Devine, Steven M.

PURPOSE The likelihood of finding a human leukocyte antigen (HLA)–matched unrelated donor (MUD) for hematopoietic cell transplantation can be predicted using a donor search prognosis score. Patients without a MUD may use alternative donors (haploidentical related, mismatched unrelated, or umbilical cord blood). METHODS This multicenter biological assignment trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1702). Eligibility criteria were broad to mirror clinical practice. The primary end point was 2-year survival from evaluability and compared between those Very Likely (>90%) and Very Unlikely (<10%) to find a MUD. All other patients, Less Likely to find a MUD, were enrolled in an observational arm. Transplant outcomes were compared for all three groups. RESULTS A total of 1,751 evaluable patients at 47 centers were Very Likely (54.7%), Less Likely (29.5%), and Very Unlikely (15.8%) to identify a MUD. Survival did not differ in univariate (hazard ratio [HR], 1.00 [95% CI, 0.82 to 1.21]; P = .98) or multivariate (HR, 1.07 [95% CI, 0.86 to 1.33]; P = .56) analyses between the Very Unlikely and Very Likely groups, measured through 2 years from the beginning of a search for a MUD or alternative donor. Of the transplanted patients (n = 1,179), MUD was used for 94% of the Very Likely, 38% of Less Likely, and 9% of Very Unlikely patients. Multivariate analyses showed no differences in relapse, treatment-related mortality, disease-free survival, and acute and chronic graft-versus-host diseases for the three search prognosis groups after transplantation. CONCLUSION Using a donor search prognosis strategy to prioritize an alternative donor for patients Very Unlikely to find a MUD resulted in survival and transplant outcomes that were not statistically different compared with those Very Likely to find a MUD.

Abstract We conducted a post hoc analysis of data from Blood and Marrow Transplant Clinical Trials Network 1506 (MORPHO), a randomized trial of gilteritinib vs placebo as posttransplantation maintenance for patients with FLT3-ITD–mutated acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT), focusing the interactions between conditioning regimen intensity, measurable residual disease (MRD), and NPM1 comutation status reported from diagnosis. Comparing FLT3-ITD MRD before and after conditioning, there was no difference between myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) in eradication or reduction of FLT3-ITD MRD. For participants who were FLT3-ITD MRD negative before HCT, there was no difference in the cumulative incidence of relapse during follow-up between those receiving MAC vs RIC. NPM1 comutation was associated with the largest magnitude of relapse-free survival benefit from post-HCT gilteritinib, and in these participants, post-HCT gilteritinib in the setting of RIC appeared to be as effective as MAC at preventing relapse. MAC appeared superior to RIC in preventing relapse only in participants who were NPM1 wild type at diagnosis and FLT3-ITD MRD positive before HCT. Our findings suggest that only a subset of patients with FLT3-ITD AML undergoing HCT may benefit from MAC and that, similar to AML therapy before HCT, the intensity of the HCT regimen should be adapted according to the molecular features of the disease. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

Abstract Severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure disorder. Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine has long been a frontline treatment option in SAA; however, its limited durability and risk of long-term complications such as secondary malignancies remain a drawback in this treatment modality. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option with significantly improved outcomes over the long term, particularly with HLA-matched related donors. However, the use of alternative donors, such as haploidentical, mismatched, or matched unrelated donors, has previously been limited due to increased transplant-related morbidity, particularly graft-versus-host disease (GVHD). HCTs have therefore been limited to young recipients and those with HLA-matched related donors, creating significant disparity for older adults and those who lack matched donor options. Nevertheless, more recent advances in HCT, such as posttransplant cyclophosphamide for GVHD prophylaxis, have led to improved outcomes of HCT with alternative donors; however, alternative donor HCT remains underused as up-front therapy, in part because of limited multicenter trial data. This review discusses current SAA treatment approaches, including both IST and HCT, and highlights remaining gaps. It also discusses how ongoing clinical trials such as CureAA and TransIT could help address these gaps. Furthermore, we discuss the importance of stakeholder engagement and implementation science in the integration of research-based evidence into clinical practice. Bridging these gaps is necessary for achieving equitable access for patients historically excluded from frontline HCT, including older adults and racially or ethnically diverse populations.

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 &lt; .0001) and worse OS (HR, 2.09; P &lt; .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.

Abstract BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 (“MORPHO”) was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD–mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

Introduction: NPM1 mutations, seen in up to 30% of adults with acute myeloid leukemia (AML), often co-occur with FLT3 internal tandem duplication (FLT3-ITD). Measurable residual disease (MRD) testing before allogeneic hematopoietic cell transplant (alloHCT) for persistence of mutated NPM1 and/or FLT3-ITD can identify patients with AML in complete remission (CR) at highest risk of relapse and death. Quantitative RT-PCR assays are currently recommended for NPM1 MRD testing, while FLT3-ITD MRD testing is DNA-based using next generation sequencing (NGS). DNA-based NGS assays for mutated NPM1 MRD testing may have several advantages but require validation. We performed NPM1 MRD detection in blood collected from patients with AML during first CR (CR1) prior to alloHCT on a subset of patients from the Pre-MEASURE study (PMID: 36881031) using a highly-sensitive, commercially available DNA-based NPM1 NGS MRD assay. Methods: Of the 531 patients aged 18 or older from the Pre-MEASURE study who received an alloHCT for NPM1mutated AML during CR1 at a CIBMTR reporting site in the USA between the years of 2013-2019, a subset of 190 were randomly selected to be included in this analysis. A commercially available research testing kit (IVS, Invivoscribe, San Diego, CA), which can detect DNA-based NPM1 MRD, was used to establish a workflow following clinical testing standards and validated to detect NPM1 insertion variants down to a variant allele fraction (VAF) of at least 0.005%. Results were compared to those previously reported using an anchored multiplex PCR-based (AMP) targeted NGS assay (detection limit 0.01%) and FLT3-ITD MRD results, where applicable. Overall survival (OS) and cumulative incidence of relapse were estimated with the day of transplant as time 0 using Kaplan-Meier estimation (log-rank tests), Fine and Gray model, and Cox proportional hazards models. Results: NPM1 NGS MRD testing was successful for 186 (98%) patients, of which 48 (26%) relapsed (median: 4.0 months; range: 0.7-52.5) and 64 (34%) died (median: 9.7 months; range: 0.4-58.9) post-alloHCT. The IVS assay detected NPM1 insertion variants in 71 patients with a median VAF of 0.0026% (range:0.0002-2.1%). Using a VAF threshold of ≥0.01% for MRD positivity, the IVS test showed that 24 patients tested positive for NPM1 MRD pre-alloHCT, which was associated with significantly increased rates of relapse (52% vs 20% at 3yrs; HR=4.3; P&lt;0.001) and decreased OS (34% vs 71% at 3yrs; HR=3.6; P&lt;0.001) compared to testing negative, in close alignment with those previously reported using the AMP assay. After removing the VAF threshold, an additional 47 patients were classified as NPM1 MRD positive, which remained associated with increased rates of relapse (40% vs 15% at 3yrs; HR=3.4; P&lt;0.001) and decreased OS (50% vs 75% at 3yrs; HR=2.9; P&lt;0.001). In multivariable analysis, residual NPM1 MRD burden prior to alloHCT was associated with risk of relapse and death in a dose-dependent manner. Patients were further subdivided based on their reported FLT3-ITD mutational status at baseline. Increased risk of relapse was seen for NPM1 MRD positive patients regardless of baseline FLT3-ITD. 123 (66%) patients were co-mutated for FLT3-ITD at baseline and previously tested for FLT3-ITD MRD using the IVS assay (PMID: 38696205). Defining MRD based on the presence of NPM1 vs NPM1 and/or FLT3-ITD revealed equivalent levels of relapse (45% vs 44%) and OS (45% vs 46%) at 3 years, with NPM1 MRD evaluation identifying 5 additional relapses. These results were confirmed in the full Pre-MEASURE cohort (n=317) using the AMP assay. NPM1 MRD positive patients receiving nonmyeloablative conditioning or reduced-intensity conditioning (RIC) without melphalan (mel) had increased risk of relapse or death compared to patients receiving myeloablative conditioning or RIC with mel, regardless of FLT3-ITD co-mutational status (3yrs: relapse 87% vs 55%, P=0.006; OS 15% vs 42%, P=0.013). Conclusions: In patients with NPM1 mutated AML from the Pre-MEASURE study, we show that detection of residual NPM1 variants in pre-transplant blood during CR1 using a highly sensitive DNA-based assay is associated in a dose-dependent manner with a significantly increased risk of relapse and death after allo-HCT, which can be mitigated in part by conditioning regimen. In patients co-mutated for both FLT3-ITD and NPM1 at diagnosis, NPM1 should be prioritized as a target for NGS-MRD if only one test is available.

Background: A donor search prognosis score based on HLA type and race/ethnicity can classify patients into 3 groups based on the likelihood of finding an HLA-matched (8/8) unrelated donor (MUD): Very Likely (44% of the population), Likely (41%) and Very Unlikely (15%). Previous studies showed that &gt;90% of Very Likely, 26% of Likely and &lt;10% of Very Unlikely patients used a MUD for their hematopoietic cell transplants (HCT), with the rest using other donor sources (mismatched unrelated donor, cord blood, or haploidentical relative). For some patients, prolonged efforts to identify a MUD might be futile and delay HCT, leading to increased morbidity, greater chance for relapse and disease resistance, and worse HCT outcomes. BMT CTN 1702 (NCT03904134) was the first national study to track the entire donor search identification process. Designed as a biologic assignment study, the goal was to estimate and compare overall survival between two arms: patients who are Very Likely to find a MUD versus those who are Very Unlikely to find a MUD. It tested whether provision of a donor search prognosis score to centers could prevent prolonged futile searches for the Very Unlikely group and improve their transplant rates and outcomes, compared to the Very Likely group. Methods: Eligible diagnoses included acute leukemia, myelodysplastic syndromes, lymphoma, acquired aplastic anemia and sickle cell disease. Patients could be consented at any time after diagnosis until an unrelated donor search was started. Consented patients became evaluable only after it was determined that no appropriate HLA-identical siblings were available. The primary endpoint was survival time after the patient was declared evaluable, regardless of whether HCT occurred, and was compared between the Very Unlikely and Very Likely groups. The target enrollment was 1732 evaluable patients. Because this was a biologic assignment trial and not a randomized trial, formal comparisons of overall survival between the Very Likely and Very Unlikely groups were done using a covariate-adjusted Cox proportional hazards model. The following covariates were a priori specified for adjustment in the model, according to the statistical analysis plan: sex, age, Karnofsky Performance Score (KPS), race/ethnicity, disease, disease status, and interval from consent to evaluability. Results: 1751 evaluable patients were enrolled at 47 centers: 44% female, median age 59.4 years (range 0.6-81.3 years), 73% were non-Hispanic White, 10% Hispanic White, 8% Black, 5% Asian/Native Hawaiian/Pacific Islander, 0.5% American Indian/Alaska Native. Among the evaluable patients, 1181 received a HCT, 827 died, and 924 are still alive with or without HCT, with a median of 25 months of follow up (range=6-54 months [mos], inter-quartile range [IQR]=25-34 mos). The distribution was: 958 Very Likely, 517 Less Likely, and 276 Very Unlikely. Individuals in the Very Unlikely group were younger and were less likely to be non-Hispanic White. The unadjusted cumulative incidences of undergoing HCT by 6 mos and 2 years [yrs], in the Very Unlikely group were 51% and 61% vs. 60% and 69% in the Very Likely Group; after adjustment, there was not a significant difference in the likelihood of undergoing HCT (Dehn et al, submitted). There was no difference in median time from evaluability to HCT: 3.4 mos Very Unlikely and 3.3 mos Very Likely. Unadjusted survival rates from the time of evaluability for the Very Unlikely and the Very Likely groups were: 6 mos (85% vs 84%), 1 yr (69% vs. 69%) and 2 yrs (55% vs. 56%). In the multivariate Cox model, there was no significant difference in the risk of death (HR = 1.07 for Very Unlikely vs. Very Likely, 95% confidence interval 0.86-1.33, p=0.56) adjusting for significant clinical covariates: age, KPS, disease status, and time from consent to evaluability were all significantly associated with overall survival. There was no significant center effect and no interaction between donor search prognosis group and clinical covariates. Conclusion: In this large multicenter BMT CTN study, using the donor selection strategy described, there was no difference in adjusted time to HCT or survival for patients Very Likely versus Very Unlikely to find an 8/8 MUD. These results suggest that patients Very Unlikely to identify a MUD should proceed to HCT using the best available alternative donor rather than delaying HCT to try to identify a MUD.

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&lt;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&lt;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&lt;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 &gt;40 years. For pts aged &lt;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 &lt; 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 &gt;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.