Haploidentical hematopoietic-cell transplantation using post-transplant cyclophosphamide(Haplo-PTCy) is a feasible procedure in children with haematologic malignancies. However, data of a large series of children with acute leukaemia(AL) in this setting is missing. We analysed 144 AL Haplo-PTCy paediatric recipients; median age was 10 years. Patients had acute lymphoblastic(ALL; n = 86) or myeloblastic leukaemia(AML; n = 58) and were transplanted in remission(CR1: n = 40; CR2: n = 57; CR3+: n = 27) or relapse (n = 20). Bone marrow was the graft source in 57%; donors were father (54%), mother (35%), or sibling (11%). Myeloablative conditioning was used in 87%. Median follow-up was 31 months. At day +100, cumulative incidence (CI) of neutrophil recovery and acute GVHD (II–IV) were 94% and 40%, respectively. At 2-years, CI of chronic GVHD and relapse, were 31%, 40%, and estimated 2-year overall survival (OS), leukaemia-free survival (LFS) and graft-versus-host-relapse-free survival (GRFS) were 52%, 44% and 34% respectively. For patients transplanted in remission, positive measurable residual disease (MRD) prior to transplant was associated with decreased LFS (p = 0.05) and GRFS (p = 0.003) and increased risk of relapse (p = 0.02). Mother donor was associated with increased risk of chronic GVHD (p = 0.001), decreased OS (p = 0.03) and GRFS (p = 0.004). Use of PBSC was associated with increased risk of chronic GVHD (p = 0.04). In conclusion, achieving MRD negativity pre-transplant, avoiding use of mother donors and PBSC as graft source may improve outcomes of Haplo-PTCy in children with AL.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
D’Souza A, Lee S, Zhu X, Pasquini M. Current Use and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant. 2017;23:1417–21. https://doi.org/10.1016/j.bbmt.2017.05.035.
Khandelwal P, Millard HR, Thiel E, Abdel-Azim H, Abraham AA, Auletta JJ, et al. Hematopoietic Stem Cell Transplantation Activity in Pediatric Cancer between 2008 and 2014 in the United States: A Center for International Blood and Marrow Transplant Research Report. Biol Blood Marrow Transplant. 2017;23:1342–9. https://doi.org/10.1016/j.bbmt.2017.04.018.
Duval M, Klein JP, He W, Cahn J-Y, Cairo M, Camitta BM, et al. Hematopoietic Stem-Cell Transplantation for Acute Leukemia in Relapse or Primary Induction Failure. J Clin Oncol. 2010;28:3730–8. https://doi.org/10.1200/JCO.2010.28.8852.
Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R, et al. HLA Match Likelihoods for Hematopoietic Stem-Cell Grafts in the U.S. Registry. N Engl J Med. 2014;371:339–48. https://doi.org/10.1056/NEJMsa1311707.
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. https://doi.org/10.1200/JCO.2014.58.9747.
Page KM, Labopin M, Ruggeri A, Michel G, Diaz de Heredia C, O’Brien T, et al. Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission. Biol Blood Marrow Transplant. 2017;23:1350–8. https://doi.org/10.1016/j.bbmt.2017.04.015.
Bertaina A, Zecca M, Buldini B, Sacchi N, Algeri M, Saglio F, et al. Unrelated donor vs HLA-haploidentical α/β T-cell– and B-cell–depleted HSCT in children with acute leukemia. Blood. 2018;132:2594–607. https://doi.org/10.1182/blood-2018-07-861575.
Pérez‐Martínez A, Ferreras C, Pascual A, Gonzalez‐Vicent M, Alonso L, Badell I, et al. Haploidentical transplantation in high‐risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH). Am J Hematol. 2020;95:28–37. https://doi.org/10.1002/ajh.25661.
Kanakry CG, Fuchs EJ, Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation. Nat Rev Clin Oncol. 2016;13:10–24. https://doi.org/10.1038/nrclinonc.2015.128.
Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–50.
Klein OR, Buddenbaum J, Tucker N, Chen AR, Gamper CJ, Loeb D, et al. Nonmyeloablative haploidentical bone marrow transplantation with post-transplantation cyclophosphamide for pediatric and young adult patients with high-risk hematologic malignancies. Biol Blood Marrow Transplant. 2017;23:325–32. https://doi.org/10.1016/j.bbmt.2016.11.016.
Symons HJ, Zahurak M, Cao Y, Chen A, Cooke K, Gamper C, et al. Myeloablative haploidentical BMT with posttransplant cyclophosphamide for hematologic malignancies in children and adults. Blood Adv. 2020;4:3913–25. https://doi.org/10.1182/bloodadvances.2020001648.
Berger M, Lanino E, Cesaro S, Zecca M, Vassallo E, Faraci M, et al. Feasibility and Outcome of Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant High-Dose Cyclophosphamide for Children and Adolescents with Hematologic Malignancies: An AIEOP-GITMO Retrospective Multicenter Study. Biol Blood Marrow Transplant. 2016;22:902–9. https://doi.org/10.1016/j.bbmt.2016.02.002
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. https://doi.org/10.1016/j.bbmt.2009.07.004.
Vigorito AC, Bouzas LF, da S, Moreira MCR, Funke VAM, Colturato VAR, et al. A multicenter feasibility study of chronic graft-versus-host disease according to the National Institute of Health criteria. Rev Bras Hematol Hemoter. 2011;33:283–9. https://doi.org/10.5581/1516-8484.20110078.
Campregher PV, Hamerschlak N, Colturato VAR, Mauad MA, de Souza MP, Bouzas LF, 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;95:421–5. https://doi.org/10.1111/ejh.12508.
Holtan SG, DeFor TE, Lazaryan A, Bejanyan N, Arora M, Brunstein CG, et al. Composite endpoint of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood. 2015;125:1333–9. https://doi.org/10.1182/blood-2014-10-609032.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, 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. Biol Blood Marrow Transplant. 2015;21:389–401. https://doi.org/10.1016/j.bbmt.2014.12.001
Bader P, Niethammer D, Willasch A, Kreyenberg H, Klingebiel T. How and when should we monitor chimerism after allogeneic stem cell transplantation?. Bone Marrow Transplant. 2005;35:107–19. https://doi.org/10.1038/sj.bmt.1704715.
Schuurhuis GJ, Heuser M, Freeman S, Béne MC, Buccisano F, Cloos J, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131:1275–91.
Borowitz MJ, Wood BL, Devidas M, Loh ML, Raetz EA, Salzer WL, et al. Prognostic significance of minimal residual disease in high risk B-ALL: A report from Children’s Oncology Group study AALL0232. Blood. 2015;126:964–71.
Ikoma-Colturato MRV, Beltrame MP, Furtado FM, Pimenta G, da Costa ES, Azambuja AP, et al. Minimal residual disease assessment in acute lymphoblastic leukemia by 4-color flow cytometry: Recommendations from the MRD Working Group of the Brazilian Society of Bone Marrow Transplantation. Hematol Transfus Cell Ther. 2020. https://linkinghub.elsevier.com/retrieve/pii/S253113792031289X.
Brodsky RA, Luznik L, Bolaños-Meade J, Leffell MS, Jones RJ, Fuchs EJ. Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone Marrow Transplant. 2008;42:523–7.
D’Souza A, Fretham C, Lee SJ, Arora M, Brunner J, Chhabra S, et al. Current Use of and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant. 2020;26:e177–82. https://doi.org/10.1016/j.bbmt.2017.05.035.
Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126:1033–40.
Kanate AS, Mussetti A, Kharfan-Dabaja MA, Ahn KW, Digilio A, Beitinjaneh A, et al. Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors. Blood. 2016;127:938–47.
Pérez-Martínez A, Ferreras C, Pascual A, Gonzalez-Vicent M, Alonso L, Badell I, et al. Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH). Am J Hematol. 2020;95:28–37.
Wawrzyniak-Dzierzek E, Gajek K, Slezak A, Rybka B, Ryczan-Krawczyk R, Gorczynska E, et al. Pediatric unmanipulated haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide and reduced intensity, TBI-free conditioning regimens in salvage transplantations. Adv Clin Exp Med. 2019;28:1223–8.
Medina D, Estacio M, Rosales M, Manzi E. Haploidentical stem cell transplant with post-transplantation cyclophosphamide and mini-dose methotrexate in children. Hematol Oncol Stem Cell Ther. 2020;13:208–13. https://doi.org/10.1016/j.hemonc.2020.01.003.
Bashey A, Zhang MJ, McCurdy SR, St Martin A, Argall T, Anasetti C, et al. Mobilized peripheral blood stem cells versus unstimulated bone marrow as a graft source for T-cell–replete haploidentical donor transplantation using post-transplant cyclophosphamide. J Clin Oncol. 2017;35:3002–9. https://doi.org/10.1200/JCO.2017.72.8428
Ruggeri A, Labopin M, Bacigalupo A, Gülbas Z, Koc Y, Blaise D, et al. Bone marrow versus mobilized peripheral blood stem cells in haploidentical transplants using posttransplantation cyclophosphamide. Cancer. 2018;124:1428–37. https://doi.org/10.1002/cncr.31228.
Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017. http://www.nejm.org/10.1056/NEJMoa1706640.
Lovisa F, Zecca M, Rossi B, Campeggio M, Magrin E, Giarin E, et al. Pre- and post-transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia. Br J Haematol. 2018;180:680–93. https://doi.org/10.1111/bjh.15086.
Mariotti J, Raiola AM, Evangelista A, Carella AM, Martino M, Patriarca F, et al. Impact of donor age and kinship on clinical outcomes after T-cell–replete haploidentical transplantation with PT-Cy. Blood Adv. 2020;4:3900–12. https://doi.org/10.1182/bloodadvances.2020001620.
Popli R, Sahaf B, Nakasone H, Lee JYY, Miklos DB. Clinical impact of H-Y alloimmunity. Immunol Res. 2014;58:249–58. https://doi.org/10.1007/s12026-014-8514-3.
Kasamon YL, Luznik L, Leffell MS, Kowalski J, Tsai H-L, Bolaños-Meade J, et al. Nonmyeloablative HLA-Haploidentical Bone Marrow Transplantation with High-Dose Posttransplantation Cyclophosphamide: Effect of HLA Disparity on Outcome. Biol Blood Marrow Transplant. 2010;16:482–9. https://doi.org/10.1016/j.bbmt.2009.11.011.
Wang Y, Chang YJ, Xu LP, Liu KY, Liu DH, Zhang XH, et al. Who is the best donor for a related HLA haplotype-mismatched transplant? Blood. 2014;124:843–50.
Stern M, Brand R, de Witte T, Sureda A, Rocha V, Passweg J, et al. Female-versus-male alloreactivity as a model for minor histocompatibility antigens in hematopoietic stem cell transplantation. Am J Transplant. 2008;8:2149–57. https://doi.org/10.1111/j.1600-6143.2008.02374.x.
We thank Dr. Giancarlo Fatobene for editing and revising the final version of the manuscript and Dr. Maura Ikoma-Colturato for the definitions of measurable residual disease in this study.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Rocha, V., Arcuri, L.J., Seber, A. et al. Impact of mother donor, peripheral blood stem cells and measurable residual disease on outcomes after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide in children with acute leukaemia. Bone Marrow Transplant (2021). https://doi.org/10.1038/s41409-021-01453-0