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Consensus opinion on immune-mediated cytopenias after hematopoietic cell transplant for inherited metabolic disorders

Bone Marrow Transplantation volume 56, pages 1238–1247 (2021)Cite this article

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Abstract

Hematopoietic stem cell transplantation (HCT) has been increasingly used for patients with inherited metabolic disorders (IMD). Immune mediated cytopenias (IMCs) after HCT, manifesting as hemolytic anemia, thrombocytopenia, and/or neutropenia, are recognized as a significant complication in this patient population, yet our understanding of the incidence, risk factors, and pathophysiology is currently limited. Review of the published literature demonstrates a higher incidence in younger patients who undergo HCT for a nonmalignant disease indication. However, a few reports suggest that the incidence is even higher among those with IMD (incidence ranging from 10 to 56%). This review summarizes the literature, provides an approach to better understanding of the possible etiology of IMCs, and proposes a diagnostic and management plan for patients with IMD who develop single or multi-lineage cytopenias after HCT.

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References

  1. Chen FE, Owen I, Savage D, Roberts I, Apperley J, Goldman JM, et al. Late onset haemolysis and red cell autoimmunisation after allogeneic bone marrow transplant. Bone Marrow Transplant. 1997;19:491–5.

    Article  CAS  PubMed  Google Scholar 

  2. Dovat S, Roberts RL, Wakim M, Stiehm ER, Feig SA. Immune thrombocytopenia after umbilical cord progenitor cell transplant: response to vincristine. Bone Marrow Transplant. 1999;24:321–3.

    Article  CAS  PubMed  Google Scholar 

  3. Horn B, Viele M, Mentzer W, Mogck N, DeSantes K, Cowan M. Autoimmune hemolytic anemia in patients with SCID after T cell-depleted BM and PBSC transplantation. Bone Marrow Transplant. 1999;24:1009–13.

    Article  CAS  PubMed  Google Scholar 

  4. Bhatt V, Shune L, Lauer E, Lubin M, Devlin SM, Scaradavou A, et al. Autoimmune hemolysis and immune thrombocytopenic purpura after cord blood transplantation may be life-threatening and warrants early therapy with rituximab. Bone Marrow Transplant. 2016;51:1579–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chang TY, Jaing TH, Wen YC, Huang IA, Chen SH, Tsay PK. Risk factor analysis of autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation in children. Medicine. 2016;95:e5396.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Daikeler T, Labopin M, Ruggeri A, Crotta A, Abinun M, Hussein AA, et al. New autoimmune diseases after cord blood transplantation: a retrospective study of EUROCORD and the Autoimmune Disease Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2013;121:1059–64.

    Article  CAS  PubMed  Google Scholar 

  7. Faraci M, Zecca M, Pillon M, Rovelli A, Menconi MC, Ripaldi M, et al. Autoimmune hematological diseases after allogeneic hematopoietic stem cell transplantation in children: an Italian multicenter experience. Biol Blood Marrow Transplant. 2014;20:272–8.

    Article  PubMed  Google Scholar 

  8. Holbro A, Abinun M, Daikeler T. Management of autoimmune diseases after haematopoietic stem cell transplantation. Br J Haematol. 2012;157:281–90.

    Article  CAS  PubMed  Google Scholar 

  9. Kruizinga MD, van Tol MJD, Bekker V, Netelenbos T, Smiers FJ, Bresters D, et al. Risk factors, treatment, and immune dysregulation in autoimmune cytopenia after allogeneic hematopoietic stem cell transplantation in pediatric patients. Biol Blood Marrow Transplant. 2018;24:772–8.

    Article  CAS  PubMed  Google Scholar 

  10. O’Brien TA, Eastlund T, Peters C, Neglia JP, Defor T, Ramsay NK, et al. Autoimmune haemolytic anaemia complicating haematopoietic cell transplantation in paediatric patients: high incidence and significant mortality in unrelated donor transplants for non-malignant diseases. Br J Haematol. 2004;127:67–75.

    Article  PubMed  Google Scholar 

  11. Page KM, Mendizabal AM, Prasad VK, Martin PL, Parikh S, Wood S, et al. Posttransplant autoimmune hemolytic anemia and other autoimmune cytopenias are increased in very young infants undergoing unrelated donor umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2008;14:1108–17.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Deambrosis D, Lum SH, Hum RM, Poulton K, Ogden W, Jones S, et al. Immune cytopenia post-cord transplant in Hurler syndrome is a forme fruste of graft rejection. Blood Adv. 2019;3:570–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gupta A, Downey M, Shanley R, Jennissen C, Miller WP, Lund TC, et al. Reduced-toxicity (BuFlu) conditioning is better tolerated but has a higher second transplantation rate compared to myeloablative conditioning (BuCy) in children with inherited metabolic disorders. Biol Blood Marrow Transplant. 2020;26:486–92.

    Article  CAS  PubMed  Google Scholar 

  14. Szanto CL, Langenhorst J, de Koning C, Nierkens S, Bierings M, Huitema ADR, et al. Predictors for autoimmune cytopenias after allogeneic hematopoietic cell transplantation in children. Biol Blood Marrow Transplant. 2020;26:114–22.

    Article  CAS  PubMed  Google Scholar 

  15. Daikeler T, Tyndall A. Autoimmunity following haematopoietic stem-cell transplantation. Best Pract Res Clin Haematol. 2007;20:349–60.

    Article  CAS  PubMed  Google Scholar 

  16. Ahmed I, Teruya J, Murray-Krezan C, Krance R. The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post-first and post-second hematopoietic stem cell transplant. Pediatr Transplant. 2015;19:391–8.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hwang-Bo S, Kim SK, Lee JW, Jang PS, Chung NG, Jeong DC, et al. Treatment and response of autoimmune cytopenia occurring after allogeneic hematopoietic cell transplantation in children. Blood Res. 2017;52:119–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Scordo SM, Shah GL, Kosuri S, Adrianzen Herrera DA, Hsu M, Devlin SM, et al. Immune-mediated hemolytic anemia (IMHA) and immune thrombocytopenia (ITP) after ex-vivo CD34+ selected allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23:S129–30.

    Article  Google Scholar 

  19. Lum SH, Selvarajah S, Deya-Martinez AA, McNaughton P, Sobh A, Waugh S, et al. Outcome of autoimmune cytopenia after hematopoietic cell transplantation in primary immunodeficiency. J Allergy Clin Immunol. 2020;146:P406–16.

    Article  CAS  Google Scholar 

  20. Griesemer AD, Sorenson EC, Hardy MA. The role of the thymus in tolerance. Transplantation. 2010;90:465–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Takahama Y, Nitta T, Mat Ripen A, Nitta S, Murata S, Tanaka K. Role of thymic cortex-specific self-peptides in positive selection of T cells. Semin Immunol. 2010;22:287–93.

    Article  CAS  PubMed  Google Scholar 

  22. Barr TA, Shen P, Brown S, Lampropoulou V, Roch T, Lawrie S, et al. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J Exp Med. 2012;209:1001–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chapoval S, Dasgupta P, Dorsey NJ, Keegan AD. Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6. J Leukoc Biol. 2010;87:1011–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. King C, Ilic A, Koelsch K, Sarvetnick N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell. 2004;117:265–77.

    Article  CAS  PubMed  Google Scholar 

  25. Roord ST, de Jager W, Boon L, Wulffraat N, Martens A, Prakken B, et al. Autologous bone marrow transplantation in autoimmune arthritis restores immune homeostasis through CD4+CD25+Foxp3+ regulatory T cells. Blood. 2008;111:5233–41.

    Article  CAS  PubMed  Google Scholar 

  26. Seidel MG, Fritsch G, Lion T, Jurgens B, Heitger A, Bacchetta R, et al. Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation. Blood. 2009;113:5689–91.

    Article  CAS  PubMed  Google Scholar 

  27. Archer LD, Langford-Smith KJ, Bigger BW, Fildes JE. Mucopolysaccharide diseases: a complex interplay between neuroinflammation, microglial activation and adaptive immunity. J Inherit Metab Dis. 2014;37:1–12.

    Article  CAS  PubMed  Google Scholar 

  28. Dani A, Chaudhry A, Mukherjee P, Rajagopal D, Bhatia S, George A, et al. The pathway for MHCII-mediated presentation of endogenous proteins involves peptide transport to the endo-lysosomal compartment. J Cell Sci. 2004;117:4219–30.

    Article  CAS  PubMed  Google Scholar 

  29. Rigante D, Cipolla C, Basile U, Gulli F, Savastano MC. Overview of immune abnormalities in lysosomal storage disorders. Immunol Lett. 2017;188:79–85.

    Article  CAS  PubMed  Google Scholar 

  30. Neely JA, Dvorak CC, Pantell MS, Melton A, Huang JN, Shimano KA. Autoimmune cytopenias in pediatric hematopoietic cell transplant patients. Front Pediatr. 2019;7:171.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Crowther M, Chan YL, Garbett IK, Lim W, Vickers MA, Crowther MA. Evidence-based focused review of the treatment of idiopathic warm immune hemolytic anemia in adults. Blood. 2011;118:4036–40.

    Article  CAS  PubMed  Google Scholar 

  32. Hartert A, Willenbacher W, Gunzelmann S, Roemer E, Basara N, Fauser AA, et al. Successful treatment of thrombocytopenia and hemolytic anemia with IvIG in a patient with lupus-like syndrome after mismatched related PBSCT. Bone Marrow Transplant. 2001;27:337–40.

    Article  CAS  PubMed  Google Scholar 

  33. Khandelwal P, Davies SM, Grimley MS, Jordan MB, Curtis BR, Jodele S, et al. Bortezomib for refractory autoimmunity in pediatrics. Biol Blood Marrow Transplant. 2014;20:1654–9.

    Article  CAS  PubMed  Google Scholar 

  34. Mehta B, Mahadeo K, Zaw R, Tang S, Kapoor N, Abdel-Azim H. Bortezomib for effective treatment of a child with refractory autoimmune hemolytic anemia post allogeneic hematopoietic stem cell transplant. Pediatr Blood Cancer. 2014;61:2324–5.

    Article  PubMed  Google Scholar 

  35. Ratnasingam S, Walker PA, Tran H, Kaplan ZS, McFadyen JD, Tran H, et al. Bortezomib-based antibody depletion for refractory autoimmune hematological diseases. Blood Adv. 2016;1:31–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE, et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016;127:17–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. O’Connell N, Goodyer M, Gleeson M, Storey L, Williams M, Cotter M, et al. Successful treatment with rituximab and mycophenolate mofetil of refractory autoimmune hemolytic anemia post-hematopoietic stem cell transplant for dyskeratosis congenita due to TINF2 mutation. Pediatr Transplant. 2014;18:E22–4.

    Article  PubMed  Google Scholar 

  38. Bowen DA, Call TG, Shanafelt TD, Kay NE, Schwager SM, Reinalda MS, et al. Treatment of autoimmune cytopenia complicating progressive chronic lymphocytic leukemia/small lymphocytic lymphoma with rituximab, cyclophosphamide, vincristine, and prednisone. Leuk Lymphoma. 2010;51:620–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Waespe N, Zeilhofer U, Gungor T. Treatment-refractory multi-lineage autoimmune cytopenia after unrelated cord blood transplantation: remission after combined bortezomib and vincristine treatment. Pediatr Blood Cancer. 2014;61:2112–4.

    Article  CAS  PubMed  Google Scholar 

  40. Blennerhassett R, Sudini L, Gottlieb D, Bhattacharyya A. Post-allogeneic transplant Evans syndrome successfully treated with daratumumab. Br J Haematol. 2019;187:e48–51.

    Article  PubMed  Google Scholar 

  41. Even-Or E, Naser Eddin A, Shadur B, Dinur Schejter Y, Najajreh M, Zelig O, et al. Successful treatment with daratumumab for post-HSCT refractory hemolytic anemia. Pediatr Blood Cancer. 2020;67:e28010.

    Article  PubMed  Google Scholar 

  42. Schuetz C, Hoenig M, Moshous D, Weinstock C, Castelle M, Bendavid M, et al. Daratumumab in life-threatening autoimmune hemolytic anemia following hematopoietic stem cell transplantation. Blood Adv 2018;2:2550–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhai J, Ding M, Yang T, Zuo B, Weng Z, Zhao Y, et al. Flow cytometric immunobead assay for quantitative detection of platelet autoantibodies in immune thrombocytopenia patients. J Transl Med. 2017;15:214.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Zhao Y, Zhu M, Jiang M, Zuo B, Wu Q, Ruan C, et al. An improved flow cytometric immunobead array to detect autoantibodies in plasma from patients with immune thrombocytopenic purpura. Clin Chim. 2015;438:396–400.

    Article  CAS  Google Scholar 

  45. Porretti L, Farruggia P, Colombo FS, Cattaneo A, Ghilardi R, Mirra N, et al. Diagnostic value of cell bound and circulating neutrophil antibody detection in pediatric neutropenia. Pediatr Blood Cancer. 2018;65:65:e26904.

    Article  CAS  Google Scholar 

  46. Salas MQ, Alahmari A, Lipton JH. Successful treatment of refractory red cell aplasia after allogeneic hematopoietic cell transplantation with daratumumab. Eur J Haematol. 2020;104:145–7.

    Article  CAS  PubMed  Google Scholar 

  47. Pavlasova G, Mraz M. The regulation and function of CD20: an “enigma” of B-cell biology and targeted therapy. Haematologica. 2020;105:1494–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Leibler C, Thiolat A, Henique C, Samson C, Pilon C, Tamagne M, et al. Control of humoral response in renal transplantation by belatacept depends on a direct effect on B cells and impaired T follicular helper-B cell crosstalk. J Am Soc Nephrol. 2018;29:1049–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This expert consensus was based on information developed for and during a meeting supported by Magenta Therapeutics. The content of this paper is solely that of the authors. Beth Kamp, PharmD, a medical writer supported by funding from Magenta Therapeutics provided initial editorial assistance to the authors during preparation of this paper.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA

    Ashish O. Gupta, Christen L. Ebens, Troy C. Lund, Angela R. Smith, John E. Wagner, Bruce R. Blazar & Paul J. Orchard

  2. Stem Cell Transplantation and Cellular Therapy, MSK Kids, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jaap Jan Boelens

  3. Marcus Center For Cellular Cures, Duke University School of Medicine, Durham, NC, USA

    Joanne Kurtzberg

  4. Department of Blood and Marrow Transplantation, Royal Manchester Children’s Hospital, Manchester, UK

    Robert Wynn

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Contributions

AG, JB, CE, TL, PO, AS, JW, and RW provided review of the literature and contributed to the development of the content of the paper. BB provided critical input regarding pathophysiology of IMC and critical review of paper. AG wrote the paper with contributions from all authors.

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Correspondence to Ashish O. Gupta.

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This expert consensus was based on information developed for and during a meeting supported by Magenta Therapeutics and subsequent data and literature review along with discussions. The content of this paper is solely that of the authors.

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Gupta, A.O., Jan Boelens, J., Ebens, C.L. et al. Consensus opinion on immune-mediated cytopenias after hematopoietic cell transplant for inherited metabolic disorders. Bone Marrow Transplant 56, 1238–1247 (2021). https://doi.org/10.1038/s41409-020-01179-5

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