Day 4 collection of granulocyte colony-stimulating factor-mobilized HLA-matched sibling donor peripheral blood allografts demonstrates no long-term increase in chronic graft-versus-host disease or relapse rates

Published:January 21, 2023DOI:


      Background aims

      In a previous pilot study of HLA-matched sibling donor hematopoietic cell transplantation (HCT), the authors determined the feasibility of day 4 versus day 5 granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) collection compared with a historical cohort. Given identified differences in the PBSC product (day 4 cohort with significantly lower infused total nucleated, mononuclear and CD3 cells compared with other collection cohorts), the authors performed a follow-up study to determine long-term post-HCT outcomes, including detailed characterization of chronic graft-versus-host disease (GVHD).


      This was a prospective observational study, and the authors collected data on chronic GVHD, staging, sites of involvement and treatments. Performance status, incidence of relapse, overall survival and duration of immunosuppressive therapy (IST) were also evaluated. Data were examined retrospectively. To account for differences in length of follow-up among cohorts, the authors also determined performance status and chronic GVHD staging, sites and treatment at 2 years post-HCT.


      At 2 years post-HCT, the overall survival rate was 71.7% in the day 4 cohort compared with 61.5%, 52% and 56% in the day 5, 2-day and historical cohorts, respectively (P = 0.283). The cumulative incidence of chronic GVHD was 65.2% in the day 4 cohort versus 46.4% in the day 5 cohort, 51.1% in the 2-day cohort and 65% in the historical cohort (P = 0.26). There was no significant difference in the maximum overall stage of chronic GVHD (P = 0.513), median number of sites involved (P = 0.401) or cumulative incidence of discontinuation of IST (P = 0.32). Death from chronic GVHD was less common in the day 4 and day 5 cohorts compared with the 2-day and historical cohorts, though this did not reach statistical significance.


      The authors’ preliminary results demonstrated that collection of allogeneic matched sibling donor PBSCs on day 4 of G-CSF was feasible, reduced donor exposure to growth factor and was associated with an initial cost savings. Importantly, the authors now demonstrate that transplantation of day 4 mobilized PBSCs is not associated with any adverse outcomes post-HCT, including late effects such as chronic GVHD. Further investigation of donor G-CSF collection algorithms is merited in other HCT settings, including unrelated and mismatched related donors.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Auletta J.J. KJ, Chen M., Shaw B.E. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides. 2021. 2021.

        • Holtick U
        • Albrecht M
        • Chemnitz JM
        • et al.
        Comparison of bone marrow versus peripheral blood allogeneic hematopoietic stem cell transplantation for hematological malignancies in adults—a systematic review and meta-analysis.
        Crit. Rev. Oncol. Hematol. 2015; 94: 179-188
        • Juric MK
        • Ghimire S
        • Ogonek J
        • et al.
        Milestones of hematopoietic stem cell transplantation—from first human studies to current developments.
        Front. Immunol. 2016; 7: 470
        • Campregher PV
        • Hamerschlak N
        • Colturato VA
        • et al.
        Survival and graft-versus-host disease in patients receiving peripheral stem cell compared to bone marrow transplantation from HLA-matched related donor: retrospective analysis of 334 consecutive patients.
        Eur. J. Haematol. 2015; 95: 421-425
        • Eapen M
        • Logan BR
        • Appelbaum FR
        • et al.
        Long-term survival after transplantation of unrelated donor peripheral blood or bone marrow hematopoietic cells for hematologic malignancy.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2015; 21: 55-59
        • Amouzegar A
        • Dey BR
        • Spitzer TR.
        Peripheral blood or bone marrow stem cells? Practical considerations in hematopoietic stem cell transplantation.
        Transfus. Med. Rev. 2019; 33: 43-50
        • Pahnke S
        • Nygell UA
        • Johansson JE
        • et al.
        Cancer incidence in healthy Swedish peripheral blood stem cell donors.
        Bone Marrow Transplant. 2022; 57: 795-802
        • Pulsipher MA
        • Chitphakdithai P
        • Logan BR
        • et al.
        Lower risk for serious adverse events and no increased risk for cancer after PBSC vs BM donation.
        Blood. 2014; 123: 3655-3663
      2. FDA. Neupogen (filgrastim). Accessed August 1, 2022.

        • Kroger N
        • Renges H
        • Kruger W
        • et al.
        A randomized comparison of once versus twice daily recombinant human granulocyte colony-stimulating factor (filgrastim) for stem cell mobilization in healthy donors for allogeneic transplantation.
        Br. J. Haematol. 2000; 111: 761-765
        • Newell LF
        • Shoop KM
        • Knight RJ
        • et al.
        Feasibility and cost analysis of day 4 granulocyte colony-stimulating factor mobilized peripheral blood progenitor cell collection from HLA-matched sibling donors.
        Cytotherapy. 2019; 21: 725-737
        • Watz E
        • Remberger M
        • Ringden O
        • et al.
        Quality of the hematopoietic stem cell graft affects the clinical outcome of allogeneic stem cell transplantation.
        Transfusion (Paris). 2015; 55: 2339-2350
        • Tanhehco YC
        • Schwartz J
        • Linenberger ML.
        Defining the quality of hematopoietic stem cell products: the devil is in the details.
        Transfusion (Paris). 2015; 55: 2300-2303
        • Remberger M
        • Torlen J
        • Ringden O
        • et al.
        Effect of total nucleated and CD34+ cell dose on outcome after allogeneic hematopoietic stem cell transplantation.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2015; 21: 889-893
        • Dominietto A
        • Raiola AM
        • van Lint MT
        • et al.
        Factors influencing haematological recovery after allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor type, cytomegalovirus infections and cell dose.
        Br. J. Haematol. 2001; 112: 219-227
        • Impola U
        • Larjo A
        • Salmenniemi U
        • Putkonen M
        • Itala-Remes M
        • Partanen J.
        Graft immune cell composition associates with clinical outcome of allogeneic hematopoietic stem cell transplantation in patients with AML.
        Front. Immunol. 2016; 7: 523
        • Cao TM
        • Wong RM
        • Sheehan K
        • et al.
        CD34, CD4, and CD8 cell doses do not influence engraftment, graft-versus-host disease, or survival following myeloablative human leukocyte antigen-identical peripheral blood allografting for hematologic malignancies.
        Exp. Hematol. 2005; 33: 279-285
        • Reshef R
        • Huffman AP
        • Gao A
        • et al.
        High graft CD8 cell dose predicts improved survival and enables better donor selection in allogeneic stem-cell transplantation with reduced-intensity conditioning.
        Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2015; 33: 2392-2398
        • Gu G
        • Yang JZ
        • Sun LX.
        Correlation of graft immune composition with outcomes after allogeneic stem cell transplantation: moving towards a perfect transplant.
        Cell. Immunol. 2018; 323: 1-8
        • Shulman HM
        • Sullivan KM
        • Weiden PL
        • et al.
        Chronic graft-versus-host syndrome in man. a long-term clinicopathologic study of 20 Seattle patients.
        Am. J. Med. 1980; 69: 204-217
        • Lee SJ
        • Klein JP
        • Barrett AJ
        • et al.
        Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse.
        Blood. 2002; 100: 406-414
        • Pintilie M.
        Competing Risks: A Practical Perspective. JohnWiley & Sons Ltd, 2006
        • Gray RJ.
        A class of K-sample tests for comparing the cumulative incidence of a competing risk.
        Annals of Statistics. 1988; 16: 1141-1154
        • Perez-Simon JA
        • Afram G
        • Martino R
        • et al.
        Evaluation of prognostic factors among patients with chronic graft-versus-host disease.
        Haematologica. 2012; 97: 1187-1195
        • Lazaryan A
        • Arora M.
        Evolving concepts in prognostic scoring of chronic GVHD.
        Bone Marrow Transplant. 2017; 52: 1361-1366
        • Pidala J
        • Kim J
        • Anasetti C
        • et al.
        The global severity of chronic graft-versus-host disease, determined by National Institutes of Health consensus criteria, is associated with overall survival and non-relapse mortality.
        Haematologica. 2011; 96: 1678-1684
        • Inamoto Y
        • Martin PJ
        • Storer BE
        • et al.
        Association of severity of organ involvement with mortality and recurrent malignancy in patients with chronic graft-versus-host disease.
        Haematologica. 2014; 99: 1618-1623
        • Jagasia MH
        • Greinix HT
        • Arora M
        • et al.
        National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 diagnosis and staging working group report.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2015; 21: 389-401.e1
        • Williams KM
        • Inamoto Y
        • Im A
        • et al.
        National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2020 etiology and prevention working group report.
        Transplant Cell Ther. 2021; 27: 452-466
        • Socie G
        • Stone JV
        • Wingard JR
        • et al.
        Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry.
        N. Engl. J. Med. 1999; 341: 14-21
        • Fraser CJ
        • Bhatia S
        • Ness K
        • et al.
        Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study.
        Blood. 2006; 108: 2867-2873
        • Arora M
        • Cutler CS
        • Jagasia MH
        • et al.
        Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2016; 22: 449-455
        • Gandelman JS
        • Byrne MT
        • Mistry AM
        • et al.
        Machine learning reveals chronic graft-versus-host disease phenotypes and stratifies survival after stem cell transplant for hematologic malignancies.
        Haematologica. 2019; 104: 189-196
        • Kitko CL
        • Pidala J
        • Schoemans HM
        • et al.
        National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IIa. The 2020 clinical implementation and early diagnosis working group report.
        Transplant Cell Ther. 2021; 27: 545-557
        • MacDonald KP
        • Hill GR
        • Blazar BR.
        Chronic graft-versus-host disease: biological insights from preclinical and clinical studies.
        Blood. 2017; 129: 13-21
        • Wolff D
        • Greinix H
        • Lee SJ
        • et al.
        Biomarkers in chronic graft-versus-host disease: quo vadis?.
        Bone Marrow Transplant. 2018; 53: 832-837
        • Crossland RE
        • Perutelli F
        • Bogunia-Kubik K
        • et al.
        Potential novel biomarkers in chronic graft-versus-host disease.
        Front. Immunol. 2020; 11602547
        • Wolff D
        • Fatobene G
        • Rocha V
        • Kroger N
        • Flowers ME.
        Steroid-refractory chronic graft-versus-host disease: treatment options and patient management.
        Bone Marrow Transplant. 2021; 56: 2079-2087
        • Zeiser R
        • Lee SJ.
        Three US Food and Drug Administration-approved therapies for chronic GVHD.
        Blood. 2022; 139: 1642-1645
        • Czerw T
        • Labopin M
        • Schmid C
        • et al.
        High CD3+ and CD34+ peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia—an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
        Oncotarget. 2016; 7: 27255-27266
        • Woolfrey A
        • Lee SJ
        • Gooley TA
        • et al.
        HLA-allele matched unrelated donors compared to HLA-matched sibling donors: role of cell source and disease risk category.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2010; 16: 1382-1387
        • Zhang Y
        • Guo C
        • Sun C
        • et al.
        High proportions of CD3+ T cells in grafts delayed lymphocyte recovery and reduced overall survival in haploidentical peripheral blood stem cell transplantation.
        Mol. Clin. Oncol. 2020; 12: 574-580
        • Pastore D
        • Delia M
        • Mestice A
        • et al.
        CD3+/Treg ratio in donor grafts is linked to acute graft-versus-host disease and immunologic recovery after allogeneic peripheral blood stem cell transplantation.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2012; 18: 887-893
        • Muller AM
        • Linderman JA
        • Florek M
        • Miklos D
        • Shizuru JA.
        Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation.
        Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 14721-14726