J Korean Med Sci.  2021 Mar;36(8):e55. 10.3346/jkms.2021.36.e55.

Current Use of Total Body Irradiation in Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation

• Jung J
• Lee H
• Suh YG
• Eom HS
• Lee E

• KMID: 2513531
• DOI: http://doi.org/10.3346/jkms.2021.36.e55

Abstract

Total body irradiation (TBI) is included in the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT), with unique advantages such as uniform distribution over the whole body and decreased exposure to cytotoxic chemotherapeutic agents. For individuals who lack matched sibling or matched unrelated donors, the use of haploidentical donors has been increasing despite challenges such as graft rejection and graft-versus-host disease (GVHD). Although a limited number of studies have been performed to assess the clinical role of TBI in haploidentical HSCT, TBI-based conditioning showed comparable results in terms of survival outcomes, rate of relapse, and GVHD in diverse hematologic malignancies such as leukemia, lymphoma, and multiple myeloma. Advances in supportive care, along with recent technical improvements such as restriction of maximum tolerated dose, appropriate fractionation, and organ shielding, help to overcome diverse adverse events related to TBI. Post-transplantation cyclophosphamide was used in most studies to reduce the risk of GVHD. Additionally, it was found that post-transplantation rituximab may improve outcomes in TBI-based haploidentical HSCT, especially in patients with B-cell lymphoma. Along with the advances of techniques and strategies, the expansion of age restriction would be another important issue for TBI-based haploidentical HSCT considering the current tendency toward increasing age limitation and lack of matched donors. This review article summarizes the current use and future perspectives of TBI in haploidentical HSCT.

Keyword

Allogeneic; Haploidentical; Total Body Irradiation; Transplantation

Reference

1. Ferrebee JW, Thomas ED. Factors affecting the survival of transplanted tissues. Am J Med Sci. 1958; 235(4):369–386. PMID: 13520720.

2. Wong JYC, Filippi AR, Dabaja BS, Yahalom J, Specht L. Total body irradiation: guidelines from the international lymphoma radiation oncology group (ILROG). Int J Radiat Oncol Biol Phys. 2018; 101(3):521–529. PMID: 29893272.

3. Paix A, Antoni D, Waissi W, Ledoux MP, Bilger K, Fornecker L, et al. Total body irradiation in allogeneic bone marrow transplantation conditioning regimens: a review. Crit Rev Oncol Hematol. 2018; 123:138–148. PMID: 29482775.

4. Labar B, Bogdanić V, Nemet D, Mrsić M, Vrtar M, Grgić-Markulin L, et al. Total body irradiation with or without lung shielding for allogeneic bone marrow transplantation. Bone Marrow Transplant. 1992; 9(5):343–347. PMID: 1617318.

5. Girinsky T, Benhamou E, Bourhis JH, Dhermain F, Guillot-Valls D, Ganansia V, et al. Prospective randomized comparison of single-dose versus hyperfractionated total-body irradiation in patients with hematologic malignancies. J Clin Oncol. 2000; 18(5):981–986. PMID: 10694547.

6. Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fisher LD, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990; 76(9):1867–1871. PMID: 2224134.

7. Clift RA, Buckner CD, Appelbaum FR, Bryant E, Bearman SI, Petersen FB, et al. Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens. Blood. 1991; 77(8):1660–1665. PMID: 2015394.

8. Baker KS, Leisenring WM, Goodman PJ, Ermoian RP, Flowers ME, Schoch G, et al. Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation. Blood. 2019; 133(26):2790–2799. PMID: 30992266.

9. Ciurea SO. Considerations for haploidentical versus unrelated donor transplants. Bone Marrow Transplant. 2019; 54(Suppl 2):738–742. PMID: 31431699.

10. 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(4):339–348. PMID: 25054717.

11. 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(8):1033–1040. PMID: 26130705.

12. Ringdén O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindeløv L, et al. A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. Blood. 1994; 83(9):2723–2730. PMID: 8167351.

13. Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, et al. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013; 122(24):3863–3870. PMID: 24065243.

14. Dholaria B, Labopin M, Angelucci E, Ciceri F, Diez-Martin JL, Bruno B, et al. Impact of total body irradiation- vs chemotherapy-based myeloablative conditioning on outcomes of haploidentical hematopoietic cell transplantation for acute myelogenous leukemia. Am J Hematol. 2020; 95(10):1200–1208.

15. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, et al. 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):1299–1307. PMID: 25797174.

16. Solomon SR, Solh M, Zhang X, Morris LE, Holland HK, Bashey A. Fludarabine and total-body irradiation conditioning before ablative haploidentical transplantation: long-term safety and efficacy. Biol Blood Marrow Transplant. 2019; 25(11):2211–2216. PMID: 31247313.

17. Yahng SA, Jeon YW, Yoon JH, Shin SH, Lee SE, Cho BS, et al. Negative impact of unidirectional host-versus-graft killer cell immunoglobulin-like receptor ligand mismatch on transplantation outcomes after unmanipulated haploidentical peripheral blood stem cell transplantation for acute myeloid leukemia. Biol Blood Marrow Transplant. 2016; 22(2):316–323. PMID: 26415557.

18. Lee KH, Lee JH, Lee JH, Kim DY, Seol M, Lee YS, et al. Reduced-intensity conditioning therapy with busulfan, fludarabine, and antithymocyte globulin for HLA-haploidentical hematopoietic cell transplantation in acute leukemia and myelodysplastic syndrome. Blood. 2011; 118(9):2609–2617. PMID: 21715313.

19. Robin M, Porcher R, Ciceri F, van Lint MT, Santarone S, Ehninger G, et al. Haploidentical transplant in patients with myelodysplastic syndrome. Blood Adv. 2017; 1(22):1876–1883. PMID: 29296834.

20. Ruggeri A, Labopin M, Battipaglia G, Chiusolo P, Tischer J, Diez-Martin JL, et al. Timing of post-transplantation cyclophosphamide administration in haploidentical transplantation: a comparative study on behalf of the acute leukemia working party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2020; 26(10):1915–1922. PMID: 32645444.

21. DeFilipp Z, Advani AS, Bachanova V, Cassaday RD, Deangelo DJ, Kebriaei P, et al. Hematopoietic cell transplantation in the treatment of adult acute lymphoblastic leukemia: updated 2019 evidence-based review from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019; 25(11):2113–2123. PMID: 31446198.

22. Kebriaei P, Anasetti C, Zhang MJ, Wang HL, Aldoss I, de Lima M, et al. Intravenous busulfan compared with total body irradiation pretransplant conditioning for adults with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2018; 24(4):726–733. PMID: 29197676.

23. Pavlů J, Labopin M, Niittyvuopio R, Socié G, Yakoub-Agha I, Wu D, et al. Measurable residual disease at myeloablative allogeneic transplantation in adults with acute lymphoblastic leukemia: a retrospective registry study on 2780 patients from the acute leukemia working party of the EBMT. J Hematol Oncol. 2019; 12(1):108. PMID: 31647022.

24. Eroglu C, Pala C, Kaynar L, Yaray K, Aksozen MT, Bankir M, et al. Comparison of total body irradiation plus cyclophosphamide with busulfan plus cyclophosphamide as conditioning regimens in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplant. Leuk Lymphoma. 2013; 54(11):2474–2479. PMID: 23442062.

25. Fu H, Xu L, Liu D, Liu K, Zhang X, Chen H, et al. Total body irradiation and cyclophosphamide plus antithymocyte globulin regimen is well tolerated and promotes stable engraftment as a preparative regimen before T cell-replete haploidentical transplantation for acute leukemia. Biol Blood Marrow Transplant. 2014; 20(8):1176–1182. PMID: 24747336.

26. Srour SA, Milton DR, Bashey A, Karduss-Urueta A, Al Malki MM, Romee R, et al. Haploidentical transplantation with post-transplantation cyclophosphamide for high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2017; 23(2):318–324. PMID: 27856368.

27. Vassilakopoulos TP, Asimakopoulos JV, Konstantopoulos K, Angelopoulou MK. Optimizing outcomes in relapsed/refractory Hodgkin lymphoma: a review of current and forthcoming therapeutic strategies. Ther Adv Hematol. 2020; 11:2040620720902911. PMID: 32110285.

28. Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26(Suppl 5):v116–25. PMID: 26314773.

29. Shanbhag S, Ambinder RF. Hodgkin lymphoma: a review and update on recent progress. CA Cancer J Clin. 2018; 68(2):116–132. PMID: 29194581.

30. Smith SM, Godfrey J, Ahn KW, DiGilio A, Ahmed S, Agrawal V, et al. Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure. Cancer. 2018; 124(12):2541–2551. PMID: 29645093.

31. Heinzelmann F, Bethge W, Beelen DW, Stelljes M, Dreger P, Engelhard M, et al. Allogeneic haematopoietic cell transplantation offers the chance of cure for patients with transformed follicular lymphoma. J Cancer Res Clin Oncol. 2018; 144(6):1173–1183. PMID: 29623467.

32. Epperla N, Hamadani M. Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: current controversies and advances. Hematol Oncol Stem Cell Ther. 2017; 10(4):277–284. PMID: 28633038.

33. Burroughs LM, O'Donnell PV, Sandmaier BM, Storer BE, Luznik L, Symons HJ, 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):1279–1287. PMID: 18940683.

34. Kanakry JA, Kasamon YL, Gocke CD, Tsai HL, Davis-Sproul J, Ghosh N, et al. Outcomes of related donor HLA-identical or HLA-haploidentical allogeneic blood or marrow transplantation for peripheral T cell lymphoma. Biol Blood Marrow Transplant. 2013; 19(4):602–606. PMID: 23370119.

35. Kanakry JA, Gocke CD, Bolaños-Meade J, Gladstone DE, Swinnen LJ, Blackford AL, et al. Phase II study of nonmyeloablative allogeneic bone marrow transplantation for B cell lymphoma with post-transplantation rituximab and donor selection based first on non-HLA factors. Biol Blood Marrow Transplant. 2015; 21(12):2115–2122. PMID: 26183076.

36. Laubach J, Garderet L, Mahindra A, Gahrton G, Caers J, Sezer O, et al. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group. Leukemia. 2016; 30(5):1005–1017. PMID: 26710887.

37. Majolino I, Davoli M, Carnevalli E, Locasciulli A, Di Bartolomeo P, Scimè R, et al. Reduced intensity conditioning with thiotepa, fludarabine, and melphalan is effective in advanced multiple myeloma. Leuk Lymphoma. 2007; 48(4):759–766. PMID: 17454635.

38. Auner HW, Szydlo R, van Biezen A, Iacobelli S, Gahrton G, Milpied N, et al. Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2013; 48(11):1395–1400. PMID: 23708704.

39. Shimoni A, Hardan I, Ayuk F, Schilling G, Atanackovic D, Zeller W, et al. Allogenic hematopoietic stem-cell transplantation with reduced-intensity conditioning in patients with refractory and recurrent multiple myeloma: long-term follow-up. Cancer. 2010; 116(15):3621–3630. PMID: 20564132.

40. Sahebi F, Garderet L, Kanate AS, Eikema DJ, Knelange NS, Alvelo OFD, et al. Outcomes of haploidentical transplantation in patients with relapsed multiple myeloma: an EBMT/CIBMTR report. Biol Blood Marrow Transplant. 2019; 25(2):335–342. PMID: 30243581.

41. Castagna L, Mussetti A, Devillier R, Dominietto A, Marcatti M, Milone G, et al. Haploidentical allogeneic hematopoietic cell transplantation for multiple myeloma using post-transplantation cyclophosphamide graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2017; 23(9):1549–1554. PMID: 28499937.

42. Chen Y, Fu WJ, Xu LP, Ren HY, Lai YR, Liu DH, et al. Comparison of outcomes after human leukocyte antigen-matched and haploidentical hematopoietic stem-cell transplantation for multiple myeloma. Chin Med J (Engl). 2019; 132(15):1765–1772. PMID: 31306219.

43. Georges GE, Storb R. Hematopoietic stem cell transplantation for acquired aplastic anemia. Curr Opin Hematol. 2016; 23(6):495–500. PMID: 27607445.

44. Clay J, Kulasekararaj AG, Potter V, Grimaldi F, McLornan D, Raj K, et al. Nonmyeloablative peripheral blood haploidentical stem cell transplantation for refractory severe aplastic anemia. Biol Blood Marrow Transplant. 2014; 20(11):1711–1716. PMID: 25016195.

45. Esteves I, Bonfim C, Pasquini R, Funke V, Pereira NF, Rocha V, et al. Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study. Bone Marrow Transplant. 2015; 50(5):685–689. PMID: 25730184.

46. Lee SE, Park SS, Jeon YW, Yoon JH, Cho BS, Eom KS, et al. Optimal conditioning regimen for haplo-identical stem cell transplantation in adult patients with acquired severe aplastic anemia: prospective de-escalation study of TBI and ATG dose. Am J Hematol. 2018; 93(11):1368–1375. PMID: 30117176.

47. McLornan DP, Yakoub-Agha I, Robin M, Chalandon Y, Harrison CN, Kroger N. State-of-the-art review: allogeneic stem cell transplantation for myelofibrosis in 2019. Haematologica. 2019; 104(4):659–668. PMID: 30872371.

48. Kröger NM, Deeg JH, Olavarria E, Niederwieser D, Bacigalupo A, Barbui T, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia. 2015; 29(11):2126–2133. PMID: 26293647.

49. Raj K, Eikema DJ, McLornan DP, Olavarria E, Blok HJ, Bregante S, et al. Family mismatched allogeneic stem cell transplantation for myelofibrosis: report from the chronic malignancies working party of European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019; 25(3):522–528. PMID: 30408564.

50. Kerbauy DM, Gooley TA, Sale GE, Flowers ME, Doney KC, Georges GE, et al. Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia. Biol Blood Marrow Transplant. 2007; 13(3):355–365. PMID: 17317589.

51. Bregante S, Dominietto A, Ghiso A, Raiola AM, Gualandi F, Varaldo R, et al. Improved outcome of alternative donor transplantations in patients with myelofibrosis: from unrelated to haploidentical family donors. Biol Blood Marrow Transplant. 2016; 22(2):324–329. PMID: 26456259.

52. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010; 363(22):2091–2101. PMID: 21105791.

53. Jiang Z, Jia J, Yue C, Pang Y, Liu Z, Ouyang L, et al. Haploidentical hematopoietic SCT using helical tomotherapy for total-body irradiation and targeted dose boost in patients with high-risk/refractory acute lymphoblastic leukemia. Bone Marrow Transplant. 2018; 53(4):438–448. PMID: 29330392.

54. Ashizawa M, Akahoshi Y, Nakano H, Kawamura S, Takeshita J, Yoshino N, et al. Updated clinical outcomes of hematopoietic stem cell transplantation using myeloablative total body irradiation with ovarian shielding to preserve fertility. Biol Blood Marrow Transplant. 2019; 25(12):2461–2467. PMID: 31394267.

55. Giebel S, Miszczyk L, Slosarek K, Moukhtari L, Ciceri F, Esteve J, et al. Extreme heterogeneity of myeloablative total body irradiation techniques in clinical practice: a survey of the acute leukemia working party of the European Group for Blood and Marrow Transplantation. Cancer. 2014; 120(17):2760–2765. PMID: 24804873.

56. Yan CH, Xu LP, Wang FR, Chen H, Han W, Wang Y, et al. Causes of mortality after haploidentical hematopoietic stem cell transplantation and the comparison with HLA-identical sibling hematopoietic stem cell transplantation. Bone Marrow Transplant. 2016; 51(3):391–397. PMID: 26691421.

57. Sabloff M, Chhabra S, Wang T, Fretham C, Kekre N, Abraham A, et al. Comparison of high doses of total body irradiation in myeloablative conditioning before hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019; 25(12):2398–2407. PMID: 31473319.

58. Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood. 2016; 127(1):62–70. PMID: 26660427.

59. Bacigalupo A, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, et al. Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update. Bone Marrow Transplant. 2015; 50(Suppl 2):S37–9. PMID: 26039205.

60. Nakamae H, Koh H, Katayama T, Nishimoto M, Hayashi Y, Nakashima Y, et al. HLA haploidentical peripheral blood stem cell transplantation using reduced dose of posttransplantation cyclophosphamide for poor-prognosis or refractory leukemia and myelodysplastic syndrome. Exp Hematol. 2015; 43(11):921–929.e1. PMID: 26284307.

61. Sauter CS, Barker JN, Lechner L, Zheng J, Devlin SM, Papadopoulos EB, et al. A phase II study of a nonmyeloablative allogeneic stem cell transplant with peritransplant rituximab in patients with B cell lymphoid malignancies: favorably durable event-free survival in chemosensitive patients. Biol Blood Marrow Transplant. 2014; 20(3):354–360. PMID: 24315843.

62. Im HJ, Koh KN, Suh JK, Lee SW, Choi ES, Jang S, et al. Haploidentical HCT using an αβ T-cell-depleted graft with targeted αβ(+) cells by add-back after a reduced intensity preparative regimen containing low-dose TBI. Bone Marrow Transplant. 2016; 51(9):1217–1222. PMID: 27159171.

63. Zhang C, Ma YY, Liu J, Liu Y, Gao L, Gao L, et al. Preventive infusion of donor-derived CAR-T cells after haploidentical transplantation: two cases report. Medicine (Baltimore). 2019; 98(29):e16498. PMID: 31335716.

64. Podoltsev NA, Stahl M, Zeidan AM, Gore SD. Selecting initial treatment of acute myeloid leukaemia in older adults. Blood Rev. 2017; 31(2):43–62. PMID: 27745715.

65. Lipof JJ, Loh KP, O'Dwyer K, Liesveld JL. Allogeneic hematopoietic cell transplantation for older adults with acute myeloid leukemia. Cancers (Basel). 2018; 10(6):E179. PMID: 29866998.

66. Dreger P, Sureda A, Ahn KW, Eapen M, Litovich C, Finel H, et al. PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL. Blood Adv. 2019; 3(3):360–369. PMID: 30723110.

67. Ciurea SO, Shah MV, Saliba RM, Gaballa S, Kongtim P, Rondon G, et al. Haploidentical transplantation for older patients with acute myeloid leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2018; 24(6):1232–1236. PMID: 28918304.