Abstract
This retrospective registry-based study investigated the role of acute GvHD in the largest reported pediatric population with acute lymphoblastic leukemia (ALL) undergoing allogeneic stem cell transplantation (HSCT). The study included 3328 children. Median age was 9.6 years (IQR 6–13.9 and range 0.4–18). Forty-nine percent were transplanted from an MSD, 37% from MUD, 14% from MMUD; 68% received a TBI-based conditioning. CSA alone or in combination with methotrexate/MMF was administered as GVHD prophylaxis in 94%. The 100-day cumulative incidence of grade II–IV acute GVHD (aGVHD) was 35% (95% CI: 34–37), while that of grade III–IV was 11% (95% CI: 10–12). Two-year cumulative incidence of chronic GVHD (cGVHD) was 17% (95% CI: 15–18)/extensive cGVHD 8% (95% CI: 7–9). With a median follow-up of 3.1 years, OS, leukemia-free survival (LFS), and GVHD-free/relapse-free survival were 74% (95% CI 72–76), 65% (95% CI 64–67) and 51% (95% CI 49–53), respectively. Using multivariable Cox models in 100-day landmark analysis, any degree of aGVHD was associated with reduced risk of relapse; grade III–IV significantly increased NRM and reduced OS; grade II aGVHD offers the best chances of achieving prolonged LFS (HR = 0.78 (0.64–0.94), p = 0.008). Overall, these data confirm that grade II aGvHD prevents the occurrence of leukaemia relapse without causing unacceptable mortality.
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References
Khoury HJ, Wang T, Hemmer MT, Couriel D, Alousi A, Cutler C, et al. Improved survival after acute graft-versus-host disease diagnosis in the modern era. Haematologica. 2017;102:958–66.
Negrin RS. Graft-versus-host disease versus graft-versus-leukemia. Hematol Am Soc Hematol Educ Program. 2015;2015:225–30.
Kato M, Kurata M, Kanda J, Kato K, Tomizawa D, Kudo K, et al. Impact of graft-versus-host disease on relapse and survival after allogeneic stem cell transplantation for pediatric leukaemia. Bone Marrow Transpl. 2019;54:68–75.
Weiden PL, Flournoy N, Thomas ED. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic marrow grafts. N Engl J Med. 1979;300:1068–73.
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. Leukaemia. 2017;31:663–8.
Yeshurun M, Weisdorf D, Rowe JM, Tallman MS, Zhang MJ, Wang HL, et al. The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia. Blood Adv. 2019;3:670–80.
Peters C, Dalle JH, Locatelli F, Poetschger U, Sedlacek P, Buechner J, et al. Total body irradiation or chemotherapy conditioning in childhood ALL: a multinational, randomized, noninferiority phase III study. J Clin Oncol. 2021;39:295–307.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation. 1974;18:295–304.
Lee S, Vogelsang G, Flowers M. Chronic graft versus host disease. Biol Blood Marrow Transpl. 2003;9:215–33.
Ruggeri A, Labopin M, Ciceri F, Mohty M, Nagler A. Definition of GvHD-free, relapse-free survival for registry-based studies: an ALWP-EBMT analysis on patients with AML in remission. Bone Marrow Transpl. 2016;51:610–1.
Iacobelli S. Suggestions on the use of statistical methodologies in studies of the European Group for Blood and Marrow Transplantation. Bone Marrow Transpl. 2013;43:S1–37.
Cox DR (1972). ‘Regression Models and Life-Tables’. J R Stat Soc B (Methodol) 34:187–220.
Biard L, Labopin M, Chevret S, Resche-Rigon M. Investigating covariate-by-centre interaction in survival data. Stat Methods Med Res. 2018;27:920–32.
Pulsipher MA, Carlson C, Langholz B, Wall DA, Schultz KR, Bunin N, et al. IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients. Blood. 2015;125:3501–8.
Hunger SP, Raetz EA. How I treat relapsed acute lymphoblastic leukemia in the pediatric population. Blood. 2020;136:1803–12.
Díaz de Heredia C, González M, Verdeguer A, Elorza I, Rodríguez A, Martínez A, et al. Long-term outcome and prognostic factors of unrelated cord blood transplantation in children with haematological malignancies: a retrospective study using the Spanish Working Party for BMT in Children (GETMON) database. Bone Marrow Transpl. 2014;49:767–72.
Iori AP, Arcese W, Milano F, Calabrese E, Torelli GF, Barberi W, et al. Unrelated cord blood transplant in children with high-risk acute lymphoblastic leukemia: a long-term follow-up. Haematologica. 2007;92:1051–8.
Ohnuma K, Isoyama K, Ikuta K, Toyoda Y, Nakamura J, Nakajima F, et al. Cord blood transplantation from HLA-mismatched unrelated donors as a treatment for children with haematological malignancies. Br J Haematol. 2001;112:981–7.
Bertaina A, Bernardo MA, Caniglia A, Vinti L, Giorgiani G, Locatelli F. Cord blood transplantation in children with heamatological malignancies. Best Pr Res Clin Haematol. 2010;23:189–96.
Chang YJ, Wu DP, Lai YR, Liu QF, Sun YQ, Hu J, et al. Antithymocyte globulin for matched sibling donor transplantation in patients with hematologic malignancies: a multicenter, open-label, randomized controlled study. J Clin Oncol. 2020;38:3367–76.
Finke J, Schmoor C, Bethge WA, Ottinger H, Stelljes M, Volin L, et al. Long-term outcomes after standard graft-versus-host disease prophylaxis with or without anti-human-T-lymphocyte immunoglobulin in haemopoietic cell transplantation from matched unrelated donors: final results of a randomised controlled trial. Lancet Haematol. 2017;4:e293–e301.
Locatelli F, Bernardo ME, Bertaina A, Rognoni C, Comoli P, Rovelli A, et al. Efficacy of two different doses of rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in children with haematological malignancies transplanted from an unrelated donor: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:1126–36.
Peters C, Cornish JM, Parikh SH, Kurtzberg J. Stem cell source and outcome after hematopoietic stem cell transplantation (HSCT) in children and adolescents with acute leukemia. Pediatr Clin North Am. 2010;57:27–46.
Akahoshi Y, Igarashi A, Fukuda T, Uchida N, Tanaka M, Ozawa Y, et al. Impact of graft-versus-host disease and graft-versus-leukemia effect based on minimal residual disease in Philadelphia chromosome-positive acute lymphoblastic leukemia. Br J Haematol. 2020;190:84–92.
Balduzzi A, Dalle JH, Wachowiak J, Yaniv I, Yesilipek A, Sedlacek P, et al. Transplantation in children and adolescents with acute lymphoblastic leukemia from a matched donor versus an HLA-identical sibling: is the outcome comparable? Results from the International BFM ALL SCT 2007 Study. Biol Blood Marrow Transpl. 2019;25:2197–210.
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The corresponding author confirms that she has had full access to the data in the study and final responsibility for the decision to submit for publication. AB, SC, PB, and JEG conceived and designed the study. AD and JEG acquired and controlled the consistency of the relevant data. ZS, AB, SC, PB, MI, and JHD played an important role in interpreting the results. GL, ZS, AB, JEG, and KK drafted the manuscript. ZS, KK, FL, MT, OMD, PS, IG, JS, VKR, AT, FF, YB, PB, and SC reviewed and approved the final version of the manuscript
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Szmit, Z., Lucchini, G., Bertaina, A. et al. Impact of acute GvHD severity on survival and disease relapse in pediatric patients undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia: an analysis based on the EBMT-PDWP registry. Bone Marrow Transplant (2026). https://doi.org/10.1038/s41409-026-02797-1
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DOI: https://doi.org/10.1038/s41409-026-02797-1