Bellach, Anna

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.

Background: Immunosuppressive therapy (IST) is considered the standard front-line treatment for acquired severe aplastic anemia (SAA) for pts >40 years. For pts aged <40 years who have a suitable human leukocyte antigen (HLA)-matched sibling donor (MSD), hematopoietic stem cell transplantation (HSCT) is recommended. This recommendation is based on the toxicity associated with alternative donors; haploidentical (HAPLO) and unrelated donor (URD) HSCT for patients who lack a MSD. However, the hematopoietic response after IST is ~ 70-80%, even after augmentation with eltrombopag in the front-line setting, and failure-free survival (FFS, defined as patients alive and in remission without clonal disease more than 10 years after IST) remains < 40%. HSCT is often employed as a second line salvage therapy for those who do not respond to IST or have disease recurrence. However, outcomes after HSCT are often compromised because of IST-related complications such as clonal evolution, development of donor specific antibodies, infectious adverse events and organ dysfunction. In contrast, a successful allogeneic HSCT leads to relatively prompt hematopoietic and immune reconstitution and mitigates the risk of secondary clonal disease. Innovations in recent decades, such as improved graft versus host disease (GVHD) prophylaxis and supportive care, have steadily reduced the morbidity and mortality of adults undergoing HSCT from unrelated or mismatched donors and expanded the donor pool such that almost all pts with SAA have a potential donor available. The use of post-transplant cyclophosphamide (PTCy) is now a well-established approach to facilitate engraftment and mitigate the risk of GVHD. It was successfully used in relapsed/refractory SAA pts using HAPLO donors in the multi-center BMT CTN #1502 trial (NCT02918292). Similar PTCy based approaches have been effective in the upfront setting with HAPLO and URD in small single center studies. Opened in July 2024, the CureAA trial (NCT06517641), seeks to increase donor options for SAA pts who have not yet received IST by using PTCy based GVHD prophylaxis for HSCT using HAPLO or URD. Study Design and Methods: This BMT CTN study (#2207) is a prospective multi-center phase II trial to assess efficacy of HSCT using HAPLO or URD bone marrow with a reduced intensity, thymoglobulin (ATG)-containing preparative regimen and PTCy GVHD prophylaxis in previously untreated SAA pts. This trial has two parallel cohorts for each donor type, HAPLO and URD, with an accrual goal of 30 participants in each cohort. All will receive ATG (0.5mg/kg on day -9 and 2mg/kg on days -8 and -7), cyclophosphamide (14.5mg/kg on days -6 and -5), fludarabine (30mg/m2 on days -6 to -2), 400 cGy total body irradiation (day -1 in a single fraction), a marrow graft (goal >2.5 x 108 nucleated cells per kg of recipient) on day 0 and PTCy (50mg/kg on days +3 and +4). Additionally, participants receive tacrolimus (until day +180) and mycophenolate mofetil days +5-35. The primary objective of the trial is to estimate the GVHD-free failure-free survival (GFFS) rate at 1 year after initiation of conditioning. GFFS is a composite endpoint of survival without grade III-IV acute GVHD, chronic GVHD requiring immunosuppression, or primary or secondary graft failure requiring second definitive therapy within 1 year after initiation of conditioning. Secondary objectives will evaluate patient survival, engraftment, transfusion dependence, cumulative incidence of GVHD and hematologic response. Health related quality of life, healthcare utilization and financial toxicity data will also be collected. These endpoints will allow clinical comparison with current results achieved with upfront IST in other studies. We hypothesize that this HSCT approach will improve survival without significant transplant-associated morbidity by using a low toxicity regimen that reduces rates of GVHD and provides rapid hematologic recovery without graft failure, thereby making HAPLO and URD HSCT a viable option for initial upfront treatment of SAA. The ability to use mismatched donors will also ensure that a HSCT option is more widely available to all racial/ethnic groups. This collaborative study was funded by grants U10HL069294, U24HL138660 to the BMT CTN from the NHLBI/ NCI, along with funding from Sanofi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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.