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Abstract Background Due to the high mortality of immune thrombotic thrombocytopenic purpura (iTTP), rapid clinical evaluation and early intervention are crucial. The PLASMIC score remains a valuable and widely used tool for predicting severe ADAMTS13 deficiency. However, recent studies have shown variable performance across different populations. In addition, its variables may often be missing during initial presentation. Refining the accuracy of early iTTP evaluation could improve timely recognition and treatment, while reducing unnecessary interventions in those eventually ruled out for iTTP. Machine learning advancements offer several advantages for enhancing clinical prediction models: the ability to assess continuous variables, capture complex interactions between them, and handle missing data. We previously utilized XGBoost (extreme gradient boosting) to develop a novel machine learning tool, TTP-14, which improved upon the PLASMIC score's predictive performance in repeat 10-fold cross-validation achieving an AUC of 0.91 (Blood. 2024;144[Suppl 1]:2617). TTP-14 generates a predicted probability for iTTP, expressed as a continuous percentage estimate of iTTP diagnostic likelihood, and is also able to do so with missing variables. However, it has not previously been externally validated. Objectives To externally validate the ability of TTP-14 to predict iTTP diagnosis and improve upon the PLASMIC score. Methods We performed an external validation of TTP-14 using an independent cohort of patients with suspected iTTP at the Mayo Clinic. These patients were not part of the original multi-center development cohort of 106 iTTP patients from the University of Utah, Case Western Reserve University, Rochester Regional Health, and University of Illinois. For the validation cohort, we identified patients who underwent ADAMTS13 activity testing between 2010 and 2025 for evaluation of thrombotic microangiopathy at the Mayo Clinic. iTTP was defined as ADAMTS13 activity <10%, and controls as ADAMTS13 activity >20%. TTP-14 variables were collected at initial presentation: platelet count, lactate dehydrogenase, creatinine, international normalized ratio, reticulocyte percentage, active cancer, indirect bilirubin, mean corpuscular volume, total bilirubin, haptoglobin, neurologic deficit, hemoglobin, age, and history of transplant. Receiver operating characteristic curve (AUC) was reported with 95% confidence intervals (CI). While the model provides a continuous estimate and is not categorical, we evaluated clinically meaningful probability thresholds to illustrate performance in decision-relevant zones. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were reported at these select thresholds and analyzed for patients with and without missing variables. Result We included 50 iTTP patients and 56 controls in the external validation cohort. 13 patients had missing PLASMIC variables. TTP-14 achieved an AUC of 0.96 (95% CI: 0.93–0.99), outperforming the PLASMIC score's AUC of 0.90 (95% CI: 0.83–0.96) in the same dataset, and improving upon TTP-14's previously reported cross-validated AUC of 0.91 (95% CI: 0.90–0.92) in the development cohort. Among patients with complete data (n = 93), applying select thresholds for clinical relevance demonstrated: Low risk cut-off (<5% predicted iTTP risk): Sensitivity = 98% Specificity = 71% PPV = 76% NPV = 97% Accuracy = 84% High risk cut-off (≥50% predicted iTTP risk): Sensitivity = 71% Specificity = 98% PPV = 97% NPV = 78% Accuracy = 85% In the full cohort (n = 106) that included those with missing PLASMIC variables, TTP-14 maintained excellent predictive performance with AUC = 0.95 (95% CI: 0.92–0.99). Performance metrics analyzed using the above thresholds also yielded similar results. Conclusion External validation of TTP-14 demonstrated high predictive accuracy for iTTP diagnosis (AUC = 0.96). TTP-14 outperformed the PLASMIC score in the validation cohort (AUC = 0.96 vs 0.90, respectively). TTP-14 offers more flexibility than the PLASMIC score by generating predictions even with incomplete data, and maintained excellent performance in the cohort that included those with missing variables (AUC = 0.95) Its refined accuracy and ability to predict iTTP despite missing data provide a key advantage, offering an alternative tool to improve rapid iTTP diagnosis. TTP-14 may help enhance early recognition and treatment of iTTP while reducing unnecessary interventions in non-TTP patients.

Abstract Introduction: Aplastic anemia (AA) affects approximately 1 in a million people per year in the United States and can present as a new diagnosis, progression, or relapse during pregnancy. Due to the rarity of the disease, there are limited data on its clinical presentation, hematologic parameters, treatment strategies, and maternal-fetal outcomes to guide diagnosis and management. Methods: We conducted a comprehensive literature review using PubMed, Google Scholar, and ScienceDirect to identify peer-reviewed studies published between 2001 and 2024. Articles were selected based on relevance and availability of clinical outcome data. We included cases of AA that were active during pregnancy—newly diagnosed, relapsed, or persistent. Data collected included patient demographics (age, sex), AA status (blood counts, disease severity, timing of presentation, management, and complications), fetal outcomes (gestational age and mode of delivery), and birth complications. Results: A total of 53 cases of AA during pregnancy were identified. Of these, 12 were diagnosed during pregnancy and 11 prior to pregnancy. For the 12 cases that developed during pregnancy, diagnoses were made across all trimesters: first (n=6), second (n=4), and third (n=2). Notably, in one patient, AA was active during the third and fourth pregnancies but not during the first or second, suggesting that AA can present intermittently across pregnancies in the same individual. The timing of diagnosis was unspecified in the remaining 30 cases. The median maternal age at AA diagnosis was 26.5 years (range: 19–38), and the median gestational age at birth was 37 weeks (range: 31–40). Among cases where timing was reported, 21% were diagnosed before pregnancy and 23% during pregnancy. Severity was reported in all 53 cases: 72% were classified as non-severe, 26% as severe, and 2% as very severe. Cesarean section was the primary delivery method in 66% of cases. At the time AA was diagnosed or active during pregnancy, median laboratory values were: hemoglobin 7.3 g/dL (range: 3.0–11.8), platelet count 26 × 10⁹/L (range: 8.0–103), and absolute neutrophil count 1.0 × 10⁹/L (range: 0.4–4.0). Maternal and fetal outcomes were reported in 60% and 59% of cases, respectively. Maternal complications included gestational hypertension (6%), gestational diabetes mellitus (6%), infections (23%), and bleeding (26%). Fetal outcomes were generally favorable, with approximately 57% of infants reported as healthy at birth. However, adverse outcomes such as preterm delivery (19%), intrauterine growth restriction (6%), low birth weight (6%), and neonatal intensive care unit admission (9%) were also observed. Maternal and fetal mortality occurred in 4% and 2% of cases, respectively. Treatments administered during pregnancy included red blood cell transfusions (17%), platelet transfusions (17%), and cyclosporine (15%). In the postpartum period, some patients required additional therapies: antithymocyte globulin (4%), eltrombopag (6%), and hematopoietic stem cell transplantation (8%). Conclusion: Aplastic anemia during pregnancy remains rare and clinically complex, with variable timing, severity, and outcomes. Our review underscores the need for early recognition and multidisciplinary management to reduce risks to both mother and fetus. The observation that AA may occur in some pregnancies but not others within the same individual raises important questions about underlying disease mechanisms. Broader, systematic studies are needed to clarify these patterns and to inform safer, more effective treatment strategies during pregnancy.

Abstract Background Chimeric antigen receptor T-cell (CAR-T) and bispecific antibody (BsAb) therapies are both effective for patients with relapsed/refractory (R/R) follicular lymphoma (FL), but differ in treatment schedules and associated “time toxicity,” or contact days spent physically interacting with the healthcare system. While contact days can be estimated from clinical trials, real-world data provides a more nuanced depiction of treatment-related time burden, which may guide treatment decision-making. The comparative time toxicity of CAR-T vs BsAb in R/R FL is not defined. Methods We conducted a multicenter retrospective study of adults with R/R grade 1-3A FL who received standard-of-care CAR-T (axi-cel, tisa-cel, liso-cel) or BsAb (mosunetuzumab, epcoritamab) in the third-line or later setting before Jan 1, 2025. Time toxicity was defined as outpatient or inpatient days with physical health care system contact, counting multiple visits on the same day as only one day. All days after treatment initiation were counted, regardless of disease progression, therapy completion, or relation to FL therapy. Median contact days over 1-year time horizon were compared, stratified by CAR-T vs BsAb, prior lines of therapy (LOT, 2 vs 3+), and time intervals (0-1, 1-3, 3-6, 6-9, and 9-12 months). Progression-free survival (PFS) and overall survival (OS) were calculated from day of CAR-T infusion or day 1, cycle 1 for BsAb. Cox regression and propensity matching (by age, ECOG, refractory to prior LOT, POD24) were used to assess predictors and survival associations with contact days. Results Among 209 patients from 15 U.S. academic centers, median age was 64, 37% were female, 61% received CAR-T (80% axi-cel, 7% liso-cel, 13% tisa-cel) and 39% BsAb (93% mosun, 7% epcor). Most had Grade 1-2 FL (72%), advanced stage (84%), and extranodal disease (51%). Median prior LOT was 3 (range 2-15), 41% were refractory to prior LOT, and 52% had POD24. Median number of BsAb doses was 10 (range 1-36). Patients receiving BsAb were significantly older (p<.01) and had higher CIRS comorbidity scores (p<.02) in both 2 and 3+ prior LOT cohorts, and had higher ECOG scores (p=.01) and were less likely to be refractory to prior LOT (p=.029) in 3+ LOT cohort. There were no differences in POD24 rates between CAR-T and BsAb. Median PFS for the entire cohort was 3.6 yrs; median OS was not reached. In the 2 prior LOT cohort (N=75), 60% received CAR-T and 40% BsAb. With median follow-up of 1.5 years, median PFS was not reached for CAR-T and 1.6 yrs for BsAb (p<.0001). In the 3+ prior LOT cohort (N=134), 62% received CAR-T and 38% BsAb. With median follow-up of 2 yrs, median PFS was 3.6 yrs for CAR-T and 1.6 yrs for BsAb (p=.0044). In propensity matched analysis, PFS was shorter for BsAb in both 2 LOT (HR 9.0, 95% CI 1.14-71.04, p=.037) and 3+ LOT (HR 3.25, 95% CI 1.06-9.97, p=.039) cohorts as compared to CAR-T. There were no significant differences in OS between CAR-T and BsAb. Median contact days were significantly higher for CAR-T vs BsAb in the 0-1 month interval: 19 vs 8 days in 2 LOT (p<.0001) and 18 vs 7 days in 3+ LOT (p<.0001) cohorts. There were no differences in contact days between CAR-T vs BsAb in subsequent time intervals. Over 1 year, CAR-T had significantly more time toxicity than BsAb: median 51 vs 36 contact days in 2 LOT (p<.0001) and 64 vs 38 days in 3L+ LOT (p<.0001) cohorts; these remained significant in the matched analysis. B symptoms (p=.04) and Grade ≥3 cytopenias (p=.007) were associated with higher contact days in 3+ LOT cohort in univariable analysis. Higher contact days were associated with inferior PFS (HR 1.01, 95% CI 1.00-1.02, p=.032) and OS (HR 1.01, 95% CI 1.00-1.02, p=.038) in 3+ LOT cohort regardless of treatment type. Discussion In this large real-world cohort of patients with R/R FL, CAR-T therapy resulted in better PFS but more time toxicity over the first year as compared to BsAb therapy. Excess time toxicity from CAR-T was driven by more contact days in the first month of treatment. This study provides benchmark data for counseling patients about expected time burden of CAR-T (51-64 days) and BsAb (36-38 days) over the first year of these therapies. Further, with superior PFS of CAR-T in this study and minimal impact of time toxicity on survival outcomes, these data can be used to better support shared decision-making in R/R FL by addressing patient preferences regarding both contact days as well as duration of disease control.

Abstract Background Hairy cell leukemia (HCL) is a rare, indolent B-cell malignancy accounting for ~1% of all lymphoid neoplasms. While purine analogs remain the standard first-line therapy, the increasing use of combination regimens and targeted agents has expanded the therapeutic landscape. Data on long-term outcomes in real-world practice remain limited. Methods This is a retrospective, multicenter cohort study. We included 104 patients aged ≥18 years with a diagnosis of HCL who had at least one oncology visit from January 1, 2010, to July 17, 2025. Patients diagnosed prior to 2010 were left-truncated to account for survivorship bias. Data were abstracted from electronic medical records. Key outcomes included treatment patterns, response rates, overall survival (OS), and progression-free survival (PFS). Results The median age at diagnosis was 56.9 years (range 32.1–83.8), and 80% were male. Most patients (77%) were diagnosed during or after 2010. The most frequent frontline therapies were cladribine (63%), cladribine with rituximab (12%), rituximab monotherapy (9.7%), vemurafenib-based regimens (7.7%), splenectomy with or without interferon (3.8%), interferon monotherapy (2.9%), and other (1.9%). The overall complete response (CR) rate to first-line therapy was 63%, with 15% achieving a partial response (PR) and 22% having stable or no response. For patients receiving cladribine with rituximab first-line (n = 12), 92% had a CR. For patients receiving cladribine monotherapy first-line (n = 65), 63% had a CR and 12% had a PR. For patients receiving rituximab monotherapy first-line (n = 10), 50% had a CR and 20% had a PR. For patients receiving vemurafenib-based regimens first-line (n = 8), 75% had a CR. Among the 39 patients who received second-line therapy, the most common regimens included cladribine (31%), rituximab (26%), cladribine plus rituximab (18%), and vemurafenib-based regimens (13%). The CR rate after second-line therapy was 72%. For patients receiving cladribine with rituximab second-line (n = 7), 86% had a CR and 14% had a PR. For patients receiving cladribine monotherapy second-line (n = 12), 67% had a CR. For patients receiving rituximab monotherapy second-line (n = 10), 80% had a CR and 10% had a PR. For patients receiving vemurafenib-based regimens second-line (n = 5), 40% had a CR and 20% had a PR. Among the 17 patients who received third-line therapy, the most common regimens included rituximab (41%), cladribine (18%), and vemurafenib-based regimens (18%). The CR rate after third-line therapy was 50%. For patients receiving rituximab monotherapy third-line (n = 7), 43% had a CR and 14% had a PR. For patients receiving cladribine monotherapy third-line (n = 3), 33% had a CR. For patients receiving vemurafenib-based regimens third-line (n = 3), 67% had a CR and 33% had a PR. Overall, treatment-related hospitalizations for first-line therapy occurred in 27% of patients. 50% of patients receiving first-line cladribine with rituximab had treatment-related hospitalizations. 25% of patients receiving first-line vemurafenib-based treatment had treatment-related hospitalizations. 23% of patients receiving first-line cladribine monotherapy had treatment-related hospitalizations. 20% of patients receiving first-line rituximab monotherapy had treatment-related hospitalizations. Overall, after a median follow-up of 6.6 years (range 0.1–46), estimated OS was 96.6% at 5 years, 85.7% at 10 years, and 80.3% at 15 years. The median OS was 24.5 years [95% CI: 18.3, not reached]. Estimated PFS was 95.1% at 1 year, 89.9% at 3 years, 74.8% at 5 years, and 50.8% at 10 years. Median PFS was 12.2 years [95% CI: 7.0, not reached]. Estimated OS for first-line cladribine monotherapy was 100% at 5 years and 86.5% at 10 years. Estimated OS for first-line vemurafenib-based treatment was 85.7% at 5 years and 85.7% at 10 years. Conclusions This large real-world cohort provides important insights into the long-term management of HCL. Cladribine-based regimens remain the predominant first-line approach, with high response rates and durable remissions. However, treatment-related toxicity is common. Outcomes in later lines remain favorable, particularly with re-treatment using purine analogs or combination regimens. These findings underscore the importance of individualized treatment planning and the continued need for real-world evidence to inform care in rare hematologic malignancies.

Abstract Background: There remains an opportunity for new therapies to improve long-term outcomes for patients with low-tumor burden follicular lymphoma (FL). Mosunetuzumab is an off-the-shelf CD20xCD3 bispecific antibody, approved as an intravenous therapy for patients with relapsed/refractory FL after ≥2 lines of systemic therapy. Mosunetuzumab can be administered in the outpatient setting as a fixed-duration regimen. In an open-label, multicenter, Phase II study conducted mainly across US community sites (MorningSun; NCT05207670), mosunetuzumab administered subcutaneously (SC) induced high response rates with a manageable safety profile in patients with previously untreated low-tumor burden FL (Burke et al. ASH 2024). Here we present updated efficacy and safety data for mosunetuzumab SC in patients with previously untreated, low-tumor burden FL. Methods: Patients had untreated Grade 1 or 2 low-tumor burden FL per Groupe d'Etude des Lymphomes Folliculaires criteria, Ann Arbor stage III/IV disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2. Mosunetuzumab SC was administered with step-up dosing in Cycle 1 (Day [D]1, 5mg; D8, 45mg; D15, 45mg), then 45mg on D1 of each 21-day cycle. Hospitalization was not mandatory. Patients with a complete metabolic response after 8 cycles could complete therapy and patients with a partial metabolic response or stable disease continued treatment for up to 17 cycles. The primary endpoint was progression-free survival (PFS) at 24 months. Key secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), duration of response (DOR), duration of complete response (DOCR), and safety. Exploratory analyses assessed pharmacodynamic changes in B-cell subsets. Here, we report interim data. Results: As of February 10, 2025 (clinical cut-off date), 101 patients were enrolled from US community (n=56) and academic (n=45) centers; 52 patients had completed treatment, 21 had discontinued (mainly due to adverse events [AEs; n=6] and progressive disease [n=5]), and 28 were ongoing on treatment. Median age was 65 years (range: 34–82). Most patients had an ECOG PS of 0 (81.2%) or 1 (18.8%) and 43 patients (42.6%) had extranodal involvement. Median duration of follow-up was 13.8 months (95% confidence interval [CI]: 11.5–16.9) and median number of cycles received was 10 (range: 3–17). The ORR was 98.0% (95% CI: 93.0–99.8) and the complete response rate was 89.1% (95% CI: 81.3–94.4). Median TTR was 2.8 months (range: 1.4–8.3). Landmark DOR and DOCR rates at 12 months were 91.8% (95% CI: 81.5–96.5) and 95.7% (95% CI: 82.6–99.0), respectively. The 12-month PFS and OS rates were 92.0% (95% CI: 83.8‒96.1) and 99.0% (95% CI: 93.2‒99.9), respectively. The most common AE was injection-site reaction (ISR, 81.2%; Grade 1, 74.3%; Grade 2, 5.9%; Grade 3, 1.0%). Grade 3/4 AEs were reported in 51.5% of patients; the most common (≥10%) events were cytopenias (36.6%) and infections (11.9%). Cytokine release syndrome (CRS) was reported in 48.5% of patients (Grade 1, 40.6%; Grade 2, 7.9%). Overall,infections occurred in 63.4% of patients (Grade 1, 7.9%; Grade 2, 42.6%; Grade 3, 11.9%; Grade 5, 1.0%) with the most common (≥10%) being upper respiratory tract infection (21.8%), COVID-19 (17.8%), sinusitis (13.9%), and pneumonia (11.9%). At the time of data cut-off, ISR, CRS, and infection AEs were resolved at rates of 98.2%, 100%, and 89.0%, respectively. Two patients had a Grade 5 AE (sepsis, n=1; unknown cause, n=1).No immune effector cell-associated neurotoxicity syndrome events were reported. B-cell depletion was observed following the first dose of mosunetuzumab, with subsequent B-cell recovery observed within six months of treatment completion. Conclusions: Fixed-duration mosunetuzumab SC demonstrates high efficacy rates with deep and sustained responses in patients with previously untreated, low-tumor burden FL. The manageable safety profile supports ease of outpatient administration without mandatory hospitalization, including in community oncology practices. Additionally, exploratory analyses demonstrating B-cell recovery after treatment completion also substantiate the use of mosunetuzumab SC as a fixed-duration regimen. These data support further evaluation of mosunetuzumab SC in patients with previously untreated, low-tumor burden FL.

Abstract INTRODUCTION Outcomes for 1st relapse of pediatric B-lymphoblastic leukemia (B-ALL), especially high/intermediate-risk (HR/IR) relapse, remain unacceptably poor. Limited enrollment of this population on cooperative group clinical trials has impeded our ability to study potentially effective regimens. In the current era, patients can access innovative immunotherapies commercially. However, there is no mechanism to capture outcomes for these off-study patients and no comparative effectiveness data to guide treatment selection. METHODS We conducted a multicenter, retrospective study of patients <30 years who initiated 1st relapse therapy at a participating center from 2018-2022 (ReCALL-1 Study). Objectives were to define real-world survival outcomes, compare response rates of reinduction strategies, describe the post-reinduction treatment landscape, and, for patients with HR/IR relapse, assess the comparative effectiveness (CE) of blinatumomab to hematopoietic cell transplant (blina/HCT) v CD19 CAR T cells (CART). For the CE analysis, we emulated an open-label, randomized study of blina/HCT v CART who achieved an M1/M2 marrow at the end of an intensive reinduction (EoRI). Patients were classified by their intended treatment at EoRI. Cox regression models were used to adjust for unbalanced patient and disease features by arms. The primary outcome was overall survival (OS) from EoRI. RESULTS The full cohort included 479 patients from 33 centers (31 US, 2 international). Median time to relapse was 31 months (m); 77% had bone marrow (BM) involvement and 31% central nervous sytem involvement. With a median follow-up of 49m from relapse, 4 year (y) OS, event-free survival (EFS), and non-relapse mortality (NRM) were 64%, 43%, and 13%, respectively. Among patients with very early BM (<18m, n=79), early BM (18-35m, n=76), late BM (≥36m, n=162), and isolated CNS (n=85) relapses, 4y OS/EFS were 29%/20%, 57%/35%, 78%/49%, and 84%/61%, respectively. Only 19% received reinduction therapy on a clinical trial. Among patients with BM disease, R3 reinduction (n=179) and VXLD (n=61) had identical MRD-negative (<0.01%) CR rates of 38% (p=1.00) and equivalent treatment failure (TF; M3 or extramedullary disease) rates: R3, 8% v VXLD 7%, p=0.79. Blina (n=33) and inotuzumab-based (n=21) reinductions achieved MRD-negative CR rates of 39% and 52%, respectively, but higher TF rates of 39% and 24%. Reinduction mortality was 2%: R3, n=5; VXLD, n=3; 3-drug reinduction, n=1. Overall, as part of 1st relapse therapy, 36% received CART (78% commercial product), 44% HCT, 40% blina, and 11% inotuzumab. The emulated trial included 159 patients, 95 on blina/HCT and 64 on CART. Study arms were well matched by demographics, cytogenetics, and relapse sites, but CART patients were more likely to have relapsed <18m from diagnosis (34% v 24%) and have EoRI M2 marrows (31% v 11%), and less likely to have private insurance (36% v 51%). Unadjusted OS was comparable between arms (log rank p=0.18): CART, 60% at 4y; blina/HCT, 71%, as was NRM (10% v 13% at 4y). EFS was lower for CART (p=0.049): 4y EFS 35% v 49% for blina/HCT. After adjustment for unbalanced covariates, the hazard of death was equivalent for CART as compared to blina/HCT (aHR 1.1, 95% CI 0.6-2.1, p=0.67) and EFS became more comparable (aHR 1.3, 95% CI 0.8-2.1, p=0.22). 91% of blina/HCT and 97% of CART received their intended cell therapy; time from EoRI to cell therapy was shorter for CART (67 v 86 days, p<.001). In the CART arm, 34% underwent consolidative HCT; 1/3 were preplanned and 2/3 due to loss of B cell aplasia or NGS-MRD positivity. Of those with a 2nd relapse, CART patients were more likely to be CD19 negative (47% v 10%, p=0.003). CONCLUSION In this multicenter, real-world cohort of children treated for 1st relapse in the immunotherapy era, suboptimal outcomes for early BM relapse persisted, with particularly dismal 4y OS of 29% for relapses <18m after diagnosis. In contrast, survival for late BM and isolated CNS relapses compared favorably to historic data. Only 1 in 5 patients initiated relapse therapy on a clinical trial and although 1st relapse is not an approved indication for commercial CART in pediatrics, 36% received CART. In an emulated trial of post-reinduction blina/HCT v CART, adjusted EFS and OS were comparable, suggesting that CART may be a viable alternative to HCT for select patients. Post hoc analyses will identify whether specific subgroups may benefit more from one strategy.

Abstract SWOG 1318 evaluated the feasibility of combining the tyrosine kinase inhibitor (TKI) dasatinib with prednisone and blinatumomab in older patients (pts) with Philadelphia chromosome positive (Ph+) B-acute lymphoblastic leukemia (ALL). Here, we present longer follow up (median follow up 5.6 years) with outcomes, predictors of response, and translational medicine studies. Methods: This trial was activated through the NCTN in January 2014 and closed to accrual in April 2021. Pt eligibility included: age > 65 years, Ph+ ALL, no evidence of central nervous system (CNS) disease, and adequate organ function. Treatment has been previously described (Blood Adv 2023; 7(7): 1279-85). Statistics: Categorical and quantitative endpoints comparisons used Fisher's exact and Wilcoxon tests. Survival endpoints used the Kaplan-Meier method and Cox regression models and were landmarked for post-baseline events as needed (i.e., number of cycles). Translational medicine studies: Single cell ATAC seq (10x genomics) was performed on 9 archived cryopreserved diagnostic samples from patients with > 500,000 cells. All samples successfully completed library preparation, sequencing, and demonstrated adequate blast clusters for analysis. Briefly, cryopreserved cells were thawed, and transposases were introduced into nuclei in single cell suspension and used to generate GEM beads. ATAC seq libraries were prepared per manufacture instructions. Libraries were then sequenced on a 25B flow cell on Novaseq X plus (Illumina). The data were analyzed with cloupe (version 9.0.0). Results: Twenty-four eligible patients were enrolled. The median age was 73 years (range 65-87). All pts had newly diagnosed Ph+ ALL. Seventy-nine percent of pts had additional cytogenetic abnormalities. Twenty-two pts (92%) achieved a complete remission (CR) during dasatinib and prednisone induction therapy. Most sites also monitored patient's blood or bone marrow with real-time quantitative PCR to quantify the BCR-ABL1 transcript for molecular response. Of 19 patients analyzed 17 (89%) were in a major or complete molecular remission at some point after treatment, with at least 12 of these patients achieving complete molecular remission. Three patients remain on maintenance. The median follow up for patients who are alive is 5.6 years (range 4.4-8.3). Five- year OS and DFS estimates are 63% (95% CI: 40-78%) and 64% (95% CI: 40-80%). Two patients relapsed in the CNS. One pt proceeded to allogeneic hematopoietic stem cell transplant (HSCT) and 1 to autologous HSCT. Increased age was associated with a decreased chance of achieving CR as best response (median age in responder group 73.2 years [range 65-82.9]; median age in non-responder group 85.5 [range 83.8-87.3]; p=0.02). Patients with extramedullary disease had shorter DFS (HR 0.22, 95% CI 0.04-1.15, p=0.07). Increased number of cycles of blinatumomab received was associated with a trend towards improved OS (HR 0.66, 95% CI 0.41-1.08, p=0.10). Translational medicine studies for chromatin accessibility in the blast clusters demonstrated improved OS in patients with homogeneous blast clusters (HR 0.42, 95% CI 0.06-3.04, p=0.39), high DUX4 differential accessibility (HR 0.26, 95% CI 0.03-2.55, p=0.25), and ATAC seq data corresponding to decreased chromatin accessibility in HOXA2 (HR 0.09, 95% CI 0.01-1.05. p=0.06). Conclusions: Despite an elderly population, this trial demonstrated impressive outcomes with longer follow-up for patients with Ph+ ALL. The number of cycles of blinatumomab and the presence of extramedullary disease may be important factors in outcome. Translational studies suggest additional markers may be predictors of overall survival, and these will need to be studied on larger scale studies. Decreased chromatin accessibility to HOXA2 was associated with a trend towards improved OS. Additional translational medicine will also be presented at the meeting.

Abstract Introduction: Brexu-cel is a highly effective treatment for R/R B-ALL, with complete responses achieved in 71% of patients (pts) treated in the pivotal ZUMA-3 trial. Patients with B-ALL with high-risk (HR) genetics are known to have inferior outcomes with chemotherapy, but little is known about the influence of HR ALL genetics on responses to chimeric antigen receptor (CAR)-T in adults. In this study, we assessed the impact of HR ALL genetics on outcomes in a large cohort of adult patients treated with brexu-cel for R/R Philadelphia chromosome (Ph)-negative B-ALL. Methods: Patient characteristics and outcomes were obtained from the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) database which includes data from 40 U.S. centers. NCCN guidelines (NCCN Guidelines in Oncology, ALL v2.2025) were used to define HR B-ALL genetics; lack of HR genetics was defined as standard-risk (SR). The primary outcome was event-free survival (EFS), defined as lack of response, disease progression, or death from any cause. Secondary outcomes were overall survival (OS), relapse free survival (RFS) and response rates including complete response (CR), CR incomplete count recovery (CRi), measurable residual disease negative CR (MRD-) by flow or NGS and progressive disease (PD). Multivariable models were adjusted for age, pre-infusion blast percentage, prior allo-HCT, and post CAR-T allo-HCT (modeled as a time-varying covariate). Results: The cohort included 286 pts: 169 with HR and 117 with SR B-ALL. The HR cohort included TP53m (n=24, 14%), KMT2Ar (n=16, 9%), CRLF2r (n=65, 39%) and other HR genetics such as JAK2 and other Ph-like, IKZF1, complex cytogenetics (n=64, 38%). Relative to SR pts, HR pts were more commonly Hispanic (50% vs 28%). HR and SR pts had similar disease burden pre-apheresis (>5% blasts: 58% vs 53%), prior blinatumomab (60% vs 58%), prior inotuzumab (42% vs 46%), and prior allo HCT (27% vs 37%). The presence of CNS disease (11% HR vs 12% SR) and extramedullary disease (EMD, 22% HR vs 29% SR) at apheresis was also similar. CR/CRi was achieved in 90.5% of evaluable HR pts (n=147) and 90.2% of evaluable SR pts (n=102); MRD- rates were also similar between HR and SR pts at 78.9% and 78.2% respectively. In unadjusted analyses, EFS did not significantly differ between HR pts (median 9.6 mos; 1-yr: 46%, 95% CI 38%-54%) and SR pts (median 11.6 mos; 1-yr: 48%, 95% CI 38%- 58%). Median RFS (HR: 12.2 mos, SR: 13.3 mos) and median OS (HR: 22.4 mos, SR: 21.0 mos) were also similar. Multivariable models demonstrated no significant associations between HR B-ALL and EFS (HR 1.09, 95% CI 0.73-1.63), RFS (HR 1.13, 95% CI 0.71-1.80), or OS (HR 0.96, 95% CI 0.62- 1.48) relative to SR ALL. 28% of HR patients and 21% of SR patients underwent consolidative allo-HCT. Among the HR subgroup, CR/CRi rate was lowest in KMT2Ar (71%) relative to TP53m (95%), CRLF2r (95%), and other HR genetics (89%). The median EFS was lowest in KMT2Ar (4.1 mos), followed by TP53m (6.9 mos), CRLF2r (11.6 mos), and other HR (11.1 mos). Median OS was also lowest in KMT2Ar (6.8 mos) vs 22.4 mos in TP53m and not reached in CRLF2r or other HR. PD was highest in KMT2Ar pts (29%), as compared to 11% HR other, 10% SR, and 5% TP53 and CRLF2r. The rate of relapse among those that achieved CR across the groups was similar and ranged between 28% -40%. Rates of CD19 negative relapse were similar between all subgroups (13%-15%), however 21% of KMT2A pts underwent myeloid transformation as compared 0% for TP53 and CRLF2 pts, and 2% among other HR and SR pts. 25% of KMT2Ar patients underwent consolidative allo-HCT as compared to 32% CRLF2 pts, 29% TP53 pts, 25% other HR pts and 21% SR pts. Multivariable models evaluating the different genomic subgroups demonstrated that relative to SR B-ALL, only KMT2Ar was associated with inferior OS (HR 3.17, 95% CI 1.53-6.58, p=0020). No associations were seen between HR subgroups and EFS. Conclusion: To our knowledge, this analysis represents the largest examination of adult B-ALL recipients of CAR-T assessed by genomic risk group. We found that response rates and survival outcomes following brexu-cel were similar among HR and SR B-ALL pts, including pts with TP53m and CRLF2r. However, pts with KMT2Ar had lower response rates and dismal EFS and OS, with higher rates of PD and myeloid transformation at relapse, suggesting that alternative strategies are necessary to improve outcomes for patients with R/R KMT2Ar B-ALL.

Abstract Cardiac involvement in AL amyloidosis significantly impacts both short and long-term survival. Achieving cardiac complete response (CarCR) is linked to excellent survival, comparable to that of the general population. We undertook this study to characterize patients with AL amyloidosis who achieved CarCR. Methods: A single-center retrospective study of patients diagnosed with cardiac AL amyloidosis between 2004 and 2023 and achieved a documented CarCR for at least 12 months. Patients were included if they had evidence of cardiac involvement confirmed by cardiac imaging (transthoracic echocardiogram or cardiac magnetic resonance) and Congo red–positive tissue (non-cardiac or heart biopsy), and were evaluable for cardiac response based on baseline NT-proBNP > 650 pg/mL or BNP > 150 pg/mL. CarCR was defined as a reduction in NT-proBNP to less than 350 pg/mL (or BNP less than 80 pg/mL). Heart transplant patients were excluded. Results: Sixty-three patients were included, representing 4.6% of the cardiac evaluable population in the study period. This proportion increased in the second period compared to the first period (7.5% vs 3.2%, P<0.001). The median age at diagnosis of 57 years (ranging from 29 to 79); 63% were male. Lambda light chain disease was evident in 63% of patients. The median difference between the involved and uninvolved light chain (dFLC) at baseline was 429 mg/L (interquartile range [IQR] 143-708). While all patients had cardiac involvement, 63% also presented with extra-cardiac involvement [kidneys (52%), liver (16%), autonomic nerves (14%), luminal gastrointestinal tract (11%), and peripheral nerves (10%)]. The median baseline NT-proBNP for the entire cohort was 1977 pg/mL (IQR 1393-3026). The median troponin T (n=43) was 0.02 ng/mL (IQR <0.01-0.05) and the median high-sensitivity troponin T (n=19) was 49 ng/L (IQR 38-79 ng/L). Cardiac stage distribution, according to the European modification of the Mayo 2004 staging model, was as follows: 59% stage II, 39% stage IIIa, and 2% stage IIIb. At baseline, echocardiogram features included a median left ventricular (LV) ejection fraction of 63%, a median intraventricular septum thickness of 14 mm, and a median average LV longitudinal strain of -12%. The most common first-line therapies were autologous stem cell transplantation (ASCT; with or without induction, 54%), bortezomib-containing therapy (22%), and daratumumab-containing therapy (13%). Hematological complete response rates at 3-month, 6-month, and best response prior to CarCR were 32%, 49% and 76%, respectively. At CarCR, the median NT-proBNP was 265 pg/mL (IQR 220-307) with a median time from treatment onset to CarCR achievement of 20.6 months. At CarCR, 33% of patients were on loop diuretics. The CarCR rate at 6, 12, 24, 36, 48 and 60 months from treatment onset was 10%, 39%, 81%, 90%, 95% and 96%, respectively. Temporary increase of NT-proBNP above 350 pg/mL with return to CarCR was documented in 46% of patients. Echocardiogram parameters also improved significantly at the time of CarCR, with average left ventricular longitudinal strain showing the greatest median improvement in relation to baseline (from -12% to -17%, p<0.001). However, echocardiographic parameters did not fully normalize in all patients. Cardiac progression was seen in 14% of patients, at a median of 7.6 years from the initial time of CarCR. In addition, subsequent clone-directed therapy was given in 44% of patients at a median of 4.6 years from the initial treatment. With a median follow-up of 9.5 years, eight patients (13%) died, 4 due to causes unrelated to AL. We compared the survival of patients who achieved CarCR to the general U.S. population, matching for age, sex, and the year treatment. The observed survival of CarCR patients was similar to that of the general population (p=0.35). Conclusion: Patients with persistent CarCR >12 months in AL amyloidosis are uncommon and demonstrate excellent outcomes. The achievement of hematological CR was required in 3 out of 4 patients reaching a CarCR. Echocardiographic changes of amyloid infiltration may still persist in this highly favorable cohort, indicating that “complete” response refers primarily to functional and prognostic improvement, not necessarily a full restoration to pre-disease cardiac morphology and function. Achieving CarCR is associated with a low risk of cardiac progression, but the need for subsequent clone-directed therapy remains elevated.

Abstract Background: Gastrointestinal (GI) symptoms are frequent in patients (pts) with systemic light chain amyloidosis (AL), yet their clinical significance remains poorly defined. We investigated the role of symptomatic GI involvement in disease burden, survival, and organ-specific outcomes in a large single-center cohort. Methods From 2010–2025, 4,396 AL pts were evaluated at our center; 560 pts (13%) had provider-attributed symptomatic GI AL. Pts with localized AL or positive biopsy without GI symptoms were excluded (n=38). We analyzed relationships between GI symptoms, anatomic/histologic involvement, laboratory parameters, survival, and need for nutritional support using Wilcoxon rank-sum, Chi-square, Kaplan-Meier, and logistic regression tests. Results GI symptoms included early satiety (n=320/57%), diarrhea (n=189/34%), nausea (n=184/33%), abdominal pain (n=148/26%), dysphagia (n=119/21%), vomiting (n=75/13%), GI bleeding (n=74/13%), and heartburn (n=71/13%). Only nausea and GI bleeding were not associated with cardiac (n=366/65%) renal (n=274/49%) or hepatic (n=84/15%) AL, whereas dysphagia, early satiety and heartburn were more frequent with cardiac (all OR=1.7), abdominal pain and diarrhea with hepatic (OR=2 and 1.6, respectively), and vomiting with renal involvement (OR=2; all p<0.04). Autonomic involvement impacted GI symptoms, often without proof of parenchymal GI amyloid. Of the 124 pts with formal autonomic testing, only 44 (35%) had positive GI biopsies as compared to AL GI pts without proven autonomic involvement (240/436, 55%). Pts with autonomic involvement were more symptomatic than pts with positive GI biopsies, suffering more often from dysphagia (29% vs 19%), diarrhea (41% vs 32%), and gastroparesis (34% vs 9%, all p<0.001). We screened changes in body weight, calcium, VitB12, Hb, PO4, and albumin at diagnosis. Of the 175 pts with documented weight loss in this cohort, pts with GI AL lost more weight compared to those with other organ involvement (21% vs 14% of weight, p=0.002), and had lower phosphate (3.7 vs 4.0 mg/dL, p=0.06). In our cohort of pts with GI symptoms, 298 (53%) had a positive GI biopsy. Biopsy-proven anatomic involvement dictated symptoms (all p<0.05): Of the 20 pts with positive esophageal biopsy, dysphagia was present in 45%; only 33% of the pts without an esophageal biopsy had dysphagia. Similar patterns were seen for the 170 pts with a positive gastric biopsy (n=170) in terms of heartburn (21% vs 11%), for the 165 pts with positive small bowel biopsies in terms of abdominal pain (68% vs 32%), and for the 130 pts with positive colon biopsies and diarrhea (46% vs 33%). Specific histopathological patterns were prognostic. Mucosal involvement (n=161) was an independent risk factor for survival compared to submucosal (n=64) and vascular (n=102) involvement throughout the GI tract (HR 1.83; p=0.03). Three-layer GI infiltration was associated with inferior mOS (2.4 vs 5.1 vs 7.8 y for 3 vs 2 vs 1-layer involvement, HR 3.19/1.56/1; p<0.05). Counterintuitively, vascular involvement had the lowest risk of bleeding in all GI anatomic sites (p=0.02). In the colon, only mucosal involvement was associated with a higher risk of bleeding (OR=5; p=0.04). GI involvement in AL pts did not worsen prognosis (mOS 10.0/6.3y, p=0.02), and pts with isolated GI AL (n=74/13%) had an even better survival (55% surviving at 10 y). Cachexia (n=120; mOS 3.5 vs 7.8 y, p<0.001), need for nutritional support (n=36; mOS 0.9 vs 7.0 y, p<0.001), and diarrhea (mOS 5.8 vs 6.9 y, p=0.06) were risk factors for death. In pts with hematologic response (≥PR), bleeding did not recur within 3 y (n=27), but even with response, diarrhea (n=160) persisted in 39%. Resolution was less frequent without hematologic response (persistence in 69%, OR=3.5). Improvement was most often due to treatment of bacterial overgrowth (11/35 pts; 68%) and loperamide (54/59 pts; 91%). Conclusion In AL, meaningful GI involvement is defined by nausea, diarrhea, occurrence of bleeding, and malnutrition. These are primarily associated with mucosal infiltration. GI symptoms can occur in the face of autonomic involvement. While long-term persistence of GI bleeding is rare after serologic response, cachexia and persistent diarrhea drive morbidity, need for nutritional support, and poor survival.