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Abstract Background: Graft-versus-host disease (GVHD) remains the leading cause of non-relapse morbidity and mortality in allogeneic hematopoietic-stem-cell transplantation (allo-HSCT) recipients. Clinical scoring systems (e.g., EBMT, HCT-CI, DRI, etc.) can stratify risk but show modest predictive performance (C-statistics 0.49–0.67) when it comes to GVHD. To address this gap, we developed GVHD-Intel 1.0, a real-time, scalable, and interpretable machine learning (ML) framework from an international study to predict both acute (aGVHD) and chronic GVHD (cGVHD), providing individual and bulk predictions using common input variables and HLA alleles. Methods: This retrospective global study, approved by respective institutional review boards, included electronic health records from three tertiary care centers in Abu Dhabi, UAE, and King Hussein Cancer Center (KHCC), Jordan, from 2009 to 2023. The model was developed in phases. The UAE399 cohort (399 HSCT recipients) served as the baseline dataset. To enhance model generalizability, 55 adult allo-HSCT recipients from KHCC were added to the training set. Two distinct test cohorts were used: UAE46 (46 allogeneic HSCT recipients from UAE) and KHCC150 (150 adult allogeneic HSCT recipients from KHCC), collected later and independently of training data. Variables included donor type, sex mismatch, disease status, time from diagnosis to transplant, and agents used in conditioning and GVHD prophylaxis (e.g., TBI, ATG, alemtuzumab use etc.). HLA alleles (A, B, C, DQ, DR) were symbolically encoded and transformed via one-hot encoding. GVHD events were classified as aGVHD (<100 days) or cGVHD (≥100 days). Missing values were excluded, and class imbalance was handled via class weighting. GVHD-Intel 1.0, co-developed with MBZ University of Artificial Intelligence, features modular ensemble architecture, drug-level feature engineering, novel HLA encoding for low-resolution compatibility scoring, and built-in interpretability using SHAP and LIME. The framework is cloud-deployable for both real-time and batch predictions. Results: The GVHD-Intel 1.0 was externally tested on two independent, temporally and institutionally distinct cohorts (UAE46 and KHCC150), demonstrating strong and consistent predictive performance for both acute and chronic GVHD. For cGVHD prediction, the model achieved an AUC (area under the curve or C-statistic for binary outcomes) of 0.832, F1 score of 0.896, accuracy of 82.7%, PPV of 0.930, sensitivity of 0.864, Brier score of 0.178, and log loss of 0.543. For aGVHD, performance metrics included an AUC of 0.802, F1 score of 0.860, accuracy of 77.6%, PPV of 0.930, sensitivity of 0.799, Brier score of 0.196, and log loss of 0.581. Model calibration remained strong across both tasks, with Brier scores <0.20. Conclusions: GVHD-Intel 1.0 is a robust, interpretable machine learning framework developed from real-world, multicenter data. By integrating widely available clinical variables and HLA allele data, it outperforms conventional clinical risk scores in predicting both acute and chronic GVHD in allo-HSCT recipients. Slightly reduced performance in aGVHD prediction is likely due to the lack of relevant variables. Next steps include prospective validation across multiple transplant centers globally and continued refinement through expanded data integration. GVHD-Intel 1.0 holds strong potential as a clinically valuable, scalable decision-support tool that can be enacted widely and easily by practicing transplant physicians worldwide in all types of settings.

Abstract Introduction: CAR T-cell therapy is an important treatment option for patients with relapsed or refractory (R/R) DLBCL. Three CAR T-cell products have received approval: axicabtagene ciloleucel (Yescarta), lisocabtagene maraleucel (Breyanzi), and tisagenlecleucel (Kymriah). Although direct head-to-head studies comparing the three therapies do not exist, clinical trials have revealed notable differences in response rates and remission rates among them. All three products induce CRS and ICANS; however, variations in the incidence and severity of these adverse effects have been observed. We utilized data from the National Inpatient Sample (NIS) to gain further insights into the incidence of various adverse events associated with different CAR-T products in DLBCL. Method: In this retrospective study, the 2022 NIS database was used to identify hospitalizations with DLBCL and those who received Yescarta, Breyanzi, or Kymriah using appropriate ICD-10-CM diagnostic and ICD-10-PCS procedure codes. Data on CRS, ICANS, infections, and adverse cardiac events were extracted using relevant ICD-10-CM codes. These outcomes were compared across different CAR-T products using Pearson's chi-square analysis. Multivariate logistic regression was also performed, adjusting for demographics, hospital-specific characteristics, and comorbidities. Results: We identified 1440 patients with DLBCL. Among these, 1100 patients (64.6% male; 70.7% Caucasian, 8.8% African American, 20.5% other ethnicities) received Yescarta, 90 patients (66.7% male; 82.4% Caucasian, 0% African American, 17.7% other ethnicities) received Kymriah and 250 patients (64% male; 82.6% Caucasian, 10.9% African American, 6.5% other ethnicities) received Breyanzi. The incidence of CRS was 52% for Breyanzi, 44.4% for Kymriah and 68.6% for Yescarta, and the difference was statistically significant by chi-square analysis (p = 0.03). This difference remained statistically significant for Kymriah after multivariate analysis [Adjusted Odds ratio (OR) = 0.3, CI 0.1 to 0.9, p=0.032], but not for Breyanzi (Adjusted OR = 0.3, CI 0.1 to 0.9, p=0.032) in comparison to Yescarta. The incidence of ICANS was 16% for Breyanzi, 22.2% for Kymriah, and 33.2% for Yescarta, with a statistically significant difference observed by chi-square analysis (p = 0.05). This difference remained statistically significant for Breyanzi after multivariate analysis [Adjusted OR = 0.3, CI 0.1 to 0.6, p=0.002], but not for Kymriah (Adjusted OR = 0.6, CI 0.1 to 2.9, p=0.551) in comparison to Yescarta. Among cardiovascular events, there was no significant difference in the incidence of acute myocardial infarction (Yescarta vs Kymriah vs Breyanzi, 0.5% vs 0% vs 0.2%, p = 0.487), stroke (0.5% vs 5.6% vs 2%, p = 0.07), cardiogenic shock (0.5% vs 0% vs 0%, p = 0.880), and arrhythmias (20.9% vs 27.8% vs 32%, p = 0.258) among these CAR T-cell therapies. Furthermore, there were no significant differences in the incidence of infectious complications, including pneumonia (5.9% vs 5.6% vs 2%, p = 0.510), sepsis (5% vs 5.6% vs 6%, p = 0.962), or septic shock (2.3% vs 0% vs 0%, p = 0.535) among these CAR T-cell therapies. There was no difference in all-cause in-hospital mortality across these therapies (2.3% vs 5.6% vs 2%, p = 0.692). Conclusion: Kymriah showed lower CRS rates and Breyanzi showed lower ICANS rates in comparison to Yescarta in our study. All CAR T-cell therapies have the potential to cause infections and cardiac events, which require monitoring, early identification and prompt treatment. When selecting among various CAR T-cell products, several factors must be considered, including the patient's lymphoma type, prior treatment history, manufacturing turnaround time, cost, availability, and potential short-term and long-term side effects. The limitations of our study include its retrospective nature, reliance on ICD-10 codes to identify patients with adverse events, and the absence of longitudinal data on long-term adverse events. Nevertheless, this study provides essential insights for hematologists regarding the incidence of specific adverse events associated with different CAR T-cell products within the real-world population.

Abstract Background: Mosunetuzumab, a CD20xCD3 bispecific antibody, can be administered in the outpatient setting for a fixed duration. Mosunetuzumab by intravenous (IV) administration is FDA- and EMA-approved in relapsed/refractory (R/R) FL after ≥2 prior lines of therapy. Interim results from the Phase II MorningSun study (NCT05207670) demonstrated promising efficacy and manageable safety of mosunetuzumab SC in pts with previously untreated HTB FL (Flinn et al. ASCO 2025). We report 12-month follow-up efficacy and safety data of mosunetuzumab SC in pts with previously untreated HTB FL in the MorningSun study, including pts who received optional maintenance therapy. Methods: Pts with previously untreated HTB FL, per Groupe D'Etude des Lymphomes Folliculaires criteria, and Eastern Cooperative Oncology Group performance status of 0–2 were enrolled, primarily from United States (US) community sites. Mosunetuzumab SC was administered as step-up dosing in Cycle (C)1 (Day [D]1, 5mg; D8, 45mg; D15, 45mg) followed by 45mg on D1 of each 21-day cycle, for up to 17 cycles (1 year). Pts with a partial or complete metabolic response (CMR) after C17 could receive optional mosunetuzumab maintenance treatment (45mg every 8 weeks for up to 1 year). The primary endpoint was progression-free survival (PFS) rate at 1 year. Key secondary endpoints included objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR) and safety. Exploratory analysis of ctDNA levels was performed using the AOA-NHL assay. Results: As of February 10, 2025, 103 pts were enrolled (n=82 pts from community sites, n=21 pts from academic sites). Overall, the median age was 65 years (range: 24–86), 51.5% of pts were female and most pts had Ann Arbor stage III/IV disease (91.3%) and a FLIPI score ≥2 (78.6%). In total, 69 pts completed initial treatment (17 cycles), 33 discontinued (primarily due to progressive disease [PD; n=18] and adverse events [AEs; n=5]), and 1 pt was continuing treatment. After 17 cycles, 68 pts were eligible for maintenance treatment, of whom 46 received maintenance, and 15 were continuing maintenance treatment at the time of data cut-off. Median duration of follow-up was 22.3 months (95% confidence interval [CI]: 20.9–24.1). The 12-month PFS rate was 85.5% (95% CI: 76.2–91.3). The ORR was 87.4% (95% CI: 79.4–93.1); 64.1% of pts had a CMR. The 12-month OS rate was 91.9% (95% CI: 84.5–95.9); the 12-month DOR and DOCR rates were 89.6% (95% CI: 80.2–94.7) and 91.1% (95% CI: 79.4–96.2), respectively. Of the 46 pts who received maintenance, no pts experienced PD, and 1 pt died (reason unknown). Of the 22 pts who were eligible but did not receive maintenance, 1 pt had PD. The most common AEs (≥30%) were injection-site reaction (67.0%), fatigue (44.7%), cytokine release syndrome ([CRS] 34.0%), headache (32.0%), and nausea (32.0%). Grade (Gr) ≥3 AEs and serious AEs were reported in 47.6% and 35.9% of pts, respectively. Five pts experienced Gr 5 AEs: COVID-19 pneumonia (n=2) and cardiogenic shock, unexplained death, pneumonia (n=1 each). Infections occurred in 77.7% of pts and were predominantly Gr 1/2 (Gr 1: 10.7%; Gr 2: 47.6%; Gr 3: 12.6%; Gr 4: 3.9%), with the most common infection being COVID-19 (24.3%). Of 3 (2.9%) Gr 5 infections reported, 1 occurred during initial treatment (COVID-19), 1 during maintenance (pneumonia), and 1 occurred 2.8 months after completion of treatment (COVID-19). AEs were reported in 80.4% of pts in the maintenance phase, mostly Gr 1/2 events. No CRS events occurred during maintenance treatment. Infections were reported in 45.7% of pts during maintenance, with the majority being Gr 1/2 events (37.0%), and were similar types of infection as during initial therapy. ctDNA levels were assessed in a subset of pts who achieved a CMR; 86.4% (19/22) of pts were minimal residual disease (MRD) negative (p-value cut-off 0.005).Conclusions: Longer follow-up of mosunetuzumab SC with optional maintenance treatment continues to demonstrate promising PFS and OS rates, and a manageable safety profile in pts with previously untreated HTB FL. Exploratory analysis of ctDNA in a subset of CMR pts showed MRD negativity in 86.4%, thus supporting fixed treatment duration of mosunetuzumab SC. Overall, these data support the outpatient administration of mosunetuzumab SC in US community practices and further evaluation of mosunetuzumab-based treatment in first-line HTB FL.

Abstract Introduction: The CARTITUDE-4 (NCT04181827) trial compared cilta-cel, a chimeric antigen receptor (CAR)-T cell treatment (tx) targeting B-cell maturation antigen (BCMA), with 2 standard-of-care regimens in patients (pts) with RRMM and 1–3 prior lines of therapy (LOT). Cilta-cel significantly improved overall survival (hazard ratio [HR] 0.55) and progression-free survival (PFS; HR 0.29). The DREAMM-7 (NCT04246047) and DREAMM-8 (NCT04484623) trials evaluated belamaf, an anti-BCMA antibody-drug conjugate (ADC), in combination with bortezomib and dexamethasone (BVd) and with pomalidomide and dexamethasone (BPd), respectively. Both trials demonstrated improved survival and response rates with belamaf in pts with ≥1 prior LOT. International Myeloma Working Group (IMWG) guidance for RRMM tx recommends using anti-BCMA T-cell redirecting therapy (TCRT), such as CAR-T (eg, cilta-cel), before anti-BCMA ADCs (eg, belamaf). As cilta-cel and belamaf have not been compared head to head, we conducted unanchored matching-adjusted indirect comparisons (MAICs) to estimate relative efficacies using CARTITUDE-4 study individual patient data (IPD) and published data from DREAMM-7 and DREAMM-8. Methods: Unanchored MAICs were performed using IPD from apheresed pts in the CARTITUDE-4 cilta-cel arm. Eligibility criteriafrom DREAMM-7 and DREAMM-8 were applied to the cilta-cel cohort. Further adjustments were made by weighting cilta-cel IPDto match reported baseline characteristics (including refractory status [for DREAMM-8], cytogenetic risk, International Staging System stage, and presence of extramedullary disease) from DREAMM-7 and DREAMM-8. Outcomes were compared using weighted IPD for cilta-cel and reported response rates and simulated IPD based on published Kaplan–Meier PFS curves for BVd and BPd. For each matched population, we compared PFS, ORR, and very good partial response or better (≥VGPR) and complete response or better (≥CR) rates. A weighted Cox proportional hazards model was used to estimate PFS HRs and 95% CIs. A weighted logistic regression analysis was used to derive relative response ratios (RRs) with 95% CIs to compare relative tx effects. Results: The MAICs included 208 apheresed pts from CARTITUDE-4 (cilta-cel), 243 pts from DREAMM-7 (BVd), and 155 pts from DREAMM-8 (BPd). To form comparable cohorts, we excluded cilta-cel pts who would not have been eligible for DREAMM-7 (n=87) or DREAMM-8 (n=55). Cilta-cel pts were most commonly excluded from the DREAMM-7 MAIC due to bortezomib refractoriness or anti-CD38 refractoriness (n=55 and n=50, respectively), and from the DREAMM-8 MAIC due to bortezomib refractoriness (n=55). After exclusions, 121 and 153 cilta-cel pts remained in the MAICs with BVd and BPd, respectively. After adjustment, cilta-cel was associated with significantly lower risk of progression or death compared with BVd (HR 0.46 [95% CI 0.28–0.75]; P=0.0020) and BPd (HR 0.61 [95% CI 0.39–0.96]; P=0.0320). ORR was significantly higher with cilta-cel vs BVd (92.9% vs 82.7%; RR 1.12 [95% CI 1.03–1.22]; P=0.0087) and vs BPd (89.3% vs 77.4%; RR 1.15 [95% CI 1.04–1.29]; P=0.0100). Rates of ≥VGPR and ≥CR were also higher with cilta-cel vs BVd (≥VGPR: 89.7% vs 65.8%; RR 1.36 [95% CI 1.21–1.53]; ≥CR: 86.0% vs 34.6%; RR 2.49 [95% CI 2.04–3.03]; both P<0.0001) and vs BPd (≥VGPR: 86.6% vs 63.9%; RR 1.36 [95% CI 1.18–1.56]; ≥CR: 81.8% vs 40.0%; RR 2.05 [95% CI 1.65–2.53]; both P<0.0001). Sensitivity analyses were consistent with the adjusted comparisons and showed statistically significant PFS and tx response benefits with cilta-cel vs BVd and BPd. Conclusions: These MAICs demonstrated superior PFS and response rates with cilta-cel compared with 2 belamaf-containing regimens (BVd and BPd). Results should be interpreted with caution as there were substantial differences in the pt populations of CARTITUDE-4 vs DREAMM-7 and DREAMM-8. However, adjusted cilta-cel cohort sizes remained large enough for robust comparisons that showed statistically significant differences across efficacy outcomes. Another limitation is the remaining potential unmeasured residual confounding differences. Nonetheless, these findings support IMWG guidance recommending anti-BCMA TCRTs prior to ADCs and provide valuable comparative evidence in the absence of head-to-head trials.

Abstract Introduction The treatment of newly diagnosed multiple myeloma (NDMM) has rapidly evolved. Quadruplet induction combining an anti-CD38 monoclonal antibody, lenalidomide, a proteasome inhibitor, and dexamethasone has become a standard of care. In this prospective randomized phase 2 trial, we evaluated the efficacy and safety of induction with a four-drug combination of daratumumab (Dara), lenalidomide (R), ixazomib (I), and dexamethasone (d) (Dara-RId) in older, transplant ineligible or deferred patients, followed by maintenance with Dara RI versus R for up to 2 years. We hypothesized that this quadruplet would offer improved tolerability with less peripheral neuropathy in this older population as well as the convenience of largely oral therapy. Herein, we present the initial results of the induction phase of the study. Methods Transplant-ineligible or deferred patients with NDMM were eligible to participate. This was a multicenter trial sponsored by the Alliance Foundation Trials, LLC, AFT-41 (NCT04009109). Each cycle of treatment was 28 days. All patients received 12 cycles of induction therapy with daratumumab 1800 mg subcutaneously on the conventional schedule, lenalidomide 15 mg orally (po) on days 1-21, ixazomib 4 mg po on days 1, 8, 15, and dexamethasone weekly. After 12 cycles, patients received maintenance based on prior randomization (1:1) to Dara-RI or R for up to 2 years. In maintenance, R was reduced to 10 mg and I was reduced to 3 mg. Randomization assignment occurred prior to starting induction. Stratification was based on presence of high-risk features defined as ISS stage III or high-risk FISH cytogenetics (del 17, t (14;16), t (14;20), t (4;14), del (1p), or gain (1q)). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and adverse events. Results We enrolled 79 patients across 7 sites from October 2020 until December 2023. Accrual was affected by the COVID19 pandemic, leading to early closure to accrual in December 2023. Median age was 74 years (range 63-86); ≥75 years of age (45.6%); female (59.5%); white (83.5%), African American (7.6%), Asian (1.3%), and Hispanic ethnicity (6.3%). Additional baseline characteristics included ISS staging I (41.8%), II (35.4%), and III (22.8%) with high-risk features in 37% by ISS stage III and/or high-risk FISH. The 12-month PFS was 92% (95% confidence interval [CI] 86.1-98.4%). The ORR (≥ partial response [PR]) during induction was 92.4% (PR 22.8%; very good partial response [VGPR] 46.8%; complete response 15.2%; stringent complete response 7.6%). Notable grade ≥3 adverse events included neutropenia (16.5%), infections (11.4%), anemia (10.1%), thrombocytopenia (8.9%), and syncope (7.6%). There was no grade ≥3 peripheral neuropathy (grade 1, 15%; grade 2, 14%). No treatment-related mortality was reported. Sixty-one patients went on to maintenance therapy and seven patients discontinued treatment for adverse events during induction (8.9%). Conclusions Dara-RId therapy in NDMM appears to be efficacious with an ORR of 92.4%; VGPR or better of 69.6% and 12-month PFS of 92%. The combination was generally tolerated well with manageable toxicity, despite 45.6% of patients being ≥75, offering the convenience of an oral proteasome inhibitor, ixazomib, that minimizes the risk of peripheral neuropathy for older, transplant-ineligible or deferred patients. Follow-up is ongoing to determine the benefit of maintenance with Dara-RI v. R alone in this population. Support: AFT, Celgene, Janssen, Takeda.

Abstract Introduction: cBTKi have made a substantial impact in pts w/ MCL, but pts who develop PD while on treatment w/ cBTKi have historically had poor responses to subsequent lines of therapy (LOT). Brexucel, lisocel, and the non-covalent BTKi pirto have been approved in this population. While two RW studies have substantiated the benefit of brexucel, similar data for pirto are lacking. Accordingly, we aimed to evaluate the outcomes of pts treated w/ pirto in the RW setting. Methods: We performed a multi-center retrospective cohort study of adult pts w/ a diagnosis of MCL who experienced PD after any approved cBTKi and subsequently received pirto. Pts who received pirto w/ bridging intent and those who switched to pirto due to intolerance of cBTKi were excluded. The 95% exact binomial confidence intervals (CI) were calculated for overall response rate (ORR) and complete response rate (CRR). Progression-free survival (PFS) and overall survival (OS) were defined as the time from pirto start to PD or death, whichever occurred first, and the time from pirto start to death, respectively, and calculated w/ the Kaplan-Meier method. The log-rank test was used to compare survival curves. A multivariate (MV) Cox proportional hazard model was built to calculate adjusted hazard ratio (aHR). Analyses were performed w/ SAS, version 9.4. Results: Data on 111 pts w/ MCL treated across 21 institutions were collected. Median (mdn) age was 72 (range 33 – 93) years. Twenty-seven pts (24%) were female, 3 (3%) were Asian, 5 (5%) Black, 9 (8%) Hispanic, 86 (77%) White. Among the 53 (48%) pts w/ available MIPI-c at diagnosis, 28 (53%) pts were high-risk. Ki67 at diagnosis was available in 84 (76%) pts: of those, 58 (69%) had a Ki67 ≥30%, and 41 (49%) ≥50%. TP53 mutational status was available in 70 (63%) pts: 33 (47%) had documented TP53 mutation and 10/52 (19%) pts had a disease w/ complex karyotype. Pts had a mdn of 3 (range 1 – 9) prior LOT (n=106). Ninety-one pts (86%) received chemo-immunotherapy (CIT), 16 (15%) autologous stem cell transplant, 19 (18%) venetoclax (ven), 29 (27%) chimeric antigen receptor T-cell, 4 (4%) allogeneic stem cell transplant. For cBTKi, 39 (35%) pts received ibrutinib, 56 (50%) pts acalabrutinib, 33 (30%) pts zanubrutinib, and 17 (15%) pts received more than one cBTKi. The mdn time from the last dose of cBTKi to pirto start was 55 (range 0 – 2587) days, w/ 51 (46%) pts who switched from a cBTKi directly to pirto. Thirty (27%) pts had no response (stable disease or PD as best response) to cBTKi, and 40 (36%) pts had no response to the last LOT. Two (2%) pts received pirto in combination w/ CIT, 8 (7%) w/ an anti-CD20 monoclonal antibody (mAb), 11 (10%) w/ ven ± a mAb, while 86 (77%) pts as single agent. In 104 (94%) pts, pirto was given at full dose, 10 (9%) pts had a subsequent dose reduction. A total of 35 serious (grade ≥3) adverse events (AE) were documented in 27 (24%) pts: 4 (4%) pts had a serious bleeding AE, 5 (5%) pts a serious cardiac AE, 10 (9%) a serious GI AE, and 16 (14%) a serious infectious AE. Ninety-eight (88%) pts were evaluable for response. The ORR was 40% (95% CI 30% – 50%) w/ a CRR of 29% (95% CI 20%– 39%). At the last follow-up, 29 (26%) pts remained on pirto w/ a mdn treatment duration of 15.1 months (range 0.4 – 26). Fifty-eight (52%) pts died, 35 (78%) because of PD. At a mdn follow-up of 15.8 (range 0.4 – 26) months among survivors, the mdn PFS was 4.7 months (95% CI 3.3 – 8.2) and the mdn OS was 13 months (95% CI 9.2 – not available). Using the log-rank test, age (quartile groups), number of LOT (1-2 vs. 3-4 vs. 5+), time from cBTKi to pirto (quartile groups), Ki67≥30%, and high MIPI-C did not result in a statistically significant difference in PFS (p>0.05). Presence of TP53 mutation was associated w/ a non-statistically significant adverse trend in PFS (p=0.0585). No response to cBTKi and Ki67≥50% were associated w/ a statistically significant inferior PFS in log-rank test (p=<0.05), which persisted in a MV Cox regression model (aHR 2.4, 95% CI 1.4-4.2, and aHR 2.6, 95% CI 1.6-4.4, respectively). Conclusions: This is the first RW report on pirto in MCL pts. In this high-risk population, ORR to pirto was comparable to the BRUIN trial, while PFS was significantly worse, especially in pts w/ no response to cBTKi and w/ a high Ki67. However, prolonged remissions were seen in a subset of pts, suggesting that a better characterization of this population w/ durable benefit from pirto is needed.

Abstract Introduction: Axi-cel, an autologous anti-CD19 CAR T-cell therapy has shown high and durable response rates and a manageable safety profile among R/R FL pts in the ZUMA-5 trial (Jacobson et al. 2022; Neelapu et al. 2024). Evidence from real-world data showed favorable early outcomes in a broader population using CIBMTR data, with comparable outcomes by ZUMA-5 eligibility, age, lines of therapy (LOT), and prior bendamustine (benda) use (Jacobson et al. 2023). This study investigated long-term outcomes and the association between age, performance status, comorbidities, and therapies given prior to infusion among R/R FL pts treated with axi-cel. Methods: Pts with R/R FL who received commercial axi-cel between 03/2021–10/2023 in the US were identified from the CIBMTR® registry; pts without consent, with prior non-transplant cellular therapy, and FL grade 3B or 3A/3B unspecified or unknown were excluded. Descriptive analyses were done among all pts and by age at infusion (<65 vs ≥65 y), Karnofsky performance score (KPS), presence of hepatic, cardiovascular (CV), or moderate to severe pulmonary comorbidities, prior treatments (benda pre-leukapheresis, autologous hematopoietic stem cell transplant [autoHSCT]), and lymphodepletion (LD) therapy. Multivariable (MV) Cox and logistic regression were used to adjust for confounders. Results: In total, 238 pts from 68 centers were included (data cut-off October 2024). Median age at infusion was 61 yr (range, 29-83; ≥65 yr, 38%), and 79% were non-Hispanic White. KPS of pts was ≤70% (11%), 80% (35%), or 90-100% (54%); 2% had ECOG ≥2. Most (75%) had ≥1 clinically significant comorbidity (hepatic, 6%; CV, 15%; pulmonary, 18%). Median (min, max) prior LOT was 4 (1,13); 74% received benda pre-leukapheresis, and 6% had benda LD therapy. At a median follow-up of 24.1 months, objective response rate (ORR) was 96% (complete response [CR] rate, 91%). The 2-yr (95% CI) DOR, PFS, and OS were 70% (63-77), 64% (57-71), and 84% (78-89) respectively. Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4% and 18% of pts (any grade, 74% and 42%), respectively. Prolonged cytopenias by day 30 occurred in 14% of pts (neutropenia [10%] and thrombocytopenia [8%]) while 29% had clinically significant infections at 6 months. Second primary malignancies occurred in 16 pts (7%), with 7 (2%) being therapy-related myeloid neoplasm. The leading primary causes of death (n=34) were relapse/progression (10; 29%), organ failure (7; 21%), and infection 5 (15%). Cumulative incidence of non-relapse mortality at 2-yr was 9%. Outcomes were generally comparable among age, autoHSCT, and comorbidity subgroups. However, effectiveness outcomes differed by prior benda use (Yes vs No): ORR (95% vs 98%); CR (88% vs 98%); DOR (65% vs 89%), PFS (58% vs 84%), and OS (82% vs 91%) at 2 years. By LD therapy (single agent benda vs cyclophosphamide + fludarabine [Cy + Flu]): the ORR was 93% vs 96%; CR rate was 57% vs 93%. On MV analysis, prior benda use was associated with (OR/HR [95% CI]): worse CR (0.02 [<0.01-0.43]), DOR (3.69 [1.51-9.02], and PFS (2.21 [1.12-4.38]). Pts given benda LD therapy had (OR/HR [95% CI]): worse CR rate (0.02 [<0.01-0.16]), DOR (7.59 [2.33-24.72]), and PFS (4.89 [1.79-13.39]) compared to those who received Cy + Flu. CRS and ICANS were lower among those with prior benda use (Yes vs No): any-grade CRS (70% vs 87%); Grade ≥3 CRS (3% vs 8%); any-grade ICANS (36% vs 61%); and grade ≥3 ICANS (17% vs 25%). By LD therapy (single agent benda vs Cy + Flu): the Grade ≥3 CRS and ≥3 ICANS were 0% vs 5% and 7% vs 19% respectively. Any-grade ICANS was higher among those aged ≥ 65 yr vs <65 yr (53% vs 35%). On MV analysis, pts who had prior benda use were less likely to have any-grade CRS (0.30 [0.12-0.75]), and any-grade ICANS (0.23 [0.11-0.50]. Pts ≥ 65 yr had higher any-grade ICANS (2.31 [1.18 – 4.50]). Summary/Conclusion: This long-term follow up of axi-cel in R/R FL shows durable responses and manageable safety similar to ZUMA-5. Outcomes among the elderly and those with comorbidities were generally comparable to the overall R/R FL population. Although benda use pre-leukapheresis was associated with less durable responses, we were unable to determine whether this association is limited to use close to axi-cel infusion, as data on timing of use was unavailable. The associations for benda LD should be interpreted with caution given the small sample size.

Abstract Introduction: Waldenström macroglobulinemia (WM) is characterized by the presence of a MYD88 mutation in >90% and a CXCR4 mutation in 30-40% of cases. The impact of these mutations on treatment responses and disease outcomes is well known. TP53 alterations (TP53ALT) have more recently been described in WM and are reported to occur in up to 25% of patients, with a higher frequency in patients with previously treated WM, especially those with prior alkylator or nucleoside analogue exposure (Tam et al Blood Adv 2024; Poulain et al CCR 2017; Tsakmaklis et al, ASH 2025). TP53 ALT WM is associated with a shorter time to disease progression, as well as worse overall survival (Poulain et al CCR 2017; Gustine et al, BJH 2019). Depth of response to BTK inhibitors is affected by TP53 status, with recent data reporting a very good partial response (VGPR) rate of 34% v. 25% and major response rates of 84% v. 73% in patients without or with a TP53 ALT (Tam et al Blood Adv 2024). No complete responses were reported and median PFS was shorter in those with a TP53ALT compared with wild-type (TP53WT). Loncastuximab tesirine is a humanized IgG1 anti-CD19 antibody that is conjugated to a pyrrolobenzodiazepine (PBD) dimer. Following internalization, the PBD dimer is released via proteolytic cleavage and binds to the DNA minor groove forming highly cytotoxic DNA inter-strand crosslinks. Cells deficient in DNA repair including TP53 alterations are vulnerable to the cytotoxic effects of loncastuximab tesirine (Tarantelli et al, Haematologica 2024). Methods: In an ongoing investigator-initiated, prospective phase II study in symptomatic patients with relapsed or refractory WM (NCT05190705), patients are receiving single agent loncastuximab tesirine. Loncastuximab tesirine is administered at 150 ug/kg in cycles 1 and 2 and 75 ug/kg in cycles 3 to 6. Each cycle is 28 days. The primary outcome measure of this study is attainment of VGPR or complete (VGPR/CR) response. The accrual goal of this trial is 20 patients, based on an alternative VGPR/CR rate ≥40% versus a null of ≤10%, with a double-sided alpha of 0.037 and a power of 87%. The study would meet its endpoint if ≥6 patients attained a VGPR/CR. Results: Of the 14 patients who have completed therapy on this trial to date, the median age is 71 years (range 53-81), 9 (64%) are male, and the median prior number of therapies is 4 (range 2-10). Median baseline hemoglobin is 9.5 g/dL (range 8.2-12.6), serum IgM is 2146 mg/dL (range 723-5955), and bone marrow involvement is 53% (range <5-90). Four patients had extramedullary disease. Twelve patients (86%) are MYD88 mutated; 8 patients (57%) are CXCR4 mutated, and 8 (57%) are TP53 altered. Nine patients completed all 6 cycles of therapy. Of the 5 other patients, treatment was stopped early due to GGT elevation (n=2), disease progression (n=1), patient decision (n=1), and skin toxicity (n=1). No IgM flare and no infusion reactions have occurred. For all patients, the median time to minor response, major response, and deepest response was 28, 55, and 172 days, respectively. The response rates include 1 (7%) CR; 9 (64%) VGPRs; 2 (14%) partial responses (PR); 1 (7%) minor response; and 1 (7%) progressive disease, for an overall response rate of 93% and a VGPR/CR rate of 71%. For the 8 patients with TP53ALT, the baseline characteristics were as follows: 50% male; median age of 70 years (range 53-77), median prior therapies is 4 (range 2-10); median IgM is 1877 mg/dL (range 723-5639); and median hemoglobin is 9.2 g/dL (range 8.2-11.6). All TP53ALT patients had an MYD88 mutation, and 6 (75%) carried a CXCR4 mutation. For those with TP53 ALT, the median time to minor response, major response, and deepest response was 28, 49, and 235 days, respectively. All TP53ALT patients attained a major response; 1 patient (13%) with a CR, 6 (75%) with a VGPR, and 1 (13%) with a PR, for an overall response rate of 100% and a VGPR/CR rate of 89%. One patient had splenomegaly and one had adenopathy, both of which resolved after treatment. Conclusion: Our findings from this ongoing, prospective trial demonstrate a high VGPR/CR rate of 71% in heavily pre-treated WM. Notable, is the VGPR/CR rate of 89% in high-risk patients with TP53ALT WM. No unexpected toxicities have been seen in this trial. Our findings identify a potentially novel time-limited therapy in relapsed or refractory WM, including patients with high-risk TP53ALT WM.

Abstract Background We performed a prospective study evaluating a baseline GA battery and clinical outcomes in fit older adults (age ≥60 years) with AML and normal cardiac and renal function in the recent E-A NCTN E2906 phase 3 study. A patient-reported outcomes (PRO) assessment of Depression, Activities of Daily Living (ADL), Cognitive Function, Social Support (SS) domains, and comorbidity was performed at study registration to evaluate the prevalence of vulnerabilities and their impact on overall survival (OS) and 30-day induction mortality rates (IM) in this cohort selected for fitness to receive IC. Methods E2906 study design and results have been presented previously [n=727, age ≥60 years, randomized 1:1 to ‘standard 7&3‘ & high dose cytarabine (Arm A) vs. single agent clofarabine (CLO, Arm B), as remission induction (Step 1) and consolidation (Step 2)]. There was no difference in composite complete remission (CCR, 50%) or IM (8.5%), and CLO was inferior for OS. A baseline GA was a key secondary protocol objective, offered to all patients, and n=532 (73%) participated. We assessed Geriatric Depression Scale (GDS, none vs. any depressive symptoms, n=524); cognitive screen using Mini-Mental Exam Section (MMES, score 8/8 vs. <8, n=516); ADL & Instrumental ADL (iADL), (need for assistances vs. not n=526); a Medical Outcomes Study SS Survey (MOS-SS, measured as per unit increase, n=527); a Comorbidity survey ( ≤4 vs. ≥5 patient-reported comorbidities, n=530), patient-reported prescription medications use (PM, 0-3 vs. ≥4, n=519); and a survey of Sexual Desire (n=491) and Sexual Activity (n=477) within 4 weeks of AML diagnosis. Association of GA domains with OS, IM, and achievement of CCR was evaluated using the Chi-squared, Fisher's exact, and Wilcoxon rank sum test. Survival analysis was performed using the Cox proportional hazards models, adjusted for treatment arm. All p-values are 2-sided. Results The median age among those participating in GA battery was 67 yrs (range 60-85), including 38% age ≥70. There were 42% females, and ECOG performance status was 0 (28%), 1 (54%), 2 (16%), or 3 (2%). Central Cytogenetic review was classified (ELN2017) as Favorable (3%), Intermediate (66%), and Adverse (31%) risk. There was a notable rate of GA scores outside ‘normal’ clinical cutoff, including Depression (GDS 31%), cognitive and functional impairment [MMSE (37%), ADL (25%) and iADL (32%)], ≥5 Comorbidities (23%), and ≥4 PM's (44%). 81% & 76%, respectively, reported no sexual activity and low/none sexual desire. MOS-SS tended to be high in this cohort [mean (SD) score 87 (17)]. We observed a significant association of GA domains with OS & IM. For OS, absence of depressive symptoms [GDS, Hazard Ratio (HR) 0.79, 95% confidence Intervals (CI) 0.64-0.97, p=0.025)], MMES 8/8 (HR 0.78, 95%CI 0.64-0.96, p=0.016), requiring no assistance with ADLs (HR 0.65, 95%CI 0.52-0.82, p<0.001) and iADLs (HR 0.69, 95%CI 0.57-0.85, p<0.001), and ≤4 Comorbidities (HR 0.68, 95%CI 0.54-0.84, p=0.001) were significant for superior OS; use of ≥4 PM's was associated with inferior OS (HR 1.32, 95%CI 1.09-1.61, p=0.005). There was no association of sexual activity/desire, BMI ≥30 kg/m2, or MOS-SS with OS. IM was significantly higher among those with any depression symptoms (GDS, p=0.005), any ADL (p=0.010) or iADL (p=0.013) impairment, ≥5 comorbidities (p=0.037) and ≥4 PM's (p=0.001); there was no association with MOS-SS or MMES. There was no significant association of GA scores with cytogenetic risk group or with CCR rates. Only ADL independence (p=0.048), and possibly Comorbidity ≤4 (p=0.071), were associated with proceeding to Step 2. Conclusions In this large prospective cohort of fit older adults with AML selected to receive IC, we observed high rates of PRO-assessed GA vulnerability, which was significantly associated with inferior OS and higher IM rates, and (for ADL impairment) lower rates of proceeding to consolidation therapy. This suggests that functional and cognitive impairments are prevalent and can significantly impact outcome even in fit older adults. Despite potential long-term OS advantages of IC previously observed in E2906, efforts to systematically recognize those at higher risk based on GA PROs are needed to help identify patients who may be more appropriate for study of lower intensity treatment options to mitigate impact on IM and OS. SImilarly we plan to evaluate the potential benefit of GA-driven supportive care to improve patients' outcomes.

Abstract Introduction: Primary central nervous system T-cell lymphoma (PCNSTL) is a rare form of PCNSL, comprising 2–8% of cases. Prognostic factors remain undefined, and no standard treatment protocol currently exists. Prior studies have been limited by small sample sizes, incomplete molecular profiling, and poor representation of novel treatment modalities. In this study, we aimed to identify clinicopathologic factors associated with patient (pt) outcomes and delineate the spectrum of treatment regimens used to inform future clinical practice. Methods A multicenter retrospective study was conducted across 15 North American academic institutions. Pts aged ≥18 years with biopsy-confirmed PCNSTL between 2009 and 2025 with no evidence of systemic disease were included. Cases with CNS relapse of systemic T-cell lymphoma were excluded. Baseline characteristics were analyzed using independent t-tests, Fisher's exact tests, or Pearson's chi-square tests. Primary endpoints were overall survival (OS) and progression-free survival (PFS), evaluated by Kaplan–Meier, log-rank tests, and Cox regression. Results: Forty-two pts met inclusion criteria. Median age was 57 (range 19–77), 69% were male, and 79% were white. Most (69%) had ECOG 0–1. No patients had HIV, hepatitis B or C, or a history of solid organ transplant. LDH was elevated at diagnosis in 38%, and 24% had B-symptoms. Mean absolute lymphocyte count at diagnosis was 1.82/µL. The most common histologic subtypes were PTCL-NOS (76%), followed by ALK-negative ALCL (12%) and γδ T-cell lymphoma (5%). All patients had parenchymal brain lesions with 57% having multifocal disease. Additionally, CSF involvement was seen in 21%, vitreoretinal involvement in 3%, and deep brain involvement in 34%. Next-generation sequencing was performed in seven pts (17%), with disease-associated variants identified in three cases. Among these, two pts had mutations in TP53, and one had a mutation in DNMT3A. Cytogenetics were obtained in 7 pts with only one exhibiting a complex karyotype. Only one pt was EBV positive by EBER-ISH. Overall, 79% received HD-MTX-based therapy. First-line treatments were mainly HD-MTX alone (38%), HD-MTX + temozolomide (17%), or vincristine + procarbazine (12%). No patients were treated on clinical trials. Median treatment duration was 78 days and median number of treatment cycles was 4 (range 1–9 cycles). One patient received radiation alone; 5% received radiation with systemic therapy. A steroid pre-phase was used in 60%, with 44% exhibiting a clinical response. Overall response rate to first-line treatment was 63% (13 CR, 12 PR). Imaging alone was used in determining response in all patients. Repeated biopsy was not performed. Twelve patients (29%) underwent consolidative autologous transplant, most commonly with thiotepa/carmustine (TT/BCNU, 69%) or BEAM conditioning (25%). Median duration of follow-up was 10.4 months. Sixty-two percent of pts progressed during the study period, with 7% experiencing extra-CNS relapse. Median PFS was 8.2 months. Improved PFS was associated with >3 cycles of therapy (p=0.03) and transplant with TT/BCNU (p=0.0004). At last follow-up, 43% were in remission and 52% were deceased, mostly due to disease progression (77%). Median OS was 17.6 months. One- and two-year OS rates were 58% and 42%, respectively. OS was associated with Nottingham/Barcelona score <2 (p=0.02), >3 treatment cycles (p=0.0008), response to first-line therapy (p=0.0007), and TT/BCNU-based transplant (p=0.0001). IELSG, Taipei, and MSKCC risk scores were not significantly associated with survival, though IELSG approached significance (p=0.09). Discussion: This study is among the largest cohorts of PCNSTL pts compiled to date. PCNSTL remains rare and heterogenous. Treatment across centers largely mirrors management of B-cell PCNSL with high utilization of HD-MTX regimens and TT/BCNU conditioning autologous transplant. Survival outcomes within our cohort are consistent with those previously reported within the literature. Receipt of >3 cycles of therapy, TT/BCNU conditioning and Nottingham/Barcelona scores were associated with longer survival within our cohort. Limitations of our study include its retrospective design and heterogeneity within pt disease characteristics, treatments utilized and disease assessment intervals. Further exploration into pathophysiology and optimal management of this unique entity is needed.