Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2021 Oct;27(10):852.e1-852.e9.
doi: 10.1016/j.jtct.2021.06.022. Epub 2021 Jun 30.

Fractionated Infusion of Hematopoietic Progenitor Cells Does Not Improve Neutrophil Recovery or Survival in Allograft Recipients

Roni Tamari  1 , Samantha Brown  2 , Sean M Devlin  2 , Satyajit Kosuri  3 , Molly A Maloy  2 , Doris M Ponce  1 , Craig Sauter  1 , Brian Shaffer  1 , Parastoo Dahi  1 , James W Young  4 , Ann Jakubowski  1 , Esperanza B Papadopoulos  1 , Hugo Castro-Malaspina  1 , Miguel-Angel Perales  1 , Sergio A Giralt  1 , Boglarka Gyurkocza  5
Affiliations
Clinical Trial

Fractionated Infusion of Hematopoietic Progenitor Cells Does Not Improve Neutrophil Recovery or Survival in Allograft Recipients

Roni Tamari et al. Transplant Cell Ther. 2021 Oct.

Abstract

Allogeneic hematopoietic cell transplantation (HCT) offers a potentially curative therapy in patients with hematologic malignancies; however, nonrelapse mortality (NRM) remains a concern. Strategies to improve neutrophil recovery and immune reconstitution are needed to decrease NRM. Murine models of allogeneic HCT suggest that fractionated hematopoietic progenitor cell (HPC) infusion may improve engraftment through improved access of HPCs to a viable hematopoietic niche. The primary objective of the present study was to determine the impact of fractionated infusion versus unfractionated (bulk) infusion of HPCs on the time to achieve neutrophil engraftment. Secondary objectives included the effect of fractionated versus bulk infusion of HPCs on platelet engraftment, immune reconstitution, the incidence of acute graft-versus-host disease (GVHD) grade II-IV, NRM, and overall survival (OS). In this randomized phase 2 study, patients with hematologic malignancies undergoing allogeneic HCT were randomized to receive HPC infusion as a bulk (bulk arm) or in fractions (fractionated arm): 4 × 106 CD34+ cells/kg recipient weight infused on day 0, with the remaining HPCs CD34+ cell-selected then infused in equally distributed aliquots on days 2, 4, and 6 post-HCT. Randomization was stratified by type of transplant, unmodified (i.e. T cell-replete graft) versus CD34+ cell-selected (T cell-depleted graft). Patients whose donor failed to collect at least 7 × 106 CD34+ cells/kg of recipient weight received bulk HPC infusions regardless of randomization, for safety. These patients continued the HCT process on study but were replaced until each arm reached the prespecified accrual target. Per protocol, these patients were not included in this modified intention-to-treat analysis. A total of 116 patients were enrolled. Donors of 42 patients failed to mobilize the minimum CD34+ cell dose (7 × 106 cells/kg recipient weight) and were excluded from the analysis. The 74 evaluable patients included 38 randomized to the bulk arm and 36 randomized to the fractionated arm. All patients engrafted. The median time to an absolute neutrophil count of ≥0.5 × 109/L was 11 days on both arms. The day +180 median CD4+ cell count was 179 cells/µL in the bulk arm and 111 cells/µL in the fractionated arm (P = .779). The cumulative incidence of grade II-IV acute GVHD on post-transplant day +100 was 32% in the bulk arm and 17% in the fractionated arm (P = .131). Two patients in the bulk arm, but none in the fractionated arm, experienced grade III-IV GVHD. The 4-year OS was 60% in the bulk arm and 62% in the fractionated arm (P = .414), whereas the 4-year cumulative incidences of NRM and relapse were similar in the 2 arms. Fractionated infusion of HPCs in allogeneic HCT recipients did not impact neutrophil or CD4+ cell recovery, NRM, relapse, or OS when compared with bulk HPC infusion. We also observed that with current mobilization techniques, it was unlikely that more than 60% of healthy donors would be able to collect >7 × 106 CD34+ cells/kg recipient weight for adult recipients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Keywords: Fractionated infusions; Hematopoietic cell transplantation; Hematopoietic progenitor cells; Immune reconstitution; Neutrophil recovery.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest statement D.M.P. has served on advisory boards for Generon, Kadmon, CareDx, and Ceramedix and as a paid consultant for Guidepoint Global Advisors and Gerson Lehrman Group. M.A.P. reports honoraria from AbbVie, Astellas, Bristol-Myers Squibb, Celgene, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Novartis, Nektar Therapeutics, Omeros, and Takeda; serves on data safety and monitoring boards for Cidara Therapeutics, Servier, and Medigene and the scientific advisory board of NexImmune; has received research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, and Novartis; and serves in a volunteer capacity as a member of the Board of Directors of Be The Match (National Marrow Donor Program), as well as on the CIBMTR Cellular Immunotherapy Data Resource Executive Committee. S.A.G. has received research funding from Actinium Pharma, Celgene, Bristol-Myers Squibb, Sanofi, Amgen, Pfizer, Jensen, and Takeda and serves as a research consultant for Kite Pharma and on advisory boards of Actinium, Celgene, Bristol-Myers Squibb, Sanofi, Amgen, Pfizer, GSK, Jazz, Jensen, and Omeros. B.G. reports research funding for a clinical trial from Actinium Pharma. The other authors have no conflicts of interest to report.

Figures

Figure 1.
Figure 1.
Trial profile; HCT: hematopoietic cell transplantation; mITT: modified intent to treat; *donors failed to collect > 7x10E6 CD34+ cells/kg recipient weight, recipients were removed from study and were replaced
Figure 2.
Figure 2.
Neutrophil (A) and lymphocyte (B) recovery in patients receiving bulk vs. fractionated infusions of hematopoietic progenitor cells
Figure 3.
Figure 3.
CD4+ (A) and CD8+ (B) lymphocyte recovery in patients receiving bulk vs. fractionated infusions of hematopoietic progenitor cells. The dashed lines represent the normal range. CD4+ lymphocyte recovery in patients receiving unmodified (C; n=16) vs. CD34+ cell selected (D; n=58) allografts, stratified by bulk vs. fractionated infusions of hematopoietic progenitor cells
Figure 4.
Figure 4.
Overall survival (A), progression-free survival (B), relapse (C) and non-relapse mortality (D) in patients receiving bulk vs. fractionated hematopoietic progenitor cell infusions.
See this image and copyright information in PMC

References

    1. Gratwohl A, Baldomero H, Aljurf M, et al.Hematopoietic stem cell transplantation: a global perspective. JAMA 2010;303(16):1617–1624. - PMC - PubMed
    1. Horowitz MM. Uses and Growth of Hematopoietic Cell Transplantation. Thomas’ Hematopoietic Cell Transplantation (eds Forman SJ, Negrin RS, Antin JH and Appelbaum FR); 2015:8–17.
    1. D’Souza A, Fretham C, Lee SJ, et al.Current Use of and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant 2020;26(8):e177–e182. - PMC - PubMed
    1. Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood 2010;115(19):3861–3868. - PubMed
    1. Bernstein ID, Boyd RL, van den Brink MR. Clinical strategies to enhance posttransplant immune reconstitution. Biol Blood Marrow Transplant 2008;14(1 Suppl 1):94–99. - PMC - PubMed

Publication types