{'fraction_non_alphanumeric': 0.03284464143652688, 'fraction_numerical': 0.022047959995454027, 'mean_word_length': 5.140614096301466, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Biologic Assignment Trial of Reduced-Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients 50-75 Years of Age With Advanced Myelodysplastic Syndrome

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined. METHODS We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration. RESULTS The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm (P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined. CONCLUSION We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS.


INTRODUCTION
Myelodysplastic syndrome (MDS) is predominantly a disease of older adults, with a median age at onset of 76 years. 1 Although there are few available therapeutic options, DNA hypomethylating agents (HMA) can improve hematologic parameters, reduce transfusion requirements, delay transformation to acute myelomonocytic leukemia (AML), and prolong progressionfree survival and overall survival (OS) in individuals with higher-risk disease. [2][3][4][5] However, fewer than half of the patients with MDS achieve objective responses to hypomethylating therapy, and these responses are usually of limited duration. When patients develop HMA resistance, prognosis is dismal with few treatment options. 6,7 Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for MDS and an established therapy for younger patients with MDS. [8][9][10] Although transplantation outcomes among selected older individuals with MDS are similar to those in younger patients with MDS, 11,12 early transplantation for older individuals is not broadly accepted. Statistical modeling analyses demonstrate the benefits of early HCT in older populations, 13,14 and two prospective studies from European groups showed a benefit of HCT over non-HCT therapy when a suitable donor is available. 15,16 We designed a clinical trial to address the research question regarding the appropriateness of allogeneic HCT in this older population within the guidelines set forth by Centers for Medicare and Medicaid Services' (CMS) decision memo. 17, 18 Although a randomized study comparing transplantation to nontransplant therapies would be optimal, this design was considered impractical. [19][20][21] We, therefore, conducted a multicenter, biologic assignment trial in subjects 50-75 years of age with advanced de novo MDS (defined as intermediate-2 or highrisk MDS risk score per the International Prognostic Scoring System [IPSS]) 22 considered eligible for a reduced-intensity conditioning (RIC) 23 allogeneic HCT, comparing outcomes of those with a suitable donor to those without a suitable donor.

Study Design
The study was an open-label, multicenter, biologic assignment trial conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1102). 19 Biologic assignment was to a Donor or No-Donor arm based on high-resolution HLA typing of eligible family members and a 90-day search of the unrelated donor registry through the National Marrow Donor Program. Subjects assigned to the Donor arm were expected to undergo RIC HCT within 6 months of enrollment, whereas those assigned to the No-Donor arm were expected to receive non-HCT therapy or best supportive care. The target enrollment was 338-400 subjects, dependent on the ratio of Donor vs. No-Donor assignment, where 60%-70% of subjects were expected to have a donor identified within 90 days. The primary end point was 3-year OS from registration in an intention-to-treat analysis. Prespecified secondary end points included 3-year leukemia-free survival (LFS), quality-of-life (QOL) measures, and cost effectiveness. Enrollment began in January 2014 and ended in November 2018. In February 2020, an independent Data and Safety Monitoring Board released the study data for analysis. Information regarding Study Oversight can be found in the Data Supplement (online only).

Subjects and Treatment
Eligible subjects were between 50 and 75 years of age and were considered to be candidates for RIC HCT from an HLA-matched related or 8/8 HLA-matched unrelated donor (HLA-A, B, C, and DR using high-resolution typing) by the treating hematologist. All subjects were required to have been diagnosed with de novo intermediate-2 or high-risk MDS by IPSS criteria. Individuals for whom a myeloablative transplant or an alternative donor transplant (mismatched unrelated, haploidentical, or umbilical cord blood) was planned were ineligible. The definition of RIC HCT regimens was based on the Center for International Blood and Marrow Transplant Research criteria. 23 All subjects provided written informed consent before enrollment. Subjects received RIC HCT or non-HCT therapy according to institutional standards. Subjects not undergoing transplantation were eligible to receive HMA therapy or supportive care at referring institutions, whereas HCT was performed at the enrolling site. More details are available in the full Protocol (online only), available on the BMT CTN website. 24

Statistical Analysis
The primary analysis was an intention-to-treat analysis of all enrolled subjects. Subjects were initially assigned to the No-Donor arm at the time of consent; subjects were immediately reassigned to the Donor arm when a suitable donor was identified, whereas those whose 90-day donor search ended without a donor identified or who died before the search ended remained in the No-Donor arm. Subjects who died or withdrew without finding a donor during the search period could potentially bias this analysis, but this was expected to occur infrequently and additional sensitivity analyses removed these cases to examine their impact. The primary analysis compared 3-year OS between arms using adjusted survival estimates 25 to account for the potential bias resulting from biologic assignment, 26 adjusting for prespecified characteristics: age, race or ethnicity, performance status, disease status, comorbidity index, IPSS score, MDS disease duration, and response to HMA therapy. Deaths from any cause were considered failures for OS; subjects followed for , 3 years were censored at their last contact date. A point-wise comparison

CONTEXT Key Objective
To determine whether having a suitable HLA-matched donor improves outcomes for older patients with higher-risk myelodysplastic syndrome (MDS) who are candidates for reduced-intensity allogeneic stem-cell transplantation.

Knowledge Generated
Overall survival and leukemia-free survival were statistically significantly and clinically meaningfully prolonged in individuals who had donors in comparison with those who did not. Quality of life was not impaired with transplantation. Relevance MDS is common among older individuals, and allogeneic stem-cell transplantation is underutilized in this age group. This study demonstrates that having a suitable donor for allogeneic stem-cell transplantation is associated with improved survival. Consultation for allogeneic stem-cell transplantation should occur early in the disease course for older individuals with higher-risk MDS to identify donors. Allogeneic transplantation should be used in this older age-group with MDS.
of three-year survival was used rather than the Cox proportional hazards model because of the potential for non-proportional hazards because of early mortality after HCT.
The targeted sample size was selected to provide at least 80% power to detect a 15% difference in the 3-year OS rate between the two study groups, assuming survival of 35%-40% in the Donor arm and 20%-25% in the No-Donor arm and 10% loss to follow-up. Since the required sample size depended also on the true, unknown proportion of donor availability, treatment assignment was monitored during the study. This study used a group sequential design with a maximum of four efficacy analyses planned, three interim and one final, the first occurring at study enrollment closure and yearly thereafter. A Bonferroni correction was used to control the overall type I error rate for multiplicity, with a Haybittle-Peto boundary of 3.00 used for interim analyses and 2.03 for the final analysis. Confidence intervals and P values for the OS primary analysis are adjusted for multiple interim analyses.
A prespecified, as-treated analyses was also performed for OS and LFS at 3 years, adjusting for the above-mentioned variables, with death and transformation to AML considered LFS failures. QOL was measured by the Functional Assessment of Cancer Therapy-General, the Medical Outcomes Study 36-Item Short Form Survey Physical Component Score and Mental Component Score, and the EuroQol-5D utility score, [27][28][29] and changes in scores from enrollment were compared between arms using analysis of covariance models adjusted for enrollment score. P values , .05 were considered statistically significant and QOL score differences greater than half a standard deviation were considered clinically meaningful. Prespecified subgroup analyses by response to HMA, age, disease duration, and IPSS were conducted using treatment interaction terms in pseudovalue regression models for 3-year OS and LFS. 30 In Donor arm subjects who underwent HCT within 6 months of biologic assignment, post-transplant outcomes of OS, disease-free survival (DFS, defined as freedom from death, MDS recurrence, and AML transformation), relapse, treatment-related mortality (TRM), and acute and chronic graft-versus-host disease (GVHD) were described using the Kaplan-Meier and Aalen-Johansen estimators. These outcomes are described through 27 months post-HCT to coincide with the primary end point's 3-year time point and the 9-month window during which Donor arm subjects are expected to undergo transplant. For these outcomes, multivariable models were constructed using stepwise variable selection to assess the potential influence of response to HMA, age, disease duration, IPSS, and Revised International Prognostic Scoring System. . In a sensitivity analysis, excluding the eight subjects assigned to the No-Donor arm who died (n 5 7) or withdrew (n 5 1) before the end of the 90-day search window had no effect on outcomes (adjusted OS: 48.0% v 28.1%; P 5 .0004). Subgroup analyses of OS found no evidence of interactions between treatment assignment and age group (older than or younger than 65 years, P 5 .73), HMA response type (P 5 .33), or other factors considered (Fig 2B).  2D).

Treatment Compliance and As-Treated Analysis
The overall noncompliance rate for the trial was 26.3% (Data Supplement). Overall, 44 subjects (16.7%) in the Donor arm did not undergo HCT because of disease progression to AML (18), subject preference (16), progressive comorbidity (7), donor or insurance issues (2), and death (1). In addition, 26 subjects (10%) in the Donor arm received a myeloablative HCT because of physician or subject preference (14), or disease-related issues (12

Quality of Life
Preliminary analyses of patient-reported QOL outcomes demonstrated no differences between Donor and No-Donor arms in any of the QOL scores at any time points evaluated (enrollment, 6, 12, 18, 24, and 36 months) that

DISCUSSION
This large, multicenter, biologic assignment trial demonstrated a significant 3-year OS and LFS advantage in older MDS subjects who were RIC HCT candidates with matched donors identified when compared with those without a donor. The benefit of having a matched donor was seen across subgroups, including those who were of Medicare age (. 65 years) and younger. Our prospective data are consistent with the survival outcomes observed in cohort studies, 6,16,32,33 retrospective comparative analyses, 13,14 and confirmed the findings from similarly designed   prospective studies conducted in Europe. 15 11 Together, the data from these two trials provide strong evidence that the use of HCT improves health outcomes in Medicare beneficiaries with MDS. Furthermore, the QOL measures between the two groups in our trial were similar, indicating that the observed survival benefit with RIC HCT was achieved without an early decrement in QOL.
Although randomized controlled trials represent the goldstandard design to compare two therapies, a study that randomly assigns subjects to transplantation is difficult to perform and poses ethical challenges, particularly when one therapy has curative potential. 26 Our approach to conduct a biologic assignment trial has been successfully used to evaluate the role of HCT in multiple scenarios. [34][35][36] Although selection bias can still arise with biologic assignment, this design was considered the most feasible for this research question. 19 To reduce bias, we enrolled subjects without knowledge of donor status and adjusted survival estimates. 25,26 Excessive early deaths before the end of the 90-day search period could have potentially biased the study in favor of the Donor arm, but there were few early deaths and excluding those subjects had no effect on outcomes. Noncompliance with prescribed therapy occurred at the predicted rate (26.3% v 25% anticipated). Noncompliance is expected in a real-world scenario, where the timing and conditioning regimen for HCT may differ from original intent because of disease progression, donor availability, and evolving comorbidity. Noncompliance in this trial was clinically appropriate, reflected best clinical care, and did not favor the Donor arm. Donor arm subjects who did not undergo HCT had worse outcomes than those who did, and subjects on the No-Donor arm who underwent HCT had better outcomes than those who did not.
Our trial excluded subjects who were considered for alternative donor HCT. No prospective study has been done to compare outcomes of alternative donor transplant to HLAmatched transplantation in MDS, although registry analyses suggest that alternative donor outcomes are either similar or only minimally inferior to HLA-matched transplantation, [37][38][39] particularly with the adoption of post-transplant cyclophosphamide as GVHD prophylaxis. 40 Although not designed to specifically evaluate this end point, the favorable outcomes seen with alternative donor transplantation in the No-Donor arm support these assertions.
We designed this trial with a focus on RIC HCT candidates to ensure enrollment of the intended age group (median of 66.7 years). The RIC regimen was left to participating centers according to their institutional guidelines; however, the two most commonly used regimens were fludarabine combined with busulfan or melphalan. Although recent registry studies suggested superior outcomes with fludarabine or melphalan in AML or MDS, 41,42 our study was not designed to address this question. Similarly, our study was not designed to address the issue of the optimal pretransplant therapeutic strategy, as the majority of subjects received HMA before the registration, reflecting current practice.
Next-generation sequencing-based mutation analysis was not initially performed as part of this trial, despite accumulating evidence that specific somatic mutations in MDS are associated with prognosis and HCT outcomes. [43][44][45][46] Future studies are warranted to better define the benefit of HCT according to molecularly informed prognosis toward personalized medicine. Additionally, better assessment tools for older patients with MDS incorporating frailty and resiliency may enhance risk-stratification for HCT (NCT03992352). 47 Despite the safety of RIC HCT, older patients with hematologic malignant diseases are not routinely offered HCT. In a large trial for older patients with high-risk MDS, only 13% of patients proceeded to HCT, 48 and in a cross-sectional survey of 101 physicians responsible for 4,154 patients with MDS, fewer than 5% of patients were evaluated for HCT. 49 Our study demonstrated a significant survival advantage in older patients with MDS who are RIC HCT candidates and have a matched donor identified when compared with those without a donor. Based on these data, HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS. Early referral to a transplant center and coverage of HCT by CMS are strongly recommended.