Abstract
The impact of acute and chronic graft-versus-host disease (GVHD) on clinical outcomes was retrospectively analyzed in 960 patients with non-malignant diseases (NMD) who underwent a first allogeneic hematopoietic stem cell transplantation (HSCT). Grade III–IV acute GVHD (but not grade I–II) was significantly associated with a lower rate of overall survival (OS), and higher non-relapse mortality (NRM) than that seen in patients without acute GVHD. Extensive (but not limited) GVHD was significantly associated with a lower OS rate and higher NRM than that seen in patients without chronic GVHD. Any grade of acute (but not chronic) GVHD was significantly associated with a lower incidence of relapse and a lower proportion of patients requiring a second HSCT or donor lymphocyte infusion for graft failure or mixed chimerism, but its impact on OS was almost negligible. Acute GVHD was significantly associated with lower OS rates in all disease groups, whereas chronic GVHD was significantly associated with lower OS rates in the primary immunodeficiency and histiocytosis groups. In conclusion, acute and chronic GVHD, even if mild, was associated with reduced OS in patients receiving HSCT for NMD and effective strategies should, therefore, be implemented to minimize GVHD.
Similar content being viewed by others
References
Jacobsohn DA, Duerst R, Tse W, Kletzel M. Reduced intensity haemopoietic stem-cell transplantation for treatment of non-malignant diseases in children. Lancet. 2004;364:156–62.
Chiesa R, Veys P. Reduced-intensity conditioning for allogeneic stem cell transplant in primary immune deficiencies. Expert Rev Clin Immunol. 2012;8:255–66.
Kato S, Yabe H, Takakura H, Mugishima H, Ishige M, Tanaka A, et al. Hematopoietic stem cell transplantation for inborn errors of metabolism: a report from the Research Committee on Transplantation for Inborn Errors of Metabolism of the Japanese Ministry of Health, Labour, and Welfare and the Working Group of the Japan Society for Hematopoietic Cell Transplantation. Pediatr Transplant. 2016;20:203–14.
Myers KC, Davies SM. Hematopoietic stem cell transplantation for bone marrow failure syndromes in children. Biol Blood Marrow Transplant. 2009;15:279–92.
Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, et al. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010;116:5824–31.
Umeda K, Adachi S, Tanaka S, Miki M, Okada K, Hashii Y, et al. Comparison of second transplantation and donor lymphocyte infusion for donor mixed chimerism after allogeneic stem cell transplantation for nonmalignant diseases. Pediatr Blood Cancer. 2016;63:2221–9.
Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555–62.
Kanda Y, Izutsu K, Hirai H, Sakamaki H, Iseki T, Kodera Y, et al. Effect of graft-versus-host disease on the outcome of bone marrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporine A and methotrexate. Leukemia. 2004;18:1013–9.
Kanda J, Morishima Y, Terakura S, Wake A, Uchida N, Takahashi S, et al. Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation. Leukemia. 2017;31:663–8.
Kato M, Kurata M, Kanda J, Kato K, Tomizawa A, Kudo K, et al. Impact of graft-versus-host disease on relapse and survival after allogeneic stem cell transplantation for pediatric leukemia. Bone Marrow Transplant. 2019;54:68–75.
Willasch A, Hoelle W, Kreyenberg H, Niethammer D, Handgretinger R, Lang P, et al. Outcome of allogeneic stem cell transplantation in children with non-malignant diseases. Haematologica. 2006;91:788–94.
Park M, Koh KN, Seo JJ, Im HJ. Clinical implications of chimerism after allogeneic hematopoietic stem cell transplantation in children with non-malignant diseases. Korean J Hematol. 2011;46:258–64.
Faraci M, Bagnasco F, Lenoni M, Giardino S, Terranova P, Subissi L, et al. Evaluation of chimerism dynamics after allogeneic hematopoietic stem cell transplantation in children with nonmalignant diseases. Biol Blood Marrow Transplant. 2018;24:1088–93.
Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP system. Int J Hematol. 2007;86:269–74.
Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628–33.
Konopacki J, Porcher R, Robin M, Bieri S, Cayuela JM, Larghero J, et al. Long-term follow up after allogeneic stem cell transplantation in patients with severe aplastic anemia after cyclophosphamide plus antithymocyte globulin conditioning. Haematologica. 2012;97:710–6.
Umeda K, Yabe H, Kato K, Imai K, Kobayashi M, Takahashi Y, et al. Impact of low-dose irradiation and in vivo T-cell depletion in hematopoietic stem cell transplantation against non-malignant diseases using a fludarabine combination reduced-intensity conditioning. Bone Marrow Transplant. 2019;54:1227.
Przepiorka D, Weisdorf D, Martin P, Klingermann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–8.
Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, et al. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204–17.
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.
Socié G, Devergie A, Girinski T, Piel G, Ribaud P, Esperou H, et al. Transplantation for Fanconi’s anaemia: long-term follow-up of 50 patients transplanted from a sibling donor after low-dose cyclophosphamide and thoraco-abdominal irradiation for conditioning. Br J Haematol. 1998;103:249–55.
Alter BP. Cancer in Fanconi Anemia, 1927–2001. Cancer. 2003;97:425–40.
de Latour RP, Porcher R, Dalle JH, Aljurf M, Korthof ET, et al. Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for blood and marrow transplantation experience. Blood. 2013;122:4279–86.
Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, et al. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors—the ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015;33:1265–74.
Beier R, Albert MH, Bader P, Borkhard A, Creutzig U, Eyrich M, et al. Allo-SCT using BU, CY, and melphalan for children with AML in second CR. Bone Marrow Transplant. 2013;48:651–6.
Horan J, Wang T, Haagenson M, Spellman SR, Dehn J, Eapen M, et al. Evaluation of HLA matching in evaluation of HLA matching in unrelated hematopoietic stem cell transplantation for nonmalignant disorders. Blood. 2012;120:2918–24.
Merli P, Bertaina A, Li Pira G, Pende D, Falco M, Pagliara D, et al. Infusion of donor T cells transduced with inducible Caspase 9 (BPX-501 cells) is a safe and effective strategy to accelerate immune recovery in patients with non-malignant disorders after T cell depleted haplo-HSCT. Bone Marrow Transplant. 2016;51:S4–5.
Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012;120:4285–91.
DeZern AE, Zahurak M, Symons H, Cooke K, Jones RJ, Brodsky RA. Alternative donor transplantation with high-dose post-transplantation cyclophosphamide for refractory severe aplastic anemia. Biol Blood Marrow Transplant. 2017;23:498–504.
Wynn RF, Wraith JE, Mercer J, O’Meara A, Tylee K, Thoenley M, et al. Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J Pediatr. 2009;154:609–11.
Tanaka A, Okuyama T, Suzuki Y, Sakai N, Takakura H, Sawada T, et al. Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: a nationwide survey in Japan. Mol Genet Metab. 2012;107:513–20.
Hartz B, Marsh R, Rao K, Henter JI, Jordan M, Filipovich L, et al. The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis. Blood. 2016;127:3281–90.
Marsh RA, Rao MB, Gefen A, Bellman D, Mehta PA, Khandelwal P, et al. Experience with alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning hematopoietic cell transplantation in patients with nonmalignant diseases reveals good outcomes and that the risk of mixed chimerism depends on underlying disease, stem cell source, and alemtuzumab regimen. Biol Blood Marrow Transplant. 2015;21:1460–70.
Dürken M, Horstmann M, Bieling P, Erttmann R, Kabisch H, Löliger C, et al. Improved outcome in haemophagocytic lymphohistiocytosis after bone marrow transplantation from related and unrelated donors: a single-centre experience of 12 patients. Br J Haematol. 1999;106:1052–8.
Baker KS, Filipovich AH, Gross TG, Grossman WJ, Hale GA, Hayashi RJ, et al. Unrelated donor hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis. Bone Marrow Transplant. 2008;42:175–80.
Horne A, Janka G, Maarten Egeler R, Gadner H, Imashuku S, Ladisch S, et al. Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis. Br J Haematol. 2005;129:622–30.
Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 2010;24:101–22.
Acknowledgements
We thank all the physicians and data managers at the transplant centers who contributed data to the Japan Society for Hematopoietic Cell Transplantation, the Japan Marrow Donor Program, the Japan Cord Blood Bank Network, and the Japanese Society of Pediatric Hematology/Oncology. We thank Dr. Junya Kanda for assistance with statistical analysis.
Author information
Authors and Affiliations
Consortia
Contributions
KU, KI, MY, HY, and TM designed the research and organized the project; KU, KI, and YA performed statistical analysis and analyzed the data; KM, YT, MK, NY, and YC, MI, and YH gathered and organized the data; KU wrote the manuscript. All authors interpreted the data and reviewed and approved the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors have no competing financial interests to declare.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Umeda, K., Imai, K., Yanagimachi, M. et al. Impact of graft-versus-host disease on the clinical outcome of allogeneic hematopoietic stem cell transplantation for non-malignant diseases. Int J Hematol 111, 869–876 (2020). https://doi.org/10.1007/s12185-020-02839-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-020-02839-4