8%, 9.3%) and 1.0% (95% CI: 0.5%, 1.8%), respectively. Predicted low EF was not associated with development of either grade 2 or grade 3 FO in this population. In summary, AI-ECG predicts episodes of AF in patients undergoing auto HCT for PCD and may augment transplant risk appraisal when considered in conjunction with other measures of comorbidity.

Background The class of CD20×CD3 bispecific antibodies (BsAbs) has emerged as an important anti-lymphoma modality for patients (pts) with R/R B-cell non-Hodgkin lymphoma. Odronextamab, a novel, off-the-shelf, CD20×CD3 BsAb, has previously demonstrated compelling efficacy in both R/R diffuse large B-cell lymphoma and R/R FL. In pts with R/R FL, odronextamab monotherapy achieved 75% complete response (CR) rates and encouraging durability of responses, and showed generally manageable safety, in the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. ASH. 2022). Here, we report the results of a second, pre-specified interim analysis of ELM-2. Methods Intravenous odronextamab was administered weekly in 21-day cycles during Cycles (C) 1-4. Optimization of the step-up regimen to further mitigate cytokine release syndrome (CRS) was reported previously (Kim TM, et al. ASH. 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1, followed by 80 mg on Days 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 160 mg every 2 weeks until disease progression or unacceptable toxicity. Pts who achieved a durable CR for ≥9 months transitioned to dosing every 4 weeks. A pre-specified interim analysis was performed when 80 pts had completed ≥12 months follow-up. The primary endpoint was objective response rate (ORR), assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included CR rate, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and changes in scores of patient-reported outcomes. Minimal residual disease (MRD) was included as an exploratory endpoint. Results At data cut off (Jan 31, 2023), the global study was fully enrolled and included 140 safety-evaluable pts with FL; 128 pts were efficacy-evaluable and 85 pts had ≥12 months follow-up. The median duration of study follow-up for efficacy was 26.6 months. In the safety-evaluable FL population, median age was 60.5 years (range 22-84), 53% were male, and pts had received a median of 3 (range 2-13) prior lines of therapy. 73% of pts were refractory to their last therapy, 41% were double refractory, and 74% were refractory to an anti-CD20 antibody. 50% of pts had progression of disease within 2 years (POD24) and 29% had a prior autologous hematopoietic stem cell transplant. ORR and CR rate by ICR were 80% (102/128) and 72% (92/128), respectively, and were consistent across pts with high-risk features. Responses were durable, with both median DoR and duration of CR of 21.7 months; the probability of maintaining CR for 24 months was 48%. Median PFS was 20.7 months (95% CI: 16.7-26.5) and median OS was not reached; the probability of survival at 3 years was 63%. Patient-reported overall quality of life (QoL) scores were maintained during the course of treatment. MRD status at 12 weeks was highly predictive of PFS. Safety was generally consistent with previous reports, and no new treatment-related Grade (Gr) 5 events were recorded since the first interim analysis. The most common treatment-emergent AEs (>30% all grades) were CRS (55%), anemia (34%), neutropenia (34%), and pyrexia (33%). With the optimized 0.7/4/20 mg step-up regimen (n=72), 98% of CRS events were Gr 1/2, and only one pt had Gr 3 CRS. All CRS events resolved with supportive measures; 13 pts received tocilizumab for CRS management with the optimized regimen. Only one low-grade ICANS event was reported with the optimized regimen. Gr ≥3 infections occurred in 50 (36%) pts (Gr 5, n=14 [10%]); COVID-19 infections were reported in 46 (35%) pts (Gr 5, n=8 [6%]). Conclusions The results of this pre-specified analysis of the Phase 2 ELM-2 study continue to demonstrate deep and durable responses with odronextamab in heavily pretreated, refractory pts with R/R FL. 90% of responders were complete responders, with a 48% probability of maintaining CR for 2 years. High CR rates appear to translate to favorable, long-term survival outcomes in the setting of incurable disease. The incidence of AEs was consistent with earlier reports, with no new treatment-related Gr 5 events. Importantly, continued treatment with odronextamab had no detrimental effects on overall QoL. These data underscore the promise of odronextamab as a potentially effective agent for the management of R/R FL. Updated data will be presented.