title: Phase II Study of Nonmyeloablative Allogeneic Bone Marrow Transplantation for B Cell Lymphoma with Post-Transplantation Rituximab and Donor Selection Based First on Non-HLA Factors.
abstract: Outcomes of nonmyeloablative (NMA), HLA-haploidentical (haplo), related-donor allogeneic blood or marrow transplantation (allo-BMT) with high-dose post-transplantation cyclophosphamide (PTCy) appear to be similar to those using HLA-matched donors. Thus, it may be possible to prioritize donor factors other than HLA matching that could enhance antitumor activity. The Fc receptor polymorphism FCGR3A-158VV may confer greater sensitivity to rituximab than FCGR3A-158FF. In a prospective phase II study of NMA, related-donor allo-BMT with PTCy and post-transplantation rituximab for patients with B cell lymphomas, we hypothesized that donor selection that prioritized FCGR3A-158 polymorphism over HLA matching would be feasible, safe, and improve outcomes. The primary endpoint was 1-year progression-free survival (PFS). Of 83 patients transplanted (median age, 59 years), 69 (83%) received haplo grafts. Fifty-four (65%) received a graft that maintained or improved their Fc receptor polymorphism status. With 2.6-year median follow-up, the 1-year PFS and overall survival (OS) probabilities were 71% and 86%, respectively, with 1-year relapse and nonrelapse mortality (NRM) probabilities of 20% and 8%. At 1 year, the probability of acute grades II to IV graft-versus-host disease (GVHD) was 41%, with acute grades III to IV GVHD probability of 5% and chronic GVHD probability of 11%. Among haplo transplants, the 1-year probabilities of PFS, OS, relapse, and NRM were 70%, 83%, 20%, and 10%, respectively. No differences in outcomes were observed based on donor FCGR3A-158 polymorphism. Excess infection risk was not apparent with post-transplantation rituximab. Although donor selection based on FCGR3A-158 polymorphism was not shown to influence PFS, this study suggests that donor selection based on criteria other than best HLA match is feasible and safe. This study opens the way for the future investigation of donor prioritization based on promising non-HLA factors that may improve antitumor activity and decrease relapse after allo-BMT. This study was registered at www.clinicaltrials.gov as NCT00946023.
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kanakry
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Gocke
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Javier
authors.initials: J
authors.lastname: Bolaños-Meade
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Gladstone
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Lode J
authors.initials: LJ
authors.lastname: Swinnen
authors.affiliation: Department of Oncology Biostatistics, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Blackford
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ephraim J
authors.initials: EJ
authors.lastname: Fuchs
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Huff
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrello
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: William H
authors.initials: WH
authors.lastname: Matsui
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
authors.affiliation: Department of Oncology Biostatistics, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Rosner
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Satish
authors.initials: S
authors.lastname: Shanbhag
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland. Electronic address: ambinder@jhu.edu.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ambinder
authors.affiliation: Department of Oncology, Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Yvette L
authors.initials: YL
authors.lastname: Kasamon
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation / Q000379:methods*; D002908:Chronic Disease; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D006650:Histocompatibility Testing; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011446:Prospective Studies; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D012008:Recurrence; D000069283:Rituximab / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D061349:Unrelated Donors
chemical_list: D000970:Antineoplastic Agents; C496124:FCGR3A protein, human; D017452:Receptors, IgG; D000069283:Rituximab
keywords: Allogeneic bone marrow transplantation; Donor prioritization; Fc receptor polymorphism; Haploidentical; Post-transplantation cyclophosphamide; Post-transplantation rituximab