Гаплоидентичная трансплантация гемопоэтических стволовых клеток у детей с острыми миелоидными лейкозами: эволюция метода и собственные данные

ТРАНСПЛАНТАЦИЯ КОСТНОГО МОЗГА , ,

Н.Н. Субботина, И.С. Долгополов, А.В. Попа, В.К. Бояршинов, Р.И. Пименов, Г.Л. Менткевич

НИИ детской онкологии и гематологии ФГБУ «РОНЦ им. Н.Н. Блохина» РАМН, Москва, Российская Федерация

РЕФЕРАТ

В настоящей работе представлены результаты проведения гаплоидентичной трансплантации гемопоэтических стволовых клеток (гаплоТГСК) детям с острыми миелоидными лейкозами (ОМЛ) крайне неблагоприятного прогноза. В исследование включено 18 пациентов в возрасте 1–18 лет. Статус заболевания на момент трансплантации: ОМЛ высокого риска в первой ремиссии (n = 4, 22 %), более двух ремиссий (n = 7, 39 %), не в ремиссии (n = 4, 22 %), вторичный ОМЛ в ремиссии (n = 3, 17 %). Всем пациентам был проведен немиелоаблативный режим кондиционирования с последующей гаплоТГСК от гаплоидентичных доноров. За счет донорского материала показатели крови восстановились у 17 из 18 пациентов: лейкоциты — в среднем на 11-й день, тромбоциты — на 12-й. От прогрессирования заболевания и инфекции без признаков восстановления кроветворения умерла 1 больная из группы «не в ремиссии на момент гаплоТГСК». Токсические проявления режима были незначительными. Острая реакция «трансплантат против хозяина» I–II степени отмечена у 88 % пациентов, III степени — у 6 %. Проявления хронической реакции «трансплантат против хозяина» наблюдались у 85 % реципиентов, у 1 больной — в тяжелой форме. Причины смертности: инфекция (n = 2, 11 %), рецидив/прогрессирование опухоли (n = 5, 28 %). Остаются под наблюдением без признаков заболевания 11 (61 %) пациентов. При среднем сроке наблюдения 84 мес. (диапазон 1–144 мес.) бессобытийная выживаемость равна 57,5 % Трансплантационная летальность составила 13,3 % при среднем сроке наблюдения 124 мес.

Ключевые слова: острые миелоидные лейкозы у детей, неблагоприятный прогноз, гаплоидентичная трансплантация гемопоэтических стволовых клеток.

Читать статью в PDF pdficon

ЛИТЕРАТУРА

  1. Rubnitz J.E. Childhood acute myeloid leukemia. Curr. Treat. Options Oncol. 2008; 9: 95–105.
  2. Creutzig U., Zimmermann M., Henze G. et al. Treatment strategies and long-term results in paediatric patients treated in four consecutive AML BFM trials. Leukemia 2005; 19(12): 2030–42.
  3. Perel Y., Auvrignon A., Vannier J.P. et al. Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit—multicenter studies of the French LAME (Leucemie Aigue Myeloblastique Enfant) Cooperative Group. Leukemia 2005; 19(12): 2082–9.
  4. August K.J., Narendran A., Neville K.A. Pediatric Relapsed or Refractory Leukemia: New Pharmacotherapeutic Developments and Future Directions. Drugs 2013; 73: 439–61.
  5. Grimwade D., Walker H., Oliver F. et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998; 92: 2322–33.
  6. Gorman M.F., Ji L., Hutchinson R. et al. Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): a Therapeutic Advances in Childhood Leukemia (TACL) Consortium study. Pediatr. Blood Cancer 2010; 55(3): 421–9.
  7. Liu D.-H., Xu L.-P., Liu K.-Y. et al. Long-term outcomes of unmanipulated haploidentical HSCT for paediatric patients with acute leukaemia. Bone Marrow Transplant. 2013; 48: 1519–24.
  8. Shaw P.J., Kan F., Pulsipher M.A. et al. Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors. Blood 2010; 116: 4007–15.
  9. Gluckman E., Vanderson R., William A. et al. Outcome of cord-blood transplantation from related and unrelated donors. N. Engl. J. Med. 1997; 337(6): 373–81.
  10. Kurtzberg J., Laughlin M., Graham M.L. et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N. Engl. J. Med. 1996; 335: 157–66.
  11. Wagner J.E., Rosenthal J., Sweetman R. et al. Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood 1996; 88: 795–802.
  12. Silberstein L.E., Jefferies L.C. Placental-blood banking — a new frontier in transfusion medicine. N. Engl. J. Med. 1996; 335: 199–201.
  13. Rubinstein P., Rosenfield R.E., Stevens C.E. Stored placental blood for unrelated bone marrow reconstitution. Blood 1993; 81: 1679–90.
  14. Rubinstein P., Dobrila L., Rosenfield R.E. et al. Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc. Natl. Acad. Sci. U S A 1995; 92: 10119–22.
  15. Rocha V., Gluckman E., Frassoni F. et al. Unrelated cord blood transplantation: outcomes after single-unit intrabone injection compared with double-unit intravenous injection in patients with hematological malignancies. Transplantation 2013; 95(10): 1284–91.
  16. Page K.M., Zhang L., Kurtzberg J. et al. Total colony-forming units are a strong, independent predictor of neutrophil and platelet engraftment after unrelated umbilical cord blood transplantation: a single-center analysis of 435 cord blood transplants. Biol. Blood Marrow Transplant. 2011; 17(9): 1362–74.
  17. Barker J.N., Scaradavou A., Stevens C.E. Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood 2010; 115: 1843–9.
  18. Sideri A., Neokleous N., Gluckman E. An overview of the progress on double umbilical cord blood transplantation. Haematologica 2011; 96(8): 1213–20.
  19. Rocha V., Crotta A., Gluckman E. et al. Double cord blood transplantation: extending the use of unrelated umbilical cord blood cells for patients with hematological diseases. Best Pract. Res. Clin. Haematol. 2010; 23(2): 223–9.
  20. Powles R.L., Morgenstern G.R., Robinson B. et al. Mismatched family donors for bone marrow transplantation as treatment for acute leukaemia. Lancet 1983; 1: 612.
  21. Beatty P.G., Clift R.A., Storb R. et al. Marrow transplantation from related donors other than HLA identical siblings. N. Engl. J. Med. 1985; 313: 765.
  22. Hows J.M., Yin J.L., Goldman J.M. et al. Histocompatible unrelated volunteer donors compared with HLA nonidentical family donors in marrow transplantation for aplastic anemia and leukemia. Blood 1986; 68(6): 1322–8.
  23. Reisner Y., Kapoor N., Good R.A. et al. Transplantation for acute leukeamia with HLA-A and B non identical parental marrow cells fractionated with soybean agglutinin and sheep red blood cells. Lancet 1981; 2(8242): 327–31.
  24. Mehta J., Singhal S., Gee A.P. et al. Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients. Bone Marrow Transplant. 2004; 33: 389–96.
  25. O’Reilly R.J., Kernan N.A., Cunningham I. Allogeneic transplants depleted of T cells by soybean lectin agglutination and E-rosette depletion. Bone Marrow Transplant. 1988; 3: 3–6.
  26. Schwartz E., Lapidot T., Reisner Y. et al. Abrogation of bone marrow allograft resistance in mice by increased total body irradiation correlates with eradication of host clonable T cells and alloreactive cytotoxic precursors. J. Immunol. 1987; 138(2): 460–5.
  27. Terenzi A., Lubin I., Rabi I. et al. Enhancement of T-cell depleted bone marrow allografts inmice by thiotepa. Transplantation 1990; 50(4): 717–20.
  28. Cobbold S.P., Martin G., Waldmann H. et al. Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance. Nature 1986; 323(6084): 164–6.
  29. Reisner Y., Itzicovitch L., Sharon N. et al. Hematopoietic stem cell transplantation using mouse bone-marrow and spleen cells fractionated by lectins. Proc. Natl. Acad. Sci. U S A 1978; 75(5): 2933–6.
  30. Aversa F., Tabilio A., Giannoni C. et al. Successful engraftment of T-celldepleted haploidentical “threeloci” 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(11): 3948–55.
  31. Aversa F., Terenzi 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(15): 3447–54.
  32. Schumm M., Lang P., Taylor G. et al. Isolation of highly purified autologous and allogeneic peripheral CD34+ cells using the CliniMACS device. J. Hematother. 1999; 8: 209–18.
  33. Klingebiel T., Cornish J., Labopin M. et al. Pediatric Diseases and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT). Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group. Blood 2010; 115: 3437–46.
  34. Ciceri F., Labopin M., Rocha V. et al. 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 highrisk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood 2008; 112(9): 3574–81.
  35. Barfield R.C., Otto M., Houston J. et al. A one-step large-scale method for T- and B-cell depletion of mobilized PBSC for allogeneic transplantation. Cytotherapy 2004; 6: 1–6.
  36. Oevermann L., Handgretinger R. New strategies for haploidentical transplantation. Pediatr. Res. 2012; 71(4 Pt. 2): 418–26.
  37. Hale G.A., Kasow K., Gan K. et al. Haploidentical Stem Cell Transplantation with CD3 Depleted Mobilized Peripheral Blood Stem Cell Grafts for Children with Hematologic Malignancies. 47th Annual Meeting of the American Society of Hematology, 10–13 December 2005, Atlanta, GA, USA.
  38. Hale G.A., Kasow K., Madden R. et al. Mismatched family member donor transplantation for patients with refractory hematologic malignancies: Long-term follow-up of a prospective clinical trial. 48th Annual Meeting of the American Society of Hematology, 9–12 December 2006, Orlando, FL, USA.
  39. Handretinger R., Chen X., Lang P. et al. Feasibility and Outcome of Reduced-Intensity Conditioning in Haploidentical Transplantation. Ann. N.Y. Acad. Sci. 2007; 1106: 279–89.
  40. Federmann B., Handgretinger R., Bethge W.A. et al. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study. Haematologica 2012; 97(10): 1523–31.
  41. Bader P., Koehl U., Klingebiel T. et al. Rapid immune recovery and low TRM in haploidentical stem cell transplantation in children and adolescence using CD3/CD19-depleted stem cells. Best Pract. Res. Clin. Haematol. 2011; 24: 331–7.
  42. Dufort G., Pisano S., Castillo L. et al. Feasibility and outcome of haploidentical SCT in pediatric high risk hematologic malignancies and Fanconianemia in Uruguay. Bone Marrow Transplant. 2012; 47(5): 663–8.
  43. Palma J., Handgretinger R., Rivera G.K. et al. Haploidentical stem cell transplantation for children with high-risk leukemia. Pediatr. Blood Cancer 2012; 59(5): 895–901.
  44. Gonzalez-Vicent M., Ramirez M., Diaz M.A. et al. Graft manipulation and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation from mismatched unrelated and mismatched/haploidentical related donors in pediatric leukemia patients. J. Pediatr. Hematol. Oncol. 2010; 32(3): e85–90.
  45. Oevermann L., Lang P., Handgretinger R. et al. Immune reconstitution and strategies for rebuilding the immune system after haploidentical stem cell transplantation. Ann. N. Y. Acad. Sci. 2012; 1266: 161–70.
  46. Locatelli F., Vinti L., Moretta L. et al. Strategies to optimize the outcome of children given T-cell depleted HLA-haploidentical hematopoietic stem cell transplantation. Best Pract. Res. Clin. Haematol. 2011; 24(3): 339–49.
  47. Azevedo R.I., Soares M.V., Sousa A.E. et al. Long-term immune reconstitution of naive and memory T cell pools after haploidentical hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 2013; 19(5): 703–12.
  48. Handgretinger R. Negative depletion of CD3(+) and TcRab(+) T cells. Curr. Opin. Hematol. 2012; 19(6): 434–9. 49. Bonneville M., O’Brien R.L., Born W.K. Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nat. Rev. Immunol. 2010; 10: 467–78.
  49. Chiplunkar S., Dhar S., Wesch D., Kabelitz D. Gammadelta T cells in cancer immunotherapy: current status and future prospects. Immunotherapy 2009; 1: 663–78.
  50. Godder K.T., Henslee-Downey P.J., Mehta J. et al. Long term diseasefree survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation. Bone Marrow Transplant. 2007; 39: 751–7.
  51. Locatelli F., Bauquet A., Bertaina A. et al. Negative depletion of a/b+ 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 Sep 30.
  52. Dodero A., Carniti C., Raganato A. et al. Haploidentical stem cell transplantation after a reduced-intensity conditioning regimen for the treatment of advanced hematologic malignancies: posttransplantation CD8-depleted donor lymphocyte infusions contribute to improve T-cell recovery. Blood 2009; 113: 4771–9.
  53. Amrolia P.J., Muccioli-Casadei G., Huls H. et al. Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood 2006; 108: 1797–808.
  54. Mielke S., Nunes R., Rezvani K. et al. A clinical-scale selective allodepletion approach for the treatment of HLA-mismatched and matched donor- recipient pairs using expanded T lymphocytes as antigen-presenting cells and a TH9402-based photodepletion technique. Blood 2008; 111: 4392–402.
  55. Feuchtinger T., Matthes-Martin S., Richard C. et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br. J. Haematol. 2006; 134: 64–76.
  56. Feuchtinger T., Opherk K., Bethge W.A. et al. Adoptive transfer of pp65- specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 2010; 116: 4360–7.
  57. Perruccio K., Tosti A., Burchielli E. et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood 2005; 106: 4397–406.
  58. Lugthart G., Albon S.J., Ricciardelli I. et al. Simultaneous generation of multivirus-specific and regulatory T cells for adoptive immunotherapy. J. Immunother. 2012; 35: 42–53.
  59. Di I.M., Falzetti F., Carotti A. et al. Tregs prevent GVHD and promote immune reconstitution in HLA haploidentical transplantation. Blood 2011; 117(14): 3921–8.
  60. Brehm C., Huenecke S., Quaiser A. et al. IL-2 stimulated but not unstimulated NK cells induce selective disappearance of peripheral blood cells: concomitant results to a phase I/II study. PLoS One 2011; 6(11): e27351.
  61. Rizzieri D.A., Storms R., Chen D.F. et al. Natural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation. Biol. Blood Marrow Transplant. 2010; 16: 1107–14.
  62. Passweg J.R., Tichelli A., Meyer-Monard S. et al. Purified donor NKlymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation. Leukemia 2004; 18(11): 1835–8.
  63. 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.
  64. Ji S.Q., Chen H.R., Xun C.Q. et al. G-CSF-primed haploidentical marrow transplantation without ex vivo T cell depletion: an excellent alternative for highrisk leukemia. Bone Marrow Transplant. 2002; 30(12): 861–6.
  65. Lu D.P., Dong L., Liu K.Y. 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. Epub 2005 Dec 27.
  66. Yabe H., Inoue H., Yabe M. et al. Unmanipulated HLA-haploidentical bone marrow transplantation for the treatment of fatal, nonmalignant diseases in children and adolescents. Int. J. Hematol. 2004; 80(1): 78–82.
  67. Ikegame K., Tanji Y., Ogawa H. et al. Successful treatment of refractory T-cell acute lymphoblastic leukemia by unmanipulated stem cell transplantation from an HLA 3-loci mismatched (haploidentical) sibling. Bone Marrow Transplant. 2003; 31(6): 507–10.
  68. Shimazaki C., Ochiai N., Nakagawa M. et al. Non-T-cell-depleted HLA haploidentical stem cell transplantation in advanced hematologic malignancies based on the feto-maternal michrochimerism. Blood 2003; 101(8): 3334–6.
  69. Huang X., Liu D., Zhang X. et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematologic malignancies in children. Biol. Blood Marrow Transplant. 2009; 15(1): 91–4.
  70. Mochizuki K., Kikuta A., Hosoya M. et al. Feasibility of tacrolimus, methotrexate, and prednisolone as a graft-versus-host disease prophylaxis in non-T-cell depleted haploidentical hematopoietic stem cell transplantation for children. Clin. Transplant. 2011; 25(6): 892–7.
  71. Субботина Н. Режимы кондиционирования со сниженной интенсивностью. Современный взгляд и собственный опыт применения в детской онкологии (обзор литературы). Дет. онкол. 2009; 3–4: 3–14. [Subbotina N. Reduced intensity conditioning regimens. Current view and own experience with usage in pediatric oncology (literature review). Det. onkol. 2009; 3–4: 3–14. (In Russ.)].
  72. Leung W., Handgretinger R., Pui C.H. et al. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood 2011; 118(2): 223–30.
  73. Grupp S.A., Kalos M., Barrett D. et al. Chimeric Antigen Receptor– Modified T Cells for Acute Lymphoid Leukemia. N. Engl. J. Med. 2013; 368(16): 1509–18.
  74. Tettamanti S., Marin V., Pizzitola I. et al. Targeting of acute myeloid leukaemia by cytokine-induced killer cells redirected with a novel CD123-specific chimeric antigen receptor. Br. J. Haematol. 2013; 161(3): 389–401.