Mattila, Deborah

Importance Allogeneic hematopoietic cell transplant (HCT) is curative for hematologic cancers, yet access remains inequitable for racially and ethnically underrepresented and socioeconomically disadvantaged populations, making the goal of having a suitable donor for every patient who needs a transplant challenging. The ACCESS trial broadened access by enrolling patients without matched donors, who instead received an HCT from a mismatched unrelated donor. Objective To compare baseline characteristics of ACCESS trial participants with participants enrolled in a similar clinical trial and a patient-reported outcome (PRO) protocol cohort. Design, Setting, and Participants This cross-sectional study included adult participants (aged ≥18 years) from 3 cohorts—the ACCESS trial (2021-2024), BMT CTN 1703 trial (2019-2021), and Center for International Blood and Marrow Transplant Research (CIBMTR) PRO Protocol observational study (2020-2025)—who completed a baseline PRO survey. The ACCESS and PRO Protocol cohorts were stratified by conditioning intensity (myeloablative [MAC] vs reduced-intensity and nonmyeloablative [RIC/NMA]); all BMT CTN 1703 participants received RIC/NMA. Exposure Hematopoietic cell transplant. Main Outcomes and Measures Racial and ethnic diversity, insurance type, education, and income were compared among cohorts using counts and percentages, and socioeconomic and structural disadvantage were measured using the Social Vulnerability Index and Comprehensive Score for Financial Toxicity–Functional Assessment of Chronic Illness Therapy. Results Baseline surveys were completed by 208 participants in the ACCESS trial (median [range] age at transplant, 62.3 [20.4-78.9] years; 108 male [51.9%]), 122 participants in the PRO Protocol study (median [range] age at transplant, 63.9 [21.1-78.0] years; 67 male [54.9%]), and 342 participants in the BMT CTN 1703 trial (median [range] age at transplant, 66.9 [20.7-78.6] years; 218 male [63.7%]). Participants in ACCESS were more racially and ethnically diverse, with 15 (7.2%), 25 (12.1%), 46 (22.2%), 110 (53.1%), and 11 (5.3%) of Asian, Black or African American, Hispanic or Latino, White, and other race and ethnicity, respectively, compared with 4 (3.3%), 2 (1.6%), 8 (6.6%) 104 (85.2%), and 4 (3.3%), respectively, in the PRO Protocol and 10 (3.0%), 0, 16 (4.8%), 302 (91.0%), and 4 (1.2%), respectively, in the BMT CTN 1703 trial. Participants in ACCESS were more likely to have Medicaid (36 [18.1%]) vs PRO Protocol (8 [6.7%]) and BMT CTN 1703 (16 [5.1%]) participants and reported lower education (some college or an associate’s degree: 103 [49.5%] vs 73 [59.8%] in the PRO Protocol; postcollege education: 34 [17.3%] vs 35 [29.2%] in the PRO Protocol) and household income (<$40 000 annually: 25 [24.0%] vs 8 [11.6%] in the PRO Protocol and 7 [38.9%] in the BMT CTN 1703 trial). Median Social Vulnerability Index scores were highest among participants in the ACCESS MAC group (median [range], 0.72 [0.01-0.97] vs 0.61 [0.16-0.78] in the PRO Protocol MAC group), and 16 participants [27.6%] in the ACCESS MAC group reported moderate to severe financial toxicity. The ACCESS participants lived closer to transplant centers, especially in the RIC/NMA group (median [IQR], 28 [14-75] miles vs 47 [16-96] miles for BMT CTN 1703 participants and 49 [21-104] miles for PRO Protocol participants). Conclusions and Relevance This cross-sectional study of clinical trial participants and a clinical cohort found that the ACCESS trial enrolled a more racially and ethnically diverse and socioeconomically disadvantaged population. Trial designs that broaden eligibility could expand access to HCT, highlighting the need for systemic interventions to ensure equity.

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< .001), increased frailty (coefficient, 0.19; CI, 0.081-0.31; P< .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< .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.

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for older adults with hematologic malignancies. Concerns on nonrelapse mortality (NRM) in older adults limit allo-HCT utilization. We executed a prospective, observational study BMT-CTN 1704 (Blood and Marrow Transplant Clinical Trials Network) enrolling allo-HCT recipients aged ≥60 years from 49 centers in the United States. We analyzed associations between 13 measurements of older adult health and NRM within 1 year to construct a comprehensive health assessment risk model (primary-CHARM) using multivariate Fine-Gray model and grouped penalized variable selection. Two machine learning (ML) models (Cox and pseudo-value boosting) were also explored. Models’ performances were compared using area under the curve (AUC), with bootstrap and cross-validation sampling to correct for optimism, decision curve analysis (DCA), calibration, and Brier scores. Among 1105 patients with median age of 67 (range, 60-82) years who received allo-HCT, NRM was 14.4% and overall survival (OS) 71.7% at 1 year. Factors statistically selected for inclusion in primary-CHARM were higher comorbidity burden, lower albumin, higher C-reactive protein, older age, higher weight-loss percentage, lower patient-reported performance score, and cognitive impairment. Primary-CHARM scores were independently associated with higher NRM (hazard ratio [HR], 2.72; P < .0001) and worse OS (HR, 2.09; P < .0001). Bootstrap bias–corrected AUC for primary-CHARM was 0.591. Comparing primary-CHARM with HCT-comorbidity index and 2 ML-CHARM models, calibration, Brier score, and DCA analysis favored primary-CHARM. Primary-CHARM, with mostly simple and readily available parameters, risk stratifies older adults for allo-HCT. Adopting primary-CHARM in practice may promote broader use of HCT by quantifying risk and enhance the design of strategies to improve outcomes. This trial was registered at www.ClinicalTrials.gov as #NCT03992352.

Introduction: The BMT CTN 1704 study developed and validated the CHARM that stratified risk for non-relapse mortality and overall mortality among older adults, performing better than the HCT-CI alone (Artz A et al, Blood. 2023;142:109) and equally to two machine learning models. CHARM assigns a total score for 7 health variables: increasing age, higher HCT-CI scores, lower albumin, higher C-reactive protein, higher percent of weight loss over the preceding year, lower patient-reported performance status scores, and lower cognitive score per Montreal cognitive assessment (MoCA). A CHARM calculator is available at:https://cibmtr.org/CIBMTR/OffNav/DevSandbox/CHARM-Risk-NRM-Calculator No multi-institutional prospective data exist on functional trajectories and morbidity after HCT in older patients. We now report on the association of CHARM to trajectories of secondary morbidity outcomes among allo-HCT survivors of this large, prospective study. Patients and Methods: Allo-HCT candidates, aged ≥60 years (yrs), were enrolled (n=1226) from 49 centers in the US between 2019 - 2021. The primary analysis includes 1105 patients proceeding to allo-HCT on study and secondary endpoints were assessed at day (D) 100, 180 and 365 except MoCA and organ toxicity were restricted to D100 and frailty had inadequate data for D100. A sequential multiple imputation strategy was implemented to impute endpoints for survivors at each time point with missing data. Analyses on multiply imputed datasets were conducted and the results combined using Rubin's rule. Associations between CHARM scores and secondary outcomes were analyzed using a multivariable Cox, Fine-Gray, Generalized Estimating Equations, and logistic regression model for survival, competing risks, continuous, and binary outcomes, respectively, with latter two focused on surviving patients. Models were adjusted for other variables including conditioning intensity, graft-versus-host disease (GVHD) prophylaxis regimen, disease-risk index, donor-recipient gender match, ethnicity, baseline value of the dependent variable, and visit timepoints. Results: Higher CHARM scores were associated with development of serious organ toxicities by D100 (OR: 2.05, [1.52-2.78], p<0.0001) and ≥2 worsening score on the MoCA (odds ratio (OR) 1.55 [1.16-2.1], p=0.003). Among survivors at all timepoints, higher CHARM scores were associated with greater disability by instrumental activities of daily living (IADL) (Slope -0.640 [-0.433-0.846], p<0.001) and worsening Patient-Reported Outcomes Measurement Reporting System (PROMIS) physical function (Slope -0.981 [-0.057 - -1.904], p=0.037), depression (Slope 0.763 [0.042-1.484], p=0.038) and in a lesser magnitude anxiety (Slope 0.659, p=0.076). Among survivors at D180 and D365, higher CHARM scores were associated with worse frailty (Slope 0.193 [0.081-0.305], p<0.001). CHARM scores were not associated with development of acute GVHD grades 2-4 or 3-4 but were associated with post-GVHD increased mortality (HR: 1.61, [1.25-2.08], p=0.0002). Higher CHARM scores are associated with a lower incidence of chronic GVHD (HR: 0.83, p=0.026), likely due to the effect of CHARM on the competing risk of death leaving fewer patients at risk for chronic GVHD. Conclusions: The novel primary CHARM, originally developed to predict risks of NRM, also predicts worse frailty, disability, cognitive decline, and serious organ toxicities; outcomes that are critically important to older recipients of allo-HCT. CHARM therefore informs risks of transplant morbidity, separate from risks of developing acute GVHD. Results further support adopting CHARM in practice to counsel patients, expedite HCT referrals for lower risk CHARM, and design trials for high CHARM score patients.

Introduction: Allogeneic hematopoietic cell transplantation (HCT) remains the only therapy for long-term disease control for many high-risk hematologic malignancies (HM). HCT use in older HM patients (pts) continues to increase. However, concerns of excessive transplant-related morbidity and non-relapse mortality (NRM) limit referrals and broader application of curative intent HCT. The HCT-comorbidity index (HCT-CI) was initially developed to improve risk-stratification of NRM. More recently, geriatric assessment (GA) and biomarkers have emerged as promising additional tools that may refine estimates of these risks. We hypothesized that a combination of health assessments by GA and biomarkers would constitute a robust and valid model, CHARM, for accurate personalized estimation of one-year (1-yr) NRM. Here, we report the results of the largest, first of its kind, prospective study of older recipients of HCT through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1704 study (NCT03992352). Patients and Methods: Adults aged ≥60 years (yrs) with HM institutionally eligible for HCT were enrolled (n=1226) from 49 centers in the US between 2019 - 2021. Within 21 days of conditioning, 13 prospectively identified older pt.-specific health variables, informed from prior studies, were collected: age, HCT-CI, % of weight loss over the past yr, pt reported Karnofsky performance status, PROMIS physical function scale, instrumental activities of daily living (IADL), number of falls, PROMIS depression scale, number of prescribed medications, 4-meter walk speed, cognition by the Montreal Cognitive Assessment (MoCA), C-reactive protein (CRP) and albumin. The CHARM score to predict NRM within 1 yr was built using a multivariable (MVA) Fine-Gray model, with multiple imputation to handle modest missingness in covariates and grouped penalized variable selection using SCAD to identify variables to retain in the model. Final variables were used as continuous. The model further considered adjustment for conditioning intensity, CMV serostatus, and donor type. Area under the ROC curve (AUC) was calculated to validate the CHARM and compare to HCT-CI alone, with bootstrap sampling to correct for optimism in the within-sample AUC. MVA of overall survival (OS) within 1 yr used the CHARM score and adjusted for other significant variables derived from stepwise regression. Results: The primary analysis included 1105 pts who were confirmed eligible and proceeded to transplant. Median age was 67 (range 60-82) and 32% were ≥ 70 yrs. AML (45%) and MDS (30%) were the most common indications and matched donors the most frequent donor type at 72%. Reduced intensity conditioning with fludarabine (flu)-melphalan (38%) and flu-busulfan (20%) were the most common regimens. Baseline geriatric vulnerabilities among evaluable pts were frequent including slow walk speed (<0.8 meter/second) in 22%, any IADL limitation in 37%, and cognitive impairment (MoCA < 23) in 12%. 1-yr NRM was lower than expected at 14.4% with 1-yr OS of 72%. In the MVA model, albumin, CRP, HCT-CI, and weight loss were independently associated with NRM (Table) and comprised the CHARM. Of note, increasing age did not significantly affect NRM. The CHARM had within sample and bootstrap corrected AUC of 0.641 and 0.607 whereas the HCT-CI alone achieved corresponding AUC values of 0.601 and 0.598. NRM by tertiles is shown in Figure. Each point increase in the CHARM (median -2.2504, range -3.6327 to 0.1381), was associated with a hazard ratio (HR) of 2.83 (95% CI 2.12 - 3.78, p < 0.0001) for NRM. The CHARM also predicted overall mortality within 1-yr with a HR of 2.04 (1.65- 2.53, p <0.0001) per one point increase, independent of the disease risk index, which had a HR of 1.5 (95% CI 1.12 - 1.99, p =0.0059) for high/very high vs low/intermediate categories. Conclusions: We report on the first prospectively established tool, CHARM, to risk-stratify older adult HCT comprised of simple and readily available parameters in transplant and oncology clinics. Adopting CHARM in practice may promote HCT referrals and access for older pts, given low risks of NRM among CHARM lower 2/3 rd tertiles. Identifying high-risk CHARM pts pre-HCT will promote developing novel strategies to reduce NRM. Further analysis of the impacts of the 13 health assessment variables on geriatric morbidity such as disability trajectories is in-process.

Introduction The Blood and Marrow Transplant Clinical Trials Network 1102 study (BMT CTN 1102, NCT02016781) was a multicenter, biologic assignment trial, where patients aged 50-75 with intermediate-2 or high risk de novo myelodysplastic syndrome (MDS) were assigned to reduced-intensity allogeneic hematopoietic cell transplantation (alloHCT) or best supportive care (non-alloHCT) based on donor availability. A parallel economic evaluation was performed alongside BMT CTN 1102. Here, we report on the financial impact of the treatment protocol on patients using a prospective cost diary study conducted within the trial. Methods BMT CTN 1102 enrollees were offered the option to participate in the parallel cost diary study at the same time of primary study enrollment. The cost diary survey instrument, comprised of 19 questions, covered the domains of out-of-pocket (OOP) costs of healthcare and financial hardship indicators. Surveys were distributed at 1- (1M), 7- (7M), and 19-months (19M) after enrollment. Study participants were grouped by actual treatment received, rather than group assignment. Responses were analyzed using univariate Fisher's exact and Wilcoxon rank sum tests for association. Results Out of 216 enrollee invitations, 138 patients (64%) returned at least one survey. Total completed surveys at the 1M, 7M, and 19M timepoints were 103 (39%), 93 (35%), and 71 (27%), respectively. 50 (36%) completed only one survey, while 41 (39%) completed surveys at all three timepoints. Of all respondents, median age was 67.7 years (IQR: 64.8-70.3), 88 (64%) were male, 128 (93%) white, and 126 (91%) were non-Hispanic. Among respondents of the 1M, 7M and 19M surveys, 82 (80%), 78 (84%), 65 (92%) received alloHCT, respectively. Mean OOP costs by category are presented in Table 1. While alloHCT patients experienced higher OOP costs compared to non-alloHCT patients across all categories (outpatient services, prescription medications, and accommodations for healthcare), none of the comparisons were statistically significant. However, total OOP costs were significantly higher among alloHCT patients at 1 and 7 months (mean over past 30 days, 1M: $889 vs. $217, p=0.046; 7M: $678 vs. $349, p=0.03; 19M: $328 vs. $103, p=0.15). Financial hardship indicators are presented in Table 2. While alloHCT patients experienced greater financial hardship compared to non-alloHCT patients across all categories (mobilized reserve funds, borrowed money to pay for care, developed debt due to care), none of the comparisons were statistically significant. However, alloHCT patients were significantly more likely to experience at least one of these factors of financial hardship at 7 months (1M: 38% vs. 19%, p=0.13; 7M: 42% vs. 13%; p=0.04; 19M: 37% vs. 0%, p=0.08). Discussion Patients with MDS who received alloHCT incurred substantially more OOP costs overall compared to patients who did not receive alloHCT, most notably for accommodations related to alloHCT. Similarly, alloHCT patients were more likely to develop financial hardship, including mobilizing reserve funds, borrowing money, and developing debt. These findings demonstrate that treatment-related OOP expenditures associated with alloHCT are substantial and may pose significant burdens for some populations receiving alloHCT. Financial navigation and assistance, which have been shown to help patients address cost burden in solid tumor settings, should be considered for MDS patients prior to alloHCT. Small final sample sizes limited our analyses significantly; further research into OOP costs and financial hardship among larger cohorts of alloHCT patients are necessary to confirm these findings. Acknowledgement Support for this study was provided by grants #U10HL069294 and #U24HL138660 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Abstract Palliative care (PC) benefits patients undergoing hematopoietic stem cell transplantation (HSCT), but it remains underutilized. Although transplant physicians report concerns regarding how patients perceive PC, HSCT recipients’ perceptions about PC remain unaddressed. We conducted a multisite, cross-sectional survey of autologous and allogeneic HSCT recipients 3 to 12 months after transplant to assess their familiarity, knowledge, and perception of PC, as well as their unmet PC needs. We computed a composite score of patients’ perceptions of PC and used a generalized linear regression model to examine factors associated with these perceptions. We enrolled 69.6% (250/359) of potential participants (median age = 58.1; 63.1% autologous HSCT). Overall, 44.3.8% (109/249) reported limited knowledge about PC and 52% (127/245) endorsed familiarity with PC. Most patients felt hopeful (54%) and reassured (50%) when they heard the term PC; 83% saw referral as a sign their doctor cared about what was happening to them. In multivariate analyses, patients who were more knowledgeable about PC were more likely to have positive perceptions of PC (B = 7.54, standard error = 1.61, P < .001). Patients’ demographics, HSCT features, quality of life, and symptom burden were not significantly associated with perceptions of PC. HSCT recipients have positive perceptions of PC, though many have limited knowledge about its role. Patients who were more knowledgeable about PC were more likely to have positive perceptions of PC. These data do not support transplant physicians’ negative concerns about how patients perceive PC and underscore the need to further educate patients and transplant physicians about PC.

Abstract Background: Palliative care (PC) benefits patients with cancer and those undergoing hematopoietic stem cell transplantation (HSCT), but remains under-utilized in HSCT. While transplant physicians have substantial concerns regarding how patients perceive PC, studies examining HSCT recipients' perceptions of PC are lacking. Methods: Between 11/2020-4/2021, the CIBMTR Survey Research Group conducted a multi-site cross-sectional survey of adult autologous and allogeneic HSCT recipients at 11 transplant centers in the United States who were 3-12 months post-transplant to assess their experience, knowledge, and perceptions of PC. Using validated questionnaires, we assessed patients' familiarity with PC, knowledge and perception of PC, unmet PC needs, quality of life, and symptom burden. We computed a composite score of patients' perceptions of PC (mean = 48.8, SD = 12.2). We used a generalized linear regression model to examine factors associated with patients' perceptions of PC. Results: Of 359 potentially eligible patients, 250 (69.6%) enrolled in the study and 249 were eligible for analysis. Median participant age was 58.1 years (IQR 16.6). Most were white (85.9%), non-Hispanic or Latino (95.2%), and male (53.0%). Overall, 63.1% underwent autologous HSCT. The most common diagnoses were multiple myeloma (42.2%), lymphoma (22.1%), leukemia (16.9%), and MDS/MPN (12.4%). Overall, 44.2% (110/249) of patients reported limited knowledge about PC and 51.0% (127/249) endorsed being familiar with PC. Most patients stated that when they hear the term PC, they feel hopeful (54%), and reassured (50%) while a minority reported feeling scared (21%), stressed (22%), or depressed (15%) [Figure 1]. Most endorsed that when a PC referral is suggested for them, they think their doctor really cares about what is happening to them (83%), and only 7% of patients stated that when a PC referral is suggested, they think their doctor has given up on them [Figure 2]. In multivariate analyses, patients who were more knowledgeable about PC were more likely to have a positive perception of PC (B = 7.54, SE=1.61, P < 0.001) compared to those who had less knowledge about PC. Patients with postgraduate education were more likely to have a negative perception of PC (B = -5.55, SE=2.60, P = 0.034) compared to those with high school education or less. Patients' demographics, HSCT type, diagnosis, unmet PC needs, quality of life, and symptom burden were not statistically significantly associated with their perceptions of PC. Conclusions: A substantial proportion of HSCT recipients report limited knowledge and familiarity with PC. Most patients reported positive perceptions of PC, and those who were more knowledgeable about PC were more likely to have positive perceptions of PC. These data do not support transplant physicians' concerns about how patients perceive PC and underscore the need for future interventions to further educate patients about PC to overcome barriers to PC utilization in HSCT. Figure 1 Figure 1. Disclosures Burns: Astellas Pharma Inc.: Research Funding; Medac GmbH: Research Funding; Sanofi: Research Funding; OncoImmune: Research Funding; Fate: Research Funding; Bristol Meyers Squibb: Research Funding; PrioThera: Research Funding; Kyowa Kirin International: Research Funding. Murthy: CRISPR Therapeutics: Research Funding. LeBlanc: Amgen: Consultancy, Other: travel; Pfizer: Consultancy, Other: Advisory Board; AstraZeneca: Consultancy, Honoraria, Other: Advisory board, Research Funding; Flatiron: Consultancy, Other: Advisory board; Agios: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Other: Travel fees, Research Funding, Speakers Bureau; Daiichi-Sankyo: Consultancy, Honoraria, Other: Advisory board; AbbVie: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Helsinn: Consultancy, Research Funding; Duke University: Research Funding; Jazz Pharmaceuticals: Research Funding; UpToDate: Patents & Royalties; NINR/NIH: Research Funding; CareVive: Consultancy, Other, Research Funding; Otsuka: Consultancy, Honoraria, Other; American Cancer Society: Research Funding; Seattle Genetics: Consultancy, Other: Advisory board, Research Funding; Astellas: Consultancy, Honoraria, Other: Advisory board; Heron: Consultancy, Honoraria, Other: advisory board.