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Abstract Introduction Pronounced disparities in pediatric B-lymphoblastic leukemia (B-ALL) outcomes by race and ethnicity persist in the contemporary era. Gaps in overall survival (OS) from initial diagnosis are wider than event-free survival, suggesting that post-relapse mechanisms may contribute. However, data on treatment and outcomes after relapse are lacking. In a large, multicenter, real-world cohort of children and young adults with high-risk 1st relapse of B-ALL, we sought to (1) define survival outcomes by race/ethnicity and (2) explore if differences in therapy utilization drive outcomes. Methods We conducted an analysis within the Retrospective Study of Contemporary Approaches to 1st Relapse in B-ALL (ReCALL-1) cohort, which includes patients <30 years who initiated 1st relapse therapy between 2018-2022. This analysis was restricted to patients treated at US centers for “high-risk” 1st relapse, defined as relapse for which hematopoietic cell transplant (HCT) is generally standard-of-care: Early relapse (medullary <36m; isolated extramedullary <18m), late relapse with persistent end of reinduction disease, Ph+ B-ALL or age ≥18 years. Patients with Trisomy 21, those who received cell therapy before relapse and those who died during reinduction were excluded. The primary exposure was race/ethnicity categorized as Hispanic, non-Hispanic Black (NHB), non-Hispanic White (NHW), and other/unknown. The primary outcome was OS from relapse. Multivariable Cox regression models were constructed to include other social drivers of health (SDOH; health insurance, preferred language) and disease characteristics. Results Of 479 patients in ReCALL-1, 311 from 31 centers met inclusion for this analysis (41% Hispanic, 7% NHB, 46% NHW, 5% NH-other/unknown). With a median follow-up of 47m, OS differed by race/ethnicity (log-rank p=0.017): Hispanic, 4y OS 59%; NHB, 37%; NHW, 68%. Compared to NHW patients, NHB patients had an increased hazard of death (HR 2.3, 95% CI 1.3-4.3, p=0.006), while Hispanic patients were more similar to NHW patients (HR 1.3, 95% CI 0.9-2.0, p=0.16). Adjustment for SDOH only marginally attenuated the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.031) and led to equivalent outcomes for Hispanic patients (aHR 0.9, 95% CI, 0.5-1.5, p=0.66). Adjusting for disease characteristics that differed by race/ethnicity at p<0.2 (time to relapse, Ph+, Ph-like, KMT2Ar, age ≥18, or relapsed infant ALL) did not diminish the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.032) while outcomes remained equivalent for Hispanic patients (aHR 1.2, 95% CI, 0.8-1.8, p=0.40). Point estimates of cumulative incidence of non-relapse mortality (NRM) were highest in NHB patients (Hispanic, 4y NRM 13%, NHB 22%, NHW 11%), but this trend was not statistically significant (Gray’s p=0.52). Only 17% of patients initiated therapy for relapse on a clinical trial with no differences observed by race/ethnicity. Most patients received definitive treatment for relapse with either CAR T cell therapy (CART) or HCT: 79% overall, 74% Hispanic, 91% NHB, and 83% NHW. CART and HCT were utilized equally (39% and 40%, respectively) and the proportion that received each therapy did not vary by race/ethnicity. Time to CART/HCT, external referral for treatment, receipt of investigational v commercial CART, and use of post-CART consolidative HCT revealed no differences by race/ethnicity. Of the 66 patients (21%) who did not receive cell therapy, 26 had planned for CART or HCT, but did not receive due to disease progression or NRM (n=24; 12 Hispanic, 10 NHW), or insurance barriers (n=2, both Hispanic). After HCT, OS was worse for NHB patients (log-rank p=0.03) with 4y OS of 42% v 85% for NHW and 75% for Hispanic. Post-CART, 4y OS was 40% for NHB v 59% for NHW and 51% for Hispanic, but this difference was not statistically significant. Conclusion In a large real-world cohort of children with high-risk 1st relapse of B-ALL, we found a two-fold increased hazard of death for NHB patients compared to NHW patients, even after adjustment for other SDOH factors and high-risk disease features. In contrast to previous studies of adult patients, children appeared to have equal access to cell therapies across races/ethnicities. We found that Hispanic patients, who comprised >40% of the cohort, had similar survival to NHW children, suggesting that availability of cellular and immunotherapies may be mitigating historically observed disparities for children with relapsed B-ALL.

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 Consumption of a Western diet and high body mass index (BMI) are risk factors for progression from premalignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (HFPBD; meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible and improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease progression trajectory improved (n = 2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma precursor state, in which a high-fiber diet (HFD) delayed disease progression through improved metabolism and microbiome composition, leading to increased short-chain fatty acid production that reinvigorated antitumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A HFD is a low-risk intervention that may delay progression to myeloma. Significance: A HFPBD in participants with precursor plasma cell disorders and an elevated BMI improved metabolic, microbiome, and immune biomarkers of disease. In a subset, it may delay progression to myeloma. In mouse models, a HFD delayed progression to myeloma independent of calorie restriction. See related commentary by Fairfield and Reagan, p. 623

BACKGROUND: Although obesity and insulin resistance (IR) are established risk factors for left heart dysfunction, their clinical impact in group 1 pulmonary hypertension (PH) remains unclear. We sought to determine the impact of excess adiposity versus IR on biventricular hemodynamic and functional reserve in group 1 PH. METHODS: Homeostasis model of insulin resistance and adiposity indices (body mass index [BMI], fat mass, waist circumference) were measured among group 1 patients with PH recruited to PVDOMICS (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Functional capacity, and dynamic pulmonary capillary wedge pressure (PCWP) and right atrial pressure responses were compared stratified by obesity (BMI≥30 kg/m 2 ) and IR status (HOMA-IR≥2.6) using repeated-measure mixed models. RESULTS: Among patients with group 1 PH (n=418), 158 (38%) had BMI≥30 kg/m 2 (94 [60%] of whom had IR), and 260 (62%) had BMI<30 kg/m 2 (74 [28%] of whom had IR). Among those with waist circumference measurement (n=375), 287 (77%) had excess adiposity by elevated waist/height ratio, with 214 (57%) having elevated waist circumference. Patients with obesity had worse quality of life, exercise capacity and left heart remodeling, along with higher resting/dynamic PCWP, right atrial pressure and cardiac output ( P <0.0001 for all). Higher PCWP response with obesity persisted after adjusting for IR (IR-adjusted PCWP+2.5 mm Hg [95% CI, +1.4 to +3.6]; P <0.0001). All adiposity indices were consistently associated with PCWP response, but IR was not. Similar associations were observed between adiposity indices with higher right atrial pressure and cardiac output. Greater visceral adiposity as measured by body shape index (hazard ratio, 2.01 [95% CI, 1.16–3.47]; P =0.01) or weight-adjusted waist index (hazard ratio, 1.64 [95% CI, 1.10–2.46]; P =0.01) was associated with worse survival. CONCLUSIONS: Excess adiposity is common in group 1 PH, occurring in 4 out of 5 patients by the more sensitive waist/height ratio, in contrast to only 2 out of 5 patients having obesity by traditional BMI criteria. Excess adiposity is associated with higher biventricular filling pressures, cardiac output demand, worse functional status and reduced survival. These data support trials of adipose-reducing therapies in patients with group 1 PH and excess adiposity.

Introduction Post‐market and multicenter studies report low complete occlusion rates (41‐49%) and higher retreatment rates (13%) following WEB deployment, compared to 3.8% with microsurgical clipping. While retreatment after WEB has been shown to be technically feasible, data on final angiographic outcomes remain limited. We performed a retrospective analysis of prospective databases from 14 cerebrovascular centers in the US to compare the safety and efficacy of retreatment versus continued observation for residual and recurrent aneurysms after initial WEB deployment. Materials/Methods Multinomial logistic regression was used to identify baseline characteristics of untreated and residual/recurrent aneurysms that may act as confounders, which then underwent propensity scored matching (PSM). Results Among 211 patients (125 observed, 86 retreated), retreatment was more common in initially ruptured aneurysms (p<0.001), which showed higher recurrence (p=0.036) and sac‐dominant residuals (p=0.004). These were primarily due to WEB compression on follow‐up (p=0.001), rather than incomplete occlusion with an appropriately sized device (p<0.001). Retreatment was associated with significantly higher rates of complete angiographic occlusion at last follow‐up compared to observation alone (p<0.001), a finding that remained consistent across subgroups defined by initial unruptured status, residual type, and recurrence patterns (all p<0.05). Clipping demonstrated higher, though statistically insignificant, rates of complete occlusion; flow diversion and stent‐assisted coil embolization yielded comparable complete occlusion rates at follow‐up. After propensity score matching, retreatment remained significantly associated with higher rates of complete angiographic occlusion (all p<0.05), with comparable outcomes observed between clipping and various endovascular approaches as above. Conclusion Retreatment improved complete occlusion rates; however, no aneurysmal hemorrhages occurred in either group. Further intervention may be unnecessary when the WEB device—whether compressed or intact (BOSS 0/1)—adequately protects the dome. In cases where WEB compression significantly exposes the aneurysm wall, stent‐assisted coiling or flow diversion can be performed safely and successfully, depending on vascular anatomy and surgeon preference. image image

OBJECTIVE Objective values on procedural risk are essential to facilitate informed consent and optimize clinical decision-making in patients with unruptured intracranial aneurysms (UIAs). While robust heuristics, such as the PHASES (population, hypertension, age, size of aneurysm, earlier subarachnoid hemorrhage, and site of aneurysm) score, are established for predicting rupture risk, contemporary and granular benchmarks for procedural safety remain scarce. The multinational Prediction of Adverse Events After Microsurgery for Intracranial Unruptured Aneurysms (PRAEMIUM) study aims to comprehensively characterize contemporary adverse event rates following microsurgical treatment at high-volume expert centers, stratified by aneurysm location, morphology, and complexity factors to better inform individual risk/benefit analyses. METHODS A cohort study among 20 participating expert centers from 9 countries was established. Patients treated microsurgically for UIAs were included. The authors describe the epidemiology of treated patients and UIAs and a comprehensive adverse event profile using 3 outcomes measured at hospital discharge: 1) poor neurological outcome (modified Rankin Scale score ≥ 3), 2) new sensorimotor neurological deficits, and 3) all-cause adverse events (Clavien-Dindo grade ≥ 1). Subgroup reports were given for aneurysm location, morphology, and complexity factors (prior aneurysm treatment, calcifications, complex angioanatomy involving critical branch vessels or perforators, and thrombosis). The authors purposely chose discharge as the time point to capture early postoperative risks and complications in patients with asymptomatic UIAs, for whom preserving neurological function is paramount. RESULTS The cohort included 3705 patients (mean age 56 [SD 12] years, 28% male). Overall, at discharge 13.9% of patients (95% CI 12.8%–15.0%) had poor neurological functional outcomes, 14.4% (95% CI 13.3%–15.5%) had new sensorimotor deficits, and 24.1% (95% CI 22.8%–25.5%) experienced all-cause adverse events. Poor neurological outcomes ranged from 8.5% (M1 aneurysms) to 37.4% (posterior circulation aneurysms), neurological deficits from 9.3% (distal anterior cerebral artery [ACA] aneurysms) to 34.2% (posterior circulation aneurysms), and all-cause adverse events from 21.2% (distal ACA aneurysms) to 31.3% (posterior circulation aneurysms). Dissecting and fusiform aneurysms showed notably high rates of poor neurological outcomes (22.0%–33.3%), new deficits (25.4%–26.7%), and adverse events (26.7%–37.0%). Complexity factors significantly influenced outcomes, with prior treatment (22.9%, 19.7%, and 30.1%), calcification (16.3%, 18.1%, and 30.5%), complex angioanatomy (13.1%, 15.9%, and 26.9%), and thrombosis (19.6%, 23.9%, and 39.6%) notably increasing the risks for poor neurological outcomes, deficits, and adverse events, respectively. CONCLUSIONS This large international cohort provides contemporary benchmarks for microsurgical treatment of UIAs, emphasizing variability in outcomes based on aneurysm location, morphology, and complexity. The presented granular and quotable adverse event rates support informed patient counseling and individualized risk/benefit assessments in comparable high-volume centers.

Glioblastoma (GBM) is an aggressive brain tumor that often progresses despite resection and treatment. Timely and continuous assessment of GBM progression is critical to expedite secondary surgery or enrollment in clinical trials. However, current progression detection requires costly and specialized MRI examinations, which, in the absence of new symptoms or signs, are usually scheduled every 2–3 months. Here, we hypothesized that changes in daily activity are associated with GBM growth and disease progression. We found that wheel-running activity in GBM-bearing mice declined as tumors grew and preceded weight loss and circadian breakdown by over a week. Temozolomide treatment in the morning, but not evening, significantly reduced tumor size and restored daily locomotion in mice. In a pilot study of 6 patients with GBM wearing an actigraphy watch, wrist movement provided a feasible and continuous longitudinal indicator of daily activity with 1-minute resolution. After tumor resection and radiation, daily activity declined in 2 patients 19 and 55 days before detection of progression by MRI but did not change for the 4 patients with stable disease. These results suggest that daily activity tracking using wearable devices may serve as a real-time indicator and potential monitoring tool for GBM progression and treatment efficacy.

Importance Assisted ventilation during delayed cord clamping (DCC) may improve the physiologic transition of extremely preterm infants immediately after birth. Objective To determine whether assisted ventilation during 120 seconds of DCC was associated with reduced higher-level resuscitative interventions (intubation, chest compressions, or epinephrine administration) compared with DCC for 30 to 60 seconds followed by resuscitation. Design, Setting, and Participants This was a secondary analysis of the VentFirst randomized clinical trial that was conducted from September 2, 2016, through February 21, 2023, at 12 centers in the US and Canada. Infants born at 23 weeks 0 days’ to 28 weeks 6 days’ gestational age (GA) were included. Intervention Infants randomized to the intervention received either positive-pressure ventilation or continuous positive airway pressure from 30 to 120 seconds after birth, followed by umbilical cord clamping. Those randomized to control received 30 to 60 seconds of DCC followed by assisted ventilation. Main Outcomes and Measures The main outcome was the odds of higher-level resuscitative interventions in the delivery room (DR). Intention-to-treat analyses within 2 a priori cohorts (infants breathing well and not breathing well 30 seconds after birth) used the Cochran-Mantel-Haenszel method to estimate the odds ratios (ORs) of intervention vs control. Results All 570 infants enrolled in the trial were included. Infants had a median (IQR) GA of 26.6 (25.2-27.9) weeks and 273 (47.9%) were female. A total of 271 infants (47.5%) were assessed as not breathing well 30 seconds after birth (150 intervention and 121 control), and 299 (52.5%) were assessed as breathing well 30 seconds after birth (128 intervention and 171 control). In the not-breathing-well cohort, 146 infants (53.9%) were intubated in the DR, 4 received chest compressions (2 intervention and 2 control), and 1 received epinephrine (control). Intubation was less frequent in the intervention group (71 infants [47.3%] vs 75 infants [62.0%]; OR, 0.52; 95% CI, 0.30-0.89). When adjusted by GA strata at randomization, infants in the 26 to 28 weeks’ GA stratum who were in the intervention group were less likely to be intubated in the DR (18 of 79 infants [22.8%] vs 29 of 60 infants [48.3%]; OR, 0.32; 95% CI, 0.15-0.65). However, there was no difference in intubation rates for infants in the 23 to 25 weeks’ GA stratum (53 of 71 infants [74.7%] vs 46 of 61 infants [75.4%]; OR, 0.96; 95% CI, 0.44-2.12). Among infants breathing well at 30 seconds, 74 (24.7%) were intubated in the DR, and none received compressions or epinephrine. Intubation rates were similar between intervention and control in the breathing-well cohort. Conclusions and Relevance While the VentFirst trial did not find a difference in death or intraventricular hemorrhage, this secondary analysis found that assisted ventilation during DCC was associated with less intubation in the DR, primarily among infants born at 26 to 28 weeks’ gestation who were not breathing well 30 seconds after birth. Additional studies are needed before implementing assisted ventilation during DCC in clinical practice. Trial Registration ClinicalTrials.gov Identifier: NCT02742454

Abstract Despite concerns about the toxicity of allogeneic hematopoietic cell transplantation (alloHCT) in older patients, prospective data characterizing prevalence or risk stratification for geriatric morbidity such as disability or frailty are limited. We prospectively assessed the prognostic impact of the novel composite health assessment risk model (CHARM), a score established to predict 1-year nonrelapse mortality (NRM), among 1105 patients aged ≥60 years enrolled on the Bone Marrow Transplant Clinical Trials Network Study 1704. Secondary end points were assessed post-alloHCT at day 100 (D100), D180, and D365 in multivariable models adjusted with predetermined clinical variables. Among alloHCT survivors, the prevalence of disability by instrumental activities of daily living (IADL), frailty by the Physical Frailty Phenotype, and physical function impairment by Patient Reported Measurement Information System (PROMIS) was highest at D100 and lower on D180 and D365. Higher CHARM scores were independently associated with greater disability (coefficient, −0.64; 95% confidence interval [CI], −0.85 to −0.43; P&lt; .001), increased frailty (coefficient, 0.19; CI, 0.081-0.31; P&lt; .001), worse PROMIS physical function, greater PROMIS depression, increased serious organ toxicity by D100, more cognitive decline at D100, and higher mortality after acute graft-versus-host disease (GVHD) but not significantly associated with PROMIS anxiety or acute GVHD. Higher CHARM scores predicted worse disability-free survival (odds ratio [OR], 2.03; CI, 1.66-2.48; P&lt; .001) and lower frailty-free survival (OR, 2.00; CI, 1.61-2.49). In summary, CHARM is an independent prognostic scoring system not only for NRM but also for geriatric morbidity and functional limitation–free survival through 1 year after alloHCT. Pre-alloHCT CHARM is a novel tool to aid shared decision-making for older patients. This trial was registered at www.clinicaltrials.gov as #NCT03992352.