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Abstract Introduction Venetoclax combined with hypomethylating agents (VEN/HMA) is an approved frontline induction therapy for older or unfit patients with acute myeloid leukemia (AML). However, data comparing its efficacy and safety to intensive chemotherapy (IC) in intermediate-risk AML—characterized by molecular and cytogenetic heterogeneity—remain limited. Methods This multicenter, real-world retrospective study analyzed newly diagnosed intermediate-risk AML patients who received either VEN/HMA or IC. We evaluated composite complete remission (CRc) rates, transfusion and infection rates, long-term outcomes including overall survival (OS) and progression-free survival (PFS), and performed subgroup analyses to identify mutation-specific predictors of treatment response. Multivariable Cox regression was used to identify independent prognostic factors. Results A total of 229 intermediate-risk AML patients were included. VEN/HMA achieved a comparable CRc rate to IC (75.3% vs. 63.4%) with lower transfusion needs and fewer infections. Patients harboring FLT3-ITD, DNMT3A, or TET2 mutations showed greater benefit from VEN/HMA, while KIT-mutated patients responded more favorably to IC. Among patients who did not undergo allo-HSCT, VEN/HMA significantly improved 3-year OS (P = 0.001) and PFS (P = 0.008). No significant OS or PFS difference was observed in the allo-HSCT subgroup. In MRD-negative patients without transplant, those treated with VEN/HMA had superior OS compared to IC. Multivariable analysis identified VEN/HMA (HR = 0.613, P = 0.038) and allo-HSCT (HR = 0.11, P = 0.001) as independent predictors of better survival. Conclusions VEN/HMA is a safe and effective induction strategy for intermediate-risk AML, particularly in patients with BCL-2 inhibitor–sensitive mutations (FLT3-ITD, DNMT3A, TET2). These findings support a genotype-guided treatment approach in AML, complementing current risk stratification frameworks and informing individualized induction therapy decisions.

Abstract Background Extramedullary disease (EMD) in multiple myeloma (MM) represents an aggressive phenotype with poor outcomes. We performed single-cell RNA sequencing (scRNA-seq) on clonal plasma cells (CPCs) from EMD tissue, solitary plasmacytomas (SPM), and bone marrow aspirates (BMAs) from patients with MM to identify transcriptional states unique to EMD. Methods We processed FFPE tumor samples from EMD and SPMs and cryopreserved CD138+ BMAs from MM, using the 10x Genomics FLEX platform. Cells/nuclei were fixed, hybridized with Human WTA probes, pooled, and sequenced (10,000–40,000 cells/library) on NovaSeq X. After removing low quality cells, data was normalized and integrated using RPCA in Seurat. Plasma cell identity was assigned via Cellarium and canonical markers. Clonality was inferred by light chain restrictions and refined via random forest modeling. Cell cycle effects were regressed out to reduce proliferation bias. Results We analyzed 128, 908 CPCs from 16 samples [8 EMD (62, 669 CPCs), 4 SPM (20, 607 CPCs), 4 BMA (45, 632 CPCs)] and identified eight transcriptionally distinct cell clusters. Differential expression and pathway comparisons were performed between EMD/SPM/BMA within each of these clusters. Integration of gene expression and pathway analyses revealed consistent upregulation of cell cycle and E2F pathways in EMD. We identified two highly proliferative cell cycle clusters (Cluster 2 with S-phase genes and Cluster 4 with a G2/M transcriptional program) that were expanded in EMD compared to BMA and SPM. Cluster 0 comprised a quiescent CPC population enriched for RNA processing pathways alongside downregulation of ER stress and autophagy. EMD cells demonstrated suppressed interleukin signaling [fold change (FC) –33.8), and class I MHC antigen processing (FC –23.5) relative to BMA, suggestive of an immune suppressive transcriptional program. Angiogenesis-related genes [VEGFA (log2FC 2.4), ADM2 (log2FC 2.2)] and EZH2 [log2FC 2.1; q<0.0001)] were upregulated in EMD. Compared to SPM, EMD plasma cells in this cluster demonstrated marked downregulation of CD74 (log2FC –2.6; q<0.0001), a key modulator of MHC class II antigen presentation. Cluster 1 comprised of metabolically stressed secretory CPCs and displayed downregulation of early growth response pathways in EMD compared to BMA, concurrent with upregulation of E2F signaling. Suppression of IL-2/STAT5, IL-6/JAK/STAT3, and TGF-β pathways in EMD suggests reduced reliance on bone marrow–derived cytokines and impaired immunoregulatory signaling. CD44 was upregulated in EMD versus BMA (log2FC 3.2), consistent with its role in EMD spread and marrow independence. Cluster 3 was enriched for extracellular matrix–interacting plasma cells (COL1A1, MMP2) with upregulated epithelial–mesenchymal transition (EMT) pathways in EMD compared to both BMA (FC 7.5) and SPM (FC 7.07). Cluster 6 was defined by a migratory, motility-primed plasma cell population (CD44, AHNAK, LMNA and S100A10). Notably, IL32 was overexpressed in EMD compared to BMA (log2FC 5.1; adj. p = 2.02×10⁻¹⁴), a finding linked to hypoxia-driven proliferation. Compared to SPM, EMD cells also had elevated MYC/E2F activity and DNA repair, hallmarks of a proliferative phenotype. Cluster 5 displayed a strong interferon-stimulated gene signature (ISG15, IFIT1, TNFSF10), with enrichment of type I IFN, JAK–STAT, and TNF pathways. Within this inflammatory cluster, EMD exhibited marked suppression of immune signaling, metabolism (TCA, OXPHOS), and TP53 programs, consistent with an immune-evasive, metabolically suppressed, and deregulated state. Finally, within Cluster 7, a smaller subset defined by NFκB–driven anti-apoptotic transcriptional activity, EMD exhibited significant downregulation of KLF2 (log2FC –3.7; adj. p = 1.77×10⁻²⁷), likely reflecting disruption of the KDM3A–KLF2–IRF4 axis, a transcriptional network critical for bone marrow homing and plasma cell survival. We consistently observed downregulation of the MAPK pathway in EMD compared to BMA, aligning with prior bulk RNA-seq data and contrasting with the near-universal presence of MAPK mutations, highlighting a disconnect between mutational status and pathway activation. Conclusion In the largest yet reported single-cell transcriptional atlas of EMD and SPM, we demonstrate EMD to be highly proliferative with metabolic reprogramming, EMT, and downregulation of key immunologic signaling pathways, indicating immune escape and microenvironmental independence.

Abstract Background: Bispecific T cell engagers (BTCEs) have transformed the treatment of multiple myeloma (MM) and B cell malignancies by redirecting cytotoxic T cells toward malignant targets. While clinical responses can be deep and durable, the immunological determinants of BTCE efficacy, and mechanisms of eventual immune escape, remain poorly understood. Regulatory T cells (Tregs), enriched early in MM, are classically immunosuppressive, but whether they are modulated by BTCEs and contribute to therapeutic outcomes has not been systematically investigated. Methods We performed longitudinal single-cell RNA/TCR/ATAC-sequencing and immune profiling of 17 newly diagnosed multiple myeloma (NDMM) patients across induction therapy. 11 patients were treated with teclistamab plus daratumumab, lenalidomide, and dexamethasone (Tec-DRD, n = 11) in the ongoing MajesTEC-5 (HD10/DSMMXX) trial (NCT05695508). As controls, patients receiving standard-of-care DRD (n = 6) were included. Functional validation used newly established NDMM plasma cell-T cell co-cultures, real-time killing assays, cytokine ELISAs, intracellular flow cytometry and arrayed quantitative PCRs of key T cell signaling pathways. Mechanistic studies employed CRISPR-mediated perturbations and combination treatments with IMiDs. Generalizability was tested using three BTCEs in vitro: teclistamab (BCMA×CD3), blinatumomab (CD19×CD3), and glofitamab (CD20×CD3) to redirect primary human Tregs towards MM (MM.1S), lymphoma (Raji), and B-ALL (NALM-6) cell lines. Non-targeting BTCEs as well as anti-CD3 antibodies were used as controls. Preclinical in vivo studies used an immunocompetent, transplantable Bcma+ Vk*MYC tumor model treated with murinized BTCE surrogates and IMiDs. Results BTCE therapy induced robust transcriptional and epigenetic reprogramming of bone marrow Tregs into a FOXP3lowIL2RAlow cytotoxic phenotype (“exTregs”) expressing NKG7, GZMA/B, TBX21, and CCL5. In contrast, this Treg phenotype conversion was absent in DRD-treated controls. Although comprising only ~2% of marrow-infiltrating T cells, exTregs mediated direct plasma cell lysis in vitro, strictly dependent on BTCE-mediated antigen-specific synapse formation and not recapitulated by CD3 stimulation alone. IMiDs synergized with BTCEs by destabilizing the suppressive Treg phenotype via Helios (IKZF2) downregulation, augmenting granzyme and cytokine production. Single-cell ATAC-seq of Tregs isolated from Tec-DRD-exposed trial participants revealed increased chromatin accessibility at AP-1 motifs and we confirmed BATF/JUNB-driven AP-1 signaling as a central transcriptional axis orchestrating Treg effector conversion in vitro. This cytotoxic reprogramming was conserved across BTCEs targeting BCMA, CD19, and CD20, and validated in immunocompetent mouse models, indicating a generalizable, BTCE-driven mechanism of Treg repurposing, rather than target- or engager-specific biology. Conclusion Our findings uncover a novel mechanism by which BTCEs actively convert suppressive Tregs into cytotoxic, pro-inflammatory effectors that contribute to tumor clearance. We identified the BATF/JUNB transcriptional axis and IMiD-mediated Helios destabilization as targetable regulators of this process. These results redefine Treg function under BTCE pressure, support rational combination regimens with IMiDs, and suggest exTreg signatures as biomarkers and therapeutic targets to enhance T cell-redirecting immunotherapies across hematological malignancies.

Abstract Background: The Multiple Myeloma Research Foundation (MMRF) and its partners launched the MyDRUG platform clinical trial (NCT03732703) to evaluate the safety and efficacy of genomically-guided treatments for functional high-risk relapsed/refractory myeloma patients (fHRMM). fHRMM patients with no discernible activating mutations and who had received 1-3 prior therapies (exposed to at least one proteasome inhibitor and an IMiD) were given a combination of daratumumab (D), ixazomib (I), pomalidomide (P) and dexamethasone (d) (D-IPd) quadruplet therapy. The goal of this study is to evaluate the immunomodulatory effects of daratumumab-(anti-CD38)-based therapy on fHRMM patients enrolled in the MMRF-sponsored MyDRUG umbrella clinical trial over the duration of therapy and to correlate immune changes with patient response immediately following the first two cycles of therapy. Methods Bone marrow (BM) aspirates were collected at baseline (BL) prior to therapy, at the end of 2 cycles (EOC2), 4 cycles (EOC4) of the quadruplet therapy and at the end of treatment (EOT) or progressive disease (PD). CD138-negative bone marrow mononuclear cells were isolated for profiling the immune microenvironment using scRNAseq, scTCRseq and CyTOF. Results Single-cell RNA and TCR profiles were generated from ~90,000 cells across 41 samples from 16 subjects. scRNAseq identified CD3+ T cells, NK cells, classical and non-classical monocytes and B cells. CD8+ T cells were further resolved into their subsets including precursor (TPEX) and terminally exhausted T cells (TEX) within the bone marrow microenvironment. Within the CD8+ T cell compartment, an expansion of the effector memory (TEM) cell population was observed following 2-cycles of therapy (EOC2). However, this TEM expansion was not sustained at timepoint EOC4. Towards the end of therapy, enrichment of precursors to putative exhausted and terminal dysfunctional effector memory cells (TEMRA) was observed. Subjects with partial (PR), very good partial (VGPR) and complete (CR) best overall responses showed an initial increase in TEM cells followed by a slow expansion of TEX and TEMRAcells over time. One patient with progressive disease (PD) maintained the highest LAG3 expression across the cohort among CD8 T cell subsets (TEMRA, EM) and CD4 Tregs at baseline while observing a significant upregulation of PDCD1 in CD4 Tregs and CD8 Naive cells by EOC2. Cell-cell communication network analysis identified secreted ligands between responders (CR/VGPR) and partial responders (PR) at EOC2. Samples with PR exhibited upregulation of signaling of TNF from the CD8 Naïve compartment (p=0.048, Wilcoxon), IFNG from the CD8 EM (p=0.073, Wilcoxon) and TEMRA (p=0.048, Wilcoxon) populations along with IFNG (p=0.073, Wilcoxon) from NK cells. CD14+ and CD14+16+ Monocytes on the other hand showed enrichment of LGALS9 (p=0.03 (CD14+), p=0.048 (CD14+CD16), Wilcoxon) in the PR group at EOC2 relative to responders. Finally, longitudinal tracking of T cell clonality showed preferential progressive expansion of TEMRA cells after the therapy. We mapped hyperexpanded (more than 16 copies) clonotypes, presumed to be tumor-reactive, to various CD8+ T cell subsets. These hyperexpanded clonotypes are mapped to the TEMRA, TEX and TEM CD8+ T cells. Analysis of TCR repertoires clonality and diversity also demonstrated a reduced richness and increased clonality of CD8+ TCRs in responders. Summary/Conclusion These preliminary analyses of D-IPd quadruplet therapy of RRMM indicate that paired single cell RNA and TCR sequencing of BM T cells suggests a selective expansion of clonotypic CD8+ T cells. When considering patient response, the only PD patient profiled in this study maintained an exhaustive signature (LAG3, PDCD1) in multiple T cell compartments at BL. The differential expression of the receptor ligand pairs after treatment between different clinical response groups suggests an altered TME response that may inform future therapeutic stratification. These results support further explorations of rational combinations of targeted and immune therapies for greater efficacy in this disease.

Abstract Background: Prior work has indicated racial, ethnic and geographic disparities in treatment access and outcomes for acute myeloid leukemia (AML). However, the relationship between social vulnerability and AML outcomes remains understudied. The study examines the association between overall Social Vulnerability Index (SVI) and its domains with crude mortality rate (CMR) in AML patients from 2010 to 2020 and describes temporal trends. Methods: County-level SVI data aggregating 15 census variables into four domains-(1) socioeconomic status, (2) household composition and disability, (3) minority status and language, and (4) housing type and transportation, assign each county a percentile score from 0 (least vulnerable) to 1 (most vulnerable). Counties were categorized into four quartiles based on SVI scores: Q1:0-0.25 (least vulnerable) to Q4:0.75-1 (most vulnerable). CMR per 100,000 patients were abstracted from CDC WONDER database for adult patients (≥25 years) with AML and reported for patients <65 and ≥65 years of age in Q1 and Q4 counties. Counties with <10 deaths (<1% deaths) were excluded. Poisson regression models, using Q1 as reference, assessed the relationship of CMR and overall SVI in each age group, and reported rate ratios (RR) and 95% confidence intervals (CI). Each SVI domain's independent association with CMR was examined in each age group. Temporal trends were assessed by comparing CMR in 2010-2014 and 2016-2020 cohorts. Results: From 2010 to 2020, 103,411 deaths in AML patients occurred (overall CMR: 5.61 per 100,000). Unexpectedly, higher overall SVI was associated with lower mortality: CMR 5.96 in Q1 vs. 5.01 in Q4. As expected, adults aged<65 had a lower mean CMR (1.74 in Q1 vs. 1.77 in Q4) compared to those ≥65 (18.81 in Q1 vs. 15.60 in Q4). In adults aged <65, higher overall social vulnerability was not significantly associated with mortality (Q2 RR 1.01, 95% CI 0.96-1.06, p = 0.75; Q3 RR 1.02, 95% CI 0.98-1.07, p = 0.33; Q4 RR 0.96, 95% CI 0.91-1.00, p=0.054). However, there were significant associations for each SVI domain. A higher SVI in the Minority Status and Language was surprisingly associated with a significantly lower CMR (RR 0.39, 95% CI 0.36-0.43, p<0.001); for the other 3 domains, a higher SVI was associated with higher mortality: Socioeconomic status (RR 1.14, 95% CI 1.04-1.25, p=0.004), Household Composition & Disability (RR 1.31, 95% CI 1.22-1.42, p<0.001) and Housing & Transportation (RR 1.13, 95% CI 1.05-1.22, p=0.001). In adults > 65, higher overall SVI quartiles were linked to lower CMR (Q2 RR 0.96, 95% CI 0.94-0.98, p < .001; Q3 RR 0.91, 95% CI 0.89-0.94, p < .001; Q4 RR 0.84, 95% CI 0.82-0.86, p < .001). As for the domains, Socioeconomic (RR 0.81, 95% CI 0.78-0.85, p<.001) and Minority status and Language (RR 0.77, 95% CI 0.75-0.80, p<.001) were associated with a lower CMR rate. Housing & Transportation was associated with a 12% higher mortality rate (RR 1.12, 95% CI 1.08-1.17, p<.001) and Household Composition & Disability had no significant effect (p=0.214). Mortality decreased over time. In adults aged <65, CMR in Q1 counties improved from 1.94 in 2010-2014 to 1.71 in 2016-2020 and from 1.72 in 2010-2014 to 1.66 in 2016-2020 in Q4 counties. In adults aged ≥65, CMR in Q1 counties improved from 19.62 in the earlier cohort to 18.70 in later cohort but worsened from 16.32 in 2010-2014 to 16.48 in Q4 counties from 2016 to 2020. Conclusions: 1. Mortality for AML has improved over time for most of the population, except among adults in high vulnerability counties. 2. As expected, mortality is higher for older patients. 3. For adults aged <65, a surprising finding was lower mortality in counties with a higher social vulnerability in the minority and language domain, whereas a higher SVI in the socioeconomic, household, and housing domains was associated with higher mortality. 4. For adults aged ≥65, higher SVI in both the socioeconomic and minority domains was associated with a lower mortality rate, and higher SVI in the housing domain with a higher mortality rate. The authors hypothesize that urban areas with a more diverse population, and therefore a higher SVI in Minority Status and Language Domain, may offer more comprehensive care to patients with AML. In addition, the SVI does not capture important clinical and treatment variables that may impact outcomes. Further research is needed to explore more specific, population based indicators to identify at-risk patients with AML.

Abstract Background: Chemotherapy-induced cardiomyopathy (CIC) is a serious, and often irreversible complication in patients treated for hematologic malignancies. While therapies for hematologic malignancies continue to evolve, data on trends in in-hospital mortality among patients with concurrent hematologic malignancies and CIC are limited, and disparities by race and sex remain poorly characterized. This study examines national trends and demographic disparities in in-hospital mortality among patients with hematologic malignancies who developed CIC. Methods: The United States (U.S) National Inpatient Sample (NIS) from 2016 to 2020 was queried for patients diagnosed with malignant hematologic and lymphoid neoplasms who also developed CIC. Hematologic malignancies were identified using ICD-10 codes C81–C96, which include: C81 for Hodgkin lymphoma; C82–C86 for non-Hodgkin lymphomas; C88 for malignant immunoproliferative diseases (e.g., Waldenström macroglobulinemia, heavy chain disease); C90–C95 for leukemias of lymphoid, myeloid, monocytic, mixed, and unspecified cell types; and C96 for other or unspecified malignant neoplasms of lymphoid, hematopoietic, and related tissue. CIC was identified using ICD-10 code I42.7. The study was exempt from institutional review board approval as the NIS database contains deidentified patient information. Multivariable regression analysis was performed to determine the odds of in-hospital mortality among patients with hematologic malignancies who developed CIC. Multivariable logistic regression followed by marginal effects was used to plot yearly trends in in-hospital mortality. All the outcomes were adjusted for gender, race, Charlson comorbidity index and hospital characteristics. P < 0.05 was used to determine statistical significance. The analysis was performed on STATA 16 software. Results: The study identified a total of 3,021,434 hospitalizations with hematologic malignancies, of which 11,115 (0.004%) had secondary diagnosis of CIC (mean age = 56.5 years, 52.5% males). Among 11,115 patients with hematologic malignancies who developed CIC, 740 (6.6%) patients died during the hospitalization. Multivariable logistic regression followed by marginal effects estimated a decrease in adjusted in-hospital mortality trend from 6.5% in 2016 to 4.3% in 2020. However, this decreasing mortality trend was not statistically significant after adjusting for gender, race, Charlson comorbidity index, and hospital characteristics (OR: 0.93; 95% CI: 0.83 – 1.05; trend p = 0.260). In-hospital mortality did not differ significantly between male vs. female patients with hematologic malignancies who developed CIC (OR: 1.02; 95% CI: 0.72 – 1.43; p = 0.921). There was no difference in overall in-hospital mortality of patients of White (reference) vs. Black (OR: 1.12; 95% CI: 0.72 – 1.76, p = 0.61) or Hispanic (OR: 0.63; 95% CI: 0.32 – 1.25, p = 0.18) race. However, males of the Black race demonstrated a lower in-hospital mortality vs. males of the White race (OR: 0.26; 95% CI: 0.09 – 0.77, p = 0.01). In addition, females of the Black race showed a higher in-hospital mortality vs. females of the White race (OR: 2.43; 95% CI: 1.40 – 4.25, p <0.01). Conclusions: In patients with hematologic malignancies who developed CIC, overall in-hospital mortality did not differ significantly by race alone. However, on sex-based stratification, Black males had lower in-hospital mortality compared to White males, while Black females had higher mortality than White females. These differences highlight potential race–sex disparities in outcomes that warrant further investigation.

Abstract Introduction Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the treatment of type 2 diabetes and obesity. Emerging evidence suggesting their potential anti-inflammatory and anti-proliferative effects as well as cardiovascular benefits. Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, has seen major therapeutic advances with tyrosine kinase inhibitors (TKIs). However, metabolic comorbidities remain widely prevalent in these patients due to both cancer-associated risk factors and the effects of therapy. Our study aims to evaluate the impact of GLP-1 receptor agonists on outcomes among patients with CML, exploring potential interactions between metabolic modulation and disease behaviour. Methods A retrospective cohort study was conducted using the US Collaborative Network TriNetX, covering January 2000 to December 2023, encompassing data from 105 global healthcare organizations. Adult patients aged 18 and above with CML and comorbid obesity were identified and then stratified into two groups based on treatment with GLP-1 agonists or not. The two groups were then propensity-matched based on age, sex, race, and comorbidities. We followed these patients for 5 years to assess outcomes, including overall mortality, myocardial infarction, ischemic stroke, sepsis, and need for mechanical ventilation and hemodialysis. Results We identified 701,767 patients with CML and obesity who received GLP-1 receptor agonists, and 6,811,928 patients with CML and obesity who did not receive GLP-1 therapy. After propensity matching, each cohort consisted of 700,998 patients with similar baseline characteristics. Our analysis found that over 5 years, patients with CML and obesity who received GLP-1 receptor agonists had a significantly lower risk of overall mortality (Hazard Ratio (HR): 0.509, 95% CI: 0.501 to 0.518, p-value <0.001), myocardial infarction (HR: 0.785, 95% CI: 0.769 to 0.801, p-value <0.001), ischemic stroke (HR: 0.665, 95% CI: 0.632 to 0.700, p-value <0.001), hemodialysis (HR: 0.445, 95% CI: 0.430 to 0.461, p-value <0.001) and sepsis (HR: 0.726, 95% CI: 0.714 to 0.738, p-value <0.001). There was no statistically significant difference in the need for mechanical ventilation between the two subgroups. Conclusion Our study revealed that patients with CML and obesity who received GLP-1 receptor agonists had a significantly lower risk of mortality, myocardial infarction, ischemic stroke, hemodialysis and sepsis. Further longitudinal cohort studies are warranted to better understand these associations and inform clinical practice guidelines.

Abstract Background: Chimeric Antigen Receptor T-cell therapy (CAR-T) has revolutionized the treatment landscape of hematological cancers, including B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL). However, the cardiac toxicity profile of this therapy is not well described in the literature. The majority of patients receiving CAR-T are older adults who may have pre-existing cardiovascular risk factors, received prior cardiotoxic therapy including anthracycline, alkylators, corticosteroids, proteosome inhibitors, radiation, autologous and allogeneic stem cell transplants. Due to a stricter patient selection for CAR-T clinical trials, cardiac adverse events (AEs) are infrequent. As the survival of patients with hematological malignancies continues to improve with advancements in therapy, it becomes critical to consider the cumulative cardiotoxic effects of these therapies. Therefore, a post-marketing pharmacovigilance analysis of the cardiac AEs reported to the FDA Adverse Event Reporting System (FAERS) for each CAR-T product was conducted to address this knowledge gap. Methods: All individual case safety reports of cardiac AEs listing any of the approved CAR-T therapies [Tisagenlecleucel (Tisa-cel), Axicabtagene ciloleucel (Axi-cel), Lisocabtagene maraleucel (Liso-cel), Brexucabtagene autoleucel (Brexu-cel), Idecabtagene vicleucel (Ide-cel), Ciltacabtagene autoleucel (Cilta-cel) and Obecabtagene autoleucel (Obe-cel)] as the suspected drug were identified from the FAERS database. Patient characteristics, including primary malignancy, age, sex, CAR-T product and AEs were described. Disproportionality analysis was performed using Reported Odds Ratio (ROR) to determine significant associations between CAR-T products and cardiac AEs. Results: There were 1362 cardiac AEs after CAR-T therapy reported in the FAERS database(602 with Axi-cel, 444 with Tisa-cel, 77 with Cilta-cel, 81 with Ide-cel, 128 with Brexu-cel, 30 with Liso-cel and 0 with Obe-cel).Of these, 57% were males, 8.6% occurred in patients <18 yrs, 35.4% in 18–64 yrs, and 32% in >65 yrs. There were 778 reports of arrythmias, 158 heart failures, 184 cardiac arrests, 43 pericardial AEs, 16 valvular AEs, 59 ischemic AEs, 10 cardiogenic shock, 8 myocarditis, and 106 other cardiac disorders (cardiac thrombus, cardiomegaly, cardiac rupture, orthostatic hypotension, hypertensive emergency/crisis etc.). In the entire cohort, males were more likely to develop pericardial (ROR=3.55, p=0.004) and valvular disorders (ROR=9.13, p=0.03), with females developing heart failure (ROR=1.61, p=0.005). Patients <18 years had a higher incidence of pericardial (ROR=3.44, p=0.006) and valvular disease (ROR=12.79, p<0.0001), while adults aged >65 had higher propensity of developing atrial tachyarrhythmias (ROR=2.74, p<0.0001), ventricular arrhythmias (ROR=3.04, p=0.001) and cardiogenic shock (ROR=8.38, p=0.05), and a trend towards higher risk of developing acute coronary syndrome (ACS) (ROR=1.79, p=0.06). For ischemic cardiac AEs, Brexu-cel was associated with increased risk of myocardial infarction (ROR=2.34, p=0.04), and Ide-cel was associated with elevated troponin levels (ROR=6.23, p=0.002). For functional cardiac AEs, Tisa-cel was associated with cardiac arrest (ROR=1.68, p=0.001), pericardial disorders (effusion, tamponade and pericarditis) (ROR=3.56, p<0.001), valvular disorders (ROR=55.97, p<0.0001), myocarditis (ROR=6.2, p=0.012) and heart failure (ROR=2.24, p<0.001). B-ALL was associated with higher odds of cardiac arrest (ROR=1.63, p=0.018). For conduction-related cardiac AEs, Brexu-cel had higher rates of brady-arrythmias (ROR=1.86, p=0.04), Cilta-cel had increased incidence of atrioventricular block (ROR=7.87, p=0.02), and tachy-arrhythmias (ROR=1.71, p=0.0001). Tisa-cel was associated with increased risk of any arrhythmias (ROR=1.68, p<0.001). Axi-cel was associated with higher odds of developing orthostatic hypotension (ROR=2.57, p=0.019). Conclusion: This post-marketing pharmacovigilance analysis highlights patterns of cardiac AEs following CAR-T therapy. Trends in AEs based on CAR-T product, age, and sex support the ongoing need for vigilance for these unique toxicities. As this study is limited by FAERS reporting bias, prospective studies to validate these associations and elucidate the underlying mechanisms are needed, incorporating prior systemic therapies and baseline characteristics of patients undergoing CAR-T therapy.

Abstract The current European Leukemia Net guidelines (ELN22) classify AML patients with intermediate-risk cytogenetics and MDS-associated mutations (MDSm, mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse-risk but do not use MDSm+ to alter the risk stratification of patients who otherwise classify as favorable-risk. NPM1 mutations (NPM1+) are one of the most common alterations in AML and remain a favorable-risk biomarker for patients without co-occurring FLT3-ITD mutations or adverse-risk cytogenetics (NPM1+/ITD-/ARcyto-). However, prior studies have shown that older patients (≥65 years) with favorable-risk AML, including NPM1+/ITD-/ARcyto- genotype, have significantly higher relapse rates and decreased survival despite receiving comparable intensive chemotherapy regimens to their younger counterparts. Given that MDSm frequency increases with age in patients with NPM1+ AML, it raises the question as to whether MDSm contribute to poorer outcomes in older patients. To date, there have been differing results in retrospective studies examining the effect of MDSm on NPM1+ AML. Some cohorts demonstrate worse outcomes in those that have NPM1+/MDSm+ AML (Chan et al., Blood Adv. 2024), whereas others do not show a significant difference in NPM1+ AML with or without MDSm (Eckardt et al., Leukemia 2023; Othman et al., Blood 2024; Ruhnke et al., Blood Adv. 2025). We examined the mutational landscape in a large group of pre-treatment, diagnostic specimens from 271 patients, which included 119 patients enrolled in SWOG clinical trials (SWOG-9031, SWOG-9333, S0106, and S0112), 96 patients from the UW/FHCC Hematopoietic Repository, and 56 patients from the BeatAML cohort. All patients were treated with curative intent as per standard practice or on clinical trials and had adequate cytogenetic information and long-term follow-up data. Event-free and overall survival (EFS, OS) were estimated using the Kaplan-Meier method and compared using Cox regression models stratified by cohort. MDSm+ occurred in 17% of patients, with the most common mutations being in SRSF2 (7%) and SF3B1 (3%). To assess the impact of MDSm on outcomes of favorable-risk NPM1+ AML, we performed univariate analyses comparing OS and EFS for NPM1+ AML grouped by ELN22 favorable risk/MDSm-, ELN22 favorable/MDSm+, and ELN22 intermediate/adverse risk. Compared to NPM1+/MDSm- (n=116), favorable-risk NPM1+/MDSm+ (n=33) had worse OS with HR 2.0 [95% CI (1.1, 3.3), p=0.008] and had similar OS to those that are classified as ELN22 intermediate/adverse risk (n=122). There was no significant difference in EFS or complete remission rates between NPM1+ favorable risk with and without MDSm (p=0.36 and p=0.6, respectively). When we grouped the ELN22 favorable risk patients by age (<65 years vs. 65+ years), MDSm+ in younger patients did not show a difference for OS (HR 0.99, p=0.98). Older ELN22 favorable-risk patients (≥65) had poor OS regardless of presence of MDSm compared to younger MDSm- patients: older MDSm- (n=91) with HR 2.4, 95% CI (1.3, 4.6), p=0.005 and older MDSm+ (n=25) with HR 3.5, 95% CI (1.9, 6.3), p<0.0001. There was a trend toward worse OS in MDSm+ compared to MDSm- older patients, but this was not statistically significant (HR 1.42, p=0.33). Since most MDSm are in splicing factor genes (SF3B1, SRSF2, U2AF1, ZRSR2), we examined the effect of splicing factor mutations vs. other MDSm+ in ELN22 favorable risk and did not find a significant difference in OS (HR=1.01, p=0.97). Those with non-splicing MDSm+ had worse EFS compared to MDSm- and splicing MDSm+ (HR 4.12, p=0.0037), although no difference in OS. In this study, MDSm+ in the context of favorable-risk NPM1+ AML are associated with worse OS in a univariate analysis. However, this difference is likely due to the increased prevalence of MDSm with increasing age and overall worse outcomes of NPM1+ AML in older patients. When stratified by age, older NPM1+ AML patients had worse OS than younger NPM1+ patients overall, although presence of MDSm trended toward even worse OS in older patients. In younger patients, MDSm+ are not associated with a significant difference in OS, which is a similar finding compared to prior studies. Our findings suggest that NPM1+ AML is not necessarily “favorable-risk” in older patients, particularly with concurrent MDSm. Therefore, further understanding of the underlying biology of age in the context of NPM1+ AML is needed to improve outcomes for older patients.

Abstract Background: Dissemination and implementation science (D+I) efforts often begin after clinical trial (CT) efficacy data are available. However, delaying this work limits opportunities to identify barriers and facilitators that can enhance adoption of evidence-based practices. Integrating D+I during trial development, activation, and conduct supports more timely, effective, and scalable implementation. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) includes >125 centers, conducting transplant and cellular therapy (TCT) trials with practice-changing potential, with >17,000 patients enrolled since 2001. Data from Center for International Blood and Marrow Transplant Research (CIBMTR) provides a way to measure real-world adoption. With this comprehensive structure in place, the BMT CTN launched a D+I Committee that established a D+I process to better understand uptake of CT findings and to leverage that information to promote adoption. Methods: Informed by established D+I frameworks, a structured, cyclical process to integrate implementation considerations spanning the CT lifecycle was developed. A multidisciplinary team including experts in D+I, clinicians, and investigators iteratively refined the proposed D+I algorithm. The process begins upstream when a trial concept is approved to move forward, it is shared with the D+I Committee for initial assessment. This includes a landscape review for studies in development using CIBMTR data, literature, and expert experience. The Committee then reviews the developing protocol with the BMT CTN protocol team to proactively identify implementation barriers and facilitators to implementation in real-world settings and outline plans for dissemination. The Committee also provides recommendations for integrating relevant implementation data collection and analyses within the protocol. After study completion, both clinical efficacy and implementation outcomes are analyzed, followed by active dissemination. Additional assessment using surveys, qualitative methods, and CIBMTR data occurs after dissemination to understand adoption. Insights gathered also inform further refinement of the process. Tools and templates are in development to build capacity and ensure consistency for Committee members. Results: To date, the Committee has published three peer-reviewed articles addressing implementation implications of three BMT CTN trials (PMC7735536, PMC8578257, PMC9364468) and a fourth is in press. Using the designed D+I process flow, a current effort used a survey sent to US CIBMTR centers, to evaluate factors influencing the implementation of results of the BMT CTN 1703 trial of post-transplant cyclophosphamide as graft-versus-host disease (GvHD) prophylaxis and assessed dissemination and adoption considerations for the upcoming BMT CTN 2203 CT of ruxolitinib as GvHD prophylaxis. CIBMTR data is being analyzed to demonstrate practice patterns before, during, and after BMT CTN 1703 study completion. This effort has allowed for further refinement of the BMT CTN D+I process flow and has highlighted critical opportunities for incorporating dissemination and implementation objectives and endpoints into BMT CTN protocols. We also used the process to guide a review of severe aplastic anemia treatment gaps and ongoing studies. This review underscored how proactive transplant and non-transplant stakeholder engagement and early implementation planning, core elements of this process, can bridge evidence to practice and advance access to care. A complementary survey on current practice patterns in severe aplastic anemia is ongoing. Conclusions: With the existing structure of the BMT CTN and associated practice registry of the CIBMTR, the BMT CTN D+I Committee developed a systematic process to build D+I considerations into trial workflows to increase real-world impact. This process aims to ensure that barriers to uptake of trial results can be identified and addressed appropriately, improving care quality for patients undergoing TCT.