Аллогенная трансплантация гемопоэтических стволовых клеток: перспективы и альтернативы, собственный опыт

Цель. Трансплантация гемопоэтических стволовых клеток (ТГСК) используется для обеспечения возможности излечения злокачественных онкогематологических заболеваний, некоторых солидных опухолей и аутоиммунных заболеваний. Целью обзора является суммирование основных данных о развитии и перспективе ТГСК, изучении новых возможностей, а также развивающихся альтернативных технологиях, усиливающих эффективность противоопухолевого потенциала аллогенной ТГСК (алло-ТГСК), и одновременно уменьшающих риски ее тяжелых осложнений.

Основные положения. Алло-ТГСК как форма иммунотерапии способствует длительным ремиссиям, но все еще ограничена связанными с трансплантацией заболеваемостью и смертностью из-за токсических эффектов на организм, инфекционных осложнений и реакции «трансплантат против хозяина» (РТПХ). Разработаны различные методы, уменьшающие побочные эффекты ТГСК. Одними из основных достижений последнего времени явились успехи в гаплоидентичной трансплантации, которая на основе новых возможностей профилактики РТПХ не только стала доступна почти для всех подходящих пациентов, но и не уступает стандартной алло-ТГСК по эффективности и безопасности. Успешно внедряется алло-ТГСК после редуцированной интенсивности кондиционирования или немиелоаблативных режимов при лечении пожилых или ослабленных пациентов с распространенными стадиями гематологических злокачественных заболеваний. Показано, как новые технологии усиливают эффективность противоопухолевого потенциала алло-ТГСК, и одновременно уменьшают риски ее тяжелых осложнений. Представлен собственный опыт алло-ТГСК у 19 пациентов. В нашем исследовании показано, что алло-ТГСК не улучшила исход для рефрактерных/рецидивирующих пациентов с острыми лейкозами, но может быть с успехом использована в фазу ремиссии.

Выводы. Роль стволовых клеток в лечении гематологических и негематологических злокачественных заболеваний (а также некоторых аутоиммунных состояний) постоянно возрастает. Всесторонние знания о возможностях применения трансплантационных технологий, современных методах клеточной терапии гемобластозов позволят уменьшить лекарственную токсичность и улучшить исходы пациентов. 

1. Maximow A. Der Lymphozyt als gemeinsame Stammzelle der verschiedenen Blutelemente in der embryonalen Entwicklung und im postfetalen Leben der Säugetiere. Originally in: Folia Haematologica 1909;8:125–34. Republished in: Cell Ther Transplant 2009;1:e.000040.01.

2. Abkowitz J.L., Catlin S.N., McCallie M.T., Guttorp P. Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood 2002;100(7):2665–7.

3. Catlin S.N., Busque L., Gale R.E. et al. The replication rate of human hematopoietic stem cells in vivo. Blood 2011;117(17):4460–6.

4. Holstege H., Pfeiffer W., Sie D. et al. Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome Res 2014;24(5):733–42.

5. Buchsel P.C., Whedon M.B. Bone Marrow Transplantation: Administrative and Clinical Strategies. Jones and Bartlett, 1995.

6. Osgood E.E., Riddle M.C., Mathews T.J. Aplastic anemia treated with daily transfusions and intravenous marrow; case report. Ann Intern Med 1939;13(2):357–67.

7. Morrison M., Samwick A.A. Intramedullary (sternal) transfusion of human bone marrow: Preliminary report. J Am Med Assoc 1940;115(20):1708–11.

8. Thomas E.D., Lochte H.L., Lu W.C., Ferrebee J.W. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med 1957;257(11):491–6.

9. Jansen J. The first successful allogeneic bone-marrow transplant: Georges Mathé. Transfus Med Rev 2005;19(3):246–8.

10. Мелкова К.Н. Аллогенная трансплантация костного мозга: ключевые аспекты и основные этапы развития. Клиническая онкогематология 2012;5(1):1–12. [Melkova K.N. Allogeneic bone marrow transplantation: key aspects and main stages of development. Klinicheskaya onkogematologiya = Clinical Oncohematology 2012;5(1):1–12. (In Russ.)].

11. Баранов А.Е., Гуськова А.К., Калюта Б.А. и др. Трансплантация костного мозга, подобранного по HLA-и MLC-антигенам, больной апластической анемией. Проблемы гематологии и переливания крови 1975;11:28–32. [Baranov A.E., Guskova A.K., Kalyuta B.A. Bone marrow transplantation, selected by HLA and MLC antigens, aplastic anemia patient. Problemy gematologii i perelivaniya krovi = Problems of Hematology and Blood Transfusion 1975;11:28–32. (In Russ.)].

12. Henig I., Zuckerman T. Hematopoietic Stem Cell Transplantation – 50 Years of Evolution and Future Perspectives. Rambam Maimonides Med J 2014;5(4):e0028.

13. Passweg J.R., Baldomero H., Bader P. et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant 2016;51(6):786–92.

14. Passweg J.R., Baldomero H., Gratwohl A. et al. The EBMT activity survey: 1990–2010. Bone Marrow Transplant 2012;47(7):906–23.

15. Farquhar C., Marjoribanks J., Basser R., Lethaby A. High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database Syst Rev 2005;(3):CD003139.

16. Farquhar C., Marjoribanks J., Lethaby A., Azhar M. High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database Syst Rev 2016; (5):CD003139.

17. Gratwohl A., Pasquini M.C., Aljurf M. et al. One million haemopoietic stem-cell transplants: a retrospective observational study. Lancet Haematol 2015;2(3):e91–100.

18. Sureda A., Bader P., Cesaro S. et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant 2015;50(8):1037–56.

19. Pilon S., Jedrysiak D., Sheppard D. et al. Current trends in clinical studies of allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2015;21(2):364–70.

20. Copelan E.A., Hamilton B.K., Avalos B. 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):3863–70.

21. Passweg J.R., Labopin M., Cornelissen J. et al. Conditioning intensity in middle-aged patients with AML in first CR: no advantage for myeloablative regimens irrespective of the risk group–an observational analysis by the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant 2015;50(8):1063–8.

22. Slavin S., Nagler A., Naparstek E. et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998;91(3):756–63.

23. Schmid C., Schleuning M., Ledderose G. et al. Sequential Regimen of Chemotherapy, Reduced-Intensity Conditioning for Allogeneic Stem-Cell Transplantation, and Prophylactic Donor Lymphocyte Transfusion in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome. J Clin Oncol 2005;23(24):5675–87.

24. Jedlickova Z., Schmid C., Koenecke C. et al. Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation. Bone Marrow Transplant 2016;51(5):663–7.

25. Detrait M.Y., Chevallier P., Sobh M. et al. Outcome of high-risk and refractory AML/MDS patients receiving a FLAMSA sequential chemotherapy regimen followed by reduced- intensity conditioning (RIC) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) [abstract]. Blood 2011;118(21):1957.

26. Cantú-Rodríguez O.G., Jaime-Pérez J.C., Gutiérrez-Aguirre C.H. et al. Outpatient allografting using non-myeloablative conditioning: the Mexican experience. Bone Marrow Transplant 2007;40(2):119–23.

27. Cantú-Rodríguez O.G., Gutiérrez-Aguirre C.H., Jaime-Pérez J.C. et al. Low incidence and severity of graft-versus-host disease after outpatient allogeneic peripheral blood stem cell transplantation employing a reduced-intensity conditioning. Eur J Haematol 2011;87(6):521–30.

28. Storb R., Gyurkocza B., Storer B.E. et al. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. J Clin Oncol 2013;31(12):1530–8.

29. Gyurkocza B., Storb R., Storer B.E. et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol 2010;28(17):2859–67.

30. Sorror M.L., Maris M.B., Storb R. et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106(8):2912–9.

31. Armand P., Gibson C.J., Cutler C. et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood 2012;120(4):905–13.

32. Armand P., Kim H.T., Logan B.R. et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 2014;123(23):3664–71.

33. Slack J.L., Dueck A.C., Fauble V.D. et al. Reduced toxicity conditioning and allogeneic stem cell transplantation in adults using fludarabine, carmustine, melphalan, and antithymocyte globulin: outcomes depend on disease risk index but not age, comorbidity score, donor type, or human leukocyte antigen mismatch. Biol Blood Marrow Transplant 2013;19(8):1167–74.

34. Storb R., Gyurkocza B., Storer B.E. et al. Allogeneic hematopoietic cell transplantation following minimal intensity conditioning: predicting acute graft-versus-host disease and graft-versus-tumor effects. Biol Blood Marrow Transplant 2013;19(5):792–8.

35. Khouri I.F., Wei W., Korbling M. et al. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood 2014;124(14):2306–12.

36. Laport G.G., Wu J., Logan B. et al. Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and High-Dose Rituximab for Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma: A Phase Two Multicenter Trial from the Blood and Marrow Transplant Clinical Trials Network. Biol Blood Marrow Transplant 2016;22(8):1440–8.

37. Anderlini P., Saliba R.M., Ledesma C. et al. Gemcitabine, Fludarabine, and Melphalan for Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma. Biol Blood Marrow Transplant 2016;22(7):1333–7.

38. Cruijsen M., Hobo W., van der Velden W.J. et al. Addition of 10-Day Decitabine to Fludarabine/Total Body Irradiation Conditioning is Feasible and Induces Tumor-Associated

39. Antigen-Specific T Cell Responses. Biol Blood Marrow Transplant 2016;22(6):1000–8.

40. Jiang H., Xu L.-P., Liu D.-H. et al. Allogeneic hematopoietic SCT in combination with tyrosine kinase inhibitor treatment compared with TKI treatment alone in CML blast crisis. Bone Marrow Transplant 2014;49(9):1146–54.

41. Ryan C.E., Sahaf B., Logan A.C. et al. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood 2016;128(25):2899–2908.

42. Pagel J.M., Gooley T.A., Rajendran J. et al. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood 2009;114(27):5444–53.

43. Mawad R., Gooley T.A., Rajendran J.G. et al. Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome. Biol Blood Marrow Transplant 2014;20(9):1363–8.

44. Chhabra A., Ring A.M., Weiskopf K. et al. Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy. Sci Transl Med 2016;8(351):351ra105.

45. Gómez-Almaguer D. The simplification of the SCT procedures in developing countries has resulted in cost-lowering and availability to more patients. Int J Hematol 2002;76 Suppl 1:380–2.

46. Ruiz-Delgado G.J., Ruiz-Argüelles G.J. A Mexican way to cope with stem cell grafting. Hematol Amst Neth 2012;17 Suppl 1:S195–7.

47. Holtick U., Albrecht M., Chemnitz J.M. et al. Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev 2014;(4):CD010189.

48. Gragert L., Eapen M., Williams E. et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med 2014;371(4):339–48.

49. Weisdorf D., Spellman S., Haagenson M. et al. Classification of HLA-matching for retrospective analysis of unrelated donor transplantation: revised definitions to predict survival. Biol Blood Marrow Transplant 2008;14(7):748–58.

50. Handgretinger R. New approaches to graft engineering for haploidentical bone marrow transplantation. Semin Oncol 2012;39(6):664–73.

51. Lang P., Teltschik H.-M., Feuchtinger T. et al. Transplantation of CD3/CD19 depleted allografts from haploidentical family donors in paediatric leukaemia. Br J Haematol 2014;165(5):688–98.

52. Maschan M., Shelikhova L., Ilushina M. et al. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant 2016;51(5):668–74.

53. Kaynar L., Demir K., Turak E.E. et al. TcRαβ-depleted haploidentical transplantation results in adult acute leukemia patients. Hematology 2017;22(3):136–44.

54. Aversa F., Terenzi A., Tabilio A. et al. Full haplotype-mismatched hematopoietic stemcell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol 2005;23(15):3447–54.

55. Lu D.-P., Dong L., Wu T. et al. 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.

56. Huang X.-J., Liu D.-H., Liu K.-Y. et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 2006;38(4):291–7.

57. Huang X.-J., Liu D.-H., Liu K.-Y. et al. Treatment of Acute Leukemia with Unmanipulated HLA-Mismatched/Haploidentical Blood and Bone Marrow Transplantation. Biol Blood Marrow Transplant 2009;15(2):257–65.

58. Bartolomeo P.D., Santarone S., Angelis G.D. et al. Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation for patients with high-risk hematologic malignancies. Blood 2013;121(5):849–57.

59. Martelli M.F., Ianni M.D., Ruggeri L. et al. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood 2014;124(4):638–44.

60. Triplett B.M., Shook D.R., Eldridge P. et al. Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies. Bone Marrow Transplant 2015;50(7):968–77.

61. Bachanova V., Cooley S., Defor T.E. et al. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood 2014;123(25):3855–63.

62. Shi J., Tricot G., Szmania S. et al. Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation. Br J Haematol 2008;143(5):641–53.

63. Locatelli F., Merli P., Rutella S. At the Bedside: Innate immunity as an immunotherapy tool for hematological malignancies. J Leukoc Biol 2013;94(6):1141–57.

64. Rubnitz J.E., Inaba H., Ribeiro R.C. et al. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol 2010;28(6):955–9.

65. Curti A., Ruggeri L., D’Addio A. et al. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 2011;118(12):3273–9.

66. Meller B., Frohn C., Brand J.-M. et al. Monitoring of a new approach of immunotherapy with allogenic (111)In-labelled NK cells in patients with renal cell carcinoma. Eur J Nucl Med Mol Imaging 2004;31(3):403–7.

67. Luznik L., Jones R.J., Fuchs E.J. High dose cyclophosphamide for GVHD prevention. Curr Opin Hematol 2010;17(6):493–9.

68. Ciurea S.O., Zhang M.-J., Bacigalupo A.A. et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood 2015;126(8):1033–40.

69. McCurdy S.R., Kanakry J.A., Showel M.M. et al. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood 2015;125(19):3024–31.

70. Kasamon Y.L., Luznik L., Leffell M.S. 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(4):482–9.

71. Kanakry J.A., Kasamon Y.L., Bolaños-Meade J. et al. Absence of post-transplantation lymphoproliferative disorder after allogeneic blood or marrow transplantation using post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant 2013;19(10):1514–7.

72. Ruggeri A., Sun Y., Labopin M. et al. Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant. Haematologica 2017;102(2):401–410.

73. Rubio M.T., Savani B.N., Labopin M. et al. Impact of conditioning intensity in T-replete haplo-identical stem cell transplantation for acute leukemia: a report from the acute leukemia working party of the EBMT. J Hematol Oncol 2016;9:25.

74. Raiola A.M., Dominietto A., Ghiso A. et al. Unmanipulated Haploidentical Bone Marrow Transplantation and Posttransplantation Cyclophosphamide for Hematologic Malignancies after Myeloablative Conditioning. Biol Blood Marrow Transplant 2013;19(1):117–22.

75. Пирогова О.В., Моисеев И.С., Бабенко Е.В. и др. Профилактика острой реакции «трансплантат против хозяина» после аллогенной неродственной трансплантации гемопоэтических стволовых клеток: сравнение эффективности программ на основе антитимоцитарного глобулина или циклофосфамида. Клиническая онкогематология 2016;9(4):391–7. [Pirogova O.V., Moiseev I.S., Babenko E.V. Prevention of acute graft-versus-host reaction after allogeneic unrelated hematopoietic stem cell transplantation: comparison of effectiveness of treatment regimens based on anti-thymocyte globulin and cyclophosphamide. Klinicheskaya onkogematologiya = Clinical Oncohematology 2016;9(4):391–7. (In Russ.)].

76. Grosso D., Carabasi M., Filicko-O’Hara J. et al. A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing. Blood 2011;118(17):4732–9.

77. Grosso D., Gaballa S., Alpdogan O. et al. A two-step approach to myeloablative haploidentical transplantation: low nonrelapse mortality and high survival confirmed in patients with earlier stage disease. Biol Blood Marrow Transplant 2015;21(4):646–52.

78. Symington F.W., Symington B.E., Liu P.Y. et al. The relationship of serum IL-6 levels to acute graft-versus-host disease and hepatorenal disease after human bone marrow transplantation. Transplantation 1992;54(3):457–62.

79. Wall D.A., Sheehan K.C. The role of tumor necrosis factor and interferon gamma in graft-versus-host disease and related immunodeficiency. Transplantation 1994;57(2):273–9.

80. Heine A., Held S.A.E., Daecke S.N. et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013;122(7):1192–202.

81. Spoerl S., Mathew N.R., Bscheider M. et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014;123(24):3832–42.

82. Choi J., Cooper M.L., Alahmari B. et al. Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect. PloS One 2014;9(10):e109799.

83. PTCy and Ruxolitinib GVHD Prophylaxis in Myelofibrosis - Full Text View - ClinicalTrials.gov. [https://clinicaltrials.gov/ct2/show/NCT02806375].

84. Zeiser R., Burchert A., Lengerke C. et al. Ruxolitinib in corticosteroid-refractory graftversus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia 2015;29(10):2062–8.

85. de Lima M., Giralt S., Thall P.F. et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer 2010;116(23):5420–31.

86. Schroeder T., Czibere A., Platzbecker U. et al. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia 2013;27(6):1229–35.

87. Schroeder T., Rachlis E., Bug G. et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions--a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant 2015;21(4):653–60.

88. Sánchez-Abarca L.I., Gutierrez-Cosio S., Santamaría C. et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood 2010;115(1):107–21.

89. Koreth J., Stevenson K.E., Kim H.T. et al. Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation. J Clin Oncol 2012;30(26):3202–8.

90. Lazarus H.M., Koc O.N., Devine S.M. et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant 2005;11(5):389–98.

91. Macmillan M.L., Blazar B.R., DeFor T.E., Wagner J.E. Transplantation of ex-vivo culture-expanded parental haploidentical mesenchymal stem cells to promote engraftment in pediatric recipients of unrelated donor umbilical cord blood: results of a phase I-II clinical trial. Bone Marrow Transplant 2009;43(6):447–54.

92. Poloni A., Leoni P., Buscemi L. et al. Engraftment capacity of mesenchymal cells following hematopoietic stem cell transplantation in patients receiving reduced-intensity conditioning regimen. Leukemia 2006;20(2):329–35.

93. Wu Y., Wang Z., Cao Y. et al. Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells with a myeloablative regimen for refractory/relapsed hematologic malignancy. Ann Hematol 2013;92(12):1675–84.

94. Di Stasi A., Milton D.R., Poon L.M. et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant 2014;20(12):197–81.

95. Raiola A.M., Dominietto A., di Grazia C. et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant 2014;20(10):1573–9.

96. Mo X.-D., Tang B.-L., Zhang X.-H. et al. Comparison of outcomes after umbilical cord blood and unmanipulated haploidentical hematopoietic stem cell transplantation in children with high-risk acute lymphoblastic leukemia. Int J Cancer 2016;139(9):2106–15.

97. Субботина Н.Н., Долгополов И.С., Попа А.В. и др. Гаплоидентичная трансплантация гемопоэтических стволовых клеток у детей с острыми миелоидными лейкозами: эволюция метода и собственные данные. Клиническая онкогематология 2014;7(2):131–6. [Subbotina N.N., Dolgopolov I.S., Popa A.V. et al. Haploidentical hematopoietic stem cell transplantation in children with acute myeloid leukemia: evolution of method and our data. Klinicheskaya onkogematologiya = Clinical Oncohematology 2014;7(2):131–6. (In Russ.)].

98. Carapito R., Jung N., Kwemou M. et al. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD. Blood 2016;128(15):1979–86.

99. Ringdén O., Labopin M., Ciceri F. et al. Is there a stronger graft-versus-leukemia effect using HLA-haploidentical donors compared with HLA-identical siblings? Leukemia 2016;30(2):447–55.

100. Gluckman E., Broxmeyer H.A., Auerbach A.D. et al. Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 1989;321(17):1174–8.

101. Kekre N., Antin J.H. Hematopoietic stem cell transplantation donor sources in the 21st century: choosing the ideal donor when a perfect match does not exist. Blood 2014;124(3):334–43.

102. Milano F., Gooley T., Wood B. et al. Cord-Blood Transplantation in Patients with Minimal Residual Disease. N Engl J Med 2016;375(10):944–53.

103. Hayani A., Lampeter E., Viswanatha D. et al. First report of autologous cord blood transplantation in the treatment of a child with leukemia. Pediatrics 2007;119(1):e296–300.

104. Porter D.L. Allogeneic immunotherapy to optimize the graft-versus-tumor effect: concepts and controversies. Hematology Am Soc Hematol Educ Program 2011;2011:292–8.

105. Nikiforow S., Alyea E.P. Maximizing GVL in allogeneic transplantation: role of donor lymphocyte infusions. Hematology Am Soc Hematol Educ Program 2014;2014(1):570–5.

106. Porter D.L., Collins R.H., Shpilberg O. et al. Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions. Biol Blood Marrow Transpl 1999;5(4):253–61.

107. Krishnamurthy P., Potter V.T., Barber L.D. et al. Outcome of Donor Lymphocyte Infusion after T Cell–depleted Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndromes. Biol Blood Marrow Transpl 2013;19(4):562–8.

108. O’Reilly R.J., Lacerda J.F., Lucas K.G. et al. Adoptive cell therapy with donor lymphocytes for EBV-associated lymphomas developing after allogeneic marrow transplants. Important Adv Oncol 1996:149–66.

109. Heslop H.E., Slobod K.S., Pule M.A. et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 2010;115(5):925–35.

110. Bollard C.M., Gottschalk S., Torrano V. et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol 2014;32(8):798–808.

111. Leen A.M., Myers G.D., Sili U. et al. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat Med 2006;12(10):1160–6.

112. Leen A.M., Heslop H.E., Brenner M.K. Antiviral T-cell therapy. Immunol Rev 2014;258(1):12–29.

113. Deo S.S., Gottlieb D.J. Adoptive T-cell therapy for fungal infections in haematology patients. Clin Transl Immunol 2015;4(8):e40.

114. Weber G., Caruana I., Rouce R.H. et al. Generation of Tumor Antigen-Specific T Cell Lines from Pediatric Patients with Acute Lymphoblastic Leukemia – Implications for Immunotherapy. Clin Cancer Res 2013;19(18):5079–91.

115. Weber G., Gerdemann U., Caruana I. et al. Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant. Leukemia 2013;27(7):1538–47.

116. Bornhäuser M., Thiede C., Platzbecker U. et al. Prophylactic transfer of BCR-ABL-, PR1-, and WT1-reactive donor T cells after T cell-depleted allogeneic hematopoietic cell transplantation in patients with chronic myeloid leukemia. Blood 2011;117(26):7174–84.

117. Gerdemann U., Katari U., Christin A.S. et al. Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat EBV negative lymphoma. Mol Ther 2011;19(12):2258–68.

118. Shafer J.A., Cruz C.R., Leen A.M. et al. Antigen-specific cytotoxic T lymphocytes can target chemoresistant side-population tumor cells in Hodgkin lymphoma. Leuk Lymphoma 2010;51(5):870–80.

119. Dudley M.E., Rosenberg S.A. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 2003;3(9):666–75.

120. Rosenberg S.A., Restifo N.P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348(6230):62–8.

121. Noonan K.A., Huff C.A., Davis J. et al. Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci Transl Med 2015;7(288):288ra78.

122. Ochi T., Fujiwara H., Okamoto S. et al. Novel adoptive T-cell immunotherapy using a WT1-specific TCR vector encoding silencers for endogenous TCRs shows marked ntileukemia

123. reactivity and safety. Blood 2011;118(6):1495–503.

124. Tawara I., Masuya M., Kageyama S. et al. Adoptive Transfer of WT1-Specific TCR Gene-Transduced Lymphocytes in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia. ASH Annual Meeting – 2015. Abstr. 97.

125. Koehne G., Kosuri S., Doubrovina E. et al. Wilms’ Tumor 1 Protein Is Highly Expressed on Malignant Plasma Cells and Provides a Novel Target for Immuno-therapeutic Approaches. ASH Annual Meeting – 2015. Abstr. 98.

126. Rapoport A.P., Stadtmauer E.A., Binder-Scholl G.K. et al. NY-ESO-1 specific TCR engineered T-cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med 2015;21(8):914–21.

127. Bacigalupo A., Sica S. HLA Haplotype Mismatch Transplants and Posttransplant Cyclophosphamide. Adv Hematol 2016;2016:7802967.

128. Nagler A., Labopin M., Gorin N.-C. et al. Intravenous busulfan for autologous stem cell transplantation in adult patients with acute myeloid leukemia: a survey of 952 patients on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Haematologica 2014;99(8):1380–6.

129. Claude Gorin N. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias. Semin Hematol 2016;53(2):103–10.

130. 128. Dai H., Wang Y., Lu X., Han W. Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy. J Natl Cancer Inst 2016;108(7):djv439.

131. Maus M.V., Grupp S.A., Porter D.L., June C.H. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 2014;123(17):2625–35.

132. Chu J., Deng Y., Benson D.M. et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia 2014;28(4):917–27.

133. Jiang H., Zhang W., Shang P. et al. Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Mol Oncol 2014;8(2):297–310.

134. Roberts M.R., Cooke K.S., Tran A.C. et al. Antigen-specific cytolysis by neutrophils and NK cells expressing chimeric immune receptors bearing zeta or gamma signaling domains. J Immunol 1998;161(1):375–84.

135. Badowski M.S., Zhang T., Tsang T.C., Harris D.T. Chimeric antigen receptors for stem cell based immunotherapy. J Exp Ther Oncol 2009;8(1):53–63.

136. Gschweng E., Oliveira S.D., Kohn D.B. Hematopoietic Stem Cells for Cancer Immunotherapy. Immunol Rev 2014;257(1):237–49.

137. https://clinicaltrials.gov/ct2/results?term=CAR+T&Search=Search.

138. Шишкин А.М. Разработка метода адоптивной иммунотерапии раковоэмбриональный антиген позитивных опухолей человека. Дис. … канд. мед. наук. М., 2015. 128 с. [Shishkin A.M. Development of the method of adoptive immunotherapy for cancer-embryonic antigen of positive human tumors. Dissert. D. Sci. Moscow, 2015. 128 p. (In Russ.)].

139. DeWitt M.A., Magis W., Bray N.L. et al. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. Sci Transl Med 2016;8(360):360ra134.

140. Ye L., Wang J., Tan Y. et al. Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia. Proc Natl Acad Sci USA. 2016;113(38):10661–5.

141. Wang J., Quake S.R. RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection. Proc Natl Acad Sci USA. 2014;111(36):13157–62.

142. Khan F.A., Pandupuspitasari N.S., Chun-Jie H. et al. CRISPR/Cas9 therapeutics: a cure for cancer and other genetic diseases. Oncotarget 2016;7(32):52541–52.

143. Hu X. CRISPR/Cas9 system and its applications in human hematopoietic cells. Blood Cells Mol Dis 2016;62:6–12.

144. Porteus M.H. Genome Editing of the Blood: Opportunities and Challenges. Curr Stem Cell Rep 2015;1(1):23–30.

145. Jiang Z., Han Y., Cao X. Induced pluripotent stem cell (iPSCs) and their application in immunotherapy. Cell Mol Immunol 2014;11(1):17–24.