Abstract
We conducted a prospective phase II trial utilizing the CliniMACs system to perform CD34+-cell selection of PBSCs from haploidentical donors to evaluate engraftment and hematoimmunological reconstitution. In total, 21 children with hematological malignancies or nonmalignant conditions underwent conditioning with 1200 cGy TBI, thiotepa, fludarabine and Thymoglobulin. Patients received megadoses of CD34+ cells (median: 22 × 106/kg) with a fixed dose of 3 × 104/kg CD3+ cells/kg, and engraftment occurred in 90% with prompt recovery of neutrophils and platelets. Grade II acute GVHD (aGVHD) was seen in 32% (95% confidence interval (CI), 15–54%) of evaluable patients, there was no grade III–IV aGVHD, and chronic extensive GVHD was seen in 35% (95% CI, 17–59%) of patients. The estimated 2-year EFS was 62% (95% CI, 48–83%) with a median survivor follow-up of 49 months (range: 18–119 months). Patients with nonmalignant diseases had an estimated 2-year EFS of 100% (95% CI, 56–100%) and patients with malignancies in remission had an estimated 2-year EFS of 56% (95% CI, 22–89%). Megadose CD34+ cells with a fixed CD3+ cell dose from haploidentical related donors resulted in good outcomes for pediatric patients with nonmalignant diseases and those with malignant diseases transplanted in remission.
This is a preview of subscription content, access via your institution
Access options
Similar content being viewed by others
References
Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005; 23: 3447–3454.
Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 1998; 339: 1186–1193.
Rachamim N, Gan J, Segall H, Krauthgamer R, Marcus H, Berrebi A et al. Tolerance induction by "megadose" hematopoietic transplants: donor-type human CD34 stem cells induce potent specific reduction of host anti-donor cytotoxic T lymphocyte precursors in mixed lymphocyte culture. Transplantation 1998; 65: 1386–1393.
Dvorak C, Hung G-Y, Horn B, Dunn E, Oon C-Y, Cowan M . Megadose CD34+ cell grafts improve recovery of T cell engraftment but not B cell immunity in patients with severe combined immunodeficiency disease undergoing haplocompatible non-myeloablative transplantation. Biol Blood Marrow Transplant 2008; 14: 1125–1133.
Chakraverty R, Robinson S, Peggs K, Kottaridis P, Watts M, Ings S et al. Excessive T cell depletion of peripheral blood stem cells has an adverse effect upon outcome following allogeneic stem cell transplantation. Bone Marrow Transplant 2001; 28: 827–834.
Dvorak C, Gilman A, Horn B, Jaroscak J, Dunn E, Baxter-Lowe L et al. Clinical and immunologic outcomes following haplocompatible donor lymphocyte infusions. Bone Marrow Transplant 2009; 44: 805–812.
Small T, Papadopoulos E, Boulad F, Black P, Castro-Malaspina H, Childs B et al. Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood 1999; 93: 467–480.
Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A, Aloisi T et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood 2007; 110: 433–440.
Kröger N, Renges H, Krüger W, Gutensohn K, Löliger C, Carrero I et al. A randomized comparison of once versus twice daily recombinant human granulocyte colony-stimulating factor (filgrastim) for stem cell mobilization in healthy donors for allogeneic transplantation. Br J Haematol 2000; 111: 761–765.
Sutherland D, Anderson L, Keeney M, Nayar R, Chin-Yee I . The ISHAGE guidelines for CD34+ cell determination by flow cytometry. International Society of Hematotherapy and Graft Engineering. J Hematother 1996; 5: 213–226.
Dvorak C, Hung G, Horn B, Dunn E, Oon C, Cowan M . Megadose CD34(+) cell grafts improve recovery of T cell engraftment but not B cell immunity in patients with severe combined immunodeficiency disease undergoing haplocompatible nonmyeloablative transplantation. Biol Blood Marrow Transplant 2008; 14: 1125–1133.
Kussmaul S, Horn B, Dvorak C, Abramovitz L, Cowan M, Weintrub P . Safety of the live, attenuated varicella vaccine in pediatric recipients of hematopoietic SCTs. Bone Marrow Transplant 2010; 45: 1602–1606.
Ozyurek E, Cowan M, Koerper M, Baxter-Lowe L, Dvorak C, Horn B . Increasing mixed chimerism and the risk of graft loss in children undergoing allogeneic hematopoietic stem cell transplantation for non-malignant disorders. Bone Marrow Transplant 2008; 42: 83–91.
Przepiorka D, Weisdorf D, Martin P, Klingemann H, Beatty P, Hows J et al. Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.
Filipovich A, Weisdorf D, Pavletic S, Socie G, Wingard J, Lee S et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.
Horn B, Bao L, Dunham K, Stamer M, Adler S, Cowan M et al. Infusion of cytomegalovirus specific cytotoxic T lymphocytes from a sero-negative donor can facilitate resolution of infection and immune reconstitution. Pediatr Infect Dis J 2009; 28: 65–67.
Dror Y, Gallagher R, Wara DW, Colombe BW, Merino A, Benkerrou M et al. Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, T-cell-depleted haplocompatible bone marrow transplantation. Blood 1993; 81: 2021–2030.
Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Roberts JL et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999; 340: 508–516.
González-Vicent M, Molina B, Andión M, Sevilla J, Ramirez M, Pérez A et al. Allogeneic hematopoietic transplantation using haploidentical donor vs. unrelated cord blood donor in pediatric patients: a single-center retrospective study. Eur J Haematol 2011; 87: 46–53.
Leung W, Campana D, Yang J, Pei D, Coustan-Smith E, Gan K et al. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood 2011; 118: 223–230.
Lang P, Greil J, Bader P, Handgretinger R, Klingebiel T, Schumm M et al. Long-term outcome after haploidentical stem cell transplantation in children. Blood Cells Mol Dis 2004; 33: 281–287.
Handgretinger R, Klingebiel T, Lang P, Schumm M, Neu S, Geiselhart A et al. Megadose transplantation of purified peripheral blood CD34(+) progenitor cells from HLA-mismatched parental donors in children. Bone Marrow Transplant 2001; 27: 777–783.
Isgrò A, Marziali M, Sodani P, Gaziev J, Erer B, Polchi P et al. Immunohematologic reconstitution in pediatric patients after T cell-depleted HLA-haploidentical stem cell transplantation for thalassemia. Biol Blood Marrow Transplant 2010; 16: 1557–1566.
Verneris M, Brunstein C, Barker J, MacMillan M, DeFor T, McKenna D et al. Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood 2009; 114: 4293–4299.
Avery S, Shi W, Lubin M, Gonzales A, Heller G, Castro-Malaspina H et al. Influence of infused cell dose and HLA match on engraftment after double-unit cord blood allografts. Blood 2011; 117: 3277–3285.
Thomson BG, Robertson KA, Gowan D, Heilman D, Broxmeyer HE, Emanuel D et al. Analysis of engraftment, graft-versus-host disease, and immune recovery following unrelated donor cord blood transplantation. Blood 2000; 96: 2703–2711.
Sauter C, Abboud M, Jia X, Heller G, Gonzales A, Lubin M et al. Serious infection risk and immune recovery after double-unit cord blood transplantation without antithymocyte globulin. Biol Blood Marrow Transplant 2011; 17: 1460–1471.
Kurtzberg J, Prasad V, Carter S, Wagner J, Baxter-Lowe L, Wall D et al. Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies. Blood 2008; 112: 4318–4327.
Jurickova I, Waller E, Yeager A, Boyer M . Generation of alloreactive anti-leukemic cytotoxic T lymphocytes with attenuated GVHD properties from haploidentical parents in childhood acute lymphoblastic leukemia. Bone Marrow Transplant 2002; 30: 687–697.
Leen A, Christin A, Myers G, Liu H, Cruz C, Hanley P et al. Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood 2009; 114: 4283–4292.
Perruccio K, Tosti A, Burchielli E, Topini F, Ruggeri L, Carotti A et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood 2005; 106: 4397–4406.
Micklethwaite KP, Savoldo B, Hanley PJ, Leen AM, Demmler-Harrison GJ, Cooper LJN et al. Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation. Blood 2010; 115: 2695–2703.
Podgorny P, Ugarte-Torres A, Liu Y, Williamson T, Russell J, Storek J . High rabbit-antihuman thymocyte globulin levels are associated with low likelihood of graft-vs-host disease and high likelihood of posttransplant lymphoproliferative disorder. Biol Blood Marrow Transplant 2010; 16: 915–926.
Seidel M, Fritsch G, Matthes-Martin S, Lawitschka A, Lion T, Pötschger U et al. Antithymocyte globulin pharmacokinetics in pediatric patients after hematopoietic stem cell transplantation. J Pediatr Hematol Oncol 2005; 27: 532–536.
Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino P, di Bartolomeo P et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood 2001; 98: 2942–2947.
Stern M, Ruggeri L, Mancusi A, Bernardo M, de Angelis C, Bucher C et al. Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor. Blood 2008; 112: 2990–2995.
Geyer M, Ricci A, Jacobson J, Majzner R, Duffy D, Van de Ven C et al. T cell depletion utilizing CD34(+) stem cell selection and CD3(+) addback from unrelated adult donors in paediatric allogeneic stem cell transplantation recipients. Br J Haematol 2012; 157: 205–209.
Bunin N, Aplenc R, Grupp S, Pierson G, Monos D . Unrelated donor or partially matched related donor peripheral stem cell transplant with CD34+ selection and CD3+ addback for pediatric patients with leukemias. Bone Marrow Transplant 2006; 37: 143–149.
Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 2011; 117: 3921–3928.
Nguyen V, Zeiser R, Dasilva D, Chang D, Beilhack A, Contag C et al. In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation. Blood 2007; 109: 2649–2656.
Acknowledgements
Portions of this data were presented as an oral abstract at the annual meeting of the American Society for Blood and Marrow Transplant, Honolulu, HI, 20 February 2011 (abstract no. 76).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Dvorak, C., Gilman, A., Horn, B. et al. Haploidentical related-donor hematopoietic cell transplantation in children using megadoses of CliniMACs-selected CD34+ cells and a fixed CD3+ dose. Bone Marrow Transplant 48, 508–513 (2013). https://doi.org/10.1038/bmt.2012.186
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/bmt.2012.186