Donor leucocyte infusion
DOI:
https://doi.org/10.46765/2675-374X.2025v6n1e309Keywords:
Lymphocyte Transfusion, Graft vs Host Disease , Mesenchymal Stem CellsAbstract
Donor-derived cellular therapies play a pivotal role in optimizing outcomes after allogeneic hematopoietic stem-cell transplantation (HCT). This article reviews three key post-transplant interventions: donor lymphocyte infusion (DLI), hematopoietic stem-cell boost, and mesenchymal stromal cell (MSC) infusion. DLI remains a cornerstone strategy for enhancing graft-versus-leukemia effects, preventing or treating relapse, and promoting immune reconstitution, while also carrying risk of graft-versus-host disease. Stem-cell boosts, typically performed using CD34⁺ selected products, offer an effective approach for managing poor graft function or mixed chimerism without significantly increasing alloimmune toxicity. MSC infusion has emerged as a promising immunomodulatory therapy for steroidrefractory graft-versus-host disease and for facilitating engraftment, owing to its anti-inflammatory and tissueregenerative properties.
References
1. Pagliuca S, Schmid C, Santoro N, Simonetta F, Battipaglia G, Guillaume T, Greco R, Onida F, Sánchez Ortega I, Yakoub-Agha I, Kuball J, Hazenberg MD, Ruggeri A; Practice Harmonization and Guidelines Committee and the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Donor lymphocyte infusion after allogeneic haematopoietic cell transplantation for haematological malignancies: basic considerations and best practice recommendations from the EBMT. Lancet Haematol. 2024;11(6):e448–58. https://doi.org/10.1016/S2352-3026(24)00098-X DOI: https://doi.org/10.1016/S2352-3026(24)00098-X
2. Filicko-O’Hara J, Grosso D, Flomenberg PR, Friedman TM, Brunner J, Drobyski W, Ferber A, Kakhniashvili I, Keever- Taylor C, Mookerjee B, Talano JA, Wagner JI, Korngold R, Flomenberg N. Antiviral responses following L-leucyl-L-leucine methyl esther (LLME)-treated lymphocyte infusions: graft-versus-infection without graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15(12):1609–19. https://doi.org/10.1016/j.bbmt.2009.08.020 DOI: https://doi.org/10.1016/j.bbmt.2009.08.020
3. Ye Y, Yang L, Yuan X, Huang H, Luo Y. Optimization of donor lymphocyte infusion for aml relapse after allo-HCT in the era of new drugs and cell engineering. Front Oncol. 2021;11:790299. https://doi.org/10.3389/fonc.2021.790299 DOI: https://doi.org/10.3389/fonc.2021.790299
4. Greiner J, Götz M, Bunjes D, Hofmann S, Wais V. Immunological and clinical impact of manipulated and unmanipulated DLI after allogeneic stem cell transplantation of AML patients. J Clin Med. 2019; 9(1): 39. https://doi.org/10.3390/jcm9010039 DOI: https://doi.org/10.3390/jcm9010039
5. Schmid C, Labopin M, Schaap N, Veelken H, Brecht A, Stadler M, Finke J, Baron F, Collin M, Bug G, Ljungman P, Blaise D, Tischer J, Bloor A, Kulagin A, Giebel S, Gorin NC, Esteve J, Ciceri F, Savani B, Nagler A, Mohty M. Long-term results and GvHD after prophylactic and preemptive donor lymphocyte infusion after allogeneic stem cell transplantation for acute leukemia. Bone Marrow Transplant. 2022;57(2):215–23. https://doi.org/10.1038/s41409-021-01515-3 DOI: https://doi.org/10.1038/s41409-021-01515-3
6. Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT, Perrelli NF, Cosentino C, Torri F, Angius A, Forno B, Casucci M, Bernardi M, Peccatori J, Corti C, Bondanza A, Ferrari M, Rossini S, Roncarolo MG, Bordignon C, Bonini C, Ciceri F, Fleischhauer K. Loss of Mismatched HLA in Leukemia after Stem-Cell Transplantation. N Engl J Med. 2009;361(5):478–88. DOI: https://doi.org/10.1056/NEJMoa0811036
7. Lamure S, Paul F, Gagez AL, Delage J, Vincent L, Fegueux N, Sirvent A, Gehlkopf E, Veyrune JL, Yang LZ, Kanouni T, Cacheux V, Moreaux J, Bonafoux B, Cartron G, De Vos J, Ceballos P. A retrospective comparison of DLI and gDLI for post-transplant treatment. J Clin Med. 2020;9(7):2204. https://doi.org/10.3390/jcm9072204 DOI: https://doi.org/10.3390/jcm9072204
8. Swaminathan VV, Uppuluri R, Patel S, Sivashankaran M, Ravichandran N, Ramanan KM, Ramakrishnan B, Vaidhyanathan L, Raj R. Safety and efficacy of fresh whole blood donor lymphocyte infusion in children. Bone Marrow Transplant. 2019;54(11):1892–7. https://doi.org/10.1038/s41409-019-0580-7 DOI: https://doi.org/10.1038/s41409-019-0580-7
9. Velázquez GF, Weller JF, Rubeck A, Arndt T, Schiele S, Mezger M, et al. Prophylactic and pre-emptive donor lymphocyte infusion in patients with acute myeloid leukemia and myelodysplastic syndrome: validation of current recommendations and proposal of a modified outcome assessment. Haematologica. 2025;110(10):2293–304. https://doi.org/10.3324/haematol.2024.287206 DOI: https://doi.org/10.3324/haematol.2024.287206
10. Wu N, Yan CH, Kong J, Lv M, Mo XD, Sun YQ, Cheng YF, Xu LP, Zhang XH, Huang XJ, Wang Y. Prophylactic versus preemptive donor lymphocyte infusion in refractory/relapsed AML post-allogeneic transplant: a retrospective comparative study. Transplant Cell Ther. 2025:S2666-6367(25)01532-5. https://doi.org/10.1016/j.jtct.2025.10.029 DOI: https://doi.org/10.1016/j.jtct.2025.10.029
11. Stadler M, Hambach L, Dammann E, Diedrich H, Kamal H, Hamwi I, Schultze-Florey C, Varvenne M, Ehrlich S, Buchholz S, Koenecke C, Beutel G, Weissinger EM, Krauter J, Eder M, Hertenstein B, Ganser A. The graft-versus-leukemia effect of prophylactic donor lymphocyte infusions after allogeneic stem cell transplantation is equally effective in relapse prevention but safer compared to spontaneous graft-versushost disease. Ann Hematol. 2023;102(9):2529–42. https://doi.org/10.1007/s00277-023-05276-5 DOI: https://doi.org/10.1007/s00277-023-05276-5
12. Santoro N, Schmid C, de Witte M, Roeven MWH, Potter V, Richardson D, Schroeder T, Válková V, Clesham K, Loron S, Passweg J, Besley C, Gruhn B, Hoogenboom JD, Mooyaart JE, Sanchez-Ortega I, Pagliuca S, Simonetta F, Battipaglia G, Guillaume T, Hazenberg MD, Malard F, Kuball J, Ruggeri A. Current use of donor lymphocyte infusions after allogenic stem cell transplantation in Europe: a survey on behalf of the cellular therapy and immunobiology working party of the EBMT. Bone Marrow Transplant. 2025;60(5):697–701. https://doi.org/10.1038/s41409-025-02555-9 DOI: https://doi.org/10.1038/s41409-025-02555-9
13. De Jong G, Gillissen MA, Spits H, Hazenberg MD. Tumour-reactive B cells and antibody responses after allogeneic haematopoietic cell transplantation. Immunooncol Technol. 2020;7:15–22. https://doi.org/10.1016/j.iotech.2020.07.002 DOI: https://doi.org/10.1016/j.iotech.2020.07.002
14. Gillissen MA, de Jong G, Levie SE, Yasuda E, Bakker AQ, Evers LM, Pals ST, Huisman C, van Helden PM, Spits H, Hazenberg MD. AML relapse after rituximab treatment for GvHD: crucial role for B cells in GvL responses. Bone Marrow Transplant. 2016;51(9):1245–8. https://doi.org/10.1038/bmt.2016.9 DOI: https://doi.org/10.1038/bmt.2016.90
15. Marjańska A, Pogorzała M, Dziedzic M, Czyżewski K, Richert-Przygońska M, Dębski R, Bogiel T, Styczyński J. Impact of prophylaxis with rituximab on EBV-related complications after allogeneic hematopoietic cell transplantation in children. Front Immunol. 2024;15:1427637. https://doi.org/10.3389/fimmu.2024.1427637 DOI: https://doi.org/10.3389/fimmu.2024.1427637
16. Niederwieser D, Baldomero H, Bazuaye N, Bupp C, Chaudhri N, Corbacioglu S, Elhaddad A, Frutos C, Galeano S, Hamad N, Hamidieh AA, Hashmi S, Ho A, Horowitz MM, Iida M, Jaimovich G, Karduss A, Kodera Y, Kröger N, Péffault de Latour R, Lee JW, Martínez-Rolón J, Pasquini MC, Passweg J, Paulson K, Seber A, Snowden JA, Srivastava A, Szer J, Weisdorf D, Worel N, Koh MBC, Aljurf M, Greinix H, Atsuta Y, Saber W. One and a half million hematopoietic stem cell transplants: continuous and differential improvement in worldwide access with the use of non-identical family donors. Haematologica. 2022;107(5):1045–53. https://doi.org/10.3324/haematol.2021.279189 DOI: https://doi.org/10.3324/haematol.2021.279189
17. Jaiswal SR, Zaman S, Chakrabarti A, Sen S, Mukherjee S, Bhargava S, Ray K, O’Donnell PV, Chakrabarti S. Improved outcome of refractory/relapsed acute myeloid leukemia after post-transplantation cyclophosphamide-based haploidentical transplantation with myeloablative conditioning and early prophylactic granulocyte colony-stimulating factor–mobilized donor lymphocyte infusions. Biol Blood Marrow Transplant. 2016;22(10):1867–73. https://doi.org/10.1016/j.bbmt.2016.07.016 DOI: https://doi.org/10.1016/j.bbmt.2016.07.016
18. Kirkham AM, Bailey AJM, Masurekar A, Shorr R, Bredeson C, Sabloff M, Allan DS. Can GCSF-stimulated donor lymphocyte infusions improve outcomes for relapsed disease following allogeneic hematopoietic cell transplantation? A systematic review and meta-analysis. Leuk Lymphoma. 2022;63(14):3276–87. https://doi.org/10.1080/10428194.2022.2118530 DOI: https://doi.org/10.1080/10428194.2022.2118530
19. Patriarca F, Sperotto A, Lorentino F, Oldani E, Mammoliti S, Isola M, Picardi A, Arcese W, Saporiti G, Sorasio R, Mordini N, Cavattoni I, Musso M, Borghero C, Micò C, Fanin R, Bruno B, Ciceri F, Bonifazi F. Donor lymphocyte infusions after allogeneic stem cell transplantation in acute leukemia: a survey from the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Front Oncol. 2020;10:572918. https://doi.org/10.3389/fonc.2020.572918 DOI: https://doi.org/10.3389/fonc.2020.572918
20. Schmid C, Labopin M, Schaap N, Veelken H, Schleuning M, Stadler M, Finke J, Hurst E, Baron F, Ringden O, Bug G, Blaise D, Tischer J, Bloor A, Esteve J, Giebel S, Savani B, Gorin NC, Ciceri F, Mohty M, Nagler A; EBMT Acute Leukaemia Working Party. Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation in acute leukaemia - a matched pair analysis by the Acute Leukaemia Working Party of EBMT. Br J Haematol. 2019;184(5):782–7. https://doi.org/10.1111/bjh.15691 DOI: https://doi.org/10.1111/bjh.15691
21. Maurer K, Antin JH. The graft versus leukemia effect: donor lymphocyte infusions and cellular therapy. Front Immunol. 2024;15:1328858. https://doi.org/10.3389/fimmu.2024.1328858 DOI: https://doi.org/10.3389/fimmu.2024.1328858
22. Booth N, Mirea L, Huschart E, Miller H, Salzberg D, Campbell C, Beebe K, Schwalbach C, Adams RH, Ngwube A. Efficacy of azacitidine and prophylactic donor lymphocyte infusion after HCT in pediatric patients with acute myelogenous leukemia: a retrospective pre-post study. Transplant Cell Ther. 2023;29(5):330.e1–e7. https://doi.org/10.1016/j.jtct.2023.02.009 DOI: https://doi.org/10.1016/j.jtct.2023.02.009
23. Huschart E, Miller H, Salzberg D, Campbell C, Beebe K, Schwalbach C, Magee K, Adams RH, Ngwube A. Azacitidine and prophylactic donor lymphocyte infusions after hematopoietic stem cell transplantation for pediatric high-risk acute myeloid leukemia. Pediatr Hematol Oncol. 2021;38(2):154–60. https://doi.org/10.1080/08880018.2020.1829220 DOI: https://doi.org/10.1080/08880018.2020.1829220
24. Suryaprakash S, Sun Y, Tang L, Keerthi D, Qudeimat A, Talleur AC, Mamcarz E, Srinivasan A, Madden R, Epperly R, Naik S, Gottschalk S, Triplett BM, Sharma A. Risk-adapted donor lymphocyte infusion after hematopoietic cell transplant in pediatric and young adult patients is associated with low risk of graft versus host disease. Transplant Cell Ther. 2024;30(2 Suppl.):S401. https://doi.org/10.1016/j.jtct.2023.12.564 DOI: https://doi.org/10.1016/j.jtct.2023.12.564
25. Tavares R, Pelegrina P. Prevention and management of relapse of acute leukemia and myelodysplastic syndrome after allogeneic hematopoietic cell transplantation in pediatric patients. J Bone Marrow Transpl Cell Ther. 2021;2(4):131. https://doi.org/10.46765/2675-374X.2021v2n4p131 DOI: https://doi.org/10.46765/2675-374X.2021v2n4p131
26. Bowman S, Stanek J, Bajwa R, Polishchuk V, Abu-Arja R, Rangarajan HG. CD34 stem cell boost in pediatric allogeneic stem cell transplant recipients: a case series and review of literature. Clin Hematol Int. 2023;5(2–3): 155–64. https://doi.org/10.1007/s44228-023-00042-w DOI: https://doi.org/10.1007/s44228-023-00042-w
27. Gaffet M, Wiedemann A, Dalle JH, Bilger K, Forcade E, Robin M, Cornillon J, Labussière-Wallet H, Ceballos P, Bulabois CE, Loschi M, Orvain C, Rubio MT, Neven B, Pagliuca S, Pochon C. Efficacy of haematopoietic stem cell boost as a rescue for poor graft function after haematopoietic stem cell transplantation: A multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). Br J Haematol. 2023;201(6):1153–8. https://doi.org/10.1111/bjh.18744 DOI: https://doi.org/10.1111/bjh.18744
28. Chandra S, Bleesing JJ, Jordan MB, Grimley MS, Khandelwal P, Davies SM, Edwards S, Leemhuis T, Marsh RA. Post-transplant CD34+ selected stem cell “boost” for mixed chimerism after reduced-intensity conditioning hematopoietic stem cell transplantation in children and young adults with primary immune deficiencies. Biol Blood Marrow Transplant. 2018;24(7):1527–9. https://doi.org/10.1016/j.bbmt.2018.03.013 DOI: https://doi.org/10.1016/j.bbmt.2018.03.013
29. Mainardi C, Ebinger M, Enkel S, Feuchtinger T, Teltschik HM, Eyrich M, Schumm M, Rabsteyn A, Schlegel P, Seitz C, Schwarze CP, Müller I, Greil J, Bader P, Schlegel PG, Martin D, Holzer U, Döring M, Handgretinger R, Lang P. CD34+ selected stem cell boosts can improve poor graft function after paediatric allogeneic stem cell transplantation. Br J Haematol. 2018;180(1):90–9. https://doi.org/10.1111/bjh.15012 DOI: https://doi.org/10.1111/bjh.15012
30. Shahzad M, Siddiqui RS, Anwar I, Chaudhary SG, Ali T, Naseem M, Ahmed TF, Ahmed Z, Khurana S, Ahmed N, Balusu R, Singh AK, Hematti P, Callander NS, Abhyankar SH, McGuirk JP, Mushtaq MU. Outcomes with CD34-selected stem cell boost for poor graft function after allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis. Transplant Cell Ther. 2021; 27(10): 877. e1–e8. https://doi.org/10.1016/j.jtct.2021.07.012 DOI: https://doi.org/10.1016/j.jtct.2021.07.012
31. Nampoothiri RV, Ho L, McEwan C, Pasic I, Lam W, Law AD, Michelis FV, Thyagu S, Kim DDH, Gerbitz A, Viswabandya A, Lipton JH, Mattsson J, Kumar R. Efficacy and cost analysis of eltrombopag in thrombocytopenia and poor graft function post allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2021;56(10):2471–6. https://doi.org/10.1038/s41409-021-01362-2 DOI: https://doi.org/10.1038/s41409-021-01362-2
32. Ghobadi A, Fiala MA, Ramsingh G, Gao F, Abboud CN, Stockerl-Goldstein K, Uy GL, Grossman BJ, Westervelt P, Di Persio JF. Fresh or cryopreserved CD34+-selected mobilized peripheral blood stem and progenitor cells for the treatment of poor graft function following allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2017;23(7):1072–7. https://doi.org/10.1016/j.bbmt.2017.03.019 DOI: https://doi.org/10.1016/j.bbmt.2017.03.019
33. Larocca A, Piaggio G, Podestà M, Pitto A, Bruno B, Di Grazia C, Gualandi F, Occhini D, Raiola AM, Dominietto A, Bregante S, Lamparelli T, Tedone E, Oneto R, Frassoni F, Van Lint MT, Pogliani E, Bacigalupo A. Boost of CD34+-selected peripheral blood cells without further conditioning in patients with poor graft function following allogeneic stem cell transplantation. Haematologica. 2006;91(7):935–40.
34. Shapiro RM, Kim HT, Dulery R, Liney D, Garrity HM, Panaro K, Au C, Gervais C, Little JS, Ho VT, Cutler CS, Koreth J, Gooptu M, Antin JH, Kelkar AH, Romee R, Wu CJ, Ritz J, Soiffer RJ, Nikiforow S. Active infection at the time of CD34+ selected stem cell boost is associated with treatment failure and poor overall survival. Blood Adv. 2024;8(17):4729–37. https://doi.org/10.1182/bloodadvances.2023012418 DOI: https://doi.org/10.1182/bloodadvances.2023012418
35. Davis JA, Sborov DW, Wesson W, Julian K, Abdallah AO, McGuirk JP, Ahmed N, Hashmi H. Efficacy and safety of CD34+ stem cell boost for delayed hematopoietic recovery after BCMA directed CAR T-cell therapy. Transplant Cell Ther. 2023;29(9):567–71. https://doi.org/10.1016/j.jtct.2023.05.012 DOI: https://doi.org/10.1016/j.jtct.2023.05.012
36. De Santis GC, de Macedo LD, Orellana MD, Innocentini LMAR, Ferrari TC, Ricz HMA, Caruso SR, Fernandes TR, Covas DT. Mesenchymal stromal cells administration for osteonecrosis of the jaw caused by bisphosphonate: report of two cases. Acta Oncol. 2020;59(7):789–92. https://doi.org/10.1080/0284186x.2020.1730004 DOI: https://doi.org/10.1080/0284186X.2020.1730004
37. Nachmias B, Zimran E, Avni B. Mesenchymal stroma/stem cells: Haematologists’ friend or foe? Br J Haematol. 2022;199(2):175–89. https://doi.org/10.1111/bjh.18292 DOI: https://doi.org/10.1111/bjh.18292
38. Xu G, Zhang L, Ren G, Yuan Z, Zhang Y, Zhao RC, Shi Y. Immunosuppressive properties of cloned bone marrow mesenchymal stem cells. Cell Res. 2007;17(3):240–8. https://doi.org/10.1038/cr.2007.4 DOI: https://doi.org/10.1038/cr.2007.4
39. Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, Litzow MR, Nieto Y, Savani BN, Schriber JR, Shaughnessy PJ, Wall DA, Carpenter PA. First- and second-line systemic treatment of acute graft versus host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2012;18(8):1150–63. https://doi.org/10.1016/j.bbmt.2012.04.005 DOI: https://doi.org/10.1016/j.bbmt.2012.04.005
40. Donadel CD, Pires BG, André NC, Costa TCM, Orellana MD, Caruso SR, Seber A, Ginani VC, Gomes AA, Novis Y, Barros GMN, Vilella NC, Martinho GH, Vieira AK, Kondo AT, Hamerschlak N, Filho JS, Xavier EM, Fernandes JF, Rocha V, Covas DT, Calado RT, Guerino-Cunha RL, De Santis GC. Umbilical cord mesenchymal stromal cells for steroid-refractory acute graft-versus-host disease. Pharmaceuticals. 2023; 16(4): 512. https://doi.org/10.3390/ph16040512 DOI: https://doi.org/10.3390/ph16040512
41. Dotoli GM, De Santis GC, Orellana MD, de Lima Prata K, Caruso SR, Fernandes TR, Rensi Colturato VA, Kondo AT, Hamerschlak N, Simões BP, Covas DT. Mesenchymal stromal cell infusion to treat steroid-refractory acute GvHD III/IV after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2017;52(6):859–62. https://doi.org/10.1038/bmt.2017.35 DOI: https://doi.org/10.1038/bmt.2017.35
42. Kurtzberg J, Abdel-Azim H, Carpenter P, Chaudhury S, Horn B, Mahadeo K, Nemecek E, Neudorf S, Prasad V, Prockop S, Quigg T, Satwani P, Cheng A, Burke E, Hayes J, Skerrett D; MSB-GVHD001/002 Study Group. A phase 3, single-arm, prospective study of remestemcel-L, ex vivo culture-expanded adult human mesenchymal stromal cells for the treatment of pediatric patients who failed to respond to steroid treatment for acute graft-versus-host disease. Biol Blood Marrow Transplant. 2020;26(5):845–54. https://doi.org/10.1016/j.bbmt.2020.01.018 DOI: https://doi.org/10.1016/j.bbmt.2020.01.018
43. Penack O, Marchetti M, Aljurf M, Arat M, Bonifazi F, Duarte RF, Giebel S, Greinix H, Hazenberg MD, Kröger N, Mielke S, Mohty M, Nagler A, Passweg J, Patriarca F, Ruutu T, Schoemans H, Solano C, Vrhovac R, Wolff D, Zeiser R, Sureda A, Peric Z. Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2024;11(2):e147–59. https://doi.org/10.1016/s2352-3026(23)00342-3 DOI: https://doi.org/10.1016/S2352-3026(23)00342-3
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Adriana Martins de Sousa, Rita de Cassia Barbosa Tavares, Gil Cunha De Santis, Adriana Seber
This work is licensed under a Creative Commons Attribution 4.0 International License.
