Advances in Clinical and Experimental Medicine
2019, vol. 28, nr 9, September, p. 1223–1228
Publication type: original article
Pediatric unmanipulated haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide and reduced intensity, TBI-free conditioning regimens in salvage transplantations
1 Department of Pediatric Bone Marrow Transplantation, Oncology and Hematology, Wroclaw Medical University, Poland
Background. Unmanipulated haploidentical stem cell transplantation (haploSCT) with post-transplant cyclophosphamide is an option for patients with advanced hematologic malignancies. It offers a platform both for non-major histocompatibility complex-restricted alloimmunity due to killer-like immunoglobulin receptor (KIR)-mediated mechanisms of natural killer lymphocyte regulation and for classical T-cell mediated antileukemic effects.
Objectives. The devastating long-term sequelae after total body irradiation (TBI) in children are encouraging omission of irradiation techniques in pediatric stem cell transplantations (SCT).
Material and Methods. Five children, 4 with acute leukemia and 1 with hemophagocytic lymphohistiocytosis, aged from 1 to 10 years, underwent haploSCT with post-transplantation cyclophosphamide. In all children, the conditioning regimen consisted of chemotherapy without TBI. The graft material was bone marrow (BM) in 4 cases and peripheral blood stem cells in 1 case. Three out of 5 leukemic patients showed better KIR haplotype associated with augmented alloreactivity.
Results. Engraftment with complete donor chimerism was achieved in 4 patients, and 1 recipient died before leukocyte recovery. Three patients developed skin acute graft-versus-host-disease (aGvHD), 1 gut aGvHD and 1 liver aGvHD. In 2 recipients, chronic graft-versus-host-disease (cGvHD) was observed (1 limited and 1 extensive). The 4 engrafted patients were alive and in complete remission 3, 9, 32, and 36 months after transplantation. A T-cell count of 200 cells/uL was reached 90 days after haploSCT in all patients.
Conclusion. HaploSCT with TBI-free protocols can be a viable option for heavily pretreated patients with advanced malignancies.
hematopoietic stem cell transplantation, pediatric, haploidentical, post-transplant cyclophosphamide, TBI-free
- Reisner Y, Kapoor N, Kirkpatrick D, et al. Transplantation for severe combined immunodeficiency with HLA-A,B,D,DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells. Blood. 1983;61(2):341–348.
- McNiece I, Briddell R, Stoney G, et al. Large-scale isolation of CD34+ cells using the Amgen cell selection device results in high levels of purity and recovery. J Hematother. 1997;6(1):5–11.
- Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Blood. 2001;98(12):3456–3464.
- Luznik L, O’Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–650.
- Bresters D, Lawitschka A, Cugno C, et al. Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters. Bone Marrow Transplant. 2016;51(11):1482–1489.
- Boztug H, Sykora KW, Slatter M, et al. European Society for Blood and Marrow Transplantation analysis of treosulfan conditioning before hematopoietic stem cell transplantation in children and adolescents with hematological malignancies. Pediatr Blood Cancer. 2016;63(1):139–148.
- Cooley S, Weisdorf DJ, Guethlein LA, et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood. 2010;116(14):2411–2419.
- Moretta L, Locatelli F, Pende D, Marcenaro E, Mingari MC, Moretta A. Killer Ig-like receptor-mediated control of natural killer cell alloreactivity in haploidentical hematopoietic stem cell transplantation. Blood. 2011;117(3):764–771.
- Ciurea SO, Zhang MJ, Bacigalupo AA, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126(8):1033–1040.
- Gu Z, Wang L, Yuan L, et al. Similar outcomes after haploidentical transplantation with post-transplant cyclophosphamide versus HLA-matched transplantation: A meta-analysis of case-control studies. Oncotarget. 2017;8(38):63574–63586.
- Pawlowska AB, Cheng JC, Karras NA et al. HLA haploidentical stem cell transplant with pretransplant immunosuppression for patients with sickle cell disease. Biol Blood Marrow Transplant. 2018;24(1):185–189.
- Llosa NJ, Cooke KR, Chen AR, et al. Reduced-intensity haploidentical bone marrow transplantation with post-transplant cyclophosphamide for solid tumors in pediatric and young adult patients. Biol Blood Marrow Transplant. 2017;23(12):2127–2136.
- Shima H, Isshiki K, Yamada Y, Yamazaki F, Takahashi T, Shimada H. Successful haploidentical BMT with post-transplant cyclophosphamide for refractory autoimmune pancytopenia after cord blood transplant in pediatric myelodysplastic syndrome. Bone Marrow Transplant. 2017;52(4):653–655.
- Thakar MS, Bonfim C, Walters MC, et al. Dose-adapted post-transplant cyclophosphamide for HLA-haploidentical transplantation in Fanconi anemia. Bone Marrow Transplant. 2017;52(4):570–573.
- Bonfim C, Ribeiro L, Nichele S, et al. Haploidentical bone marrow transplantation with post-transplant cyclophosphamide for children and adolescents with Fanconi anemia. Biol Blood Marrow Transplant. 2017;23(2):310–317.
- Solomon SR, Sizemore CA, Sanacore M, et al. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: Results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012;18(12):1859–1866.
- Shah NN, Freeman AF, Su H, et al. Haploidentical related donor hematopoietic stem cell transplantation for dedicator-of-cytokinesis 8 deficiency using post-transplantation cyclophosphamide. Biol Blood Marrow Transplant. 2017;23(6):980–990.
- Berger M, Lanino E, Cesaro S, 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(5):902–909.
- Kreetapirom P, Hongeng S, Manuyakorn W, et al. Successful HLA haploidentical HSCT with post-transplant cyclophosphamide in Wiskott-Aldrich syndrome. Bone Marrow Transplant. 2017;52(6):913–914.
- Ouederni M, Mellouli F, Khaled MB, Kaabi H, Picard C, Bejaoui M. Successful haploidentical stem cell transplantation with post-transplant cyclophosphamide in a severe combined immune deficiency patient: A first report. J Clin Immunol. 2016;36(5):437–440.
- Bahr TL, Lund T, Sando NM, Orchard PJ, Miller WP. Haploidentical transplantation with post-transplant cyclophosphamide following reduced-intensity conditioning for osteopetrosis: Outcomes in three children. Bone Marrow Transplant. 2016;51(11):1546–1548.
- Weissert R, Wiendl H, Pfrommer H, et al. Action of treosulfan in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis and human lymphocytes. J Neuroimmunol. 2003;144(1–2):28–37.
- Klaudel-Dreszler MA, Kalwak K, Kurenko-Deptuch M, et al. Treosulfan-based conditioning regimen in a second matched unrelated peripheral blood stem cell transplantation for a pediatric patient with CGD and invasive aspergillosis, who experienced initial graft failure after RIC. Int J Hematol. 2009;90(5):571–575.
- Oevermann L, Michaelis SU, Mezger M, et al. KIR B haplotype donors confer a reduced risk for relapse after haploidentical transplantation in children with ALL. Blood. 2014;124(17):2744–2747.
- Wanquet A, Bramanti S, Harbi S, et al. Killer cell immunoglobulin-like receptor-ligand mismatch in donor versus recipient direction provides better graft-versus-tumor effect in patients with hematologic malignancies undergoing allogeneic T cell-replete haploidentical transplantation followed by post-transplant cyclophosphamide. Biol Blood Marrow Transplant. 2018;24(3):549–554.
- Solomon SR, Aubrey MT, Zhang X, et al. Selecting the best donor for haploidentical transplant: Impact of HLA, killer cell immunoglobulin-like receptor genotyping, and other clinical variables. Biol Blood Marrow Transplant. 2018;24(4):789–798.
- Russo A, Oliveira G, Berglund S, et al. NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: Dynamics and clinical implications. Blood. 2018;131(2):247–262.
- Dufort G, Castillo L, Pisano S, et al. Haploidentical hematopoietic stem cell transplantation in children with high-risk hematologic malignancies: Outcomes with two different strategies for GvHD prevention. Ex vivo T-cell depletion and post-transplant cyclophosphamide: 10 years of experience at a single center. Bone Marrow Transplant. 2016;51(10):1354–1360.
- Ruggeri A, Labopin M, Bacigalupo A, et al. Bone marrow versus mobilized peripheral blood stem cells in haploidentical transplants using posttransplantation cyclophosphamide. Cancer. 2018;124(7):1428–1437.
- Jaiswal SR, Chakrabarti A, Chatterjee S, Ray K, Chakrabarti S. Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: The need to look beyond post-transplantation cyclophosphamide in younger children. Pediatr Transplant. 2016;20(5):675–682.
- Bashey A, Zhang MJ, McCurdy SR, 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(26):3002–3009.
- Wiebking V, Hütker S, Schmid I, Immler S, Feuchtinger T, Albert MH. Reduced toxicity, myeloablative HLA-haploidentical hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for sickle cell disease. Ann Hematol. 2017;96(8):1373–1377.
- Anurathapan U, Hongeng S, Pakakasama S, et al. Hematopoietic stem cell transplantation for homozygous β-thalassemia and β-thalassemia/hemoglobin E patients from haploidentical donors. Bone Marrow Transplant. 2016;51(6):813–818.