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Allogeneic Hematopoietic Cell Transplantation Improves Outcome in Myelodysplastic Syndrome Across High-Risk Genetic Subgroups: Genetic Analysis of the Blood and Marrow Transplant Clinical Trials Network 1102 Study

Jurjen Versluis

1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

2 Erasmus University Medical Center Cancer Institute, Rotterdam, the Netherlands

3 Medical College of Wisconsin, Milwaukee, WI

Harrison K. Tsai

Christopher J. Gibson

Laura w. dillon.

4 Laboratory of Myeloid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD

Asmita Mishra

5 Moffitt Cancer Center, Tampa, FL

Joseph McGuirk

6 University of Kansas Cancer Center, Kansas City, KS

Richard T. Maziarz

7 Oregon Health and Science University, Portland, OR

Peter Westervelt

8 Washington University in Saint Louis, Saint Louis, MO

Pranay Hegde

Devdeep mukherjee, michael j. martens, brent logan.

Mary Horowitz

Christopher S. Hourigan

9 Myeloid Malignancies Program, National Institutes of Health, Bethesda, MD

Ryotaro Nakamura

10 City of Hope National Medical Center, Duarte, CA

Corey Cutler

R. Coleman Lindsley

Associated Data

The authors attest that all genetic data required for replication are contained in the article and Data Supplement.

Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor v no donor) study.

We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with TP53 mutations were classified as TP53 multihit if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity).

The distribution of gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P = .89), ASXL1 (23% v 29%; P = .37), and SRSF2 (16% v 16%; P = .99) being most common. OS in patients with a TP53 mutation was worse compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P < .001). Among those with a TP53 mutation, OS was similar between TP53 single versus TP53 multihit (22% ± 8% v 20% ± 6% at 3 years; P = .31). Considering HCT as a time-dependent covariate, patients with a TP53 mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P = .04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P < .001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a TP53 mutation was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years; P = .001).

HCT improved OS compared with non-HCT treatment in patients with TP53 mutations irrespective of TP53 allelic status. Patients with IPSS-M very high risk without a TP53 mutation had favorable outcomes when a donor was available.

INTRODUCTION

Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for patients with myelodysplastic syndrome (MDS). Two biological assignment studies demonstrated improved overall survival (OS) for older patients with high-risk MDS and an available donor compared with those without a donor. 1 , 2 Although the survival benefit of HCT was observed across different clinical parameters, these studies did not assess somatic or germline gene mutations, which have been shown to predict outcomes after allogeneic HCT in retrospective cohorts. 3 - 7

• Key Objective
• To determine whether the improved survival of allogeneic hematopoietic cell transplantation (HCT) in a high-risk myelodysplastic syndrome (MDS) biological assignment trial of HCT was independent of gene mutations.
• Knowledge Generated
• Overall survival was significantly improved by HCT in high-risk genetic subgroups including TP53 -mutated MDS and International Prognostic Scoring System-Molecular very high risk. The improvement by HCT was independent of baseline clinical or genetic characteristics including TP53 mutational clearance.
• Relevance (C.F. Craddock)

*Relevance section written by JCO Associate Editor Charles F. Craddock, MD.

Mutations in TP53 are unequivocally associated with dismal outcomes after HCT because of high rates of disease relapse or progression to AML. 3 - 5 Consequently, the role of HCT for patients with TP53 -mutated MDS or AML is debated. 8 Retrospective analyses have evaluated the potential impact of disease-, patient-, and transplant-related variables, but results are conflicting, and conclusions are fundamentally limited by the lack of a comparative non-HCT group. 3 , 7 , 9 , 10

We performed a genetic analysis of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1102 study of older patients with advanced MDS to identify whether the survival benefit observed in patients biologically assigned to HCT compared with non-HCT approaches was independent of gene mutations. We specifically focused on mutations associated with outcome in this high-risk MDS cohort, including TP53 .

Clinical Cohort

Samples were obtained from the BMT CTN 1102 study (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT02016781","term_id":"NCT02016781"}} NCT02016781 ), a multicenter trial comparing reduced intensity conditioning (RIC) HCT with hypomethylating therapy or best supportive care in patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk de novo MDS. 1 Frozen whole blood collected at the time of enrollment was available from 309 of 384 enrolled patients in the Center for International Blood and Marrow Transplant Research (CIBMTR) Research Sample Repository or the NMDP Repository (Fig ​ (Fig1). 1 ). Sample availability was higher in patients assigned to the donor arm compared with the no donor arm (n = 229, 88.1% v n = 80, 64.5%; P < .001). Patient characteristics and clinical outcomes were aligned with those previously reported for this trial. Baseline characteristics were not significantly different between patients with an available sample compared with those without (Data Supplement [Table S1], online only) and, among patients with samples, were similar in the donor and no donor group. The median follow-up in survivors was 32 months (range, 6-38). All patients provided written informed consent to participate in both the BMT CTN 1102 trial and the CIBMTR research database. This study was approved by the BMT CTN and CIBMTR and conducted with approval of the Dana-Farber Cancer Institute institutional review board.

Patients included in this study. BMT CTN, Blood and Marrow Transplant Clinical Trials Network.

Genetic Analysis

Targeted DNA sequencing on samples at the time of enrollment was performed on 113 genes known to be recurrently mutated in myeloid malignancies or associated with germline predisposition to develop myeloid malignancies (Data Supplement [Table S2]), using a variant allele fraction (VAF) cutoff of 0.02 (Custom SureSelect, Agilent Technologies, Santa Clara, CA). TP53 mutation allele abundance was quantified just before transplantation in DNA extracted from preconditioning blood samples using a custom targeted error-corrected DNA sequencing panel covering the entire coding sequence of the TP53 gene (VariantPlex, ArcherDx, Boulder, CO). 11 Detailed sequencing information is provided in the Data Supplement (Appendix). MDS with TP53 mutations was further categorized on the basis of the number of TP53 mutations (single-nucleotide variants or small indels) and the presence of TP53 deletion or copy-neutral loss of heterozygosity (CN-LOH). Those with ≥2 TP53 mutations or ≥1 point mutation in combination with TP53 CN-LOH, TP53 deletion, or chromosome 17/17p deletion by karyotype were classified as TP53 multihit , whereas those with a single TP53 point mutation without LOH were classified as TP53 single . 12 , 13 FLT3 internal tandem duplications and KMT2A partial tandem duplications were identified as described. 14 , 15 The genetic analysis was locked before merging with clinical data.

Statistical Analysis

To identify mutations associated with OS in the whole study cohort, we evaluated 17 genes that were mutated in ≥10 patients in the study cohort (Data Supplement [Fig S1 and Table S3]). Genes that were mutated less frequently were subject to descriptive analysis. OS was considered as the time from consent until death from any cause or until censoring at the date of last contact being alive. OS curves were estimated using the Kaplan-Meier method, and cumulative incidences of relapse or progression to leukemia were estimated with the Aalen-Johansen method, with death without relapse or disease progression being treated as competing events. Outcomes were compared in univariate analysis of survival and competing risks using log-rank and Gray's test, respectively. Comparisons between the two groups were performed using the Mann-Whitney U test for continuous variables, whereas the Fisher's exact test was used for categorical variables.

The impact of allogeneic HCT was assessed using two methods: (1) a time-dependent analysis allowing the HCT covariate to change at the time of HCT, where OS curves were shown using Simon-Makuch plots 16 and (2) a dynamic landmarking analysis at 3, 6, and 9 months from consent by treatment arm in which patients were assigned to no HCT group if they were not transplanted at the landmark time. 17 , 18

Multivariable analysis was performed using a Cox proportional hazards model with adjustment for prespecified variables, which included age at enrollment (older than 65 v 65 years and younger), performance status (Karnofsky <90 v 90-100 or Eastern Cooperative Oncology Group 1 v 0), IPSS risk status (high v intermediate-2), and MDS disease duration (≥3 v <3 months). Stepwise selection of variables with an univariate of P < .2 for OS was used to generate a multivariable model integrating the remaining clinical and genetic features, with P < .1 as the threshold for variable inclusion in the model.

Genetic Characteristics

We identified ≥1 mutation in 272 of 309 (88%) patients. The overall distribution of somatic gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P = .89), ASXL1 (23% v 29%; P = .37), SRSF2 (16% v 16%; P = .99), and DNMT3A (17% v 10%; P = .20) being the most common (Fig ​ (Fig2). 2 ). Inferred germline mutations in DDX41 were found in 7% (n = 23) of patients, and rare variants affecting core telomerase components TERT (n = 9) or TERC (n = 1) were observed in 3% of patients, consistent with a recent report. 6 The frequency and distribution of gene mutations in the BMT CTN 1102 cohort were similar to those from a retrospective registry-level MDS transplant cohort (n = 227) matched for age, IPSS risk group, and primary versus therapy-related MDS status (Fig ​ (Fig2 2 ). 3

Spectrum of myeloid driver mutations in the BMT CTN 1102 study. A comutation plot shows mutations in individual genes per study arm as labeled on the top. Mutations are depicted by colored bars and each column represents one of the 309 patients. a Significant with P < .05 (Fisher's exact test). b Selection of patients with de novo MDS with IPSS intermediate-2 or high risk age 50-75 years from a matched retrospective cohort. 3 BMT CTN, Blood and Marrow Transplant Clinical Trials Network; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome.

Clinical and Genetic Characteristics of TP53 Mutations

Among 87 patients with a TP53 mutation, 48 (55%) were classified as TP53 multihit , including 27 with ≥2 TP53 mutations, 15 with one TP53 mutation and TP53 LOH identified by NGS, and six with one TP53 mutation and deletion of chromosome 17/17p by karyotype (Data Supplement [Fig S2]). The presence of a TP53 mutation, but not TP53 allelic state, was significantly associated with clinical and molecular characteristics, including a higher frequency of complex karyotype ( TP53 multihit = 67% and TP53 single = 62% v TP53 WT = 10%; P < .001 and P < .001, respectively) and lower platelet count at enrollment ( TP53 multihit = 42 × 10 9 /L and TP53 single = 62 × 10 9 /L v TP53 WT = 90 × 10 9 /L; P = .002 and P = .032, respectively; Data Supplement [Table S4]). Consistent with these differences, patients with a TP53 mutation were significantly more likely to have IPSS high-risk disease than those without a TP53 mutation (52% v 26%; P < .001). Other clinical and transplant characteristics were not different between patients with and without a TP53 mutation (Data Supplement [Table S4]).

Genetic Determinants of Outcomes

In univariate analysis, the presences of a TP53 mutation and KMT2A PTD were significantly associated with shorter OS compared with patients without those mutations ( TP53 : 21% ± 5% [SE] v 52% ± 4% at 3 years; hazard ratio [HR], 2.55; 95% CI, 1.86 to 3.50; P < .001; KMT2A PTD : 8% ± 7% v 45% ± 3% at 3 years; HR, 2.21; 95% CI, 1.22 to 3.99; P = .009), whereas the presence of a germline DDX41 mutation (74% ± 9% v 41% ± 3% at 3 years; HR, 0.39; 95% CI, 0.17 to 0.87; P = .022) and somatic mutations in STAG2 (HR, 0.57; 95% CI, 0.34 to 0.96; P = .034) was associated with favorable OS (Data Supplement [Table S3]). OS at 3 years was similar in patients with TP53 single and TP53 multihit allelic states (22% ± 8% v 20% ± 6%; HR, 1.29; 95% CI, 0.79 to 2.11; P = .31; Fig ​ Fig3A). 3 A). The cumulative incidence of MDS relapse or progression to AML was significantly higher in patients with a TP53 mutation compared with those without a TP53 mutation (68% ± 5% v 42% ± 4% at 3 years; P < .001), and among patients with a TP53 mutation, the incidence was significantly higher in those with TP53 multihit compared with TP53 single (74% ± 6% v 62% ± 8% at 3 years; P = .03; Fig ​ Fig3B). 3 B). Similarly, OS and cumulative incidence of MDS relapse or progression to AML were not different comparing TP53 with or without complex karyotype or deletion 17/17p (Data Supplement [Fig S3]).

Clinical outcomes by TP53 allelic state. (A) OS by TP53 allelic state. (B) Cumulative incidence of MDS relapse or progression to AML by TP53 allelic state, with death considered as a competing event. Time is measured from consent. MDS, myelodysplastic syndrome; OS, overall survival.

Outcome Analysis Adjusted for Clinical and Genetic Variables

To identify the impact of (1) donor availability and (2) the actual application of HCT in this high-risk MDS cohort, we constructed two multivariable models adjusted for prespecified clinical variables including age at enrollment, performance status, IPSS risk status, MDS disease duration, and clinical and genetic variables identified with stepwise selection. The first model is based on the random assignment on the basis of donor availability, whereas the second model addresses the HCT versus no HCT comparison, where HCT was treated as a time-dependent covariate.

In the donor versus no donor analysis, TP53 , KMT2A PTD , and DDX41 mutations were associated with OS after adjustment for covariates (Fig ​ (Fig4A). 4 A). Patients who were assigned to the donor arm had improved OS compared with patients in the no donor arm (HR, 1.60; 95% CI, 1.10 to 2.32; P = .013; Fig ​ Fig4A). 4 A). TP53 allelic state was associated with worse outcome, particularly patients with TP53 multihit compared with those without TP53 mutations (HR, 2.22; 95% CI, 1.35 to 3.65; P = .002; Fig ​ Fig4A). 4 A). Applying that multivariable model to patients with a TP53 mutation, we found that patients in the donor arm had a nonsignificant improved OS compared with those in the no donor arm (HR, 1.76; 95% CI, 0.95 to 3.26; P = .073; Data Supplement [Fig S4]). No interactions were found between treatment arms and mutations in both multivariable models.

Forest plots of the multivariable analysis. Forest plot of subgroup analyses showing the HR for death and 95% CI in (A) the multivariable analysis of the donor versus no donor comparison and (B) the multivariable time-dependent analysis where HCT was considered as a time-dependent variable. Multivariable Cox regression analysis was used, with adjustment for treatment arm (A) or HCT (B), TP53 allelic state, DDX41 mutation, KMT2A PTD , complex karyotype, duration of disease, IPSS score, sex, age, and performance score. ECOG, Eastern Cooperative Oncology Group; HCT, hematopoietic cell transplantation; HR, hazard ratio; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; OS, overall survival.

In the time-dependent analysis of HCT, we included 197 patients who actually received HCT after RIC and 78 patients who did not receive HCT (Data Supplement [Fig S5]). Using a multivariable model in which HCT was considered as time-dependent covariate, adjusted for age, sex, performance status, IPSS, MDS duration, and complex karyotype, TP53 and KMT2A PTD were associated with differential survival (Fig ​ (Fig4B). 4 B). HCT was associated with a 2-fold lower instantaneous risk of death compared with patients not receiving HCT after adjustment for covariates (HR, 2.31; 95% CI, 1.53 to 3.49; P < .001). To assess the impact of HCT in the subset of patients with the highest risk of death, we specifically applied this multivariable time-dependent model to patients with a TP53 mutation (Fig ​ (Fig5A). 5 A). We found that patients with a TP53 mutation who were not transplanted had reduced OS compared with patients who received HCT (HR, 3.89; 95% CI, 1.87 to 8.12; P < .001; Fig ​ Fig5A), 5 A), indicating that HCT might improve long-term survival in patients with mutated TP53 , independent of other risk factors. No interactions were found between HCT and mutations in both multivariable models. OS in patients with TP53 mutations who actually received RIC HCT estimated 23% ± 7% at 3 years which was significantly improved compared with no HCT in a time-dependent survival analysis (Fig ​ (Fig5B). 5 B). These observations were also consistently found at multiple landmark time points, although only significant at the 9-month landmark (Data Supplement [Fig S6]).

Forest plot of the multivariable analysis in patients with mutated TP53 . (A) Forest plot of subgroup analyses in patients with mutated TP53 showing the HR for death and 95% CI in the multivariable time-dependent analysis where HCT was considered as a time-dependent variable. Multivariable Cox regression analysis was used, with adjustment for HCT, TP53 allelic state, DDX41 mutation, KMT2A PTD , complex karyotype, duration of disease, IPSS score, sex, age, and performance score. (B) OS in patients with TP53 mutations in which HCT is considered as a time-dependent covariate according to a Simon-Makuch plot. Time is measured from consent and patients switch from the no HCT to the HCT at the time of HCT if they received HCT. (C) Serial analysis of enrollment and pre-HCT TP53 samples (n = 35). Patients with pre-HCT TP53 VAF ≥5% (left) and pre-HCT TP53 VAF <5% (right) are shown. (D) OS in patients with TP53 mutations by pre-HCT TP53 VAF cutoff of 5%. Time is measured from transplantation. ECOG, Eastern Cooperative Oncology Group; HCT, hematopoietic cell transplantation; HR, hazard ratio; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; OS, overall survival; VAF, variant allele fraction.

Molecular Clearance of TP53 Mutation Before HCT Does Not Predict Long-Term Survival

It has been proposed that long-term survival after HCT of patients with TP53 -mutated MDS is limited to those whose mutation burden can be reduced below a VAF of 5%. 19 Therefore, we obtained samples from all patients who received HCT and had an available sample in the CIBMTR Research Sample Repository (n = 35 of n = 55 total) and then performed targeted, error-corrected sequencing of the TP53 coding sequence. We determined whether TP53 variants present at the time of enrollment were persistent in the preconditioning blood sample, quantified the allele abundance, and analyzed the association between quantitative molecular responses and clinical outcome. Using a high-sensitivity analysis, we found that 33 of 35 patients (94%) had persistent TP53 mutations (median VAF, 0.045; range, 0.0049-0.489; Fig ​ Fig5C). 5 C). Using a 5% VAF cutoff per previous published analyses, 17 of 35 (48.6%) had persistent mutations. To test the hypothesis that pre-HCT molecular clearance explained the observed long-term survival among patients with TP53 -mutated MDS, we analyzed the association between pre-HCT molecular positivity (at either 2% or 5% VAF cutoffs) with OS after transplantation. OS at 3 years was similar for patients with a pre-HCT TP53 VAF cutoff of ≥5% versus <5% (22% ± 12% v 18% ± 10%; P = .95; Fig ​ Fig5D) 5 D) and also not different for a cutoff of ≥2% versus <2% (24% ± 9% v 11% ± 11%; P = .26; Data Supplement [Fig S7]).

Outcome on the Basis of Molecular IPSS Risk Classification

The molecular IPSS (IPSS-M) is a six-tiered MDS risk classification that was developed by combining hematologic parameters, cytogenetic risk, and somatic mutations in 31 genes. 13 Since the relative weights of selected variables in the IPSS-M were determined in an unselected cohort that spanned IPSS low- and high-risk disease and in which <10% received allogeneic transplantation, we sought to determine whether IPSS-M risk model was predictive of transplantation outcomes. In the donor versus no donor analysis, only the IPSS-M very high-risk subgroup was associated with inferior survival compared with very low-risk patients after adjustment for clinical- and transplant-related covariates (HR, 2.43; 95% CI, 1.17 to 5.07; P = .018; Fig ​ Fig6A). 6 A). Patients in the IPSS-M very high-risk subgroup had a heterogeneous molecular profile, with 57% having a TP53 mutation (of which 79% were TP53 multihit ), and the remaining 43% with TP53 wild-type disease most commonly had ASXL1 , RUNX1 , and SRSF2 mutations (Fig ​ (Fig6B). 6 B). Although patients with IPSS-M very high risk with a TP53 mutation had poor outcome irrespective of donor availability (26% ± 8% v 14% ± 13% at 3 years; P = .28; Fig ​ Fig6C), 6 C), IPSS-M very high risk without a TP53 mutation had significantly improved survival in those with a donor compared with those in the no donor arm (68% ± 10% v 0% ± 12% at 3 years; P = .001; Fig ​ Fig6D). 6 D). No interactions were found between treatment arms and IPSS-M risk groups.

Outcome based on IPSS-M risk classification. (A) Forest plot of subgroup analyses showing the hazard ratio for death and 95% CI in the intention-to-treat analysis of donor versus no donor. Multivariable Cox regression analysis was used, with adjustment for treatment arm, IPSS-M score, duration of disease, age, and performance score. (B) A comutation plot shows mutations in individual genes in patients with IPSS-M very high risk per TP53 mutation status as labeled on the top. Mutations, cytogenetic abnormalities, hemoglobin, platelet count, and bone marrow blasts are depicted by colored bars and each column represents one of the 69 patients. For hemoglobin, platelet count, and bone marrow blast, the color scheme ranges from red (high-risk value) to blue (low-risk value). (C) OS (left) and cumulative incidence of MDS relapse or progression to AML (right) by donor versus no donor comparison in patients with IPSS-M very high risk with a TP53 mutation. (D) OS (left) and cumulative incidence of MDS relapse or progression to AML (right) by donor versus no donor comparison in patients with IPSS-M very high risk without a TP53 mutation. Time is measured from consent. ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; IPSS-M, molecular International Prognostic Scoring System; MDS, myelodysplastic syndrome; OS, overall survival.

Outcomes in Patients With Germline DDX41 Mutations

Inferred germline DDX41 mutations were present in 7% (n = 23) of patients with MDS in this study. Patients with mutated DDX41 had higher hemoglobin levels at enrollment (11.6 v 9.1 g/dL; P < .001) and higher bone marrow blast count (12% v 8%; P = .040) compared with patients without DDX41 mutations (Data Supplement [Table S5]). Other clinical and transplantation characteristics were not significantly different among patients with a germline DDX41 mutation versus those without.

The presence of a germline DDX41 mutation was associated with favorable outcomes, consistent with previous studies. 13 , 20 Twenty of 23 patients proceeded to HCT (Table ​ (Table1). 1 ). Only one patient, who also had somatic biallelic TP53 mutations, experienced MDS relapse after HCT. Non-relapse mortality (NRM) was observed in five patients, including one patient who received myeloablative conditioning, three of seven who received melphalan, and one patient who received fludarabine, cycloposphamide, and total body irradiation who had HCT-CI score ≥3. There was no NRM among DDX41 patients receiving fludarabine with 2 days of busulfan or fludarabine and total body irradiation.

Characteristics of Patients With DDX41 Mutations

Allogeneic HCT confers superior survival in transplant eligible patients with high-risk MDS and an available donor. 1 , 2 , 21 Analyses of retrospective, registry-level transplant cohorts have suggested that the benefit of transplantation may not extend across MDS molecular subtypes, 3 - 5 , 13 , 22 but these studies all lacked direct comparison with non-HCT treatment. To determine directly whether HCT improves MDS outcomes independent of gene mutations, we performed genetic analysis of the prospective BMT CTN 1102 biologic assignment trial. Even after adjustment for genetic variables, survival after allogeneic HCT remained superior compared with non-HCT treatment with no interaction between genetic subtype and treatment effect.

Previous retrospective studies have found that the presence of a TP53 mutation is the most powerful predictor of poor survival of patients with MDS after transplantation, with long-term survival varying from 0% to 25% across studies. 3 - 5 , 7 , 23 The absence of a non-HCT control group in such retrospective analyses has thus called into question whether the long-term survival observed in these studies was reasonably attributable to the transplantation intervention. In this study, we directly addressed this question and now conclude definitively that reduced intensity transplantation mediates long-term survival for patients with TP53 -mutated MDS compared with non-HCT treatment. Moreover, we show that the benefit of HCT over non-HCT treatment was independent of TP53 allelic state and not restricted to specific subgroups of TP53 mutated MDS, including VAF, complex karyotype, or mutation clearance after pre-HCT hypomethylating agent treatment.

Together, these data indicate that no patient with TP53 -mutated MDS should be excluded from consideration for HCT a priori on the basis of TP53 status alone. Despite the relative benefit of HCT over non-HCT treatment, however, the absolute survival benefit remains modest, meriting value-based discussions between physicians and patients on the appropriateness of transplantation. Recent data have indicated that TP53 -mutated disease consists of an immune-privileged, evasive phenotype in the bone marrow microenvironment, which might result in reduced sensitivity to alloreactive T cells. 24 Strategies to exploit alloreactivity and restore the microenvironment might improve outcomes after HCT. Several other approaches could be considered to improve long-term outcomes, including early allogeneic HCT in patients with TP53 -mutated MDS 25 or pre-, peri-, and post-HCT interventions aimed at mitigating the risk of relapse. Pretransplant treatment with hypomethylating agents has been associated with clinical responses in patients with mutated TP53 , which has also been shown feasible to bridge time to HCT during a donor search period. 19 , 26 , 27 Combination of hypomethylating treatment with novel agents, for example eprenetapopt or magrolimab, yielded promising results with high rates of complete remission, mutational clearance, and prolonged survival in patients with TP53 -mutated myeloid disease. 28 - 31 Data on efficacy and especially tolerability of these combinations for disease reduction before HCT are needed.

With the development of the IPSS-M, prognostic modeling in MDS now integrates clinical variables, cytogenetic risk, and molecular genetic profile to define six risk categories based on leukemia-free survival and OS outcomes. 13 However, in the IPSS-M cohort, fewer than 10% of patients received allogeneic HCT, raising the possibility that the relative weights of selected variables could differ in the context of transplantation. In the BMT CTN 1102 cohort, half of patients fell within the IPSS-M high-risk and very high-risk groups (28% and 22%, respectively), consistent with the clinical practice to prioritize higher-risk patients for transplantation. Although we found that patients in the IPSS-M very high-risk group had inferior transplant outcomes, we noted that this group was heterogeneous, including patients with biallelic TP53 mutations and patients without TP53 mutations who had a rather different clinical and genetic profile, including ASXL1 , RUNX1 , and splicing factor mutations in the context of relatively high blast counts. In the relatively small subgroup of IPSS-M very high-risk patients without TP53 mutations who had no available donor, we observed poor outcomes, consistent with the non-HCT IPSS-M model. However, when a donor was available, outcomes of these IPSS-M very high-risk patients were favorable. These findings indicate that IPSS-M very high risk MDS without a TP53 mutation may be very sensitive to allogeneic HCT and could be ideal candidates for early transplantation as a path to long-term survival. 32

We found germline DDX41 mutations in 7% of patients, and these were associated with favorable outcomes with a low risk of relapse, consistent with previous reports. 33 , 34 The only patient with germline DDX41 mutation who experienced disease relapse had somatic biallelic TP53 alterations. These data indicate that MDS with a DDX41 mutation is highly curable with RIC-HCT, and treatment strategies should focus on minimizing toxicity to reduce the risk of NRM.

In conclusion, our data indicate that the benefit of HCT in patients with IPSS intermediate-2 and high-risk MDS extends to high-risk genetic subgroups. Moreover, patients with TP53 -mutated MDS, irrespective of additional clinical or genetic variables, including allelic state, VAF, and pre-HCT mutation clearance, have superior survival with RIC allogeneic HCT compared with non-HCT treatment approaches, indicating that these patients should not be excluded for HCT on the basis of genetic findings alone, further reinforcing the conclusion that such patients should be offered transplantation when a donor is available. Patients with IPSS-M very high-risk MDS without a TP53 mutation had favorable outcomes when a donor was available, suggesting that such patients see particular benefit from early transplantation.

ACKNOWLEDGMENT

The authors thank the transplantation center teams for enrolling patients in this trial and the National Marrow Donor Program and Center for International Blood and Marrow Transplant Research for collecting samples and patient data.

This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.

Honoraria: AbbVie

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Honoraria: Kite, a Gilead company, AlloVir, Magenta Therapeutics, Nektar, Sana Biotechnology

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Research Funding: Novartis (Inst), Fresenius Biotech (Inst), Astellas Pharma (Inst), Bellicum Pharmaceuticals (Inst), Novartis (Inst), Gamida Cell (Inst), Pluristem Therapeutics (Inst), Kite, a Gilead company (Inst), AlloVir (Inst)

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Research Funding: Bristol Myers Squibb/Celgene/Juno, ORCA Therapeutics, Gamida Cell, Allovir, Novartis

Patents, Royalties, Other Intellectual Property: Athersys, Inc shared patent re: use of mesenchymal stromal cells for treatment of GVHD

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Stock and Other Ownership Interests: Bluebird Bio, Verastem, Northwest Biotherapeutics, Actinium Pharmaceuticals, 2Seventy Bio, Alimera Sciences

Honoraria: Omeros, Janssen, Cimeio, Deciphera, Jazz Pharmaceuticals, Incyte, Sanofi, Bristol Myers Squibb, Mallinckrodt, CTI BioPharma Corp, Jasper Therapeutics, CSL Behring, InhibRx, Astellas Pharma, Rigel, Oxford Immune Algorithmics

Consulting or Advisory Role: Incyte, Jazz Pharmaceuticals, CareDX, Mallinckrodt/Therakos, Sanofi, CTI BioPharma Corp, Equillium, Bristol Myers Squibb, Cimeio, Editas Medicine

Uncompensated Relationships: Kadmon

Consulting or Advisory Role: Bluebird Bio, Takeda, Sarepta Therapeutics, Vertex, Verve Therapeutics, Qiagen, Jazz Pharmaceuticals

Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2020/049257. Title: CRISPR effector system based multiplex cancer diagnostics. International Filing Date: September 3, 2020. Inventors: Jonathan Gootenberg, Omar Abudayyeh, Jeremy Koob, Rahul Vedula, Coleman Lindsley, Feng Zhang Publication No/Date: WO 2021/046257, March 11, 2021. Applicants: The Broad Institute, Inc, Massachusetts Institute of Technology, and Dana-Farber Cancer Institute, Inc. Broad Ref: BI-10578 MIT Ref: 21822JR DFCI Ref.: DFCI 2775.010 JMIN Ref: BROD-4630WP

No other potential conflicts of interest were reported.

PRIOR PRESENTATION

Presented in abstract form at the 50th Tandem Meetings, Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, Salt Lake City, UT, April 23-26, 2022.

The Center for International Blood and Marrow Transplant Research is supported primarily by U24CA076518; the Health Resources and Services Administration, Department of Health and Human Services contract HHSH250201200016C; and the Office of Naval Research grants N00014-17-1-2388 and N00014-16-1-2020. Support for this study was provided by grants U10HL069294 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 National Institutes of Health (NIH). This work was supported by a Scholar award from The Leukemia & Lymphoma Society (R.C.L.), the Edward P. Evans Center for myelodysplastic syndrome at Dana-Farber Cancer Institute (R.C.L.), the NIH P01CA229092 (R.C.L.), Rubicon fellowship from the Netherlands Organization for Scientific Research (J.V.), Erasmus Medical Center Foundation-Daniel den Hoed (J.V.), Rene Vogels stipend (J.V.), and the Intramural Research Program of the National Heart, Lung, and Blood Institute (C.S.H).

CLINICAL TRAIL INFORMATION

{"type":"clinical-trial","attrs":{"text":"NCT02016781","term_id":"NCT02016781"}} NCT02016781 (BMTCTN1102)

DATA SHARING STATEMENT

Author contributions.

Conception and design: Jurjen Versluis, Wael Saber, Brent Logan, Ryotaro Nakamura, Corey Cutler, R. Coleman Lindsley

Financial support: Ryotaro Nakamura, R. Coleman Lindsley

Administrative support: R. Coleman Lindsley

Provision of study materials or patients: Joseph McGuirk, Richard T. Maziarz, Peter Westervelt, Mary Horowitz, Corey Cutler

Collection and assembly of data: Jurjen Versluis, Wael Saber, Laura W. Dillon, Asmita Mishra, Pranay Hegde, Devdeep Mukherjee, Mary Horowitz, Ryotaro Nakamura, Corey Cutler, R. Coleman Lindsley

Data analysis and interpretation: Jurjen Versluis, Wael Saber, Harrison K. Tsai, Christopher J. Gibson, Laura W. Dillon, Asmita Mishra, Joseph McGuirk, Richard T. Maziarz, Peter Westervelt, Devdeep Mukherjee, Michael J. Martens, Brent Logan, Mary Horowitz, Christopher S. Hourigan, Ryotaro Nakamura, R. Coleman Lindsley

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center .

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians ( Open Payments ).

Use of biological assignment in hematopoietic stem cell transplantation clinical trials

Affiliation.

• 1 Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA. [email protected]
• PMID: 19029209
• PMCID: PMC2671015
• DOI: 10.1177/1740774508098326

Background: When comparing treatments for a specific illness, it is sometimes impractical or impossible to conduct a randomized clinical trial (RCT). Biological assignment trials are one alternative design. In hematopoietic stem cell transplantation (HCT) trials, a human leukocyte antigen (HLA)-matched sibling donor is considered optimal, but such donors are available for only 20-30% of otherwise eligible patients. Rather than randomizing only those with a matched sibling donor, in a recent multiple myeloma trial, the type of HCT each patient received was biologically based, i.e., chosen according to whether or not the patient had a matched sibling donor.

Purpose: This article describes the design and implementation of biological assignment trials as well as their advantages and disadvantages.

Methods: We focus on several aspects of such trials, including efficiency of trial duration, ethical issues, and potential sources of bias. Statistical issues are considered including sample size calculations, monitoring for biased enrollment, and adjustments for imbalances in patient characteristics. A multiple myeloma trial is used as an illustration.

Results: Although they often require a larger sample size, biological assignment trials can provide substantial efficiency in terms of study duration over randomized trials when accrual to a randomized trial would be slow. Determination of sample size requires consideration of the anticipated proportion of patients with a biologically favored (HLA-matched sibling) donor. An add-on randomization of patients without a matched sibling donor may alleviate ethical concerns about applicability of study results to all patients regardless of whether the biological assignment groups differ with respect to outcome.

Limitations: Prognostic factor imbalance and enrollment bias can occur in a biological assignment trial. Statistical adjustment for potential imbalance in prognostic factors is important, as is monitoring center accrual for enrollment bias and performing an appropriate intention-to-treat analysis.

Conclusions: A biological assignment trial can be a reasonable way to compare treatments which are biologically based, such as HLA-matched sibling transplants, when the gold-standard randomized trial design is impractical or impossible. Implementing such a trial requires careful consideration of the ethical issues and potential biases.

Publication types

• Research Support, N.I.H., Extramural
• Feasibility Studies
• HLA Antigens*
• Hematopoietic Stem Cell Transplantation / methods
• Histocompatibility Testing*
• Multiple Myeloma / immunology
• Multiple Myeloma / therapy
• Patient Selection*
• Random Allocation*
• Randomized Controlled Trials as Topic*
• Selection Bias
• Transplantation, Autologous
• Transplantation, Homologous
• HLA Antigens

Grants and funding

• U10 HL069294/HL/NHLBI NIH HHS/United States
• U24 CA076518/CA/NCI NIH HHS/United States
• U10 HL069330/HL/NHLBI NIH HHS/United States
• U01-HL-69294/HL/NHLBI NIH HHS/United States
• U01 HL069294/HL/NHLBI NIH HHS/United States
• U01 HL069294-07/HL/NHLBI NIH HHS/United States

ASH Annual Meeting

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75 A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102

Ryotaro Nakamura, M.D. 1 , Wael Saber, MD, MS 2 , Michael J Martens, PhD 3 * , Alyssa Ramirez 3 * , Bart L. Scott, MD 4 , Betul Oran, MD, MS 5 , Eric Leifer, Ph.D. 6 * , Roni Tamari, MD 7 , Asmita Mishra, MD 8 * , Richard T. Maziarz, MD 9 , Joseph P. McGuirk, DO 10 , Peter Westervelt, MD, PhD 11 , Sumithra Vasu, MD, MBBS 12 , Mrinal M. Patnaik, MD, MBBS 13 , Rammurti Kamble, MD 14 , Stephen J. Forman, MD 1 , Mikkael A. Sekeres 15 , Frederick R. Appelbaum, MD 4 , Adam M. Mendizabal, MS 3 * , Brent Logan, PhD 16 * , Mary M. Horowitz, MD, MS 16 and Corey Cutler, MD, MPH, FRCPC 17

1 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 2 CIBMTR, Medical College of Wisconsin, Milwaukee, WI 3 The Emmes Company, Rockville, MD 4 Fred Hutchinson Cancer Research Center, Seattle, WA 5 Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX 6 Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 7 Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY 8 Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 9 Knight Cancer Institute, Oregon Health and Science University, Portland, OR 10 Department of Blood and Bone Marrow Transplant, The University of Kansas Medical Center, Kansas City, KS 11 Washington University School of Medicine, Saint Louis, MO 12 Ohio State University Wexner Medical Center, Columbus, OH 13 Division of Hematology, Mayo Clinic, Rochester, MN 14 Baylor College of Medicine Methodist Hospital, Houston, TX 15 Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 16 Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI 17 Division of Stem Cell Transplantation and Cellular Therapy, Dana-Farber Cancer Inst., Boston, MA

Background: Recent advances in the treatment of myelodysplastic syndrome (MDS) have improved patient survival and quality of life (QOL), while reducing transfusion burden. However, allogeneic hematopoietic cell transplantation (HCT), widely used in younger MDS patients, remains the only curative therapy for MDS. While transplantation outcomes among selected older patients with MDS are similar to younger patients with MDS, early transplantation for older patients is infrequently offered since the relative benefits of HCT over non-HCT therapy in have not been well defined in this patient group. We conducted a multi-center, biologic assignment trial in older individuals with high risk MDS to define the benefit of HCT over non-HCT therapy.

Methods: The study was a multicenter, biologic assignment trial in subjects aged 50-75 with higher risk de novo MDS (IPSS Intermediate-2 (Int-2) or High) who were candidates for reduced-intensity conditioning (RIC) allogeneic HCT, comparing outcomes of those with a suitable 8/8 HLA-matched donor to those without a donor. The trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1102, NCT02016781). Eligible subjects were enrolled prior to a formal donor search, and before or after MDS treatment was initiated. Biological assignment to the Donor or No Donor arm was based on high-resolution HLA typing of eligible family members and a search of the unrelated donor registries. Subjects were initially assigned to the No Donor arm and re-assigned to the Donor arm when a suitable donor was identified. Subjects who died or whose 90-day donor search ended without identifying a suitable donor remained in the No Donor arm. Subjects in the Donor arm were expected to undergo RIC HCT within 6 months of enrollment. Subjects underwent RIC HCT or non-HCT therapy according to institutional standards. The primary analysis compared three-year overall survival (OS) between arms using adjusted survival estimates to account for the potential bias resulting from biological assignment. The sample size was selected to provide at least 80% power to detect a difference of 15% in 3-year OS. Between January 2014 and November 2018, 384 subjects (Donor n=260, No Donor n=124) were enrolled at 34 centers. The study arms were well balanced for age, gender, KPS, IPSS risk, MDS disease duration and responsiveness to hypomethylating therapy (Table). The median follow-up time for surviving patients 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.

Results: In an intent-to-treat analysis, adjusted OS at 3 years from study enrollment in the Donor arm was 47.9% (95% CI: 41.3%-54.1%) compared with 26.6% (95% CI: 18.4%-35.6%) in the No Donor arm (p=0.0001, absolute difference 21.3%, 95% CI: 10.2%-31.8%)(Figure). A sensitivity analysis excluding subjects assigned to the No Donor arm who died or withdrew prior to the end of the 90-day search window showed no effect on outcome (Adjusted OS: 48.0% vs. 28.1%, p=0.0004). Leukemia-free survival (LFS) at 3 years was greater in the Donor arm (35.8%, 95% CI: 29.8%-41.8%) compared with the No Donor arm (20.6%, 95% CI: 13.3%-29.1%, p=0.003), with no changes in the sensitivity analysis. An OS and LFS benefit was seen across all subgroups tested (Figure).

There were no clinically significant differences in QOL between Donor and No Donor arms as measured by the FACT-G, the MOS-SF36 Physical and Mental Component Scores and the EQ-5D utility score at all time points.

The overall non-compliance rate for the trial was 26.3%. Reasons for non-compliance included the use of myeloablative conditioning or failure to proceed to RIC transplant in the Donor arm, and the use of alternative donors in the No Donor arm. In an as-treated analysis, comparison of the HCT and No HCT arms demonstrated a significant advantage in 3-year OS (47.4% vs. 16.0%, p<0.0001) and LFS (39.3% vs. 10.9%, p<0.0001) for subjects who underwent HCT.

Disclosures: Nakamura: Magenta Therapeutics: Other: Advisory board meeting ; Kyowa-Kirin: Other: Support on a meeting presentation ; Alexion: Other: Support on a meeting presentation ; Merck: Other: advisory board meeting ; NapaJen Pharma: Consultancy ; Kadmon Corporation: Other: Advisory board meeting ; Celgene: Other: Support on seminar ; Viracor: Consultancy . Scott: Alexion, Incyte, Novartis, Regeneron: Consultancy ; Agios, BMS: Honoraria ; BMS, Novartis: Research Funding . Oran: ASTEX: Research Funding ; Celgene: Consultancy ; Arog Pharmaceuticals: Research Funding . Maziarz: Athersys: Patents & Royalties ; Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria ; Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy ; Novartis and Juno: Research Funding ; Novartis and Athersys: Other: DSMB participant . McGuirk: Gamida Cell: Research Funding ; Bellicum Pharmaceutical: Research Funding ; Pluristem Ltd: Research Funding ; Kite Pharmaceuticals: Consultancy , Honoraria , Research Funding , Speakers Bureau ; Juno Therapeutics: Consultancy , Honoraria , Research Funding ; Novartis: Research Funding ; Allo Vir: Consultancy , Honoraria , Research Funding ; Astellas: Research Funding ; Fresenius Biotech: Research Funding . Sekeres: BMS: Consultancy , Membership on an entity's Board of Directors or advisory committees ; Pfizer: Consultancy , Membership on an entity's Board of Directors or advisory committees ; Takeda/Millenium: Consultancy , Membership on an entity's Board of Directors or advisory committees . Cutler: Mesoblast: Consultancy , Membership on an entity's Board of Directors or advisory committees ; Generon: Consultancy , Membership on an entity's Board of Directors or advisory committees ; Medsenic: Consultancy , Membership on an entity's Board of Directors or advisory committees ; Jazz: Consultancy , Membership on an entity's Board of Directors or advisory committees ; Kadmon: Consultancy , Membership on an entity's Board of Directors or advisory committees ; Incyte: Consultancy , Membership on an entity's Board of Directors or advisory committees .

Introduction

Conflict-of-interest disclosure, off-label drug use, allogeneic transplantation for advanced acute leukemia.

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Daniel Weisdorf; Allogeneic transplantation for advanced acute leukemia. Hematology Am Soc Hematol Educ Program 2022; 2022 (1): 534–538. doi: https://doi.org/10.1182/hematology.2022000352

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Outcomes of allogeneic hematopoietic cell transplantation (HCT) for patients with advanced acute leukemia and myelodysplastic syndromes (MDS) remain uncertain. All published series include the important and often not stated selection bias that influences outcome. Performance status, patient age, prompt donor availability, risk phenotype of the leukemia, and tumor burden all influence the decision-making process about HCT with active disease. In addition, patients with MDS do not achieve a true pre-HCT complete remission, and thus much less stringent measures are used to indicate suitability for allografting in that disease. Post-HCT maintenance or investigational approaches for tumor depletion may improve the outcomes.

Provide indications for transplantation of leukemia not in remission

Indicate conditional outcomes for leukemia not in remission

Outcomes of allogeneic hematopoietic cell transplantation (HCT) for patients with advanced acute leukemia remain uncertain. All published series include the important and often not stated selection bias that influences outcome. Therefore, it is often difficult to appreciate and interpret the most important and unreported findings indicating who did not receive a transplant . 1-5   Factors influencing the decision about utilization of HCT and then outcome are shown in Figure 1 .

Factors influencing decisions for transplantation in advanced leukemia.

Who receives an allogeneic transplant while not in remission

While allografting with persisting leukemia still is chosen as therapy for ~300 (of ~3200 allografts) patients yearly with acute myeloid leukemia (AML), it is much less common in acute lymphoblastic leukemia (ALL) (~30/year of ~1300 allografts). 6  

Those proceeding to allotransplantation while not in complete remission (CR) most often have certain well- recognized favorable characteristics. These include generally favorable performance status, limited disease burden, no active infections, good organ function, and usually younger age. Those undergoing transplantation in second but incomplete remission generally have had long initial remissions but failed to achieve CR with repeat reinduction. Modern widespread utilization of venetoclax plus decitabine, azacytidine, or cytarabine can yield good tumor reduction but sometimes persisting detectable (and measurable) residual disease (MRD). 7   Earlier reports using these novel and highly effective induction regimens most often failed to note or formally present detailed data on MRD for those reported in CR. Depth of remission manifesting as incomplete recovery of peripheral counts may also affect outcomes post-HCT with CR with incomplete recovery and MRD each associated with adverse post-HCT outcomes ( Figure 2 ). 8  

Independently adverse outcomes with CR with incomplete recovery and/or MRD. Adapted with permission from Percival et al. 8  

In contrast, for myelodysplastic syndromes (MDS), transplant with active disease is the rule, as CR is rarely a goal and rarely achieved prior to HCT. An often stated cutpoint for MDS is therapy to reduce the pre-HCT blast count to <5%—thus, gross residual disease is regularly apparent in HCT patients with MDS. High-risk cytogenetics and blast counts >10% predict poor outcomes for allogeneic HCT in MDS, but little refined data are available to determine a meaningful cutpoint for proceeding to HCT. Revised International Prognostic Scoring System cutpoints show higher post-HCT relapse risk and poorer overall survival for patients who score intermediate, high, or very high, reflecting cytopenias, blast counts, and cytogenetic characteristics independent of other HCT features. 8-15   HCT remains a preferred therapy for those with advanced MDS (intermediate, high, and very high Revised International Prognostic Scoring System), although in population-based studies, patients with advanced disease were less often able to receive an allograft. 13  

Measurable residual disease prior to HCT

Outcomes of allografting with MRD are also difficult to interpret. 15-18   Relevant covariates include sensitivity of the MRD testing. Certain mutations, of course, are also more easily detected as always pathogenic (NPM1 [nucleophosmin 1] mutated) vs those quantitative allelic ratio tumor burden measures such as AML with FLT3 ITD (FMS-like tyrosine kinase interval tandem duplication). Assays using flow cytometry for aberrant antigen expression or recognition of the original diagnostic phenotype may be valuable but less sensitive than molecular assays and depend on the breadth of the antigen panel tested and the sensitivity of the flow cytometry analysis. Some highly sensitive MRD measures (sequence-based analysis or digital droplet polymerase chain reaction [PCR]) may identify many more patients with residual disease than flow cytometry or fluorescence in situ hybridization or even conventional PCR. 19-24   Use of these different assays, therefore, may influence the number of MRD-negative vs MRD-positive patients, even among those in clinical or cytomorphologic CR. This has been recently evaluated in a formal position paper by the European Leukemia Net and related commentaries. 25  

Conditioning regimen intensity and outcome

Persisting MRD may be overcome (or not) by the planned pretransplant conditioning intensity and perhaps yield different outcomes using reduced intensity regimens of different composition. The BMT CTN 0901 prospective randomized trial of myeloablative vs reduced intensity conditioning (RIC) HCT demonstrated improved outcome for those in CR. 26   However, when recategorized by retesting available samples using targeted next-generation sequencing with focused validation by a highly sensitive droplet digital PCR, the myeloablative conditioning (MAC) regimen was superior only for those with persisting pre-HCT MRD, suggesting some clinical misclassification of negative MRD by the original clinical assays. 27   In contrast, these “truly” MRD-negative patients had similar outcomes with either MAC or RIC transplantation.

Only a modest number of patients with active disease proceed to transplantation using RIC. 28   However complete remission with detectable MRD happens more frequently. Pre-HCT conditioning intensity is often chosen by the patient's age, performance status, and comorbidity rather than the residual disease burden. Some series have compared melphalan-based RIC (most often fludarabine/melphalan) to alternatives, often with busulfan. 29-32  

A recent Center for International Blood and Marrow Transplant Research analysis using highly sensitive MRD measures demonstrated a favorable outcome using fludarabine/melphalan for MRD-positive allografts compared with all other RIC regimens. More widely available and less sensitive assays blur the distinction between true MRD-negative and MRD-positive pre-HCT status. Therefore, outcomes reported with less sensitive assays emphasize each MRD assay's internal validity but confound the comparability of these newer data to earlier reports.

How difficult it was to get a transplant or to achieve CR and its influence on HCT outcomes

Importantly, the extent of therapy prior to a decision to proceed to allotransplantation while not in CR may also influence the reported outcomes. Low-level residual disease after only 2 induction cycles is likely more amenable to a promising outcome then gross persisting relapse after 3 to 4 or more cycles of therapy or trials of investigational treatments prior to transplantation. Little data are available to guide this decision-making, which amplifies the selection bias of those reporting HCT with persisting leukemia.

Some specifics can help guide decision-making about transplantation with active leukemia. 33   A large series from the Center for International Blood and Marrow Transplant Research published some years ago reported 16% (ALL) and 19% (AML) 3-year survival for allografts during relapse ( Figure 3 ). 34   In multivariate analysis, outcomes for AML HCT in relapse were worse if the first CR duration was shorter than 6 months or there were persisting circulating blasts, use of a donor other than a human leukocyte antigen (HLA)-identical sibling, a Karnofsky or Lansky score <90, and poor-risk cytogenetics. ALL outcomes were worse in first refractory or second or greater relapse or when there were ≥25% marrow blasts, a cytomegalovirus-seropositive donor was used, and in recipients aged ≥10 years.

Survival after HCT for advanced AML based on 5 risk factors: first CR duration <6 months, circulating blasts, non-HLA-identical sibling donor, performance score <90%, and poor-risk cytogenetics. CI, confidence interval. Adapted with permission from Duval et al. 33  

A more recent series addressing pre-HCT therapy and its influence on post-HCT outcome has analyzed the extent of prior treatment and time from diagnosis to transplantation for patients with primary induction failure (PIF). 35   After MAC HCT for AML, survival was 1.3-fold better for those in first CR (CR1) after 1 cycle than for those requiring more than 2 cycles to CR1 ( P  < .01) and 1.47-fold better than with those with ≥3 cycles ( P  < .01).

This poorer survival in those requiring added therapy to achieve CR1 was a consequence of higher post-HCT relapse risk (1.65-fold greater) in patients needing ≥3 cycles to achieve CR ( P  < .01). However, after RIC allo-HCT, the number of induction cycles did not influence overall survival (OS), yet compared with CR1 achieved in 1 cycle, relapse risk after RIC HCT was 1.24- to 1.41-fold greater in patients receiving either 2 or ≥3 cycles to CR1. 35  

Importantly, outcomes for patients with AML undergoing transplantation during PIF yielded only limited survival beyond 2 years. However, allograft outcomes during PIF were still acceptable for some patients. Recognizing the selection influencing which patients proceeded to HCT with persisting leukemia, after MAC HCT in PIF, 3-year probability of OS was 30% (95% confidence interval, 25.1%-35.1%), and after RIC, the 3-year probability of OS was 26.3% (95% confidence interval, 19.1%-34.2%; P  = .43). However, transplantation in complete remission even requiring numerous cycles to achieve CR was always favorable to transplantation during PIF. After MAC HCT, 5-year survival was only 25% in PIF patients vs 46% to 59% for those in CR after 1, 2, or 3+ cycles. After RIC, 1-year survival (too few to analyze at 5 years) was 49.8% for PIF vs 57% to 65% for those in CR.

Summary and application to clinical decision-making

Allogeneic transplantation for acute leukemia in relapse still has potential value but only for a restricted population. Younger patients with good performance status and with only a small tumor burden may have acceptable although still unfavorable outcomes using myeloablative conditioning and with a well-matched donor available at the proper time. This must be balanced against the toxicity of further reinduction attempts, which can compromise performance status and associated extended neutropenia yielding difficult infections—either of which might increase non-relapse mortality. Thus, HCT with some reduced but persisting disease burden may be justified, but selectively. RIC has limited value for those in relapse or those with MRD detectable in their pretransplant marrow assessments. Novel and more potent antileukemic tools must be added to the backbone of an RIC HCT for those with persisting disease.

The traditional model implied that conditioning and graft vs leukemia would encompass all the antileukemic benefit of an allograft. However, for patients with persisting morphologic or molecularly measurable disease, augmented induction or conditioning intensity, 36   posttransplant consolidation or maintenance therapy, 37- 42   or immunotherapy 42   may improve outcomes. Yet today, we do not have clear data outlining a data-driven clinical algorithm. These options all require careful study and objective comparability of patients' relapse risk to assess the value of these new antileukemic interventions. There may be more to add to an allograft, but new measures need disciplined evaluation to prove their value in reducing relapse risks and expanding the curative potential of transplantation.

Daniel Weisdorf has no competing financial interests to declare.

Daniel Weisdorf: nothing to disclose.

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Multicenter biologic assignment trial comparing reduced-intensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50 to 75 with intermediate-2 and high-risk myelodysplastic syndrome: Blood and Marrow Transplant Clinical Trials Network #1102 study rationale, design, and methods.

Author information, affiliations.

• Le Rademacher J 1
• Horowitz MM 1
• Sekeres M 2
• Mendizabal A 3
• Appelbaum FR 5

ORCIDs linked to this article

• Sekeres M | 0000-0003-2009-6524

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation , 24 Jun 2014 , 20(10): 1566-1572 https://doi.org/10.1016/j.bbmt.2014.06.010   PMID: 24972249  PMCID: PMC4169902

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Abstract 

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Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Intermediate-2 and High Risk Myelodysplastic Syndrome Blood and Marrow Transplant Clinical Trials Network #1102 Study Rationale, Design and Methods

1 Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin, Milwaukee, WI

Jennifer Le Rademacher

Mikkael sekeres.

2 Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

Brent Logan

Moira lewis.

3 The EMMES Corporation, Rockville, MD

Adam Mendizabal

Eric leifer.

4 The National Heart, Lung, and Blood Institute, Bethesda, MD

Frederick R. Appelbaum

5 Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, WA

Mary M Horowitz

Ryotaro nakamura.

6 City of Hope National Medical Center, Duarte, CA

Corey S. Cutler

7 Dana Farber Cancer Institute, Boston, MA

Associated Data

Table 1s. Survival Probabilities by Donor Type

Table 2s. Univariate Analysis of Transplantation Outcomes for MDS Patients by Conditioning Regimen and Donor Type

Table 3s. Outcomes of Non-Transplant Therapy in MDS

Table 4s: Estimated Annual Accrual

Table 5s: Power to Detect 15% Increase in OS Probability in the Transplant Arm for Various Survival Probabilities and Proportions of Donor Availability

The introduction of reduced intensity conditioning regimens (RIC) made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared to novel non-transplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT to non-transplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age & response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT.

Introduction

Myelodysplastic syndromes (MDS) represent a heterogeneous group of acquired malignant bone marrow disorders characterized by high rates of apoptosis leading to ineffective hematopoiesis. 1 An acquired bone marrow failure picture ensues and leads to varying degrees of peripheral blood cytopenias and potentially fatal complications, including infection and bleeding. 1 , 2 MDS is most often diagnosed in elderly individuals with a median age of 76 years at diagnosis, 3 , 4 . Overall, about 30% of individuals with MDS progress to acute myeloid leukemia (AML), although the probability of progression is largely determined by disease risk at presentation 4 , 5 (e.g. the 2-year risk of progression to AML is 80% for those with high-risk disease but only 10% among those with low risk disease). 6

The most widely used prognostic classification system for MDS is the International Prognostic Scoring System (IPSS), which takes into account the number of bone marrow blasts, cytogenetic abnormalities, and cytopenias. 5 The IPSS classifies patients into low-risk, intermediate-1, intermediate-2, and high-risk stages. The median survival ranges from 5.7 years for those with low-risk disease to being only measured in months for those with high-risk disease. 5 Very recently, a newer IPSS was published (IPSS-R), 7 but to date most clinical experience and conduct of investigative clinical trials for MDS have used the original IPSS.

A wide range of therapeutic approaches exist for patients with MDS, which are typically selected based on the patient's estimated risk of death. 5 - 9 And treatment guidelines have been developed by independent groups. 10 , 11 Introduction of hypomethylating agents (HMA) prolongs progression-free survival, 12 overall survival, 13 , 14 and delays transformation to AML. 12 - 14 However, to date, allogeneic hematopoietic cell transplantation (alloHCT) remains the only curative therapeutic modality available. Despite its curative potential, because of the risk of non-relapse mortality with alloHCT in a population of mostly older individuals, many patients with MDS are still not referred for transplant evaluation. 15 A recent query of transplantation activity reported to the Center for International Blood & Marrow Transplant Research (CIBMTR) showed that out of a total of 3,101 alloHCTs performed in the US between 2000 and 2010 for MDS, only 232 (7.5%) were among persons aged 65 years and older (unpublished data; W.S., personal communication). Recent studies, however, have shown that among patients who were considered to be candidates for alloHCT and were referred to the transplant programs, age was not an important predictor of post-transplant outcomes. 16 - 18 With the introduction of reduced intensity conditioning regimens (RIC) alloHCT, which have been shown to be associated with promising results in MDS, 19 - 21 as well as expanded coverage for the alloHCT by Medicare under the Coverage-with-Evidence-Development (CED) mechanism, 22 more patients are now undergoing this curative therapy. 23

To better define the value of alloHCT comparative analyses are needed. Few such analyses have been performed. In a retrospective cohort analysis, alloHCT (n=103) recipients were 70% less likely to die (p=.007) compared to patients that only received hypomethylating agents (HMA). 24 However, this particular study did not control for lead time bias, 24 and therefore, the results should be interpreted with great caution. 25 In a recent retrospective analysis, the investigators employed a multistate statistical model to define the optimal timing of alloHCT for MDS patients aged 60-70 (n=514). 26 This analysis demonstrated that among those with low risk MDS (IPSS low-risk/intermediate-1), non-transplant therapies provided a higher life expectancy, while among those with high risk MDS (IPSS intermediate-2/high-risk) proceeding immediately to alloHCT was associated with higher life expectancy than non-transplant approaches. 26 A small prospective study compared alloHCT to non-transplant approaches using a “donor vs. no donor” comparison. 27 One hundred and sixty three patients with intermediate/high risk MDS were enrolled. The distribution of donor status was as follows: 34 had no donors; 115 had a human leukocyte antigen (HLA) matched donor (identical sibling or well matched (HLA 10/10) unrelated donor [WMUD]); 14 had partially matched (HLA 9/10) unrelated donor (PMUD). The primary outcome (overall survival at 48 months) was significantly different among the three groups (p=0.01). The corresponding survival probabilities were 17% (95% confidence intervals [CI] 6-43), 35% (95% CI 26-49), and 8% (95% CI 1-55). Whether the difference between the no donor arm and the HLA matched donor group was significant is unclear, however. Given the wide confidence intervals around these estimates, these results need confirmation in larger studies.

Given the lack of definitive prospective data evaluating the relative risks/benefits of alloHCT compared to non-transplant approaches among older MDS patients, and as a response to the Centers for Medicare & Medicaid Services (CMS) CED for National Coverage Determination of Stem Cell Transplantation, The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) has launched BMT CTN 1102 prospective study to address this knowledge gap. 28 In this paper, we discuss the design of BMT CTN 1102 and steps taken to address potential sources of bias.

Study Overview

The fundamental question being addressed is whether patients aged 50-75 years with high-risk MDS referred to transplantation centers, and for whom a suitable donor is available, have a 3-year survival advantage with RIC alloHCT compared to non-transplant based therapies (offered to those without a suitable donor but transplant eligible). Other key outcomes include leukemia-free survival, quality of life, and cost-effectiveness.

Figure 1 depicts the overall study schema. Subjects are enrolled at the referral visit to the transplant center. Subjects for whom a search for an unrelated donor was initiated prior to their referral to the transplant center will not be eligible for participation in this study. However, subjects for whom sibling tissue typing was initiated prior to their referral will be allowed to participate. All subjects are initially assigned to the no donor arm at the time of enrollment. Subjects with a suitable donor will be reassigned to the donor arm when a donor is identified. A suitable donor is defined as either an HLA-matched related donor, or an 8/8 (HLA-A, -B, -C, and -DRB1) matched unrelated donor (by confirmatory typing). If no suitable donor is identified during a 90-day interval (from enrollment), subjects will be permanently assigned to the no donor arm. The 90-day interval was chosen based on prior experience from the National Marrow Donor Program that if a donor is not found in this time frame, the subsequent likelihood of finding a donor is very small.

Key Issues in Study Design

Randomization vs. biologic assignment.

Randomized controlled trials (RCT) represent the gold standard design when one wishes to compare two therapies. However, among patients who are referred for transplant evaluation, and for whom an HLA matched donor has been identified, it is generally viewed as not feasible to conduct a true RCT (i.e. randomize patients with HLA matched donors to alloHCT vs. non transplant). 29 , 30 An alternative approach is to conduct a biological assignment trial, which means that patients with a suitable HLA-matched donor are assigned to the alloHCT arm, while patients who do not have such a donor are assigned to the non-transplantation arm. Biologic assignment trials have been used successfully to evaluate the role of alloHCT across multiple hematologic malignancies. 31 - 36 . With this design, accrual is significantly enhanced, and therefore this is a more feasible design compared to a RCT. 37 Given prior beliefs and misconceptions regarding the value of alloHCT among those with a donor, biologic assignment design provides a reasonable platform upon which the study can be performed. 37 BMT CTN 1102 is designed as a prospective, comparative biologic assignment study of RIC alloHCT from related and unrelated donors vs. hypomethylating therapy/best supportive care among patients with intermediate-2/high-risk de novo MDS.

Although selection bias can arise in biologic assignment, it is the most feasible design for this trial. The study was carefully designed and adjusted analysis was planned to minimize potential bias as discussed below.

Enrolling at Referral to Transplant Program vs. Other Time points (e.g. at Diagnosis or at Complete Remission)

Since most newly diagnosed MDS patients are treated by community oncologists, it is difficult to recruit patients at diagnosis before they have received therapy.

Unlike acute leukemias where a complete remission is the objective of induction chemotherapy (and therefore would be an ideal time to enroll patients onto a study that evaluates consolidative strategies), induction chemotherapy is rarely used at the time of initial MDS diagnosis and a complete remission occurs in a minority of MDS patients on HMAs, rendering enrollment at CR neither a clinically meaningful nor a feasible time point. 12 , 14 BMT CTN 1102 is addressing the fundamental question of whether RIC alloHCT offers a survival advantage compared to non-transplant therapies, among older MDS patients who are felt to be transplantation candidates. Therefore, enrolling patients at the time of referral would seem to be a reasonable approach.

Enrollment Bias and Prognostic Factor Imbalances

Given the lack of randomization, biologic assignment trials are inherently vulnerable to enrollment bias and prognostic factor imbalances. A detailed discussion of enrollment bias in the setting of biologic assignment trials has been published elsewhere. 37 In order to reduce bias and assemble the proper control group for the “donor-arm,” it is critical to enroll patients without knowledge of whether a donor is available or not. Therefore, patients whose tissue typing for unrelated donors was initiated prior to referral will not be eligible. Patients whose tissue typing for a sibling donor was initiated prior to referral will still be eligible. The latter should not risk enrollment bias, because for those patients in whom the tissue typing rules out available sibling donors, they will still be considered for a HLA-matched unrelated donor transplant. Additionally, a multivariate analysis is planned that will adjust for any serious imbalances in baseline characteristics.

Potential Bias Introduced During Donor Search

Excessive early deaths (early indicates no suitable donor is identified and the 90-day window is not yet reached) could potentially bias the study in favor of the RIC alloHCT arm, since subjects who die before a donor is identified will be analyzed in the no-donor arm. Conversely, subjects with an already identified sibling donor (which means immediate assignment to the donor arm) who are referred to the transplant center who experience early death (early indicates death occurring less than 90 days from enrollment and before RIC alloHCT is actually performed) are analyzed in the donor group, which could bias the study in favor of the non-transplant arm. The protocol team will monitor the rates of early death carefully and will report them to the Data Safety Monitoring Board. The protocol team expects that these early deaths rates will be very small given that these patients were felt to be eligible to undergo alloHCT within the preceding 2-3 months.

Eligibility Criteria

Patients with de novo MDS are eligible irrespective of how long they had MDS. 38 Patients must have (or previously had) an intermediate-2 or high-risk IPSS stage. 5 Our intent is to include patients in whom a RIC alloHCT is preferred based on physician's assessment. Patients younger than 50 years of age typically undergo high intensity conditioning alloHCT. 23 Therefore, subjects aged 50-75 years will be eligible to participate.

For subjects to be assigned to the donor arm, a suitable donor must be identified, which as previously stated is defined as either HLA matched related donor or 8/8 HLA well matched unrelated donor. Two recent analyses informed the decision to restrict donor types to only these two. We recently reported outcomes of 701 MDS patients (median age 53 years (range 22-78)) after HLA-identical sibling versus 8/8 (HLA-A, -B, -C, and DRB1) matched unrelated donor vs. 7/8 HLA-partially matched unrelated donor alloHCT. 39 In multivariate analysis, HLA-identical sibling HCT recipients had similar survival compared to 8/8 matched unrelated donor HCT recipients, and both HLA-identical sibling and 8/8 matched unrelated donor groups had superior survival compared to 7/8 HLA-partially matched unrelated HCT recipients ( Table 1 ). 39

Adapted from Saber et al. 39

Additionally, using data from the CIBMTR, we recently conducted an exploratory analysis to determine the impact of different donor sources on post alloHCT outcomes in patients with MDS (unpublished data). We selected patients who were at least 21 years of age that received an alloHCT for MDS between 2000 and 2010 in the United States. Donor sources were: HLA-identical sibling (n=1458), well matched unrelated donors (n=1091), partially matched unrelated donors (n=273), cord blood (n=153), and haploidentical donors (n=95). Median age at HCT was 54 (range 21-81) and age distribution was similar across the 5 groups. In univariate analysis, survival was significantly lower for partially matched unrelated donors, umbilical cord graft and haploidentical donor alloHCT compared to HLA-identical sibling and well matched unrelated donor alloHCT (p<0.001). Survival was not significantly different (p=0.56) among the three alternative donor groups ( Table 1s ).

Together, these analyses suggest that transplantation from alternative donors is associated with significantly poorer outcomes than transplantation from HLA-identical sibling and well matched unrelated donor. Therefore, only HLA-identical siblings or 8/8 HLA well matched unrelated donors are considered suitable donor types in this study. Physicians and patients participating in this study should have no intention to pursue alternative donor HCT if a suitable donor is not available. In addition, if a suitable donor is available, the intention should be to proceed to RIC alloHCT as soon as possible.

The outcomes of therapy-related MDS with non-transplant therapies are quite dismal. A recent analysis by Bally et al. suggests a 2-year survival of 14% with DNA hypomethylating agents. 40 Given the grim prognosis with HMA, these patients may benefit from an alloHCT from an alternative donor even if a suitable donor is not available, and therefore patients with therapy-related MDS are excluded from this study.

RIC AlloHCT Regimens

The actual choice of regimen is left to the discretion of the treating physician. However, regimens must be declared by the center as a preferred regimen in order to assure that alloHCT is performed according to the institutional standard. The rationale for not specifying a particular RIC regimen is further supported by recent analysis of data reported to the CIBMTR (unpublished). In univariate analysis of outcomes of MDS patients aged 50-75 that underwent RIC alloHCT between 2005 and 2011, and controlling for donor type, we found no significant difference in survival between the different reduced intensity conditioning regimens ( Table 2s ).

Non-Transplant Regimens

The protocol does not mandate particular non-transplant therapy. However, we expect that the vast majority of patients will be treated with HMA. We acknowledge that non-transplant treatments used for patients in the control arm may vary. However, there are no non-transplant therapies that produce cures in patients with high-risk MDS, and most non-transplant patients will receive the few FDA-approved and available therapies when appropriate. The poor outcomes associated with these therapies are demonstrated in Table 3s . Data on the type of non-transplant therapies will be captured (i.e. whether HMA were received or not, number of cycles, duration of therapy).

Feasibility

Based on historical CIBMTR data and assuming an accrual rate of 40%, we expect annual enrollment of 84 patients to the RIC alloHCT arm. The length of time required to accrue the targeted sample size for this study depends on the proportion of enrolled patients with a suitable donor. Table 4s provides estimated annual accruals for various proportions of donor availability. Based on these assumptions, it is estimated that 2.5-3.5 years of accrual will be necessary to enroll the targeted sample size.

Data Collection for Subjects Assigned to the No Donor Arm

Subjects assigned to the no donor arm will continue to be followed by their primary hematologists. The HCT centers which enrolled and registered the patients will be responsible for periodic contact (every 3 months for Year 1 and 2, every 6 months in Year 3: +/- 1 month) with the primary hematologists. Documentation of transformation to AML will be requested, as well as treatment history. Vital status (death or alive), and date of the last follow up or death will be recorded.

Data Collection for Subjects Assigned to the Donor Arm

The schedule of follow up for subjects assigned to the donor arm but had not yet undergone alloHCT will follow the same schedule outlined above for the no-donor arm. Once transplanted, the follow up will be through submission of CIBMTR pre- and post-transplant comprehensive Report Forms. In the event that patients with donors DO NOT undergo transplantation, the follow up will remain the responsibility of the transplant center, with the same schedule outlined above for the no-donor arm.

Key Issues in Study Analysis

Intention-to-treat vs. as treated analysis.

To minimize bias that may occur post assignment, intention to treat (ITT) analysis is planned as the primary analysis. Table 2 gives examples that illustrate how the ITT principle will be maintained when events occur during the 90-day interval and beyond. Additional sensitivity analyses excluding patients who died or dropped out before 90 days from enrollment as well as a secondary analysis using as-treated principle will also be conducted.

Statistical Power

Secondary analyses of published data from CIBMTR for high-risk MDS patients older than age 50 suggest three-year OS estimates between 35-40%. 39 Based on data from a compassionate use program of DNA hypomethylating agents, the three-year OS probabilities for the non-transplant arm are estimated to range between 20% and 25%. 41 Based on these data, we expect to observe an absolute difference of 15% in three-year OS probabilities in favor for patients assigned to the RIC alloHCT. Table 5s gives the estimated sample size and power (at least 80% power) for various combinations of baseline survival probability and donor availability. It is expected that 60% - 70% of patients will have a donor. The required sample size increases with higher percentage of donor availability.

Planned Subgroup Analyses

The value of HMA therapy pre-HCT- and more specifically, the “optimal” timing to refer a patient on HMA therapy for transplantation evaluation- remains unknown. Retrospective analyses have examined the impact of pre-HCT HMA therapy on post-HCT outcomes. The largest study included 163 individuals who underwent HCT after azacitidine, after leukemia-type induction chemotherapy. There were no differences in post-HCT outcomes. 42 A smaller study from Seattle demonstrated a slight advantage to pre-HCT therapy with azacitidine over induction chemotherapy, potentially because of reduced toxicity. 43 Both of these studies, however, lack the size of the original patient population initially considered for transplantation—the actual denominator—without which it is impossible to determine the role of one pre-HCT approach vs another. Other retrospective analyses compared pre-HCT HMA therapy with no treatment, and showed no benefit to HMA therapy. These studies were affected by similar selection biases as mentioned above. 44 , 45 Predefined subgroup analyses to determine the impact of pre-HCT HMA therapy (including response to HMA therapy) on the study outcomes will be performed to address this important question.

Additional predefined subgroup analyses will examine the impact of the following factors on treatment effect: patient age (<65 years vs. ≥65 years); disease duration; IPSS and IPSS-R.

Discussion/Conclusions

Understanding the relative risks/benefits of alloHCT can move the field significantly forward. We believe that the current study design affords the best practical approach to achieving this goal in a relatively unbiased fashion. Despite potential limitations discussed above, the strength of the current design is that it is likely to result in successful accrual by: 1) having eligibility criteria that will capture a large segment of the patients referred for transplantation; 2) allowing flexibility in both transplant and non-transplant therapies administered; 3) minimizing the data collection burden; and, 4) providing the optimal comparator groups given the constraints discussed above. It also allows for quality-of-life and cost-effectiveness studies, which are being planned in a “real-world” population of patients. Recently, a Data Safety Monitoring Board recommended that NHLBI prematurely terminate BMT CTN 0901 (Cinicaltrials.gov identifier: NCT01339910 46 ) due to preliminary data suggesting that high intensity regimens were associated with superior outcomes compared to RIC regimens permitted in the study among patients with AML and MDS who were eligible to get either regimen intensities . Since the data were not sufficiently mature to perform subgroup analysis based on disease type, it is not known currently whether these preliminary findings are consistent among AML vs. MDS patients. These analyses will be performed in the future. We acknowledge that these preliminary results might lead some physicians to prefer higher intensity regimens in some patients otherwise eligible for BMT CTN 1102. However, we believe the proportion will be relatively low, since the eligibility criteria for BMT CTN 1102 from the start were only patients felt to be candidates for RIC alloHCT and NOT high intensity regimens (because of comorbidities or age). Patients who are candidates for higher intensity regimens are NOT currently eligible for enrollment onto BMT CTN 1102.

The results of BMT CTN 1102 have the potential to change practice. If this study demonstrates a significant survival advantage with alloHCT, we expect that the number of patients transplanted would increase significantly, setting the stage for more refined studies. In fact, emerging data from an ongoing single arm prospective study conducted at the CIBMTR to evaluate safety of alloHCT for older MDS patients, 18 also made possible by the expanded coverage for the alloHCT by Medicare under the CED mechanism, 22 clearly show that under this coverage mechanism the number of HCTs have risen dramatically ( Figure 2 ). These data strongly support that barriers to access to alloHCT care is affecting the decision to refer patients for transplant evaluation. BMT CTN 1102 has recently gained approval by CMS, and therefore, costs of alloHCT for Medicare beneficiaries enrolled onto this study will be covered. If the study demonstrates survival advantage with alloHCT, this will have significant implications with respect to coverage of costs of alloHCT for MDS by CMS for all Medicare beneficiaries in the future. Alternatively, if the study fails to show an advantage to allogeneic HCT, it will make us dramatically rethink how we approach the problem of MDS in this patient population. Finally, if the study fails to accrue adequate numbers of patients for completion a timely manner, there is the definite risk that Medicare will choose to no longer continue coverage and we will never know the answer.

Supplementary Material

Acknowledgments.

The design and conduct of BMT CTN 1102 is supported by a Grant/Cooperative Agreement U10 HL069294 from the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI) of the National Institutes of Health (NIH).

Data collection on alloHCT recipients will be through the CIBMTR, which is supported by Public Health Service Grant/Cooperative Agreement U24 CA076518 from the NCI, the NHLBI and the National Institute of Allergy and Infectious Diseases (NIAID); a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-12-1-0142 and N00014-13-1-0039 from the Office of Naval Research; and grants from Allos Therapeutics, Inc.; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.;Gentium SpA; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; TerumoBCT; Teva Neuroscience, Inc.; THERAKOS, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government

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Allos Therapeutics, Inc.

Amgen, inc., anonymous donation to the medical college of wisconsin, ariad pharmaceuticals, be the match foundation, blue cross and blue shield association, fresenius-biotech north america, inc., gamida cell teva joint venture ltd., genentech, inc., gentium spa, genzyme corporation, glaxosmithkline, histogenetics, inc., kiadis pharma, merck & co., inc., millennium: the takeda oncology co., milliman usa, inc., miltenyi biotec, inc., nci (1).

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Seattle genetics, sigma-tau pharmaceuticals, soligenix, inc., stemcyte, a global cord blood therapeutics co., stemsoft software, inc., swedish orphan biovitrum, tarix pharmaceuticals, teva neuroscience, inc., texas instruments inc., the leukemia & lymphoma society, the medical college of wisconsin, wellpoint , inc..

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Thousands to be offered blood tests for dementia in UK trial

More than 50 clinics will offer tests to about 5,000 people who are worried about their memory in five-year trial

Thousands of people across the UK who are worried about their memory will receive blood tests for dementia in two trials that doctors hope will help to revolutionise the low diagnosis rate.

Teams from the University of Oxford and University College London will lead the trials to research the use of cheap and simple tests to detect proteins for people with early stages of dementia or problems with cognition, with the hope of speeding up diagnosis and reaching more people.

Currently, getting a formal diagnosis in the UK relies on mental ability tests, brain scans or invasive and painful lumbar punctures, where a sample of cerebrospinal fluid is drawn from the lower back.

About 1 million people are living with the condition in Britain, and this is expected to rise to about 1.7 million by 2040 – with potentially grim consequences. In 2022, dementia took the lives of 66,000 people in England and Wales, and it is now the leading cause of death in Britain, with Alzheimer’s accounting for two-thirds of cases.

Patients and their families have been reported to wait for up to four years to get an appointment and the results, according to charities. More than one in three people living with dementia in England are yet to receive a formal diagnosis.

The tests are highly effective in research settings, so if they prove as useful in real life, they could make the diagnosis of Alzheimer’s more accessible.

They could provide results to patients much sooner and accelerate the introduction of new Alzheimer’s drugs that rely on early diagnosis. The trial will help determine if they can be rolled out routinely on the NHS.

Fiona Carragher, the director of research and influencing at the Alzheimer’s Society, said the reliance on specialised tests had led to “unnecessary delays, worry and uncertainty” that meant people often could not access the care they needed early on.

“Dementia is the UK’s biggest killer, yet a third of people living with dementia don’t have a diagnosis, which means they’re not able to access care and support. At the moment, only 2% of people with dementia can access the specialised tests needed to demonstrate eligibility for new treatments, leading to unnecessary delays, worry and uncertainty,” she said.

The research teams are sponsored by Alzheimer’s Research UK and the Alzheimer’s Society, with £5m of funding from the People’s Postcode Lottery.

Dr Sheona Scales, the director of research at Alzheimer’s Research UK, said: “We’ve seen the enormous potential that blood tests are showing for improving the diagnostic process for people and their loved ones in other disease areas. Now we need to see this same step change in dementia, which is the greatest health challenge facing the UK.

“It’s fantastic that through collaborating with the leading experts in the dementia community, we can look to bring cutting-edge blood tests for diagnosing dementia within the NHS. And this will be key to widening access to groundbreaking new treatments that are on the horizon.”

More than 50 memory clinics across the UK will be offering blood tests to about 5,000 volunteers as part of the five-year trial.

Jonathan Schott, the chief medical officer at Alzheimer’s Research UK, will lead a trial on the most promising blood biomarker in tests on 1,100 people across the UK.

The second trial will test for multiple forms of dementia, including Alzheimer’s disease, vascular dementia, frontotemporal dementia and dementia with Lewy bodies on about 4,000 people.

• Alzheimer's
• Medical research
• Mental health
• Neuroscience

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Early blood test to predict dementia is step closer as biological markers identified

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Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome

Ryotaro Nakamura, Wael Saber, Michael J. Martens, Alyssa Ramirez, Bart Scott, Betul Oran , Eric Leifer, Roni Tamari, Asmita Mishra, Richard T. Maziarz, Joseph McGuirk, Peter Westervelt, Sumithira Vasu, Mrinal Patnaik, Rammurti Kamble, Stephen J. Forman, Mikkael A. Sekeres, Frederick Appelbaum, Adam Mendizabal, Brent Logan Mary Horowitz, Corey Cutler Show 2 others Show less

• Stem Cell Transplantation

Research output : Contribution to journal › Article › peer-review

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 5 .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 5 .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.

ASJC Scopus subject areas

• Cancer Research

Access to Document

• 10.1200/JCO.20.03380

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• Link to publication in Scopus

Fingerprint

• Myelodysplastic Syndromes Medicine & Life Sciences 100%
• Cell Transplantation Medicine & Life Sciences 95%
• Tissue Donors Medicine & Life Sciences 69%
• Arm Medicine & Life Sciences 52%
• Survival Medicine & Life Sciences 21%
• Intention to Treat Analysis Medicine & Life Sciences 11%
• Allogeneic Cells Medicine & Life Sciences 10%
• Cell- and Tissue-Based Therapy Medicine & Life Sciences 9%

T1 - Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome

AU - Nakamura, Ryotaro

AU - Saber, Wael

AU - Martens, Michael J.

AU - Ramirez, Alyssa

AU - Scott, Bart

AU - Oran, Betul

AU - Leifer, Eric

AU - Tamari, Roni

AU - Mishra, Asmita

AU - Maziarz, Richard T.

AU - McGuirk, Joseph

AU - Westervelt, Peter

AU - Vasu, Sumithira

AU - Patnaik, Mrinal

AU - Kamble, Rammurti

AU - Forman, Stephen J.

AU - Sekeres, Mikkael A.

AU - Appelbaum, Frederick

AU - Mendizabal, Adam

AU - Logan, Brent

AU - Horowitz, Mary

AU - Cutler, Corey

N1 - Publisher Copyright: © 2021 by American Society of Clinical Oncology.

PY - 2021/10/20

Y1 - 2021/10/20

N2 - 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 5 .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 5 .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.

AB - 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 5 .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 5 .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.

UR - http://www.scopus.com/inward/record.url?scp=85112086284&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85112086284&partnerID=8YFLogxK

U2 - 10.1200/JCO.20.03380

DO - 10.1200/JCO.20.03380

M3 - Article

C2 - 34106753

AN - SCOPUS:85112086284

SN - 0732-183X

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

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Guest Essay

The Problem With Saying ‘Sex Assigned at Birth’

By Alex Byrne and Carole K. Hooven

Mr. Byrne is a philosopher and the author of “Trouble With Gender: Sex Facts, Gender Fictions.” Ms. Hooven is an evolutionary biologist and the author of “T: The Story of Testosterone, the Hormone That Dominates and Divides Us.”

As you may have noticed, “sex” is out, and “sex assigned at birth” is in. Instead of asking for a person’s sex, some medical and camp forms these days ask for “sex assigned at birth” or “assigned sex” (often in addition to gender identity). The American Medical Association and the American Psychological Association endorse this terminology; its use has also exploded in academic articles. The Cleveland Clinic’s online glossary of diseases and conditions tells us that the “inability to achieve or maintain an erection” is a symptom of sexual dysfunction, not in “males,” but in “people assigned male at birth.”

This trend began around a decade ago, part of an increasing emphasis in society on emotional comfort and insulation from offense — what some have called “ safetyism .” “Sex” is now often seen as a biased or insensitive word because it may fail to reflect how people identify themselves. One reason for the adoption of “assigned sex,” therefore, is that it supplies respectful euphemisms, softening what to some nonbinary and transgender people, among others, can feel like a harsh biological reality. Saying that someone was “assigned female at birth” is taken to be an indirect and more polite way of communicating that the person is biologically female. The terminology can also function to signal solidarity with trans and nonbinary people, as well as convey the radical idea that our traditional understanding of sex is outdated.

The shift to “sex assigned at birth” may be well intentioned, but it is not progress. We are not against politeness or expressions of solidarity, but “sex assigned at birth” can confuse people and creates doubt about a biological fact when there shouldn’t be any. Nor is the phrase called for because our traditional understanding of sex needs correcting — it doesn’t.

This matters because sex matters. Sex is a fundamental biological feature with significant consequences for our species, so there are costs to encouraging misconceptions about it.

Sex matters for health, safety and social policy and interacts in complicated ways with culture. Women are nearly twice as likely as men to experience harmful side effects from drugs, a problem that may be ameliorated by reducing drug doses for females. Males, meanwhile, are more likely to die from Covid-19 and cancer, and commit the vast majority of homicides and sexual assaults . We aren’t suggesting that “assigned sex” will increase the death toll. However, terminology about important matters should be as clear as possible.

More generally, the interaction between sex and human culture is crucial to understanding psychological and physical differences between boys and girls, men and women. We cannot have such understanding unless we know what sex is, which means having the linguistic tools necessary to discuss it. The Associated Press cautions journalists that describing women as “female” may be objectionable because “it can be seen as emphasizing biology,” but sometimes biology is highly relevant. The heated debate about transgender women participating in female sports is an example ; whatever view one takes on the matter, biologically driven athletic differences between the sexes are real.

When influential organizations and individuals promote “sex assigned at birth,” they are encouraging a culture in which citizens can be shamed for using words like “sex,” “male” and “female” that are familiar to everyone in society, as well as necessary to discuss the implications of sex. This is not the usual kind of censoriousness, which discourages the public endorsement of certain opinions. It is more subtle, repressing the very vocabulary needed to discuss the opinions in the first place.

A proponent of the new language may object, arguing that sex is not being avoided, but merely addressed and described with greater empathy. The introduction of euphemisms to ease uncomfortable associations with old words happens all the time — for instance “plus sized” as a replacement for “overweight.” Admittedly, the effects may be short-lived , because euphemisms themselves often become offensive, and indeed “larger-bodied” is now often preferred to “plus sized.” But what’s the harm? No one gets confused, and the euphemisms allow us to express extra sensitivity. Some see “sex assigned at birth” in the same positive light: It’s a way of talking about sex that is gender-affirming and inclusive .

The problem is that “sex assigned at birth”— unlike “larger-bodied”— is very misleading. Saying that someone was “assigned female at birth” suggests that the person’s sex is at best a matter of educated guesswork. “Assigned” can connote arbitrariness — as in “assigned classroom seating” — and so “sex assigned at birth” can also suggest that there is no objective reality behind “male” and “female,” no biological categories to which the words refer.

Contrary to what we might assume, avoiding “sex” doesn’t serve the cause of inclusivity: not speaking plainly about males and females is patronizing. We sometimes sugarcoat the biological facts for children, but competent adults deserve straight talk. Nor are circumlocutions needed to secure personal protections and rights, including transgender rights. In the Supreme Court’s Bostock v. Clayton County decision in 2020, which outlawed workplace discrimination against gay and transgender people, Justice Neil Gorsuch used “sex,” not “sex assigned at birth.”

A more radical proponent of “assigned sex” will object that the very idea of sex as a biological fact is suspect. According to this view — associated with the French philosopher Michel Foucault and, more recently, the American philosopher Judith Butler — sex is somehow a cultural production, the result of labeling babies male or female. “Sex assigned at birth” should therefore be preferred over “sex,” not because it is more polite, but because it is more accurate.

This position tacitly assumes that humans are exempt from the natural order. If only! Alas, we are animals. Sexed organisms were present on Earth at least a billion years ago, and males and females would have been around even if humans had never evolved. Sex is not in any sense the result of linguistic ceremonies in the delivery room or other cultural practices. Lonesome George, the long-lived Galápagos giant tortoise , was male. He was not assigned male at birth — or rather, in George’s case, at hatching. A baby abandoned at birth may not have been assigned male or female by anyone, yet the baby still has a sex. Despite the confusion sown by some scholars, we can be confident that the sex binary is not a human invention.

Another downside of “assigned sex” is that it biases the conversation away from established biological facts and infuses it with a sociopolitical agenda, which only serves to intensify social and political divisions. We need shared language that can help us clearly state opinions and develop the best policies on medical, social and legal issues. That shared language is the starting point for mutual understanding and democratic deliberation, even if strong disagreement remains.

What can be done? The ascendance of “sex assigned at birth” is not an example of unhurried and organic linguistic change. As recently as 2012 The New York Times reported on the new fashion for gender-reveal parties, “during which expectant parents share the moment they discover their baby’s sex.” In the intervening decade, sex has gone from being “discovered” to “assigned” because so many authorities insisted on the new usage. In the face of organic change, resistance is usually futile. Fortunately, a trend that is imposed top-down is often easier to reverse.

Admittedly, no one individual, or even a small group, can turn the lumbering ship of English around. But if professional organizations change their style guides and glossaries, we can expect that their members will largely follow suit. And organizations in turn respond to lobbying from their members. Journalists, medical professionals, academics and others have the collective power to restore language that more faithfully reflects reality. We will have to wait for them to do that.

Meanwhile, we can each apply Strunk and White’s famous advice in “The Elements of Style” to “sex assigned at birth”: omit needless words.

Alex Byrne is a professor of philosophy at M.I.T. and the author of “Trouble With Gender: Sex Facts, Gender Fictions.” Carole K. Hooven is an evolutionary biologist, a nonresident senior fellow at the American Enterprise Institute, an associate in the Harvard psychology department, and the author of “T: The Story of Testosterone, the Hormone That Dominates and Divides Us.”

The Times is committed to publishing a diversity of letters to the editor. We’d like to hear what you think about this or any of our articles. Here are some tips . And here’s our email: [email protected] .

Follow The New York Times Opinion section on Facebook , Instagram , TikTok , WhatsApp , X and Threads .

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Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome

Ryotaro Nakamura, Wael Saber, Michael J. Martens, Alyssa Ramirez, Bart Scott, Betul Oran, Eric Leifer, Roni Tamari, Asmita Mishra, Richard T. Maziarz, Joseph McGuirk, Peter Westervelt, Sumithira Vasu, Mrinal Patnaik, Rammurti Kamble, Stephen J. Forman, Mikkael A. Sekeres, Frederick Appelbaum, Adam Mendizabal, Brent Logan Mary Horowitz, Corey Cutler Show 2 others Show less

• Division of Oncology
• Section of Bone Marrow Transplant & Leukemia
• Institute of Clinical and Translational Sciences (ICTS)
• Siteman Cancer Center

Research output : Contribution to journal › Article › peer-review

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 5 .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 5 .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.

Access to Document

• 10.1200/JCO.20.03380

Other files and links

• Link to publication in Scopus

Fingerprint

• Myelodysplastic Syndromes Medicine & Life Sciences 100%
• Cell Transplantation Medicine & Life Sciences 95%
• Tissue Donors Medicine & Life Sciences 69%
• Arm Medicine & Life Sciences 52%
• Survival Medicine & Life Sciences 21%
• Intention to Treat Analysis Medicine & Life Sciences 11%
• Allogeneic Cells Medicine & Life Sciences 10%
• Cell- and Tissue-Based Therapy Medicine & Life Sciences 9%

T1 - Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome

AU - Nakamura, Ryotaro

AU - Saber, Wael

AU - Martens, Michael J.

AU - Ramirez, Alyssa

AU - Scott, Bart

AU - Oran, Betul

AU - Leifer, Eric

AU - Tamari, Roni

AU - Mishra, Asmita

AU - Maziarz, Richard T.

AU - McGuirk, Joseph

AU - Westervelt, Peter

AU - Vasu, Sumithira

AU - Patnaik, Mrinal

AU - Kamble, Rammurti

AU - Forman, Stephen J.

AU - Sekeres, Mikkael A.

AU - Appelbaum, Frederick

AU - Mendizabal, Adam

AU - Logan, Brent

AU - Horowitz, Mary

AU - Cutler, Corey

N1 - Publisher Copyright: © 2021 by American Society of Clinical Oncology.

PY - 2021/10/20

Y1 - 2021/10/20

N2 - 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 5 .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 5 .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.

AB - 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 5 .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 5 .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.

UR - http://www.scopus.com/inward/record.url?scp=85112086284&partnerID=8YFLogxK

U2 - 10.1200/JCO.20.03380

DO - 10.1200/JCO.20.03380

M3 - Article

C2 - 34106753

AN - SCOPUS:85112086284

SN - 0732-183X

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology