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Purpose: Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD)., Methods: This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or severe) or relapse-free survival (CRFS)., Results: Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio [HR] compared with control, 0.80; 95% CI, 0.56 to 1.15; P = .24), 48.1% for PTCy (HR, 0.86; 0.61 to 1.23; P = .41), and 41.0% for control. Corresponding rates of overall survival were 60.1% (HR, 1.74; 1.09 to 2.80; P = .02), 76.2% (HR, 1.02; 0.60 to 1.72; P = .95), and 76.1%. CD34 selection was associated with lower moderate to severe cGVHD (HR, 0.25; 0.12 to 0.52; P = .02) but higher transplant-related mortality (HR, 2.76; 1.26 to 6.06; P = .01). PTCy was associated with comparable cGVHD and survival outcomes to control, and a trend toward lower disease relapse (HR, 0.52; 0.28 to 0.96; P = .037)., Conclusion: CNI-free interventions as performed herein did not result in superior CRFS compared with tacrolimus and methotrexate with BM. Lower rates of moderate and severe cGVHD did not translate into improved survival., Competing Interests: Leo LuznikConsulting or Advisory Role: Gilead Sciences, Talaris Therapheutics, Precision BioSciences, Rubius Therapheutics, WindMiL TherapheuticsResearch Funding: Genentech, Amgen (I)Patents, Royalties, Other Intellectual Property: Patent holder WindMIL therapheuticsUncompensated Relationships: WindMIL therapheutics Marcelo C. PasquiniHonoraria: HonorariaConsulting or Advisory Role: Pfizer, Medigene (Inst), Amgen¸ Bristol Myers SquibbResearch Funding: Kite/Gilead (Inst), Novartis (Inst), Bristol Myers Squibb (Inst) Brent LoganConsulting or Advisory Role: Daiichi Sankyo, Enlivex Therapeutics Ltd, Gamida Cell Robert J. SoifferLeadership: Kiadis Pharma, Be the Match/NMDPConsulting or Advisory Role: Juno Therapeutics, Gilead Sciences, Rheos Medicines, Cugene, Jazz Pharmaceuticals, Precision Biosciences, Takeda, Jasper Therapeutics, Alexion PharmaceuticalsExpert Testimony: PfizerTravel, Accommodations, Expenses: Gilead Sciences Steven M. DevineThis 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: Kiadis PharmaConsulting or Advisory Role: Bristol Myers SquibbResearch Funding: Orca Bio (Inst), Kiadis Pharma (Inst)Travel, Accommodations, Expenses: Orca Bio Sergio GiraltThis 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: Celgene, Takeda, Amgen, Jazz Pharmaceuticals, SanofiConsulting or Advisory Role: Celgene, Takeda, Sanofi, Jazz Pharmaceuticals, Amgen, Janssen, Actinuum, Bristol Myers Squibb, Johnson & Johnson, PfizerResearch Funding: Celgene (Inst), Takeda, Miltenyi Biotec (Inst), Johnson & Johnson, Amgen, Actinuum, SanofiTravel, Accommodations, Expenses: Celgene, Sanofi, Amgen, Jazz Pharmaceuticals Helen E. HeslopStock and Other Ownership Interests: Marker Therapeutics, Allovir, Fresh Wind BiotechnologiesConsulting or Advisory Role: Gilead Sciences, Novartis, Kiadis Pharma, Tessa Therapeutics, Marker Therapeutics, PACT Pharma, Mesoblast, GlaxoSmithKline, Takara BioResearch Funding: Tessa Therapeutics (Inst) Mary M. HorowitzConsulting or Advisory Role: MedacResearch Funding: Biovitrum (Inst), Jazz Pharmaceuticals (Inst), Magenta Therapeutics (Inst), Novartis (Inst), Kite/Gilead (Inst), Actinium Pharmaceuticals (Inst), Amgen (Inst), Bluebird Bio (Inst), Bristol Myers Squibb (Inst), Chimerix (Inst), CSL Behring¸ Daiichi Sankyo (Inst), Gamida Cell (Inst), GlaxoSmithKline (Inst), Mesoblast (Inst), Miltenyi Biotec (Inst), Oncoimmune (Inst), Pfizer (Inst), Pharmacyclics (Inst), Regeneron (Inst), Sanofi (Inst), Seattle Genetics (Inst), Shire (Inst), Astellas Pharma, Xenikos (Inst) Mark R. LitzowConsulting or Advisory Role: Omeros, Jazz PharmaceuticalsResearch Funding: Amgen, Astellas Pharma, Actinium Pharmaceuticals, Pluristem Therapeutic, AbbVie/Genentech, Tolero Pharmaceuticals, AbbVieOther Relationship: Biosight Lori MufflyStock and Other Ownership Interests: Corvus PharmaceuticalsHonoraria: UpToDateConsulting or Advisory Role: Pfizer, Amgen, medexus, Jazz PharmaceuticalsSpeakers' Bureau: Adaptive BiotechnologiesResearch Funding: Shire, Adaptive Biotechnologies, Astellas Pharma, Jasper Therapeutics Eneida R. NemecekConsulting or Advisory Role: Medexus, Medac, Novartis, Atara Biotherapeutics Richard J. O'ReillyConsulting or Advisory Role: Atara BiotherapeuticsResearch Funding: Atara BiotherapeuticsPatents, Royalties, Other Intellectual Property: I have received royalties following licensure of the EBV-specific T-cell bank by Atara Biotherapeutics Johannes ScheteligHonoraria: Roche, AbbVie, Janssen, Bristol Myers Squibb/Sanofi, Gilead Sciences, AstraZenecaConsulting or Advisory Role: AstraZeneca, AbbVie, Janssen Sumithira VasuConsulting or Advisory Role: Omeros, Johnson and JohnsonResearch Funding: SanofiOpen Payments Link: https://openpaymentsdata.cms.gov/physician/725618 Vincent T. HoConsulting or Advisory Role: Jazz Pharmaceuticals, Janssen, Alexion Pharmaceuticals, OmerosResearch Funding: Jazz Pharmaceuticals Miguel-Angel PeralesStock and Other Ownership Interests: NexImmuneHonoraria: MorphoSysConsulting or Advisory Role: Incyte, Merck, Servier/Pfizer, NexImmune, Novartis, MolMed¸ Medigene, Takeda, Nektar, AbbVie, Cidara Therapeutics, Celgene, Kite/Gilead, Bristol Myers Squibb, Omeros, Vor BiopharmaResearch Funding: Incyte (Inst), Miltenyi Biotec (Inst), Novartis (Inst), Kite, a Gilead company (Inst), Nektar (Inst)No other potential conflicts of interest were reported.

Currently, stem cell donor registries include more than 35 million potential donors worldwide to provide HLA-matched stem cell products for patients in need of an unrelated donor transplant. DKMS is a leading stem cell donor registry with more than 9 million donors from Germany, Poland, the United States, the United Kingdom, India and Chile. DKMS donors have donated hematopoietic stem cells more than 80,000 times. Many aspects of donor registry work are closely related to topics from immunogenetics or population genetics. In this two-part review article, we describe, analyse and discuss these areas of donor registry work by using the example of DKMS. Part 1 of the review gives a general overview on DKMS and includes typical donor registry activities with special focus on the HLA system: high-throughput HLA typing of potential stem cell donors, HLA haplotype frequencies and resulting matching probabilities, and donor file optimization with regard to HLA diversity., (© 2020 The Authors. International Journal of Immunogenetics. Published by John Wiley & Sons Ltd.)