The success of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has driven efforts to optimize partner therapies that balance GVHD and relapse prevention. We report phase I dose-finding results of PTCy, sirolimus (SIR), and VIC-1911, a selective oral Aurora kinase A (AURKA) inhibitor, following myeloablative allogeneic hematopoietic cell transplantation (alloHCT). Results from murine and in vitro studies informed the development of the novel drug combination. In the phase I trial (NCT05120570), patients aged 18-60 years received myeloablative conditioning, followed by, PTCy (50 mg/kg, days +3/+4), SIR (from day +5, target 8-12 ng/ml), and VIC-1911 (25, 50, or 75 mg BID, days +5 to +45). The primary endpoint was achieving <54% pH3ser10 expression in CD4+ T cells by day +21. Preclinical models show that combining SIR with AURKA inhibition suppresses signaling downstream of CD28, enhancing GVHD prevention while leveraging the anti-leukemia activity of AURKA inhibition. In the phase I trial, the optimal VIC-1911 dose achieving target pathway inhibition without dose-limiting toxicities was 75 mg BID. Clinical outcomes included no grade III-IV acute GVHD through day 180 (0%) and low rates of moderate/severe chronic GVHD (6%) and relapse (0%) through 1 year (5/16 received maintenance). The 1-year overall survival for this cohort was 94%.VIC-1911 at 75 mg BID, combined with PTCy and SIR, effectively suppresses AURKA activity, offering promising GVHD and relapse prevention with a favorable safety profile and promising early clinical outcomes.

We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD]neg) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel-treated patients achieving MRDneg. Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRDneg. ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRDneg remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.

Late cytopenia (beyond day+30 post-CAR T-cell) is a significant complication following CD19-directed chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). However, available data remain limited and heterogeneous. In this retrospective multicenter study, we evaluated the incidence, patterns, risk factors, and impact of late cytopenia in patients treated with CD19 CAR T-cells. A total of 444 patients with R/R LBCL at eight academic centers within the Cell Therapy Consortium between April 2016 and May 2023 were included. After excluding patients with events (relapse, new treatment, death) or lost to follow-up, grade ≥3 cytopenias were observed in 47%, 34%, 19%, 21%, and 11% of patients with available data at 1, 2, 3, 6, and 12 months post-infusion. Among 307 patients with complete hematologic data, neutropenia consistent with late immune effector cell-associated hematotoxicity was identified in 103 patients (33.6%) between days 30 and 100. Multivariable analysis identified a high CAR-HAEMATOTOX score (≥2) as a predictor of cytopenia at 3 months whereas receipt of bridging systemic chemotherapy and axicabtagene ciloleucel was associated with cytopenia at 6 months post-CAR T-cell. The presence of late cytopenia was associated with a higher 1-year non-relapse mortality (11% vs 4.4%, P=0.038), worse 2-year progression-free survival (38% vs 67%, P=0.035) and worse 2-year overall survival (60% vs 76%, P=0.016). In conclusion, late cytopenia is a common and clinically meaningful toxicity after CD19 CAR T-cell therapy. Recognition of risk factors and consistent monitoring are essential for optimizing post-CAR T-cell care and reducing treatment-related mortality.

ABSTRACT:The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T-cell (CAR-T) therapy is not well established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017 to 2020 were selected from the Center for International Blood and Marrow Transplant Research registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91 years). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37 [95% confidence interval [CI], 1.16-1.62; P < .001]; CT-CI 2: HR, 1.49 [95% CI, 1.17-1.89; P = .001]; CT-CI ≥ 3: HR, 2.55 [95% CI, 1.90-3.42; P< .001]). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T-related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.

ABSTRACT:The use of chimeric antigen receptor (CAR) T-cell therapy is increasing for adult B-cell acute lymphoblastic leukemia (B-ALL), with 3 CD19 CAR T-cell products commercially available. Several key clinical questions related to best practices for CAR T-cell administration in this population exist, and limited prospective randomized trials have been conducted to fill these knowledge gaps. Thus, to help guide clinical practice, we conducted a modified Delphi study to develop and validate consensus recommendations on the administration of commercially available CAR T-cell therapy for adults with B-ALL. Consensus panelists (n = 9) included principal investigators (PIs) from Real World Outcomes Collaborative of CAR T-Cell Therapy in Adult ALL (ROCCA) consortium sites and were selected based on expertise and CAR T-cell center volume. Final panel consensus recommendations were distributed for rating by the remaining PIs from ROCCA consortium sites, which served as the validation group (n = 27). Consensus topics included patient selection, bridging and pre-CAR T-cell leukemia staging, lymphodepletion, and CAR T-cell treatment setting, specific toxicity prevention and management, post-CAR T-cell response assessment and disease monitoring, and the role of consolidation and/or maintenance therapies after CAR T-cell therapy. Initially, 58 recommendation statements were evaluated for consensus. After 2 panel meetings, a total of 34 statements achieved consensus rating among the expert panel. After rating by the validation group, all but 1 recommendation statement continued to meet consensus, for a total of 33 consensus recommendation statements on the administration of CAR T-cell therapy in adult B-ALL.

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.

Introduction Tisagenlecleucel (tisa-cel), a CD19-directed CAR T-cell therapy, has transformed treatment in children with relapsed/refractory B-cell acute lymphoblastic leukemia. Over 80% achieve complete remission, however 40–50% relapse within a year. Lymphodepleting chemotherapy (LD) with fludarabine (FLU) and cyclophosphamide (Cy) enhances CAR-T expansion and persistence. Prior studies highlight the importance of minimum FLU exposure. Substantial interpatient variability exists in FLU pharmacokinetics (PK) with body surface area dosing in children. A priori PK modeling predicts FLU exposure from patient-specific variables. We hypothesized that model-predicted FLU area-under-the-curve (AUC, mg·hr/L) would affect outcomes in pediatric tisa-cel recipients and aimed to identify optimal exposure targets. Methods This retrospective single center cohort study included pediatric tisa-cel recipients on standard LD (FLU + Cy) between November 2017 - October 2024 at the University of Minnesota. All patients received FLU 30 mg/m²/day for 4 days. Individual FLU AUCs were retrospectively calculated using a validated population PK model via Bayesian estimation (Brooks, 2022). Outcomes included 1- year overall survival (OS), relapse-free survival (RFS), and relapse-free, loss of B-cell aplasia (LBCA)-free survival. The cumulative incidence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) was evaluated at Day 100. Disease burden immediately prior to LD and infusion was defined as High (>5%), Low (<5%), or Negative as measured by flow cytometry. Recursive partitioning (RPART) identified optimal AUC cutoffs for RFS. Survival outcomes and toxicity incidence were analyzed using Kaplan-Meier, cumulative incidence functions with competing risks, and Fine and Gray regression. Group comparisons used Wilcoxon rank-sum and chi-square tests. Results 34 patients were included, median age 14.4 years (range 1.2–24.4) and median weight 50.0 kg (range 9.8–97.3). RPART identified three FLU AUC groups: LOW (< 18.5 mg·hr/L, n=8), OPTIMAL (18.5–21.7, n=11), and HIGH (≥ 21.7, n=15). Age, weight and disease burden were similar across FLU AUC groups. Outcomes and toxicity are in Table 1 and Figure 1. In multivariate analysis controlling for disease burden, hazard ratio (HR) for RFS in the OPTIMAL cohort was 0.16 (95% CI:0.03-0.83), HIGH 0.42 (0.13-1.34), relative to LOW at 1.00 (p=0.07). HR for 1-year relapse in OPTIMAL was 0.15 (0.03-0.73), HIGH 0.29 (0.09-0.90), relative to LOW 1.00 (p=0.02). Figure 2 depicts HR for relapse/death by FLU AUC. Conclusions Model-predicted FLU AUC correlates with key outcomes in children treated with tisa-cel. These findings support the utility of model-informed target AUCs to guide personalized FLU dosing which may offer a feasible, impactful approach to enhance long-term CAR T-cell efficacy in children.

Introduction Levofloxacin (Levaquin, LQ) is the first line agent for bacterial infection prophylaxis during hematopoietic cell transplant (HCT)-related pre-engraftment neutropenia. However, due to side effect concerns and the desire to use a minimum effective dose, our center shifted from 500 mg (Standard Dose, SD) to 250 mg (Low Dose, LD) daily in mid-2013. Objectives To compare clinical outcomes and safety of a reduced-dose LQ protocol (250 mg) against the national guideline of 500 mg. Methods Retrospective cohort study of HCT recipients at the University of Minnesota transplanted between July 1, 2002, to June 30, 2024. Patients (pts) were excluded for syngeneic HCT (8), non-standard conditioning regimens (56), or a LQ allergy listed in the electronic medical record at the time of HCT (70). For pts transplanted from 2002-2011, the intent was to receive SD (unaudited). For pts transplanted 2012- 2024 who received at least 1 pre-engraftment dose of LQ, through Informatics Technology and chart audits (17% of the cohort), we assigned pts to LD or SD categories. Pts who received 250 mg as a renal adjustment from 500 mg were assigned to SD. Pediatric (peds) pts receiving 5-10 mg/kg q24hour were assigned LD and q12hour SD. LQ orders cancelled prior to the day-1 start (treatment for neutropenic fever, treatment of known infection, QTc prolongation, Clostridioides difficile (C diff) history, or a non-allergy symptom issue) were grouped as No LQ use. Results Of 5135 HCTs, 3093 were unique pts undergoing first allogeneic (allo) (36% pediatric) (fig. 1), 1719 were unique first autologous (auto) (7% pediatric), and 323 were second or more HCT. Median days to engraftment after alloHCT was 15 (range, 0-42) for both adult and peds pts. One-year survival was better for adult (78% vs 64%, p<0.0001, fig. 2) and peds (90% vs 82%, p = 0.0310, fig. 3) alloHCT recipients (2012-2024) receiving LD vs SD. However, LD pts were transplanted in later years with fewer cord blood HCT (adult 18% LD vs 39% SD, peds 36% vs 44%), less myeloablative conditioning (adult 41% vs 46%, peds 80% vs 83%), more PTCy-based GVHD prophylaxis (adult 42% vs 7%), and more non-malignant disease (peds 75% vs 60%). No LQ use had 69% survival. From 2002 to 2011, the 500 mg LQ group had a 1-year survival of 59% for adults and 76% for peds pts. One-year survival for autoHCT was 96% (LD), 93% (SD), 95% (No use), and 88% (2002-2011, Intent to use SD). Descriptive analysis of non-first HCT is planned. Conclusion One-year survival for LD vs SD groups will require adjusted analysis for potential confounders, e.g., examining cohorts matched for stem cell source and non-relapse mortality. We will compare rates of prophylaxis failure, defined as the incidence and time to first positive blood cultures and number of blood cultures drawn after day 0 until engraftment and day+100, resistance profiles of breakthrough organisms, C diff infections, and other clinical parameters.

Background Tisagenlecleucel (tisa-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy that provides meaningful responses and survival for children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Although more than 80% of those treated achieve complete remission, lack of CAR-T cell persistence remains a concern, and 40-50% experience relapse within a year. Lymphodepleting chemotherapy (LD) with fludarabine (FLU) and cyclophosphamide (Cy) is essential for CAR-T expansion and persistence. In children, FLU pharmacokinetic (PK) variability occurs using conventional body-surface–area–based dosing. Population pharmacokinetic (popPK) modeling enables individualized prediction of FLU exposure using patient-specific characteristics and administered FLU dosing information. Objective We hypothesized that popPK-model-predicted FLU cumulative area under the curve (cAUC; mg·hr/L) would be associated with clinical outcomes after tisa-cel infusion in pediatric and AYA recipients. We sought to characterize exposure-response relationships and identify FLU exposure ranges associated with improved clinical outcomes. Study Design We conducted a retrospective, single-center cohort study of pediatric patients receiving standard LD (FLU + Cy) before tisa-cel between November 2017 and October 2024 at the University of Minnesota. Patients were administered FLU at a dose of 30 mg/m2 intravenous daily for four days per institutional standard of care. Individual FLU cAUC values were retrospectively calculated using a validated popPK model implemented through Bayesian estimation. Outcomes included 1-year relapse-free survival (RFS), overall survival (OS), and relapse-free, loss-of-B-cell-aplasia (LBCA)–free survival. Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were assessed through Day 100. Pre-LD disease burden was categorized as high (>5%), low (<5%), or negative by flow cytometry. Hazard Ratio (HR) function-derived exposure threshold analysis was used to identify FLU cAUC cutoffs for 1-year RFS. Survival and toxicity analyses employed Kaplan–Meier estimates, cumulative incidence with competing risks, and Fine-Gray regression. Group comparisons used Wilcoxon rank-sum and chi-square tests. Results Thirty-four patients were included (median age 14.4 years, range 1.2–24.4; median weight 50.0 kg, range 9.8–97.3). HR function-derived exposure threshold analysis identified three FLU exposure groups: LOW (<18.5 mg·hr/L, n=8), OPTIMAL (18.5–21.7, n=11), and HIGH (≥21.7, n=15). Age, weight, and disease burden distributions were similar across exposure groups.In univariate analysis (UVA), 1-year RFS differed significantly by FLU exposure group, with rates of 25% (95% CI, 4–56%) in LOW, 81% (95% CI, 42–95%) in OPTIMAL, and 60% (95% CI, 32–80%) in HIGH exposure groups (p = 0.04). In multivariable analysis adjusted for disease burden, patients in the OPTIMAL and HIGH exposure groups demonstrated a trended towards improved 1-year RFS compared to LOW exposure group (HR 0.16 (95% CI 0.03–0.83) and 0.42 (0.13–1.34); p=0.07)). Patients with low or negative disease burden had significantly better 1-year OS (90%, 95% CI, 65–98%) compared with those with high burden (55%, 95% CI, 26–76%; p < 0.01). Conclusion Lower model-predicted FLU exposure was associated with inferior relapse-related outcomes following tisa-cel infusion in pediatric and AYA patients. These findings support further evaluation of popPK-guided model-based dosing strategies to individualize FLU dosing and avoid underexposure during LD as a practical approach to improving long-term CAR-T effectiveness.

e23264 Background: While chimeric antigen receptor T-cell therapy (CAR-T) is remarkably efficacious in achieving remissions, limited prospective data exists on financial toxicity (FT) during therapy. We report interim results from an ongoing prospective study at the University of Minnesota investigating FT and out-of-pocket (OOP) costs in adult commercial CAR-T recipients. Methods: Patients completed a survey before apheresis (baseline), D+30, and D+90 post CAR-T assessing self-reported sociodemographic factors, OOP costs, and FT. FT was measured by the validated Comprehensive Score for Financial Toxicity (COST) score and defined as COST score < 26. Results: From 01/2025 to 01/2026, 116 pts were screened and 50 enrolled. Out of 25 pts who completed the study, the median age was 69 (39-87) and 18 (72%) were retired. One had acute lymphoblastic leukemia, 13 had multiple myeloma, and 11 had lymphoma. Ten (40%) were females. One had Medicaid, 16 had Medicare, and 8 had commercial insurance. Twelve (48%) had a bachelor’s degree or higher, and 17 (77%) had an annual income > 65,000. At baseline, D+30, and D+90, 7 (28%), 8 (33.3%), and 7 (31.8%) pts reported FT (COST score < 26), respectively. One and 3 COST scores were missing at D+30 and D+90, respectively, due to loss to follow-up or death. Baseline COST scores were used to define FT groups using an optimal cutoff identified by classification tree analysis ( < 33 vs. ≥33). Patients with baseline COST scores ≥33 had higher odds of improved or stable FT status at D+90 compared to those with baseline scores < 33 (odds ratio [OR] = 12.6, 95% CI 1.19–133.8). Change in COST score from baseline to D+90 (ΔCOST) differed by baseline group. Among pts with baseline scores < 33 (n = 8), the mean change was 4.25 (SD 3.33), with a median of 4.5 (IQR 3, 6.5). In contrast, pts with baseline scores ≥33 (n = 14) had a mean change of –0.19 (SD 7.44), with a median of –2.65 (IQR –5.5, 5.5). This difference in ΔCOST between the two groups was marginally statistically significant based on the Wilcoxon rank-sum test (p = 0.091). Among those with baseline COST score < 33, median age was 68, average income was 144K, 10 (71%) had Medicare, and 8 (57%) had a complete response (CR). Among those with baseline scores >33, median age was 68, average income was 222K, 5 (62%) had Medicare, and 8 (100%) achieved a CR. Median cumulative OOP cost at D+90 was $610 (IQR: $247.5–$2280). Largest OOP costs by category were living accommodations (33.8%), medications (27.1%), doctors/hospital visits (19.9%), travel/parking (9.6%), and other costs (9.6%). Conclusions: In our cohort of predominantly well-insured, high-earning, and educated pts, 28% experienced FT throughout the first 3 months, highlighting short-term FT as a challenge in a subset of pts after CAR-T. Those with baseline COST score >33 had 12.6-fold higher odds of being improved/stable at D+90 compared with those with scores < 33. This cutoff may help to identify low vs. high-risk patients who may benefit from financial navigation.

Background The most common strategy to enhance the expansion of CAR-T products is to induce lymphodepletion with low dose fludarabine and cyclophosphamide. E7777 is a recombinant fusion toxin consisting of full-length human IL-2 fused to the catalytic domains of diphtheria toxin which preferentially binds and is internalized by cells expressing the high affinity IL-2 receptor. Regulatory T cells (Tregs) constitutively express the IL-2 receptor, whereas other T cells do so transiently, upon activation. Increased Tregs levels in DLBCL patients can limit the therapeutic function of CAR-T cell therapy. Thus, transiently depleting Tregs with E7777 could help enhance CAR-T responses. We designed a trial to augment lymphodepletion of Tregs prior to CAR-T cells by the administration of E7777. Methods A phase I portion determined the maximum tolerated dose (MTD) of denileukin diftitox E7777 before commercial CAR-T19 for patients with relapsed/refractory DLBCL at high-risk of CAR-T failure. Patients received E7777 once on day -7 and we measured PB Treg at baseline and on day -6. Three dose levels (5 (n=2), 7 (n=2) and 9 μg/kg/day (n=10) were evaluated. Fludarabine/cyclophosphamide lymphodepleting chemotherapy was administered on days -5,-4,-3. An extension component estimated efficacy of E7777 at the MTD. Results We enrolled 14 patients into a single arm Phase 1 dose escalation trial at University of Minnesota and City of Hope. The median age was 66 yrs (range 27-80); 71% were female and all had high risk features including primary refractory disease (50%), extranodal disease (36%) or high ≥3 IPI (42%). Axi-cel (n=5), liso-cel (n=5) and tisa-cel (n=4) were infused at day 0. All patients completed treatment and were evaluable. E7777 attributable toxicities included grade 1,2 capillary leak syndrome (n=3), gr 1 fever (n=1), gr 1 AST/ALT elevation (n=2). Grade 3 toxicities were limited to low lymphocyte, neutrophil and platelet counts (n=3). There were no DLTs observed up to MTD at 9 μg/kg/day. CRS occurred in 43% of patients (all were gr 1/2). ICANS occurred in 3 patients (21%) with gr 1 (2 pts) and 4 (1 pt). The overall response rate at 1 month was 86% (57% CR, 29% PR) The 1-year progression-free survival was 77% (95%CI 43-92%) and 1-year overall survival was 84% (95%CI 49-96%). A single E7777 dose resulted in a transient decrease in blood Tregs in all except one patient, with delta (baseline to post E7777 on day -6) ranging between 3.5% to 0.25% or depletion of median 24 Tregs/μL (range 8-65). Treg nadir occurred at day +1. The clinical outcomes and CAR-T and Treg subset pharmacodynamics will be compared to standard CAR-T matched controls. Conclusions Trial results demonstrate safety and promising efficacy of enhancing standard lymphodepletion with T-cell targeting immunotoxin E7777 (denileukin diftitox-cxdl, LYMPHIRTM). Future strategies to optimize E7777 given prior to CAR-T cell infusion will be discussed.

In this real-world, large, observational study from the Center for International Blood and Marrow Transplant Research (CIBMTR), we examined the association between pre-transplant measurable residual disease (MRD) detected by multiparameter flow cytometry (MFC) test results and outcomes after allogeneic hematopoietic cell transplantation (alloHCT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1). We included 2,544 patients who underwent transplant during 2013-2019; 11% had detectable MRD prior to alloHCT. Patients’ median age was 58 years. Among MRD-negative and MRD-positive groups, 48% vs 52% received myeloablative conditioning, and 37% vs 29% had matched unrelated donors, respectively. The 1-year cumulative incidence of relapse was 35% in the MRD-positive group and 25% in the MRD-negative group (P < .001). MRD positivity was associated with inferior overall survival (hazard ratio [HR], 1.27; 95% CI, 1.06-1.51; P = .009) and disease-free survival (HR, 1.31; 95% CI, 1.11-1.53; P = .001), and increased relapse risk (HR, 1.42; 95% CI, 1.17-1.72; P < .001), but not with non-relapse mortality. Notably, patients with pre-alloHCT MRD negativity remained at high risk of relapse, underscoring the limited prognostic utility of registryreported MFC-MRD testing due to variability in methods and thresholds. Survival analyses across the 12 largest centers demonstrated substantial variability in the prognostic impact of MRD. These findings underscore that although pre-alloHCT MRD by MFC remains a clinically relevant prognostic biomarker, its reliability is contingent upon methodological standardization across centers. These findings highlight the need for standardized MRD assessment to improve risk stratification in AML.

Abstract: Brexucabtagene autoleucel (brexu-cel) is an autologous chimeric antigen receptor T-cell (CAR-T) therapy directed at CD19 that is approved for use in adults with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Pivotal trial data and real-world experience (RWE) studies show high response rates, but also relatively high rates of grade 3+ cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). In this RWE study, we sought to better characterize the toxicity profile of brexu-cel in adult patients with R/R B-ALL. To that end, we examined outcome data from our RWE database including 292 adult patients treated with brexu-cel between October 2021 and June 2024. We found numerically comparable levels of grade 3+ ICANS (28.8%) to those reported in the pivotal ZUMA-3 study, but numerically lower rates of grade 3+ CRS (9.8%). Other clinically-relevant findings included 20.5% of patients requiring intensive care unit–level care, and a rate of death by day +28 after CAR-T of 5.2%. The hazard ratio for death among patients with vs without grade 3+ CRS was 2.24 (95% confidence interval [CI], 1.27-3.94; P = .005). Compared with patients without prior allogeneic hematopoietic cell transplantation (HCT), the odds of grade 3+ CRS for those with prior HCT was 0.35 (95% CI, 0.14-0.89; P = .03). Although brexu-cel had high response rates in both the trial setting and RWE, our data suggest that severe toxicities (particularly ICANS) remain a distinct challenge with this product. Careful attention to patient selection for brexu-cel is warranted, particularly as new CAR-T agents become available in this disease space.

Background Reduced-intensity conditioning (RIC) regimens have expanded allogeneic hematopoietic cell transplantation (AHCT) for older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Prior single center study suggests improved outcomes with the fludarabine and melphalan 100 mg/m2 (FM100) regimen over more intensive ones. (Ciurea S et al. Blood 2020) However, the optimal regimen remains unclear. We analyzed a large national registry to compare outcomes of 5 commonly used RIC regimens in older AML/MDS patients. Methods The study analyzed data of AML/MDS patients aged >/= 50 who underwent their first AHCT between 2013 and 2022, reported to the CIBMTR. All patients received 1 of 5 fludarabine-based RIC/NMA regimens: fludarabine with 2 days of busulfan (FB2), fludarabine/melphalan 100 mg/m² (FM100) or 140 mg/m² (FM140), fludarabine/cyclophosphamide/2 gy TBI (FCT), or fludarabine/2 gy TBI (FT). Patients who received haploidentical transplants or ex vivo T cell-depleted grafts were excluded from the analysis. Results A total of 11,731 patients were analyzed, including FB2 (n=4,571), FM100 (n=1,666), FM140 (n=4,242), FCT (n=786), and FT (n=466). Donor types included MSD (27%), MUD (60%), MMUD (7%), other related donors (2%).The adjusted 5-year OS probability of patients in FB2, FM100, FM140, FCT and FT group were 40.4%, 42.4%, 46.0%, 38.6% and 30.5%, respectively (p <0.0001). (Figure 1).In multivariable analysis (MVA) using PS-IPW with FB2 as reference, FM140, FCT, and FT showed inferior early (=6 months) OS (p=0.036). In the late period (>6 months), FM100 (HR=0.79, p=0.0005) and FM140 (HR=0.77, p<0.0001) were linked to superior OS than FB2. Both FM regimens also outperformed FCT and FT (p<0.0001). OS was similar between FM100 and FM140 in the late period.For disease-free survival (DFS), stratification by transplant period showed that in the most recent period (2019-2022), FM100 (HR 0.67, p < 0.0001), FM140 (HR 0.76, p < 0.0001), and FCT (HR 0.83, p = 0.002) were associated with improved DFS compared to FB2. Superior DFS was noted in the FM100 group compared to FCT (p=0.002) and FT (p=0.007), while other pairwise comparisons showed no difference. Similar trends were also observed in the MVA for GRFS, with FM100 and FM140 associated with improved late GRFS compared to other regimens.The survival benefit of FM regimens was driven by significantly lower relapse rates compared to the other regimens (P<0.0001), with no significant difference in relapse rates between FM100 and FM140. Although early non-relapse mortality (NRM) was higher with FM regimens, they did not significantly affect NRM beyond 6 months post-transplant. Conclusion In the largest analysis to date of RIC regimens for older patients, we show that, despite higher early NRM, FM regimens result in lower relapse rates and improved long-term survival in older AML/MDS patients undergoing AHCT.

Introduction and Objective Pathogenic or likely pathogenic germline variants (PGVs) occur in ∼10% of myelodysplastic syndrome (MDS) patients as well as in related and unrelated donors. The impact of PGVs in donors (D) and/or recipients (R) on post-allogeneic hematopoietic cell transplantation (HCT) outcomes is unknown. We evaluated post-HCT outcomes in MDS patients where the R and/or D had PGVs. Methods Paired D/R peripheral blood samples from MDS patients undergoing HCT were subjected to whole exome or genome sequencing (30–40x) in two CIBMTR-sponsored studies. Variants in hematologic cancer predisposition genes were quality-filtered and retained if gnomAD allele frequency (AF) ≤0.005 (or ≤0.05 for high-AF genes CHEK2, DDX41). Likely germline classification was based on multiple-criteria decision analysis and/or somatic frequency in COSMIC. ACMG/AMP pathogenicity was manually curated. Outcomes analysis included Fine-Gray competing risk or Cox PH, with multivariable modeling for significant variables. Results In the first cohort (n=404), 13.9% (56/404) of R had PGVs, most commonly DDX41 (1.5%, 6/404), GATA2 (1.2%, 5/404), and SBDS (bi-allelic 0.7%, 3/404; mono-allelic 0.2%, 1/404). All were related D and 9.4% (38/404) had PGVs, most commonly SBDS (bi-allelic 0.5%, 2/404; mono-allelic 0.5%, 2/404), BRCA2 (0.7%, 3/404), and BRIP1 0.7%, 3/404). In the second cohort (N=494), 15.2% (75/494) of R had PGVs, most commonly DDX41 (3.0%, 15/494), RUNX1 (2.6%, 13/494), and CHEK2/BRCA2 (both 1.2%, 6/494). PGVs were seen in 5.2% (5/97) of related D and 4.0% (16/397) of unrelated D, most commonly CHEK2 (0.8%, 4/494), BRCA2 (0.8%, 4/494), and BRCA1 (0.4%, 2/494).Amongst patients in the outcomes cohort (N=842), PGVs were seen in neither donors nor recipients (D-/R-) in 83.8% (706/842), donors only (D+/R-) in 1.8% (15/842), recipients only (D-/R+) in 9.9% (83/842), and both donors and recipients (D+/R+) in 4.5% (38/842). Baseline features are in Table 1. Median age at HCT for D-/R- was 64.5 yrs vs. D+/R+ at 58.1 yrs. The D type was related for D-/R- in 54.7% (386/706) vs. D+/R+ in 92.1% (35/38).Post-HCT outcomes are in Table 2. No differences were seen in cumulative incidence (CI) of primary graft failure (few events) or post-HCT relapse. CI of non-relapse mortality was lower for PGV D+/R+ (hazard ratio (HR) 0.34, p=0.029); this was not significant after covariate adjustment (HR 0.42, p=0.11). There was a significant effect for disease-free survival (DFS) in PGV R+ (HR 0.76, p=0.037), which was robust to covariate adjustment (HR 0.71, p=0.013), and a trend for D+/R+ (HR 0.65, p=0.056). There was no effect on overall survival. Discussion Although PGVs are seen in >5% of donors, their impact on post-HCT outcomes is complex. We found an effect for R+ status on DFS and a trend for D+/R+ status, although unexpectedly in a protective direction. The risk conferred by D/R PGV status is heterogeneous and likely gene specific.

Introduction Pivotal trials that led to the approval of autologous anti-CD19 CAR T-cell therapy (CART) either excluded patients with prior CD19-directed therapy or required CD19 expression. Therefore, the activity of anti-CD19 CART in patients with CD19-negative lymphoma remains unknown. While due to practice heterogeneity and technical sensitivity, accurate detection of CD19 expression by immunohistochemistry (IHC) or flow cytometry may be limited, these are the only two assays clinically available. As CD19-negative large B-cell lymphoma (LBCL) cases are becoming increasingly frequent, we present the first retrospective multi-center real world experience using CART in patients with CD19-negative LBCL. Method Retrospective data from the Cell Therapy Consortium were utilized for this analysis. LBCL patients treated with autologous anti-CD19 CART in second line and beyond between April 2016 and June 2021, and with available CD19 expression status by either IHC or flow cytometry, were included in this study. Patients who had received prior CD19-directed therapy were excluded. Baseline characteristics prior to the initiation of lymphodepleting chemotherapy were collected. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy guidelines, and response was assessed by investigator according to the Lugano 2014 criteria. Chi-square test or Fisher's exact test was used to evaluate the association between baseline categorical characteristics and CD19 expression, while Wilcoxon rank sum test was used to evaluate the difference in continuous variables between CD19 expression groups. Log-rank test was used to compare the differences in progression-free survival (PFS) or overall survival (OS) between/among patient groups. Results Among 211 LBCL patients, 81 (38.4%) had CD19 status available by IHC, 193 (91.5%) by flow cytometry, and 63 (29.9%) by both. Of interest, no patient who received CART in the second line had CD19 status available, and all patients included in the analysis had received CART in the third line and beyond. Overall, 37 patients (17.5%) were CD19-negative before CAR T-cell therapy by either test. No significant differences in baseline characteristics were observed when comparing CD19-negative to CD19-positive cases, including age, sex, histology, product type, performance status, international prognostic index, refractory status, history of autologous or allogenic stem cell transplant, bridging therapy, and prior lines of treatment, except for a significantly lower median hemoglobin in CD19-positive patients (10.6 vs. 12.0 g/dL, p = 0.0054). CD19-negative patients experienced a 2-fold lower incidence of ICANS of any grade (21.6% vs. 43.1%, p = 0.0151) and over 5-fold lower G3-5 ICANS (5.4% vs. 28.7%, p = 0.0015). No significant differences in CRS of any grade (67.6% vs. 73.0%, p = 0.50), G3-4 CRS (5.4% vs. 8.0%, p = 0.74), and day-30 G3-4 cytopenia (40.0% vs. 54.0%, p = 0.24) were observed when comparing the two groups. At day-90 assessment, no difference in overall response rate (51.7% vs. 60.0%, p = 0.41) or complete response rate (37.9% vs. 51.1%, p = 0.20) was observed when comparing CD19-negative to CD19-positive patients. With a median follow up of 18.7 months (95% confidence interval 14.4 – 21.5), no significant difference in PFS (median 3.48 vs. 7.33 months, estimated 2-year 30.1% vs. 30.6%, p = 0.55) or OS (median 22.3 vs. 13.7 months, estimated 2-year 45.7% vs. 44.4%, p = 0.84) was observed when comparing the two groups. Conclusion Our large real-world experience shows that, when using IHC or flow cytometry for CD19 expression assessment, patients with CD19-negative LBCL experience lower ICANS rates with anti-CD19 CART, potentially due to lower CD19 density, but overall efficacy is comparable to what is observed in CD19-positive LBCL. While our results support the use of anti-CD19 CART in CD19-negative LBCL, future larger studies with more sensitive CD19 testing than IHC and/or flow cytometry are warranted.

Introduction CAR T cells provide durable clinical benefit in patients with relapsed or refractory large B cell lymphoma (r/r LBCL), but remain an economically intense therapy. We aimed to characterize resources utilized from the time of CAR T cell administration through Day 28 related to product and toxicity excluding drug cost. Methods Using retrospectively collected data from the Cell Therapy Consortium registry, pts over age 18 with r/r LBCL who received commercial axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), or tisagenlecleucel (tisa-cel), from 4/2016 – 6/2023 at 8 academic US medical centers were evaluated. Inpatient length of stay (Inpt LOS) was defined as the total number of days from Day 0-28 a pt was admitted including the index admission of CAR T infusion plus any readmissions. Outpatient (outpt) LOS was defined as the number of outpt visits from Day 0-28. LOS and RU variables were compared across CAR T products using Kruskal-Wallis tests for continuous and chi-squared or Fisher's exact tests for categorical variables. Results Of the 601 pts, 52%, 11%, and 37% received axi-cel, liso-cel, and tisa-cel, respectively, with a median age of 64yrs (IQR 56-70), 63% male, 85% non-Hispanic white, and 26% ECOG 0 and 61% ECOG 1 at apheresis. Pts had a median of 3 prior lines (IQR 2-4), with an elevated LDH pre-lymphodepletion (LD) in 45% and 78% received fludarabine and cyclophosphamide for LD. LD was administered outpatient for 78%, 81%, and 83% (p=0.7) with CAR T infusion inpatient for 96%, 82%, and 53% (p<0.001) for axi-cel, liso-cel, and tisa-cel, respectively. Median inpt LOS was significantly longer for axi-cel [15 days (IQR 11-20)] vs liso-cel [10 days (IQR 7-16)] and tisa-cel [9 days (IQR 4-14)], p<0.001, and conversely outpt LOS was shorter [5 days (IQR 3-8) vs 6 days (IQR 3-8) and 7 days (IQR 5-11), p<0.001]. More axi-cel pts were admitted to the ICU 29% vs 23% vs 9.9% (p<0.001), but intubation rate was not different (7.2% vs 4.5% vs 5.2%, p=0.6). Following the index hospitalization, 21% vs 20% vs 17% (p=0.8) were readmitted with 13%, 10%, and 20% for CRS; 30%, 40%, and 20% for ICANS; and 10%, 20%, and 0% for infection (p=0.6). Tocilizumab was given in 63%, 32%, and 35% (p<0.001) for axi-cel, liso-cel, and tisa-cel, respectively. The number of pRBC transfusions was similar (range 0-18, 0-5, 0-10; p=0.7), while the number of platelet transfusions varied by product (range 0-18, 0-12, 0-20; p<0.009). G-CSF was administered after Day 14 in 59%, 40%, and 48% (p=0.004) and thrombopoietin receptor agonist in 10% vs 1.5% vs 7.9% (p=0.065), respectively. Conclusion Health care resource utilization can be influenced by site of care and length of hospitalization for r/r LBCL, which is impacted to a degree by CD19 CAR T product. Quantifying these differences may enable more informed patient care planning. Additional analyses evaluating the effect of CRS and ICANS through Day 100 are ongoing.

Patients with classic Hodgkin lymphoma (cHL) with primary refractory disease, early relapse, or extranodal disease have a higher risk of relapse after salvage therapy and autologous stem cell transplant (ASCT). Post-ASCT brentuximab vedotin (BV) maintenance improved progression-free survival (PFS) in high-risk relapsed/refractory (R/R) cHL in the AETHERA trial, but subgroup analysis suggested that the benefit in patients transplanted in complete metabolic response (CMR) is unclear. In a large international real-world cohort, we assessed the efficacy of BV maintenance stratified by pre-ASCT metabolic response and by the number of clinical risk factors as defined in the AETHERA trial. Adult patients with R/R cHL who met AETHERA risk criteria were included. Utilizing propensity score analyses, PFS and OS were assessed overall and in subgroups of CMR (442 pts) and partial metabolic response (PMR, 249 pts). We observed that post-ASCT BV maintenance was associated with significantly higher PFS in the subgroup with PMR (5-year PFS: 59.6% vs 43.3% HR = 0.52, CI95: 0.33-0.82; p = 0.007). In the subgroup of patients with CMR, BV maintenance did not significantly improve PFS (5-year PFS: 75.8% vs 62.3% HR = 0.88, CI95: 0.59-1.32; p = 0.29). However, when focusing on patients with CMR treated post-FDA approval of BV, there was a significant PFS benefit observed in those treated with BV maintenance vs. not (5-year PFS: 81.2% vs 55.2% HR = 0.40, CI95: 0.22-0.72; p = 0.003). Overall, BV maintenance after ASCT remains an important therapy for high-risk R/R cHL patients, especially for those in PMR or those in CMR.