National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide

Abstract

Purpose: Hematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT.

Patients and methods: We performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy.

Results: Notably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS.

Conclusion: Our prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.

Trial registration: ClinicalTrials.gov NCT02793544.

Conflict of interest statement

Bronwen E. ShawHonoraria: TherakosConsulting or Advisory Role: Orca Bio Brent R. LoganConsulting or Advisory Role: Daiichi Sankyo, Enlivex Therapeutics Ltd, Gamida Cell Farhad KhimaniResearch Funding: Bristol Myers Squibb Brian C. ShafferConsulting or Advisory Role: Hansa BiopharmaResearch Funding: Miltenyi Biotec Nirav N. ShahStock and Other Ownership Interests: Exelixis, GeronHonoraria: Miltenyi Biotec, Loxo/LillyConsulting or Advisory Role: Kite, a Gilead company, Celgene, Verastem, Loxo/Lilly, Legend Biotech, TG Therapeutics, EpizymeResearch Funding: Miltenyi BiotecTravel, Accommodations, Expenses: Miltenyi Biotec Alisha MussetterResearch Funding: Magenta Therapeutics Inc Xiao-Ying TangResearch Funding: Jazz Pharmaceuticals, OncoImmune, Gamida Cell, Merck, Kyowa Kirin International, Bristol Myers Squibb John M. McCartyHonoraria: Kite, a Gilead company, Anthem WellpointResearch Funding: Celgene/Bristol Myers Squibb, Celgene, FATE Therapeutics, Seattle Genetics Nosha FarhadfarConsulting or Advisory Role: IncyteResearch Funding: CSL Behring Nancy M. HardyConsulting or Advisory Role: Kite, a Gilead company, Gilead Sciences, American Gene TechnologiesResearch Funding: Incyte, TakedaTravel, Accommodations, Expenses: Kite/GileadUncompensated Relationships: GPB Claudio AnasettiStock and Other Ownership Interests: Ionis PharmaceuticalsHonoraria: Gilead SciencesConsulting or Advisory Role: Gilead Sciences Miguel-Angel PeralesStock and Other Ownership Interests: NexImmuneConsulting or Advisory Role: Incyte, Merck, Servier/Pfizer, NexImmune, Novartis, MolMed, Medigene, Takeda, Nektar, Abbvie, Cidara Therapeutics, Celgene, Kite/Gilead, Bristol Myers Squibb, OmerosResearch Funding: Incyte, Miltenyi Biotec, Novartis Krishna V. KomanduriHonoraria: Takeda, Kadmon, Kite/Gilead, Kiadis Pharma, Novartis, Incyte, AutolusConsulting or Advisory Role: Kiadis Pharma, Kite/Gilead, Novartis, Takeda, Incyte, Autolus, Kadmon, Genentech/Roche, Iovance Biotherapeutics, Gamida CellExpert Testimony: Kite/Gilead Leo LuznikConsulting or Advisory Role: Gilead Sciences, Talaris Therapeutics, Precision BioSciences, Rubius Therapeutics, WindMIL TherapeuticsResearch Funding: Genentech, AmgenPatents, Royalties, Other Intellectual Property: Patent holder WindMIL TherapeuticsUncompensated Relationships: WindMIL Therapeutics Maxim NorkinResearch Funding: Celgene Joseph A. PidalaConsulting or Advisory Role: Syndax, CTI BioPharma Corp, Amgen, Regeneron Steven M. DevineHonoraria: Kiadis PharmaConsulting or Advisory Role: Bristol Myers SquibbResearch Funding: Orca Bio, Kiadis PharmaTravel, Accommodations, Expenses: Orca Bio Mary M. HorowitzConsulting or Advisory Role: Magenta Therapeutics, Janssen Research & Development, MedacResearch Funding: Biovitrum, Jazz Pharmaceuticals, Magenta Therapeutics, Novartis, Kite/Gilead, Actinium Pharmaceuticals, Amgen, Amneal Pharmaceuticals, Anthem, Bluebird Bio, Bristol Myers Squibb, Chimerix, CSL Behring, Cyto-Sen Therapeutics, Daiichi Sankyo, Gamida Cell, GlaxoSmithKline, Mesoblast, Miltenyi Biotec, Neovii, Oncoimmune, Pfizer, Pharmacyclics, Regeneron, Sanofi, Seattle Genetics, Shire Javier Bolaños-MeadeOther Relationship: IncyteNo other potential conflicts of interest were reported.

Figures

FIG 1.

OS, stratified by conditioning intensity. MAC, myeloablative conditioning; OS, overall survival; RIC, reduced-intensity conditioning.

FIG 2.

aGVHD by strata. aGVHD, acute graft-versus-host disease; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning.

FIG 3.

cGVHD by strata. cGVHD, chronic graft-versus-host disease; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning.

FIG 4.

Relapse or NRM by strata. MAC, myeloablative conditioning; NRM, nonrelapse mortality; RIC, reduced-intensity conditioning.