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Abstract Background: Population registries and the Alliance co-operative group database have highlighted racial disparities in AML survival attributed to differential prevalence and impact of oncogenic drivers on disease biology. However, the small number of Black patients with well-annotated genomic profiles limits the validity of these findings. The current study leverages ECOG-ACRIN cytogenetic and outcomes data from newly diagnosed adult AML patients treated on intensive chemotherapy-based clinical trials over three decades. Methods: Self-reported race was categorized as White, Black or Other. Descriptive statistics were used to summarize baseline characteristics using the Wilcoxon rank-sum and Fisher's exact tests. Multivariable Cox proportional hazards regression models evaluated the association between race and survival outcomes adjusting for age, hemoglobin, platelet count, white blood cell count, blast percentage, performance status and ELN cytogenetic risk score (RS). All Cox models were stratified by protocol. Subgroup analyses of overall survival (OS) and disease-free survival (DFS) were performed using Kaplan-Meier curves stratified by race using log-rank tests. All statistical tests were two-sided. Analyses included only patients with complete data for the variables of interest. Results: Data was collected across 10 phase II and III interventional trials for newly diagnosed adult AML that accrued patients between 1984 and 2019. The study population included 3469 White, 184 Black, and 156 Other patients with a Black representation of 1.1-11% across trials. Blacks were significantly younger at diagnosis with a median age of 47.9 years compared to 53.5 years in Whites (p<0.001). Racial groups were well matched for gender and performance status. Black race was an independent prognostic factor for inferior OS (HR 1.212, CI 1.01 – 1.453; p = 0.0383) and DFS (HR 1.313, CI 1.05-1.641; p = 0.017). Complete cytogenetic results were available for 117 Black and 2162 White patients and revealed no significant racial differences in the distribution of ELN 2017 cytogenetic RS, although core binding factor AML was non-significantly enriched in Black patients (12.8% vs 8.3%). No difference was observed between Blacks and Whites in the prevalence of complex karyotype (CK), CK with -5/del(5q), -7/del(7q), or -17/del(17p), and AML-MRC including +8 and del(20q). Notably, the ELN 2017 cytogenetic RS effectively predicted OS in Black (57.8 vs 14.2 vs 5.8 months in favorable, intermediate and adverse RS, p = 0.018), and White patients (60.1 vs 15.2 vs 7.1 months, p < 0.0004 for Whites) but only predicted DFS for White AML patients (p < 0.0001 for Whites, p=0.48 for Blacks). In patients with molecular data for FLT3-ITD (n=1218), CEBPA (n=576), TP53 (n=572), or NPM1(n=683), no racial difference in the prevalence of these mutations was observed. However, NPM1 mutations were associated with inferior OS in Blacks compared to Whites (19.1 vs 8.9 months; p = 0.0095). Black and White AML patients had similar responses with complete remission rates of 58.2% vs 57.5%, p=0.55, and treatment tolerability with 30-day mortality of 7.1% vs 8.9%, p=0.50. However, consolidation approaches differed significantly. Among patients that underwent stem cell transplant (SCT), a significantly higher percentage of White patients received allogenic SCT compared to Blacks (48.5% versus 37.1%, p <0.01). Conclusions: This study represents one of the largest race-based comparisons of cytogenetic abnormalities and clinical outcomes in prospective trials of intensive chemotherapy in AML . Our data confirms the independent prognostic relevance of race in AML survival and validates the predictive ability of the ELN 2017 cytogenetic RS for OS across racial groups. There is ancestry-based attenuation of the survival benefit of NPM1 mutations as previously reported, underscoring the need to tailor the current treatment approach to NPM1 mutated AML based on race. The availability of NGS data limited the genomic analysis to a subset of patients. Future studies should examine the depth of treatment response incorporating MRD biomarkers and explore the effect of race on co-occurring mutations and the leukemic stem cell transcriptome to better explain the observed disparities. Finally, persistent disparities in access to allo-SCT even within the context of clinical trials reinforces the need to address diversity in the stem cell donor pool and social barriers to transplant.

Abstract Introduction Nadir bone marrow biopsies (BM Bx) are routinely performed around day 14 to assess early response to AML intensive induction therapy. The presence of residual disease prompts initiation of reinduction therapy, often with another cycle of intensive chemotherapy. Whether there are characteristics of nadir BM Bx that predict for response to intensive reinduction is unknown. To evaluate this, we analyzed data from ECOG-ACRIN clinical trials in AML of intensive induction chemotherapy with nadir biopsy information available to determine predictors of outcomes after reinduction. Methods We included patients from ECOG-ACRIN E1900 (Fernandez NEJM 2009) and arm A of E2906 (Foran ASH 2015) who received induction therapy with daunorubicin and cytarabine (7+3), had residual disease (blasts ≥5% or cellularity ≥20%) at nadir BM Bx and received reinduction chemotherapy. Nadir BM Bx characteristics that were evaluated included blast percentage and cellularity as well as both absolute and relative (percentage change, e.g. 20% to 10% = -50%) differences calculated between diagnosis and nadir for each parameter. Complete remission (CR) after reinduction therapy, disease free survival (DFS) and overall survival (OS) were outcomes for all analyses. Logistic regression models were used to evaluate associations with CR, and Cox proportional hazards models were used for DFS and OS. For models evaluating changes in blast percentage or cellularity as predictors, baseline blast percentage or cellularity was included as a covariate, respectively. Results Of 1013 patients identified, 750 (74%) had a nadir biopsy, 233 (23%) had evidence of residual disease, received reinduction therapy, and were included in the primary analysis. The median age was 58 and 42% were female. Cytogenetic risk category (by ELN2017) was adverse in 31%, intermediate in 66% and favorable in 3%. The median nadir BM Bx blast was 30% (range 0 to +97%) and cellularity was 20% (0 to +100%). The median absolute difference in blast percentage between baseline and nadir BM Bx was -15% (-95% to +66%) with a median relative difference of -36% (-100% to +400%). After reinduction, 118 patients (52%) achieved a CR. Neither absolute difference in blast percentage (OR 0.99, 95%CI 0.98-1.00, p=0.20) nor relative difference (OR 1.00, 95%CI 0.99-1.00, p=0.33) predicted CR. There was similarly no association with DFS (HR = 1.00, 95%CI: 0.99-1.01, p=0.65) or OS (HR = 1.00, 95%CI 0.99-1.01, p=0.76). Blast reduction ≥50% similarly did not predict these outcomes. We also evaluated the impact of any reduction in blast percentage (responders) from baseline to nadir and again found no association with CR (OR 1.65, 95%CI 0.90-3.03, p=0.11). Similarly, there was no association with DFS (HR 0.74, 95%CI 0.51-1.09, p=0.13) or OS (HR 0.81, 95%CI 0.58-1.13, p=0.21) in responders vs nonresponders. No association with CR, DFS or OS were identified when performing the same analysis in intermediate and adverse cytogenetic subgroups. We found no association with CR when nadir cellularity was assessed as a continuous variable (OR 0.99, 95%CI 0.98-1.00, p=0.10) or by relative difference (OR 0.99, 95%CI 0.99-1.00, p=0.10). There was a trend towards association with absolute reduction in cellularity from baseline to nadir and CR (OR 0.99, 95%CI 0.98-1.00, p=0.06). No association was identified between relative difference in cellularity and DFS and OS, nor was there an association among cytogenetic risk subgroups with any outcome. Discussion In intensively treated patients with residual disease at nadir BM Bx (i.e. day 14) who received intensive reinduction, the likelihood of achieving a CR was not influenced by the magnitude of disease reduction nor the extent of disease at the time of nadir biopsy. Similarly, there were no nadir biopsy features that predicted DFS or OS after intensive reinduction therapy. Given alternative reinduction therapies such as hypomethylating agents and venetoclax are available, these results suggest that the decision to attempt a second intensive induction cycle following the unequivocal presence of residual disease should not be influenced by characteristics of the nadir BM Bx. Although patient-specific factors such as patient fitness may favor a switch to less intensive options, these results support consideration of intensive reinduction therapy in patients with residual disease at nadir biopsy, even without changes in blasts or cellularity.

Abstract Introduction: CD19-directed CAR T-cell (CAR-T) therapy has substantially improved clinical outcomes for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, notable toxicities are associated with CAR-T, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Variable practice patterns have emerged regarding the use of CRS/ICANS prophylaxis (ppx) via corticosteroids and/or other pharmacologic agents, but the utility of these approaches on reducing CRS or ICANS following CAR-T in B-ALL remains unknown. Thus, we utilized the Real-World Outcomes Collaborative for CAR T in ALL (ROCCA) database to evaluate associations between ppx and the development and severity of CRS or ICANS following brexucabtagene autoleucel (brexu-cel) for B-ALL. Methods: Adult patients (pts) who received standard-of-care brexu-cel for relapsed/refractory B-ALL across 40+ US centers were included. Primary endpoints were the incidence of CRS and ICANS within 28 days of CAR-T infusion. Secondary endpoints included timing of CRS and ICANS onset, progression-free survival (PFS) and overall survival (OS). Univariable and multivariable logistic regression evaluated associations between ppx and incidence of CRS/ICANS; KM and log-rank methods were used for survival analyses. Results: A total of 378 pts were included: 53 pts (14.0%) received CRS/ICANS ppx and 325 (86.0%) received no ppx. Ppx agents included steroids only (26.4%), steroid and anakinra (52.8%), anakinra only (15.1%), and steroid and tocilizumab (5.7%). Pts in the ppx group had a higher proportion of Hispanic pts (64% vs 34%), Ph-like (36% vs 19%) and a lower proportion had 0-5% bone marrow blasts at apheresis (38% vs 53%). The ppx and no ppx groups were similar in age, prior therapies, CAR-T indication, and marrow blasts >50%. Cumulative incidence of any grade (gr) CRS was 94% with ppx and 86% with no ppx (p=0.025), of any gr ICANS was 53% with ppx and 51% with no ppx (0= 0.85). Cumulative incidence of gr 3-4 CRS was 9% in the ppx group and 10% in the no ppx group (p=1.00), of gr 3-4 ICANS was 26% in the ppx group and 29% in the no ppx group (p=0.71). Median time to onset for any gr CRS or any gr ICANS was identical in the ppx and no ppx cohorts (CRS: 5 days, range ppx 1-9 days, no ppx 0-14 days; ICANS: 7 days, ppx 1-20 days, no ppx 0-16 days). Univariate logistic regression analyses showed no significant association between ppx and the incidence of gr 2-4 CRS (OR 1.34, 95% CI: 0.75-2.40, p=0.326) or gr 3-4 ICANS (OR 0.88, 95% CI: 0.46-1.70, p=0.708). Multivariate analysis adjusting for ethnicity, leukemia genetic sub-type, and pre-apheresis disease burden similarly found no significant associations between ppx and gr 2-4 CRS (adjusted OR 1.06, 95% CI: 0.55-2.01, p=0.870) or gr 3-4 ICANS (OR 1.23, 95% CI: 0.59-2.55, p=0.584). When comparing steroid-only ppx (N=14) to steroid combinations or other drug ppx (N=39), there was no significant differences in gr 2-4 CRS (57% vs 44%, p=0.345) or gr 3-4 ICANS (43% vs 21%, p=0.115). Comparing cumulative incidence of dexamethasone (dex) exposure, pts in the ppx group had numerically greater dex exposure than pts in the no ppx group, with median (range) dosing of 182 mg (10-1386mg) and 100mg (1-4000mg), respectively. Finally, we found no significant differences in PFS or OS based on ppx. Median PFS was 9.6 months in the ppx group vs 13.3 months in the no ppx group (p=0.646) and median OS was 17.2 months in the ppx group vs 34.4 months in the no ppx group (p=0.170). Conclusions: In this large cohort of adult patients with R/R ALL receiving brexu-cel CAR-T therapy, prophylaxis intended to prevent CRS/ICANS was ineffective at reducing CRS/ICANS incidence, time to onset, or overall steroid exposure. Furthermore, PFS and OS were comparable between patients who received prophylaxis and those who did not. In the absence of prospective trials in B-ALL, these data suggest that current strategies of CRS/ICANS prophylaxis has limited benefit.

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.

Background There is limited evidence on the epidemiology and prognostic significance of acid-base disorders in the cardiovascular intensive care unit (CICU). This study examines the association of acid-base status at admission with in-hospital mortality among CICU patients. Methods We conducted a retrospective analysis of adults admitted to the Mayo Clinic CICU from 2007-2018 with available blood gas data, utilizing values obtained closest to CICU admission. Arterial pH, serum bicarbonate, base excess, and partial pressure of carbon dioxide (PaCO 2 ) were examined as predictors of in-hospital mortality. Multivariable logistic regression was used to assess associations, with adjustment for demographics, comorbidities, illness severity, and interventions. Results Among 3229 patients included for analysis, acidemia (pH < 7.35) emerged as the strongest predictor of in-hospital mortality (adjusted odds ratio [aOR] 1.60, 95% confidence interval [CI] 1.29-1.98, P < .003). Metabolic acidosis (HCO3 < 20 mEq/L, aOR 1.55, 95% CI 1.24-1.95, P < .001) and respiratory acidosis (PaCO2 > 45 mm Hg, aOR 1.44, 95% CI 1.14-1.81, P = .002) were associated with higher in-hospital mortality, whereas metabolic and respiratory alkalosis were not. After adjustment, lower pH and more negative base excess were associated with higher in-hospital mortality (both P < .001), whereas HCO3 and PaCO2 were not ( P = .053 and P = .051, respectively). Patients with combined metabolic and respiratory acidosis had the highest in-hospital mortality (56.3%). Conclusions Short-term survival in CICU patients decreases progressively with worse acidemia, especially in the context of combined metabolic and respiratory acidosis. Incorporating metabolic acid-base disorders as key therapeutic targets in randomized cardiogenic shock trials may improve outcomes in this complex population by addressing hemometabolic shock.

Abstract Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease linked to repetitive traumatic brain injury, but its prevalence and risk factors in the general population remain poorly defined. We investigated CTE neuropathological changes (CTE-NC) in an admixed, population-based clinicopathological cohort. Neuropathological evaluation was conducted on brain samples from 1151 individuals in the University of São Paulo Biobank for Aging Studies collected from 2004 to 2022. CTE-NC and aging-related tau astrogliopathy (ARTAG) were assessed across 14 963 histological slides using p-tau immunostaining. Clinical, cognitive, and neuropsychiatric data were obtained via informant interviews; information on sports exposure and traumatic brain injury history was limited. Seven cases (0.6%) met criteria for CTE-NC, mean age at death 73.4 ± 12.5 years; 1 was female. Dementia was present in 43% of CTE-NC cases; 57% exhibited neuropsychiatric symptoms. Most common co-pathologies were Alzheimer disease-type changes, ARTAG, and argyrophilic grain disease. Comprehensive exposure histories were unavailable for most cases; 2 had documented soccer involvement. These findings indicate that CTE-NC is rare in this population-based Brazilian cohort and predominantly affects males with frequent coexisting neuropathologies. Findings align with reports from high-income countries and support prioritizing primary prevention by reducing exposure to repetitive head impacts in sport and other settings.

In 2023, the American Congress of Rehabilitation Medicine Brain Injury Interdisciplinary Special Interest Group (ACRM BI-ISIG) Mild Traumatic Brain Injury (TBI) Task Force published updated diagnostic criteria for mild TBI. These criteria were developed in collaboration with a panel of 32 subject matter experts in mild TBI using the Delphi method. The 2023 ACRM diagnostic criteria marked the first update since 1993, incorporating three decades of research advancements in our understanding of mild TBI. To facilitate the consistent use of the new diagnostic criteria, the ACRM BI-ISIG Mild TBI Task Force initiated a special project in September 2023 to develop a structured interview to apply the ACRM diagnostic criteria for mild TBI in clinical and research settings. The purpose of this article is to describe the development of the ACRM Structured TBI Interview and the accompanying documents. The ACRM Structured TBI Interview was developed in four phases: (1) initial development of a draft interview by two project leads, (2) review and revision over three rounds by 17 members of the ACRM BI-ISIG Mild TBI Task Force, (3) external review by 19 subject matter experts in mild TBI, and (4) field testing of the ACRM Structured TBI Interview by 11 interviewers who completed 25 diagnostic interviews. In addition to the ACRM Structured TBI Interview, three other documents were developed to help facilitate the administration of the interview (Administration Guide) and to apply the diagnostic criteria (Diagnostic Coding Form and Diagnostic Flow Diagram). A Short Form was also developed for use in contexts where administering the full structured interview is not feasible due to time constraints.

Abstract Description Since cancer is an evolving disease with rapid proliferation and dynamic evolution, maintaining efficient killing of cancer cells by cytotoxic T lymphocytes (CTLs) is necessary for immunotherapy to be effective. However, the regulation of the cytotoxic capacity has not been clearly defined in CD8 T cells in responses to cancer immunotherapy. We previously identified ETS proto-oncogene 1 (ETS1) as a negative regulator of NKG7 as well as granzyme B, two key effector molecules in cytotoxic CD8 T cells. Although ETS1 downregulation using siRNA in healthy donor CD8 T cells leads to higher cytotoxicity, the tumor growth was faster and response to immunotherapy was poor in ETS1 CD8 conditional knockout model (CD8cre ETS-1fl/fl) compared to control mice. To address the dual regulatory role of ETS1 in CD8 T cell function, we found an activation-induced alternative splice event which leads to the expression of p27 of ETS1, which functions as a dual-dominant negative regulator of canonical ETS-1 (p51). From our cross-analysis of ATAC and TAF-ChIP NGS data from human CD8 T cells, we found that upon activation there is greater ETS-1 binding to open chromatin. To determine the role of each ETS1 isoform, we over-expressed p51, p42, and p27 in human CD8 T cells and found each isoform varies in their regulation of T cell cytotoxicity and degranulation. Our results suggest ETS1 is a temporal regulator of effector molecules in cytotoxic CD8 T cells via activation-induced alterative splicing. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)