Myeloablative Versus Nonmyeloablative Conditioning Regimen in Haploidentical Transplantation: Does It Matter and How Best to Select Between the Two?

  • Andrea Bacigalupo
  • Patrizia Chiusolo
  • Simona Sica
Chapter
Part of the Advances and Controversies in Hematopoietic Transplantation and Cell Therapy book series (ACHTCT)

Abstract

We review the role of conditioning regimens in patients undergoing an allogeneic hematopoietic cell transplantation (HCT) from HLA-haploidentical family donors. As with other types of transplants, the effect of the regimen intensity cannot be entirely dissected from other important components of a haploidentical transplant such as graft composition, graft source, immunosuppression, etc., all of which influence transplant outcomes. In general transplant programs involving ex vivo T-cell depletion (TCD) use myeloablative conditioning (MAC) regimens, whereas nonmyeloablative (NMA) regimens are used for both ex vivo and in vivo TCD. NMA regimens are associated with a low risk of graft-versus-host disease (GvHD) and non-relapse mortality (NRM), with higher risk of relapse compared to MAC regimens. MAC regimens are required for most young patients with acute leukemias, or aggressive disease. Currently the combination of different alkylating agents, such as busulfan (Bu) and thiotepa or Bu and melphalan (Mel), can achieve significant disease control, with acceptable toxicity. In a nutshell, the intensity of the conditioning regimen does matter and represents an important part of the haploidentical hematopoietic cell transplantation (haplo-HCT).

Keywords

Conditioning regimen Haploidentical transplant Myeloablative Nonmyeloablative GvHD T-cell depletion Relapse Marrow Peripheral blood 

References

  1. 1.
    Passweg JR, Baldomer H, Bader P, Bonini C, Cesaro S, Dreger P, Duarte RF, Dufour C, Falkenburg JHF, Farge-Bancel D, Gennery A, Kröger N, Lanza F, Nagler A, Sureda A, Mohty M, for the European Society for Blood and Marrow Transplantation (EBMT). Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplant. 2015;50:476–82.CrossRefGoogle Scholar
  2. 2.
    Aversa F, Tabilio A, Terenzi A, et al. Successful engraftment of T-cell-depleted haploidentical “three-loci” incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood. 1994;84:3948–55.PubMedGoogle Scholar
  3. 3.
    Locatelli F, Bauquet A, Palumbo G, Moretta F, Bertaina A. Negative depletion of α/β+ T cells and of CD19+ B lymphocytes: a novel frontier to optimize the effect of innate immunity in HLA-mismatched hematopoietic stem cell transplantation. Immunol Lett. 2013;155(1–2):21–3.CrossRefGoogle Scholar
  4. 4.
    Dao-Pei L, Dong L, Tong W, Huang X-J, Zhang M-J, Han W, Chen H, Liu D-H, Gao Z-Y, Chen Y-H, Lan-Ping X, Zhang Y-C, Ren H-Y, Li D, Liu K-Y. Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood. 2006;107(8):3065–73.CrossRefGoogle Scholar
  5. 5.
    Luznik L, O’Donnel PV, Simons HJ, et al. HLA-Haploidentical bone marrow transplantation for hematological malignancies using nonmyeloablative conditioning regimen and high dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–50.CrossRefGoogle Scholar
  6. 6.
    Ciceri F, Labopin M, Aversa F, Rowe JM, Bunjes D, Lewalle P, Nagler A, Di Bartolomeo P, Lacerda JF, Lupo Stanghellini MT, Polge E, Frassoni F, Martelli MF, Rocha V, Acute Leukemia Working Party (ALWP) of European Blood and Marrow Transplant (EBMT) Group. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood. 2008;112(9):3574–81.CrossRefGoogle Scholar
  7. 7.
    Aversa A, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, Felicini R, Falcinelli F, Velardi A, Ruggeri L, Aloisi T, Saab JP, Santucci A, Perruccio K, Martelli MP, Mecucci C, Reisner Y, Martelli MF. 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;23:3447–54.CrossRefGoogle Scholar
  8. 8.
    Airoldi I, Bertaina A, Prigione I, Zorzoli A, Pagliara D, Cocco C, Meazza R, Loiacono F, Lucarelli B, Bernardo ME, Barbarito G, Pende D, Moretta A, Pistoia V, Moretta L, Locatelli F γ. T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes. Blood. 2015;125(15):2349–58.CrossRefGoogle Scholar
  9. 9.
    Lang P, Feuchtinger T, Teltschik HM, Schwinger W, Schlegel P, Pfeiffer M, Schumm M, Lang AM, Lang B, Schwarze CP, Ebinger M, Urban C, Handgretinger R. Improved immune recovery after transplantation of TCRαβ/CD19-depleted allografts from haploidentical donors in pediatric patients. Bone Marrow Transplant. 2015;50(Suppl 2):S6–10.CrossRefGoogle Scholar
  10. 10.
    Martelli MF, Di Ianni M, Ruggeri L, Falzetti F, Carotti A, Terenzi A, Pierini A, Massei MS, Amico L, Urbani E, Del Papa B, Zei T, Iacucci Ostini R, Cecchini D, Tognellini R, Reisner Y, Aversa F, Falini B, Velardi A. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014;124(4):638–44.CrossRefGoogle Scholar
  11. 11.
    Bashey A, Zhang X, Jackson K, Brown S, Ridgeway M, Solh M, Morris LE, Holland HK, Solomon SR. Comparison of outcomes of hematopoietic cell transplants from T-replete haploidentical donors using post-transplantation cyclophosphamide with 10 of 10HLA-A, -B, -C, -DRB1, and -DQB1 allele-matched unrelated donors and HLA-identical sibling donors: a multivariable analysis including disease risk index. Biol Blood Marrow Transpl. 2016;22:125–33.CrossRefGoogle Scholar
  12. 12.
    Rashidi A, DiPersio JF, Westervelt P, Vij R, Schroeder MA, Cashen AM, Fehniger TA, Romee R. Comparison of outcomes after peripheral blood haploidentical versus matched unrelated donor allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia: a retrospective single-center review. Biol Blood Marrow Transplant. 2016;22:1696e1701.Google Scholar
  13. 13.
    Wang Y, Liu D-H, Liu K-Y, Xu L-P, Zhang X-H, Han W, Chen H, Chen Y-H, Wang F-R, Wang J-Z, Sun Y-Q, Huang X-J. Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia. Nine years of experience at a single center. Cancer. 2013;119:978–85.CrossRefGoogle Scholar
  14. 14.
    Ji S-Q, Chen H-R, Yan H-M, et al. Anti-CD25 monoclonal antibody (basiliximab) for prevention of graft-versus-host disease after haploidentical bone marrow transplantation for hematological malignancies. Bone Marrow Transplant. 2005;36(4):349–54.CrossRefGoogle Scholar
  15. 15.
    Di Bartolomeo P, Santarone S, De Angelis G, Picardi A, Bavaro P, Di Bartolomeo E, Olioso P, Di Nicola M, De Felice L, Cudillo L, Cerretti R, Arcese W. Unmanipulated bone marrow transplantation from haploidentical related donors for patients with high risk hematologic malignancies. Blood. 2010;116:abstract 2350.Google Scholar
  16. 16.
    Sanz J, Boluda JC, Martín C, González M, Ferrá C, Serrano D, de Heredia CD, Barrenetxea C, Martinez AM, Solano C, Sanz MA, Sanz GF. Single-unit umbilical cord blood transplantation from unrelated donors in patients with haematological malignancy using busulfan, thiotepa, fludarabine and ATG as myeloablative conditioning regimen. Bone Marrow Transplant. 2012;47:12897–3.CrossRefGoogle Scholar
  17. 17.
    Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, Bregante S, Van Lint MT, Geroldi S, Luchetti S, Ballerini F, Miglino M, Varaldo R, Bacigalupo A. Unmanipulated haploidentical bone marrow transplant and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant. 2013;19:117–22.CrossRefGoogle Scholar
  18. 18.
    Bacigalupo A, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, Bregante S, Van Lint MT, Geroldi S, Luchetti S, Grasso R, Pozzi S, Colombo N, Tedone E, Varaldo R, Raiola AM. Unmanipulated haploidentical bone transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update. Bone Marrow Transplant. 2015;50(Suppl 2):S37–9.CrossRefGoogle Scholar
  19. 19.
    Bashey A, Zhang X, Jackson K, Brown S, Ridgeway M, Solh M, Morris LE, Holland HK, Solomon SR. Comparison of outcomes of hematopoietic cell transplants fromt-replete haploidentical donors using post-transplantation cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 allele-matched unrelated donors and HLA-identical sibling donors: a multivariable analysis including disease risk index. Biol Blood Marrow Transplant. 2016;22(1):125–33.CrossRefGoogle Scholar
  20. 20.
    Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK, Morris LE, Solomon SR. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol. 2013;31(10):1310–6.CrossRefGoogle Scholar
  21. 21.
    Cieri N, Greco R, Crucitti L, Morelli M, Giglio F, Levati G, Assanelli A, Carrabba MG, Bellio L, Milani R, Lorentino F, Stanghellini MTL, De Freitas T, Marktel S, Bernardi M, Corti C, Vago L, Bonini C, Ciceri F, Peccatori J. Post-transplantation cyclophosphamide and sirolimus after hploidentical hematopoietic stem cell transplantation using a treosulfan-based myeloablative conditioning and peripheral blood stem cells. Biol Blood and Marrow Transplant. 2015;21:1506–14.CrossRefGoogle Scholar
  22. 22.
    Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey A. Total body irradiation-based myeloablative haploidentical stem cell transplantation is a safe and effective alternative to unrelated donor transplantation in patients without matched sibling donors. Biol Blood Marrow Transplant. 2015;21(7):1299–307.CrossRefGoogle Scholar
  23. 23.
    Rashidi A, DiPersio JF, Westervelt P, Vij R, Schroeder MA, Cashen AF, Fehniger TA, Romee R. Comparison of outcomes after peripheral blood haploidentical versus matched unrelated donor allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia: a retrospective single-center review. Biol Blood Marrow Transplant. 2016;22(9):1696–701.CrossRefGoogle Scholar
  24. 24.
    McCurdy SR, Kanakry JA, Showel MM, et al. Risk stratified outcomes of nonmyeloablative HLA-haploidentical BMT with-high dose posttransplantation cyclophosphamide. Blood. 2015;125:3024–31.CrossRefGoogle Scholar
  25. 25.
    Armand P, Kim HT, Logan BR, et al. Validation and refinement of the disease risk index for allogeneic stem cell transplantation. Blood. 2014;123:3664–71.CrossRefGoogle Scholar
  26. 26.
    Sugita J, Kawashima N, Fujisaki T, et al. HLA-haploidentical peripheral blood stem cell transplantation with post-transplanbt cyclophosphamide after busulfan-containing reduced-intensity conditioning. Biol Blood Marrow Transplant. 2015;21:1646–52.CrossRefGoogle Scholar
  27. 27.
    Brammer JE, Khouri I, Gaballa S, Anderlini P, Tomuleasa C, Ahmed S, Ledesma C, Hosing C, Champlin RE, Ciurea SO. Outcomes of haploidentical stem cell transplantation for lymphoma with melphalan-based conditioning. Biol Blood Marrow Transplant. 2016;22(3):493–8.CrossRefGoogle Scholar
  28. 28.
    Jaiswal SR, Chakrabarti A, Chatterjee S, Bhargava S, Ray K, O’Donnell P, Chakrabarti S. Haploidentical peripheral blood stem cell transplantation withpost-transplantation cyclophosphamide in children with advanced acute leukemia with fludarabine-, busulfan-, and melphalan-based conditioning. Biol Blood Marrow Transplant. 2016;22(3):499–504.CrossRefGoogle Scholar
  29. 29.
    Blaise D, Fürst S, Crocchiolo R, El-Cheikh J, Granata A, Harbi S, Bouabdallah R, Devillier R, Bramanti S, Lemarie C, Picard C, Chabannon C, Weiller PJ, Faucher C, Mohty B, Vey N, Castagna L. Haploidentical T cell-replete transplantation with post-transplantation cyclophosphamide for patients in or above the sixth decade of age compared with allogeneic hematopoietic stem cell transplantation from an human leukocyte antigen-matched related or unrelated donor. Biol Blood Marrow Transplant. 2016;22(1):119–24.CrossRefGoogle Scholar
  30. 30.
    Raj K, Pagliuca A, Bradstock K, et al. Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related haploidentical donors after reduced intensity conditioning. Biol Blood Marrow Transplant. 2014;20:890–5.CrossRefGoogle Scholar
  31. 31.
    Castagna L, Crocchiolo R, Furst S, et al. Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2014;20:724–9.CrossRefGoogle Scholar
  32. 32.
    Bradstock K, Bilmon I, Kwan J, et al. Influence of stem cell source on outcomes of allogeneic reduced intensity conditioning therapy transplants using haploidentical related donors. Biol Blood Marrow Transplant. 2015;21:1641–5.CrossRefGoogle Scholar
  33. 33.
    Kasamon YL, Bolanos-Meade J, Prince GT, et al. Outcomes of nonmyeloablative HLA-haploidentical blood or marrow transplantation with high dose post-transplantation cyclophosphamide in older adults. J Clin Oncol. 2015;33:3152–61.CrossRefGoogle Scholar
  34. 34.
    Devillier R, Granata A, Furst S, et al. Low incidence of chronic GVHD after haploidentical peripheral blood stem cell transplantation with post transplantation cyclophosphamide in older patients. Brit J Haematol. 2016;176:132–5.CrossRefGoogle Scholar
  35. 35.
    Burroughs LM, O’Donnell PV, Sandmaier BM, et al. Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2008;14(11):1279–87.CrossRefGoogle Scholar
  36. 36.
    Raiola A, Dominietto A, Varaldo R, Ghiso A, Galaverna F, Bramanti S, Todisco E, Sarina B, Giordano L, Ibatici A, Santoro A, Clavio M, Bacigalupo A, Castagna L. Unmanipulated haploidentical BMT following non-myeloablative conditioning and post-transplantation CY for advanced Hodgkin’s lymphoma. Bone Marrow Transplant. 2014;49(2):190–4.CrossRefGoogle Scholar
  37. 37.
    Brusamolino E, Bacigalupo A, Barosi G, et al. Classical Hodgkin’s lymphoma in adults: guidelines of the Italian Society of Hematology, the Italian Society of Experimental Hematology, and the Italian Group for Bone Marrow Transplantation on initial work-up, management, and follow-up. Haematologica. 2009;94(4):550–65.CrossRefGoogle Scholar
  38. 38.
    Ghiso A, Raiola AM, Gualandi F, Dominietto A, Varaldo R, Van Lint MT, Bregante S, Di Grazia C, Lamparelli T, Galaverna F, Stasia A, Luchetti S, Geroldi S, Grasso R, Colombo N, Bacigalupo A. DLI after haploidentical BMT with post-transplant CY. Bone Marrow Transplant. 2015;50(1):56–61.CrossRefGoogle Scholar
  39. 39.
    Yared JA, Hardy N, Singh Z, Hajj S, Badros AZ, Kocoglu M, Yanovich S, Sausville EA, Ujjani C, Ruehle K, Goecke C, Landau M, Rapoport AP. Major clinical response to nivolumab in relapsed/refractory Hodgkin lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51(6):850–2.CrossRefGoogle Scholar
  40. 40.
    Clift RA, Buckner CD, Appelbaum FR, Sullivan KM, Storb R, Thomas ED. Long-term follow-Up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplants during first remission of acute myeloid leukemia. Blood. 1998;92(4):1455–6.PubMedGoogle Scholar
  41. 41.
    Pozzi S, Geroldi S, Tedone E, Luchetti S, Grasso R, Colombo N, Di Grazia C, Lamparelli T, Gualandi F, Ibatici A, Bregante S, Van Lint MT, Raiola AM, Dominietto A, Varaldo R, Signori A, Bacigalupo A. Leukaemia relapse after allogeneic transplants for acute myeloid leukaemia: predictive role of WT1 expression. Br J Haematol. 2013;160(4):503–9.CrossRefGoogle Scholar
  42. 42.
    Kröger N, Holler E, Kobbe G, Bornhäuser M, Schwerdtfeger R, Baurmann H, Nagler A, Bethge W, Stelljes M, Uharek L, Wandt H, Burchert A, Corradini P, Schubert J, Kaufmann M, Dreger P, Wulf GG, Einsele H, Zabelina T, Kvasnicka HM, Thiele J, Brand R, Zander AR, Niederwieser D, de Witte TM. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2009;114(26):5264–70.CrossRefGoogle Scholar
  43. 43.
    Bacigalupo A, Soraru M, Dominietto A, Pozzi S, Geroldi S, van Lint MT, Ibatici A, Raiola AM, Frassoni F, De Stefano F, Verdiani S, Casarino L, Barosi G. Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type. Bone Marrow Transplant. 2010;45:458.CrossRefGoogle Scholar
  44. 44.
    Rondelli D, Goldberg JD, Isola L, Price LS, Shore TB, Boyer M, et al. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. Blood. 2014;124(7):1183–91.CrossRefGoogle Scholar
  45. 45.
    Bregante S, Dominietto A, Ghiso A, Raiola AM, Gualandi F, Varaldo R, Di Grazia C, Lamparelli T, Luchetti S, Geroldi S, Casarino L, Pozzi S, Tedone E, Van Lint MT, Galaverna F, Barosi G, Bacigalupo A. Improved outcome of alternative donor transplantations in patients with myelofibrosis: from unrelated to haploidentical family donors. Biol Blood Marrow Transplant. 2016;22(2):324–9.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Andrea Bacigalupo
    • 1
  • Patrizia Chiusolo
    • 1
  • Simona Sica
    • 1
  1. 1.Istituto di Ematologia e Trapianto di Midollo Osseo, Policlinico GemelliUniversita’ CattolicaRomaItaly

Personalised recommendations