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Figure 1.  Disease-Free Survival by Donor Type
Disease-Free Survival by Donor Type
Figure 2.  Overall Survival by Donor Type
Overall Survival by Donor Type
Figure 3.  Cumulative Incidence of Relapse
Cumulative Incidence of Relapse
Table.  Multivariable Analysis of Main Effect on Outcomes
Multivariable Analysis of Main Effect on Outcomes
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Seebach  JD, Stussi  G, Passweg  JR,  et al; GVHD Working Committee of Center for International Blood and Marrow Transplant Research.  ABO blood group barrier in allogeneic bone marrow transplantation revisited.   Biol Blood Marrow Transplant. 2005;11(12):1006-1013. doi:10.1016/j.bbmt.2005.07.015 PubMedGoogle ScholarCrossref
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Alousi  AM, Le-Rademacher  J, Saliba  RM,  et al.  Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer?   Blood. 2013;121(13):2567-2573. doi:10.1182/blood-2012-08-453860 PubMedGoogle ScholarCrossref
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Jaiswal  S, Fontanillas  P, Flannick  J,  et al.  Age-related clonal hematopoiesis associated with adverse outcomes.   N Engl J Med. 2014;371(26):2488-2498. doi:10.1056/NEJMoa1408617 PubMedGoogle ScholarCrossref
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Miller  RA.  The aging immune system: primer and prospectus.   Science. 1996;273(5271):70-74. doi:10.1126/science.273.5271.70 PubMedGoogle ScholarCrossref
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Chambers  SM, Shaw  CA, Gatza  C, Fisk  CJ, Donehower  LA, Goodell  MA.  Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation.   PLoS Biol. 2007;5(8):e201. doi:10.1371/journal.pbio.0050201 PubMedGoogle Scholar
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Liang  Y, Van Zant  G, Szilvassy  SJ.  Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells.   Blood. 2005;106(4):1479-1487. doi:10.1182/blood-2004-11-4282 PubMedGoogle ScholarCrossref
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Kröger  N, Zabelina  T, de Wreede  L,  et al; MDS subcommittee of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).  Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings.   Leukemia. 2013;27(3):604-609. doi:10.1038/leu.2012.210 PubMedGoogle ScholarCrossref
17.
Yam  C, Crisalli  L, Luger  SM,  et al.  Unrelated donors are associated with improved relapse-free survival compared to related donors in patients with myelodysplastic syndrome undergoing reduced intensity allogeneic stem cell transplantation.   Am J Hematol. 2016;91(9):883-887. doi:10.1002/ajh.24424 PubMedGoogle ScholarCrossref
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Horowitz  M.  The role of registries in facilitating clinical research in BMT: examples from the Center for International Blood and Marrow Transplant Research.   Bone Marrow Transplant. 2008;42(suppl 1):S1-S2. doi:10.1038/bmt.2008.101 PubMedGoogle ScholarCrossref
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Kollman  C, Howe  CW, Anasetti  C,  et al.  Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age.   Blood. 2001;98(7):2043-2051. doi:10.1182/blood.V98.7.2043 PubMedGoogle ScholarCrossref
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Carreras  E, Jiménez  M, Gómez-García  V,  et al.  Donor age and degree of HLA matching have a major impact on the outcome of unrelated donor haematopoietic cell transplantation for chronic myeloid leukaemia.   Bone Marrow Transplant. 2006;37(1):33-40. doi:10.1038/sj.bmt.1705195 PubMedGoogle ScholarCrossref
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Shaw  BE, Logan  BR, Spellman  SR,  et al.  Development of an unrelated donor selection score predictive of survival after HCT: donor age matters most.   Biol Blood Marrow Transplant. 2018;24(5):1049-1056. doi:10.1016/j.bbmt.2018.02.006 PubMedGoogle ScholarCrossref
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Fine  JP, Gray  RJ.  A proportional hazards model for the subdistribution of a competing risk.   J Am Stat Assoc 1999;94:496–509. doi:10.1080/01621459.1999.10474144 Google ScholarCrossref
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Greenberg  PL, Tuechler  H, Schanz  J,  et al.  Revised international prognostic scoring system for myelodysplastic syndromes.   Blood. 2012;120(12):2454-2465. doi:10.1182/blood-2012-03-420489 PubMedGoogle ScholarCrossref
24.
Sorror  ML, Maris  MB, Storb  R,  et al.  Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.   Blood. 2005;106(8):2912-2919. doi:10.1182/blood-2005-05-2004 PubMedGoogle ScholarCrossref
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Scheid  C, de Wreede  L, van Biezen  A,  et al.  Validation of the revised IPSS at transplant in patients with myelodysplastic syndrome/transformed acute myelogenous leukemia receiving allogeneic stem cell transplantation: a retrospective analysis of the EBMT chronic malignancies working party.   Bone Marrow Transplant. 2017;52(11):1519-1525. doi:10.1038/bmt.2017.171 PubMedGoogle ScholarCrossref
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Original Investigation
January 13, 2022

Relapse and Disease-Free Survival in Patients With Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation Using Older Matched Sibling Donors vs Younger Matched Unrelated Donors

Author Affiliations
  • 1Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee
  • 2Department of Medicine, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee
  • 3Division of Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee
  • 4Division of Infectious Diseases, Department of Medicine, Medical College of Wisconsin, Milwaukee
  • 5Department of Oncology, King Faisal Specialist Hospital Center and Research, Riyadh, Saudi Arabia
  • 6Department of Hematology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
  • 7Division of Hematology, Oncology, and Stem Cell Transplant, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
  • 8Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 9Division of Transplantation and Cellular Therapy, University of Miami, Miami, Florida
  • 10Ottawa Hospital Transplant and Cellular Therapy Program, The Ottawa Hospital, Ottawa, Ontario, Canada
  • 11Department of Hematology, CHU Grenoble Alpes, Université Grenoble Alpes, Grenoble, France
  • 12Division of Hematology-Oncology, Department of Medicine, University of Massachusetts Medical Center, Worcester
  • 13Department of Hematology and Oncology, Hospital Infantil Universitario Niño Jesus, Madrid, Spain
  • 14Division of Hematology and Oncology, University of Florida College of Medicine, Gainesville
  • 15Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK
  • 16Division of Hematological Malignancy and Cellular Therapeutics, University of Kansas Health System, Kansas City
  • 17Division of Hematological Malignancies, Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
  • 18Markey Cancer Center, University of Kentucky College of Medicine, Lexington
  • 19Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina
  • 20Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
  • 21Department of Medicine, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
  • 22Division of Hematology and Oncology, Stem Cell Transplant Program, Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
  • 23Blood and Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
  • 24Divsion of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
  • 25Division of Hematology-Oncology, Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, Florida
  • 26Department of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio
  • 27Department of Medicine, University of Rochester Medical Center, Rochester, New York
  • 28Division of Hematology and Transplant Center, Mayo Clinic Rochester, Rochester, Minnesota
  • 29Adult Bone Marrow Transplant, University Hospitals Bristol National Health Service Trust, Bristol, UK
  • 30Section of Bone Marrow Transplant and Cell Therapy, Rush University Medical Center, Chicago, Illinois
  • 31Cleveland Clinic Foundation, Cleveland, Ohio
  • 32Department of Blood and Marrow Transplant and Cellular Immunotherapy Moffitt Cancer Center, Tampa, Florida
  • 33Blood and Marrow Transplant Program, Huntsman Cancer Institute, University of Utah, Salt Lake City
  • 34Blood and Marrow Transplantation Program, Division of Hematology and Oncology, Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor
  • 35Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina
  • 36Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 37Department of Hematology and Oncology, Dokkyo Medical University, Tochigi, Japan
  • 38Blood and Marrow Transplant Group of Georgia, Northside Hospital, Atlanta
  • 39Division of Hematology, Oncology, and Cell Therapy, Rush University, Chicago, Illinois
  • 40Maastricht University Medical Center, Maastricht, the Netherlands
  • 41Department of Hematology and Oncology, Isala Clinic, Zwolle, the Netherlands
  • 42Division of Hematology and Oncology, Washington University School of Medicine, St Louis, Missouri
  • 43Bone Marrow Transplant Program, Penn State Cancer Institute, Hershey, Pennsylvania
  • 44Division of Cancer Medicine, Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston
  • 45Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California
  • 46Fred Hutchinson Cancer Research Center, Seattle, Washington
JAMA Oncol. 2022;8(3):404-411. doi:10.1001/jamaoncol.2021.6846
Key Points

Question  In adults with myelodysplastic syndrome, could allogeneic hematopoietic cell transplantation (allo-HCT) using younger matched unrelated donors help reduce relapse and improve disease-free survival compared with older matched sibling donors?

Findings  In this cohort study of 1761 patients with myelodysplastic syndrome, allo-HCT using younger matched unrelated donors was associated with significantly lower relapse rates and higher disease-free survival compared with allo-HCT using older matched sibling donors.

Meaning  These results suggest that the use of younger matched unrelated donors could be a potential way to help prevent relapse after allo-HCT in myelodysplastic syndrome given limited treatment options and poor prognosis for relapsed disease.

Abstract

Importance  Matched sibling donors (MSDs) are preferred for allogeneic hematopoietic cell transplantation (allo-HCT) in myelodysplastic syndrome even if they are older. However, whether older MSDs or younger human leukocyte antigen–matched unrelated donors (MUDs) are associated with better outcomes remains unclear.

Objective  To investigate whether allo-HCT for myelodysplastic syndrome using younger MUDs would be associated with improved disease-free survival and less relapse compared with older MSDs.

Design, Setting, and Participants  This retrospective cohort study assessed data reported to the Center for International Blood and Marrow Transplant Research database from 1761 adults 50 years or older with myelodysplastic syndrome who underwent allo-HCT using an older MSD or younger MUD between January 1, 2011, and December 31, 2017, with a median follow-up of 48 months. Data analysis was performed from January 8, 2019, to December 30, 2020.

Interventions/Exposures  Allo-HCT from an older MSD (donor age ≥50 years) or a younger MUD (donor age ≤35 years).

Main Outcomes and Measures  The primary outcome was disease-free survival. Secondary outcomes were overall survival, relapse, nonrelapse mortality, acute graft-vs-host disease (GVHD), chronic GVHD, and GVHD-free relapse-free survival.

Results  Of 1761 patients (1162 [66%] male; median [range] age, 64.9 [50.2-77.6] years in the MSD cohort and 66.5 [50.4-80.9] years in MUD cohort), 646 underwent allo-HCT with an older MSD and 1115 with a younger MUD. In multivariable analysis, the rate of disease-free survival was significantly lower in allo-HCTs with older MSDs compared with younger MUDs (hazard ratio [HR], 1.17; 95% CI, 1.02-1.34; P = .02), whereas the difference in overall survival rate of allo-HCT with younger MUDs vs older MSDs was not statistically significant (HR, 1.13; 95% CI, 0.98-1.29; P = .07). Allo-HCT with older MSDs was associated with significantly higher relapse (HR, 1.62; 95% CI, 1.32-1.97; P < .001), lower nonrelapse mortality (HR, 0.76; 95% CI, 0.59-0.96; P = .02), lower acute GVHD (HR, 0.52; 95% CI, 0.42-0.65; P < .001), chronic GVHD (HR, 0.77; 95% CI, 0.64-0.92; P = .005), and a lower rate of GVHD-free relapse-free survival beyond 12 months after allo-HCT (HR, 1.42; 95% CI, 1.02-1.98; P = .04).

Conclusions and Relevance  This cohort study found higher disease-free survival and lower relapse for allo-HCT in myelodysplastic syndrome using younger MUDs compared with older MSDs. The risk of nonrelapse mortality and GVHD was lower with older MSDs. These results suggest that the use of younger MUDs should be considered in the donor selection algorithm for myelodysplastic syndrome, in which it is pivotal to minimize relapse given limited treatment options for managing relapsed disease.

Introduction

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for myelodysplastic syndrome. With the advent of reduced-intensity conditioning and more donor options, the use of allo-HCT has increased over time.1 However, the benefits need to be weighed against the risk of complications because these patients are often older adults.2 Disease relapse remains a major issue after allo-HCT and portends a poor prognosis.3 Efforts to minimize relapse and understand the causes of treatment failure are important in improving the long-term prognosis. Although several factors influence the outcomes of allo-HCT, donor age and donor-recipient human leukocyte antigen (HLA) match are of crucial importance.4-10 A large study10 from the Center for International Blood and Marrow Transplant Research of more than 10 000 patients found that donor-recipient HLA mismatch and older donor age were associated with poor outcomes. Similarly, another study11 that evaluated the association of donor-recipient HLA match with outcomes in hematological malignant cancers found that HLA-matched sibling donors (MSDs) are associated with improved outcomes. Hence, in clinical practice, MSDs are considered the preferred choice.

Still, one must take into consideration that myelodysplastic syndrome is a disease of older adults and sibling donors are also likely to be older with issues such as comorbidities, risk of clonal hematopoiesis of indeterminate potential, and impaired immune and regenerative potential of stem cells.12-15 Although younger HLA-matched unrelated donors (MUDs) are an important alternative in this context, it remains unclear whether the use of MUDs is associated with better outcomes. Prior single-center and registry studies10,16,17 that addressed this question yielded conflicting results and were not focused exclusively on myelodysplastic syndrome. Hence, we sought to determine the association of donor age and type with the outcomes of allo-HCT for myelodysplastic syndrome by comparing 2 common donor groups: older MSDs and younger MUDs. We hypothesized that allo-HCT using younger MUDs compared with older MSDs would be associated with improved disease-free survival and lower relapse.

Methods
Study Objectives and Data Source

This cohort study compares the disease-free survival, overall survival, relapse, nonrelapse mortality, acute graft-vs-host disease (GVHD), chronic GVHD, and GVHD-free relapse-free survival in 1761 patients with myelodysplastic syndrome undergoing allo-HCT from older MSDs or younger MUDs. The Center for International Blood and Marrow Transplant Research is a combined research program of the Medical College of Wisconsin and the National Marrow Donor Program that comprises a voluntary network of more than 450 transplantation centers that contribute baseline and posttransplantation data on consecutive hematopoietic cell transplantations to a centralized statistical center.18 Observational studies with this database are performed in compliance with all applicable federal regulations pertaining to the protection of human research participants. All participants provided written informed consent. Protected health information used in the performance of such research is collected and maintained in the researchers’ capacity as a public health authority under the Health Insurance Portability and Accountability Act Privacy Rule. The institutional review boards of the Medical College of Wisconsin and the National Marrow Donor Program approved this study. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Patients and Outcomes

Adults 50 years and older with myelodysplastic syndrome who underwent first allo-HCT with an older MSD (donor age ≥50 years) or a younger 8/8 HLA-matched (HLA-A, -B, -C, and -DRB1) MUD (donor age ≤35 years) were included. Patients with primary and secondary myelodysplastic syndrome (including therapy related) were eligible. The study was performed from January 1, 2011, to December 31, 2017, to include a recent cohort of patients from the data set. Data analysis was performed from January 8, 2019, to December 30, 2020. Because prior studies10,16,19-21 using unrelated donors reported a survival advantage with younger MUDs between the ages of 30 and 36 years, we restricted the MUD arm to a donor age of 35 years or younger because including older MUDs would not support our study hypothesis. Given that sibling donors are likely to be around the same age as recipients, a donor age of 50 years or older was used for MSDs. Key exclusion criteria were allo-HCT from mismatched unrelated-donor, haploidentical-donor, syngeneic-donor, cord blood, and ex vivo T-cell depleted or CD34 selected grafts. To ensure homogeneity, patients receiving posttransplant cyclophosphamide for GVHD prophylaxis were excluded (eFigure 1 in the Supplement).

The primary outcome was disease-free survival. Secondary outcomes were overall survival, relapse, nonrelapse mortality, acute GVHD, chronic GVHD, and GVHD-free relapse-free survival (definitions provided in the eMethods in the Supplement).

Statistical Analysis

Baseline characteristics were summarized using descriptive statistics with median (range) for continuous variables and numbers (percentages) for categorical variables. Cumulative incidence estimates were calculated for competing risks outcomes, including acute GVHD, chronic GVHD, nonrelapse mortality, and relapse. The Kaplan-Meier method was used to estimate survival probabilities. Multivariable Cox proportional hazards regression analysis for survival and the Fine-Gray model22 for competing risks outcomes were used. The proportional hazards assumption was examined and covariates that violated the assumption were added as time-dependent covariates. In the absence of binary end points, hazard ratios (HRs) and 95% CIs were reported. Factors considered for multivariable analysis included patient age, donor age, sex match, cytomegalovirus match, ABO blood type match, disease subtype (primary, therapy related, or antecedent hematologic disorder), Revised International Prognostic Scoring System (IPSS-R) score at allo-HCT,23 Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score,24 Karnofsky Performance Scale score, prior therapy, interval between diagnosis and transplant, conditioning intensity, stem cell source, GVHD prophylaxis, use of antithymocyte globulin and alemtuzumab, and year of transplant. A stepwise selection method was used to identify the final model with significance level of .05, and only factors that attained that significance are given (eTable 3 in the Supplement). Because of the potential for recipient age to influence outcomes, it was forced on all multivariable models. A pairwise comparison within the nonreference groups was also performed in multivariable models to demonstrate their association and shown as contrasts. Center effect was tested using the score test proposed by Commenges and Andersen,25 and marginal Cox proportional hazards regression models were used for adjustments. Center effect was significant for all outcomes except overall survival and was adjusted accordingly. Missing category was included as 1 group to avoid loss of data and power.26 All analyses were performed at a 2-sided significance level of P < .05 using SAS software, version 9.4 (SAS Institute Inc).

Results
Baseline Characteristics

Among 1761 eligible patients in this cohort study (1162 [66%] male; median [range] age, 64.9 [50.2-77.6] years in the MSD cohort and 66.5 [50.4-80.9] years in MUD cohort), 646 underwent allo-HCT with an older MSD and 1115 with a younger MUD. Baseline characteristics are summarized in eTable 1 in the Supplement. Most patients underwent allo-HCT with peripheral blood grafts, reduced-intensity conditioning, and tacrolimus-based GVHD prophylaxis. Notable differences in the MUD cohort included longer median interval from diagnosis to transplant (8.4 vs 7.3 months, P = .02), a higher percentage of bone marrow grafts (10.0% vs 2.0%, P < .001), a lower percentage of female donor–male recipient pairs (12.0% vs 31.0%, P < .001), a higher ABO blood type mismatch rate (48.0% vs 32.0%, P < .001), and higher antithymocyte globulin and alemtuzumab use (37.0% vs 14.0%, P < .001) compared with the MSD cohort. Median follow-up was 48.1 months (range, 3.2-99.5 months) in the MSD cohort and 46.0 months (range, 3.1-98.2 months) in the MUD cohort.

Survival

In univariate analysis (eTable 2 in the Supplement), 5-year disease-free survival was significantly higher in patients undergoing allo-HCT with younger MUDs (30.6%; 95% CI, 27.4%-33.8%) than with older MSDs (24.9%; 95% CI, 21.1%-28.9%; P = .01). In multivariable analysis, compared with allo-HCT with younger MUDs, disease-free survival was significantly lower in patients undergoing allo-HCT with older MSDs (HR, 1.17; 95% CI, 1.02-1.34; P = .02) (Table and Figure 1). Other factors significantly associated with disease-free survival were HCT-CI score, IPSS-R score, disease type, GVHD prophylaxis, and use of antithymocyte globulin and alemtuzumab (eTable 3 in the Supplement). The 5-year overall survival in univariate analysis was 37.1% (95% CI, 33.6%-40.6%) for patients undergoing allo-HCT with younger MUDs and 33.9% (95% CI, 29.6%-38.4%) for patients undergoing allo-HCT with older MSDs (P = .19). Overall survival was significantly associated with HCT-CI score, IPSS-R score, and antithymocyte globulin and alemtuzumab use but not donor type (older MSDs: HR, 1.13; 95% CI, 0.98-1.29; P = .07) (Figure 2; eTable 3 in the Supplement).

Relapse

Cumulative incidence of relapse at 5 years was significantly lower for patients undergoing allo-HCT with younger MUDs (37.3%; 95% CI, 34.3%-40.3%) than with older MSDs (49.6%; 95% CI, 45.5%-53.7%; P < .001) (eTable 2 in the Supplement). In multivariable analysis, the risk of relapse was significantly higher for allo-HCT with older MSDs (HR, 1.62; CI, 1.32-1.97; P < .001) compared with younger MUDs (Table and Figure 3). Other factors significantly associated with relapse included recipient age, use of antithymocyte globulin and alemtuzumab, IPSS-R score, and the interval between diagnosis to transplant (eTable 3 in the Supplement).

Nonrelapse Mortality

In univariate analysis, nonrelapse mortality at 5 years was 32.2% (95% CI, 29.0%-35.4%) for patients undergoing allo-HCT with younger MUDs and 25.5% (95% CI, 21.8%-29.4%) with older MSDs (P = .002) (eTable 2 in the Supplement). In multivariable analysis, a lower risk of nonrelapse mortality was seen for patients undergoing allo-HCT with older MSDs (HR, 0.76; 95% CI, 0.59-0.96; P = .02) (Table; eFigure 2 in the Supplement). Other factors significantly associated with nonrelapse mortality included HCT-CI score and Karnofsky performance score (eTable 3 in the Supplement).

Graft-vs-Host Disease

The 1-year incidence of acute GVHD grade II to IV was 39.3% (95% CI, 35.5%-43.1%) for patients undergoing allo-HCT with older MSDs and 48.3% (95% CI, 45.4%-51.3%) for patients undergoing allo-HCT with younger MUDs (P = .001) (eTable 2 in the Supplement). The 1-year incidence of grade III to IV acute GVHD was 17.2% (95% CI, 14.4%-20.3%) for patients undergoing allo-HCT with older MSDs and 20.0% (95% CI, 17.7%-22.4%) for patients undergoing allo-HCT with younger MUDs (P = .14). The 5-year incidence of chronic GVHD was 49.0% (95% CI, 44.9%-53.0%) for patients undergoing allo-HCT with older MSDs and 53.9% (95% CI, 50.7%-57.1%) for patients undergoing allo-HCT with younger MUDs (P = .08). On multivariable analysis, older MSDs were associated with a lower risk of acute GVHD grades II to IV (HR, 0.52; 95% CI, 0.42-0.65; P < .001) and III to IV (HR, 0.55; 95% CI, 0.39-0.79; P < .001), and chronic GVHD (HR, 0.77; 95% CI, 0.64-0.92; overall P = .005) (Table; eFigures 3-5 in the Supplement). Other factors significantly associated with GVHD were conditioning intensity, GVHD prophylaxis, donor-recipient sex match, and HCT-CI score for acute GVHD and graft source, and antithymocyte globulin and alemtuzumab for chronic GVHD (eTable 3 in the Supplement).

GVHD-Free Relapse-Free Survival

Despite a small difference (6.3% vs 9.3% at 5 years in univariate analysis), older MSDs were associated with significantly lower GVHD-free relapse-free survival beyond 12 months of allo-HCT (HR, 1.42; 95% CI, 1.02-1.98; P = .04) but not within the first 12 months (analysis separated by these time points because of nonproportional hazard assumption). In addition, HCT-CI score, IPSS-R score, year of transplant, and graft type were also significantly associated with GVHD-free relapse-free survival (eFigure 6 and eTable 3 in the Supplement)

Discussion

Using the 2 most common donor groups for allo-HCT in myelodysplastic syndrome, this cohort study found higher disease-free survival, better GVHD-free relapse-free survival, and lower relapse rates for patients undergoing allo-HCT with younger MUDs compared with older MSDs. The difference in overall survival was not statistically significant, likely reflecting the effect of lower nonrelapse mortality and GVHD with MSDs. Several research efforts are currently focused on minimizing relapse after allo-HCT. Although many factors influence this outcome, donor age and HLA match status play vital roles.27-29 If an older MSD and a younger MUD are available as donors, a common clinical question is whether one would be a better donor than the other. Although the conventional choice is MSDs, these donors are more likely to be older and to have age-related issues, including a decline in CD8 T lymphocytes and impaired T-cell–mediated graft-vs-tumor effect.30 Younger MUDs are less likely to have these problems and could serve as a reasonable choice. We evaluated this question specifically in myelodysplastic syndrome, and our results enhance the clinical decision-making process.

Although prior studies10,11,19,21 have evaluated the effect of donor age in different hematologic malignant cancers, myelodysplastic syndrome represented a smaller proportion (12%-13%) of the population studied. Some studies16,17,31 have analyzed the impact of donor age specifically in MDS. A study by Saber et al31 showed similar survival between MSD and MUD allo-HCT in myelodysplastic syndrome, although a comparison between younger MUDs vs older MSDs was not performed. A study16 from the European Society for Blood and Marrow Transplantation showed higher overall survival with MUDs (age <30 years) compared with MSDs, although it included both patients with myelodysplastic syndrome and acute myeloid leukemia, introducing heterogeneity about the underlying disease. Our study provides a clear comparison between allo-HCT with younger MUDs vs older MSDs specifically in myelodysplastic syndrome. Other factors, such as conditioning intensity and donor-recipient sex match, mainly influenced the risk of GVHD. Disease subtype (primary vs therapy-related myelodysplastic syndrome) did not significantly influence overall survival.

To justify the rationale for preferring younger MUDs to minimize relapse, it is important to ensure that the time involved in waiting to find one does not compromise the outcomes. As expected, the time from diagnosis to allo-HCT was longer with MUDs, raising the possibility of those patients being stable to wait for allo-HCT. However, the difference in median time from diagnosis to allo-HCT between the 2 cohorts was only 1.1 months (7.3 vs 8.4 months) (eTable 1 in the Supplement). In addition, we checked for associations between time from diagnosis to allo-HCT and the main effect (older MSD vs younger MUD) in all multivariable models and did not find significant associations. Although the aspect of waiting for an appropriate donor vs immediately proceeding to allo-HCT with the earliest available donor is best analyzed through prospective clinical trials, our current models have carefully assessed this aspect and do not demonstrate any associations that would suggest bias toward the MUD cohort. Similarly, the possibility of disease risk (low vs high) affecting the timing of allo-HCT and the donor choice (older MSD vs younger MUD) was assessed through associations between these factors in multivariable models, and no significant associations were found. Last, given the lack of effective therapies for managing relapsed and refractory myelodysplastic syndrome, preventing relapse and improving the disease-free survival is an important, clinically meaningful end point to be considered while choosing donors.

Limitations

The study has some limitations. Despite the large sample size, our study is limited because of a lack of information on HLA-DP status, genomic mutations, donor clonal hematopoiesis, and T-cell repertoire changes, which could explain the differences in outcomes. Given the retrospective design, we lacked information on pretransplant disease course, physicians’ decisions, and time between donor search initiation and identification. Although we restricted the analyses to MSDs and 8/8 MUDs to minimize the effect of HLA mismatching, the latter group could have some mismatches if 9/10 or 10/10 HLA matching was available and influenced graft alloreactivity. Because of the nature of GVHD reporting in the data set, chronic GVHD was assessed as a whole outcome without further stratification (mild vs moderate vs severe). Some factors that attained statistical significance in multivariable analysis (eg, history of antecedent hematologic disorder) are limited by smaller sample size to draw meaningful inferences.

Conclusions

This cohort study suggests that allo-HCT with younger MUDs is associated with lower relapse rates, improved disease-free survival, and better GVHD-free relapse-free survival compared with allo-HCT with older MSDs in myelodysplastic syndrome. Given the higher risk of relapse with reduced-intensity conditioning commonly considered in older patients, choosing a younger MUD might potentially reduce relapse, provided the risk of GVHD and nonrelapse mortality is considered. Strategies to mitigate GVHD could reduce its morbidity and mortality and potentially improve overall survival. The results of this study add important information to the donor selection algorithms for these patients.

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Article Information

Accepted for Publication: October 19, 2021.

Published Online: January 13, 2022. doi:10.1001/jamaoncol.2021.6846

Corresponding Author: Guru Subramanian Guru Murthy, MD, MS, Division of Hematology and Oncology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226 (gmurthy@mcw.edu).

Author Contributions: Drs Guru Murthy and Saber had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Guru Murthy, Kim, Hu, Aljurf, Beitinjaneh, Cahn, Cerny, Gale, Gergis, Hashmi, Hossain, Marks, Nazha, Savani, Solh, van der Poel, Wirk, Oran, Nakamura, Scott, Saber.

Acquisition, analysis, or interpretation of data: Guru Murthy, Kim, Hu, Estrada-Merly, Abid, Aljurf, Bacher, Badawy, Beitinjaneh, Bredeson, Cahn, Cerny, Diaz Perez, Farhadfar, Ganguly, Hildebrandt, Grunwald, Hashmi, Hossain, Kalaycio, Kamble, Kharfan-Dabaja, Hamilton, Lazarus, Liesveld, Litzow, Murthy, Nathan, Nishihori, Patel, Pawarode, Rizzieri, Savani, Seo, Solh, Ustun, van der Poel, Verdonck, Vij, Nakamura, Scott, Saber.

Drafting of the manuscript: Guru Murthy, Kim, Estrada-Merly, Aljurf, Beitinjaneh, Cerny, Gale, Gergis, Hossain, Kamble, Liesveld, Nazha, Savani, Verdonck, Vij, Wirk, Oran, Scott, Saber.

Critical revision of the manuscript for important intellectual content: Guru Murthy, Hu, Estrada-Merly, Abid, Aljurf, Bacher, Badawy, Beitinjaneh, Bredeson, Cahn, Cerny, Diaz Perez, Farhadfar, Gale, Ganguly, Hildebrandt, Grunwald, Hashmi, Hossain, Kalaycio, Kamble, Kharfan-Dabaja, Hamilton, Lazarus, Liesveld, Litzow, Marks, Murthy, Nathan, Nazha, Nishihori, Patel, Pawarode, Rizzieri, Savani, Seo, Solh, Ustun, van der Poel, Verdonck, Wirk, Nakamura, Scott, Saber.

Statistical analysis: Guru Murthy, Kim, Hu, Estrada-Merly, Aljurf, Badawy, Cahn, Diaz Perez, Farhadfar, Savani, Solh, Saber.

Administrative, technical, or material support: Guru Murthy, Badawy, Cerny, Grunwald, Hossain, Nathan, Patel, Verdonck, Oran, Nakamura, Scott, Saber.

Supervision: Guru Murthy, Badawy, Cerny, Ganguly, Hashmi, Kamble, Nazha, Patel, van der Poel, Wirk, Nakamura, Scott, Saber.

Conflict of Interest Disclosures: Dr Guru Murthy reported receiving honoraria from Cardinal Health, TG Therapeutics, DAVA Oncology, and Curio Science and serving as a consultant for Cancerexpert, Qessential, and Techspert outside the submitted work. Dr Hu reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Cerny reported receiving personal fees from the Allovir Inc Data Safety Monitory Board, the Pfizer Inc Advisory Board, the Amgen Inc Advisory Board, and the Jazz Pharmaceuticals Advisory Board and owning stocks in Actinium Pharmaceuticals, Bluebird Bio Inc, Dynavax Pharma, Atyr Pharma, Gamida Cell, Miragen Therapeutics, Mustang Bio, Novavax, Ovid Therapeutics, Sorrento Therapeutics, TG Therapeutics, Vaxart Inc, and Veru Inc outside the submitted work. Dr Ganguly reported receiving personal fees from Seattle Genetics, Kite Pharma, Sanofi, Janssen, Astra Zeneca, Bristol Myers Squibb, Daiichi Sankyo, and Astellas outside the submitted work. Dr Grunwald reported receiving personal fees from AbbVie, Agios, Amgen, Astellas, Blueprint Medicines, Bristol Myers Squibb, Cardinal Health, Daiichi Sankyo, Gamida Cell, Genentech/Roche, Gilead, Incyte, Invitae, Karius, Ono Pharmaceutical, Pfizer, Premier, Sierra Oncology, Stemline, and Trovagene, nonfinancial support from Amgen, Incyte, and Genentech/Roche, and grants from Janssen and Incyte outside the submitted work. Dr Kharfan-Dabaja reported receiving consultancy fees from Daiichi Sankyo outside the submitted work. Dr Hamilton reported serving on the advisory boards of Syndax and Equilium outside the submitted work. Dr Liesveld reported receiving honoraria from Bristol Myers Squibb and Blueprint sciences and serving on the Onconova Data Safety Monitoring Board outside the submitted work. Dr Murthy reported receiving consultancy fees from CRISPR Therapeutics Research Funding outside the submitted work. Dr Nazha reported owning stock in Amazon Web Services outside the submitted work. Dr Nishihori reported receiving trial support and funding from Novartis and Karyopharm outside the submitted work. Dr Patel reported receiving personal fees from Kite Pharma, GLG Pharma, and Medexus outside the submitted work. Dr Pawarode reported receiving grants from Celgene Cooperation and Angiocrine Bioscience outside the submitted work. Dr Seo reported receiving personal fees from Janssen Pharmaceutical KK outside the submitted work. Dr Ustun reported receiving honoraria from Blueprint and Novartis outside the submitted work. Dr Scott reported receiving grants from Celgene/Bristol Myers Squibb outside the submitted work. No other disclosures were reported.

Funding/Support: The Center for International Blood and Marrow Transplant Research is supported primarily by Public Health Service grant U24CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases; grant HHSH250201700006C from the Health Resources and Services Administration; and grants N00014-20-1-2705 and N00014-20-1-2832 from the Office of Naval Research. Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and the following commercial entities: AbbVie; Accenture; Actinium Pharmaceuticals Inc; Adaptive Biotechnologies Corporation; Adienne SA; Allovir Inc; Amgen Inc; Astellas Pharma US; Bluebird Bio Inc; Bristol Myers Squibb Co; CareDx; CSL Behring; CytoSen Therapeutics Inc; Daiichi Sankyo Co Ltd; Eurofins Viracor; ExcellThera; Fate Therapeutics; Gamida-Cell Ltd; Genentech Inc; Gilead; GlaxoSmithKline; Incyte Corporation; Janssen/Johnson & Johnson; Jasper Therapeutics; Jazz Pharmaceuticals Inc; Karyopharm Therapeutics; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Magenta Therapeutics; Medac GmbH; Merck & Co; Millennium, the Takeda Oncology Co; Miltenyi Biotec Inc; MorphoSys; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncopeptides Inc; Orca Biosystems Inc; Pfizer Inc; Pharmacyclics LLC; Sanofi Genzyme; Seagen Inc; Stemcyte; Takeda Pharmaceuticals; Tscan; Vertex; Vor Biopharma; and Xenikos.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the US Department of the Navy, the US Department of Defense, the Health Resources and Services Administration, or any other agency of the US government.

Meeting Presentation: Presented in part as an abstract at the American Society of Hematology Annual Meeting [virtual]; December 7, 2020.

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