Иммунотерапия классической лимфомы Ходжкина


DOI: https://dx.doi.org/10.18565/pharmateca.2019.7.64-72

Л.В. Филатова (1, 2)

1) Национальный медицинский исследовательский центр онкологии им. Н.Н. Петрова, Санкт-Петербург, Россия; 2) Северо-Западный государственный медицинский университет им. И.И. Мечникова, Санкт-Петербург, Россия
Высокодозная химиотерапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВДХТ c аутоТГСК) служит современным стандартом лечения первично рефрактерных форм и первых рецидивов лимфомы Ходжкина (ЛХ). ВДХТ с аутоТГСК эффективна для 50–60% пациентов при первом позднем химиочувствительном рецидиве ЛХ.
Современные методы терапии лечения ЛХ с высокой эффективностью и низкой токсичностью особенно актуальны для пациентов с ЛХ, которые не являются кандидатами для ВДХТ с аутоТГСК, а также при возникновении рецидивов ЛХ после ВДХТ с аутоТГСК. Аллогенные трансплантации гемопоэтических стволовых клеток (аллоТГСК) могут проводиться при рецидивах ЛХ после ВДХТ c аутоТГСК с сохраненной химиочувствительностью, предпочтительно для молодых пациентов в рамках проспективных клинических исследований. Брентуксимаб ведотин зарегистрирован для лечения пациентов с классической ЛХ после неудачи (прогрессирование или ранний рецидив) ВДХТ с аутоТГСК или пациентов – не кандидатов для ВДХТ с аутоТГСК, при неудаче двух и более линий химиотерапии (ХТ), для консолидации после ВДХТ с аутоТГСК у пациентов с ЛХ с высоким риском возникновения рецидива или прогрессирования, в терапии первой линии при распространенных стадиях ЛХ, наиболее предпочтительно для молодых пациентов, пациентов с высоким риском возникновения рецидива. Высокая активность отмечена у ингибиторов контрольных точек PD-1/PD-L1, активирующих противоопухолевый иммунитет (ниволумаб, пембролизумаб), у пациентов с рецидивами ЛХ. Терапевтическая эффективность ингибиторов контрольных точек PD-1/PD-L1 не зависит от ответа на предшествовавшие режимы терапии (первичная рефрактерность или рефрактерность к брентуксимабу ведотину). Перспективные направления терапии ЛХ связаны с дальнейшим изучением новых мишеней опухолевых клеток и их сигнальных путей.
Ключевые слова: лимфома Ходжкина, вторая линия терапии («спасения»), высокодозная химиотерапия с аутологичной трансплантацией гемопоэтических стволовых клеток, аллогенная трансплантация гемопоэтических стволовых клеток, брентуксимаб ведотин, ниволумаб, пембролизумаб

Литература


1. Diehl V., Franklin J., Pfreundschuh M., Lathan B.,et al. Standard and increased–dose BEACOPP chemotherapy compared with COPP–ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348:2386–95. Doi: 10.1056/NEJMoa022473.

2. Engert A., Diehl V., Franklin J., et al. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol 2009;27:4548–54. Doi: 10.1200/JCO.2008.19.8820.

3. Armitage J.O. Early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363:653–62. Doi: 10.1056/NEJMra1003733

4. Schmitz N., Pfistner B., Sextro M., et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomized trial. Lancet. 2002;359:2065–71. Doi: 10.1016/S0140-6736(02)08938-9.

5. Majhail N.S., Weisdorf D.J., Defor T.E., et al. Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin’s lymphoma. Biol Blood Marrow Transplant. 2006;12:1065–72. Doi: 10.1016/j.bbmt.2006.06.006.

6. Sureda A., Constans M., Iriondo A., et al. Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin’s lymphoma autografted after a first relapse. Ann Oncol. 2005;16:625–33. Doi: 10.1093/annonc/mdi119

7. Horning S.J., Chao N.J., Negrin R.S., et al. High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: analysis of the Stanford University results and prognostic indices. Blood. 1997;89:801–13.

8. Lavoie J.C., Connors J.M., Phillips G.L., et al. High-dose therapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver. Blood. 2005;106:1473–78. Doi: 10.1182/blood-2004-12-4689.

9. Gerrie A.S., Power M.M., Shepherd J.D., et al. Chemoresistance can be overcome with high-dose chemotherapy and autologous stem-cell transplantation for relapsed and refractory Hodgkin lymphoma. Ann Oncol. 2014;25:2218–23. Doi: 10.1093/annonc/mdu387.

10. Arai S., Fanale M., DeVos S., et al. Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leuk Lymphoma. 2013;54(11):2531–33. Doi: 10.3109/10428194.2013.798868.

11. Reyal Y., Kayani I., Bloor A.J., et al. Impact of pretransplantation (18)F-fluorodeoxyglucose-positron emission tomography on survival outcomes after T cell-depleted allogeneic transplantation for Hodgkin lymphoma. Biol Blood Marrow Transplant. 2016;22(7):1234–41. Doi: 10.1016/j.bbmt.2016.03.034

12. Farina L., Castagna L., Farina L., et al. Allogeneic transplantation improves the overall and progression–free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood. 2010;115:3671–77. Doi: 10.1182/blood-2009-12-253856.

13. Thomson K.J., Peggs K.S., Smith P., et al. Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin’s lymphoma following autologous stem cell transplantation. Bone Marrow Transplant. 2008;41(9):765–70. Doi: 10.1038/sj.bmt.1705977.

14. Sarina B., Castagna L., Farina L., et al; Gruppo Italiano Trapianto di Midollo Osseo. Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood. 2010;115(18): 3671–77. Doi: 10.1182/blood-2009-12-253856.

15. Younes A., Bartlett N.L., Leonard J.P., et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363:1112–21. Doi: 10.1056/NEJMoa1002965.

16. Fanale M.A., Forero-Torres A., Rosenblatt J.D., et al. A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive Hematologic Malignancies. Clin Cancer Res. 2012;18:248–55. Doi: 10.1158/1078-0432.CCR-11-1425.

17. Younes A., Gopal A.K., Smith S.E., et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30:2183–89. Doi: 10.1200/JCO.2011.38.0410.

18. Gopal A.K., Chen R., Smith S.E., et al. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood. 2015;125:1236–43. Doi: 10.1182/blood-2014-08-595801.

19. Chen R., Gopal A.K., Smith S.E., et al. Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2016; 128(12):1562–66. Doi: 10.1182/blood-2016-02-699850.

20. Perrot A., Monjanel H., Bouabdallah R., et al. Lymphoma Study Association (LYSA). Impact of post-brentuximab vedotin consolidation on relapsed/refractory CD30+ Hodgkin lymphomas: a large retrospective study on 240 patients enrolled in the French Named-Patient Program. Haematologica. 2016;101:466–73. Doi: 10.3324/haematol.2015.134213.

21. Moskowitz C.H., Nadamanee A., Masszi T., et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385:1853–62. Doi: 10.1016/S0140-6736(15)60165-9.

22. Moskowitz A.J., Schöder H., Gavane S., et al. Baseline metabolic tumor volume is an independent prognostic factor for relapsed and refractory Hodgkin lymphoma patients receiving PET-adapted salvage therapy with brentuximab vedotin and augmented ICE

23. Herrera A., Palmer J.M., Martin P., et al. Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Ann Oncol. 2017;29: 724–30. Doi: 10.1093/annonc/mdx791.

24. Herrera A.F., Moskowitz A.J., Bartlett N.L., et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018;131:1183–94. Doi: https://doi.org/10.1182/blood-2017-10-811224.

25. LaCasce A.S., Bociek G., Sawas A., et al. Brentuximab Vedotin Plus Bendamustine: A Highly Active Salvage Treatment Regimen for Patients with Relapsed or Refractory Hodgkin Lymphoma. Blood. 2015;126(23):3982.

26. Garcia-Sanz R., Sureda A., Gonzalez A.P., et al. Brentuximab vedotin plus ESHAP (BRESHAP) is a highly effective combination for inducing remission in refractory and relapsed Hodgkin lymphoma patients prior to autologous stem cell transplant: a trial of the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO). Blood. 2016;128:1109.

27. Cassaday R.D., Fromm J., Cowan A.J., et al. Safety and activity of brentuximab vedotin (BV) plus ifosfamide, carboplatin, and etoposide (ICE) for rel/ref (rel/ref) classical Hodgkin lymphoma (cHL): initial results of a phase I/II trial. Blood. 2016;128:1834.

28. Hagenbeek A., Zijlstra J., Lugtenburg P., et al. Transplant brave: combining brentuximab vedotin with DHAP as salvage treatment in rel/ref Hodgkin lymphoma. A phase 1 dose-escalation study. Haematologica. 2016;101:44.

29. Younes A., Сonnors J.M., Park S.I., et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study. Lancet. Oncology. 2013;14:1348–56. Doi: 10.1016/S1470-2045(13)70501-1.

30. Connors J.M., Ansell S.M., Fanale M., et al. Five- year follow-up of brentuximab vedotin combined with ABVD or AVD for advanced-stage classical Hodgkin lymphoma. Blood. 2017;130:1375–77. Doi: 10.1182/blood-2017-05-784678.

31. Connors J.M., Jurczak W., Staus D.J., et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378:331–44. Doi: 10.1056/NEJMoa1708984.

32. Eichenauer D.A., Plutxchow A., Kreissl S., et al. Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin’s lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group. Lancet. Oncol. 2017;18:1680–87. Doi: 10.1016/S1470-2045(17)30696-4.

33. Abramson J.S., Arnason J.E., LaCasce A.S., et al. Brentuximab vedotin plus AVD for non-bulky limited stage Hodgkin lymphoma: a phase II trial. J Clin Oncol. 2015;33(Suppl. 15):850–55.

34. Park S.I., Olajide O., Reddy N.M., et al. Brentuximab vedotin consolidation to reduce radiation use in patients with limited stage non-bulky Hodgkin lymphoma: an update from a phase 2 clinical trial

35. Kumar A., Casulo C., Yahalom J., et al. Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma. Blood. 2016;128: 1458–64. Doi: 10.1182/blood-2016-03-703470.

36. Kumar A., Casulo C., Ranjana H., et al. A pilot study of brentuximab vedotin and AVD chemotherapy followed by 20 Gy involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma. Blood. 2017;130(Suppl. 1):734.

37. Evens A.M., Hong F., Gordon L.I., et al. The efficacy and tolerability of ABVD and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol. 2013;161:76–86. Doi: 10.1111/bjh.12222.

38. Forero-Torres A., Holkova B., Goldschmidt J., et al. Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood. 2015;126:2798–804. Doi: 10.1182/blood-2015-06-644336.

39. Gibb A., Pirrie S., Linton K., et al. Results of a phase II study of brentuximab vedotin in the first line treatment of Hodgkin lymphoma patients considered unsuitable for standard chemotherapy (BREVITY). Hemmatol Oncol. 2017;35(Suppl. 2):80–1.

40. Friedberg J.W., Forero-Torres A., Bordoni R.E., et al. Frontline brentuximab vedotin in combination with dacarbazine or bendamustine in patients aged ⩾60 years with HL. Blood. 2017;130(26):2829–37. Doi: 10.1182/blood-2017-06-787200.

41. Gallamini A., Rambaldi A., Bijou F., et al. A Phase 1/2 clinical trial of brentuximab-vedotin and bendamustine in elderly patients with previously untreated advanced Hodgkin lymphoma (HALO STUDY. NCT identifier, 02467946): preliminary report. Blood. 2016;128:4154.

42. Gallamini A., Bijou F., Viotti J., et al. Brentuximab-vedotin and bendamustine is a feasible and effective drug combination as front-line treatment of Hodgkin lymphoma in the elderly (HALO TRIAL). Hematol Oncol. 2017;35(Suppl. 2):170.

43. Evens A.M., Advani R.H., Fanale M.A., et al. Sequential brentuximab vedotin (Bv) before and after Adriamycin, Vinblastine, and Dacarbazine (Bv-AVD) for older patients with untreated Classical Hodgkin Lymphoma (cHL): final results from a multicenter phase II study. Blood. 2017:130;733.

44. Bartlett N.L., Chen R., Fanale M., et al. Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. J Hematol Oncol. 2014;7:24. Doi: 10.1186/1756-8722-7-24.

45. Chen R., Hou J., Newman E., et al. CD30 Downregulation, MMAE Resistance, and MDR1 upregulation are all associated with resistance to brentuximab vedotin. Mol Cancer Ther. 2015;14:1376–84. Doi: 10.1158/1535-7163.MCT-15-0036.

46. Chen R.W., Palmer J.M., Herrera A.F., et al. Phase II study of brentuximab vedotin plus ibrutinib for patients with relapsed/refractory Hodgkin Lymphoma. Blood. 2017;130(Suppl. 1):738.

47. O’Connor O.A., Lue J.K., Sawas A., et al. Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin’s lymphoma: an international, multicentre, single-arm, phase 1–2 trial. Lancet. Oncol. 2018;19:257–66.

48. Diefenbach C.S., Hong F., Cohen J.B., et al. Preliminary safety and efficacy of the combination of brentuximab vedotin and ipilimumab in relapsed/refractory Hodgkin Llymphoma: a trial of the ECOG-ACRIN Cancer Research Group (E4412). Blood. 2015;126:585.

49. Diefenbach C.S. Safety and efficacy of combination of brentuximab vedotin and nivolumab in rel/ref Hodgkin lymphoma: a trial of the ECOG-ACRIN cancer research group (E4412). Hematol Oncol. 2017;35(S2):84–5.

50. Swaika A., Yammond W.A., Joseph R.W. Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol Immunol. 2015;67(2 Pt. А):4–17. Doi: 10.1016/j.molimm.2015.02.009.

51. Green M.R., Monti S., Rodig S.J., et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116:3268–77. Doi: 10.1182/blood-2010-05-282780.

52. Green M.R., Rodig S., Juszczynski P., et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: Implications for targeted therapy. Clin Cancer. Res. 2012;18:1611–18. Doi: 10.1182/blood-2010-05-282780.

53. Paydas S., Bagir E., Seydaoglu, G., et al. Programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and EBVencoded RNA (EBER) expression in Hodgkin lymphoma. Ann Hematol. 2015;94:1545–52. Doi: 10.1007/s00277-015-2403-2.

54. Chu F., Neelapu S.S. Anti-PD-1 antibodies for the treatment of B-cell lymphoma: Importance of PD-1+ T-cell subsets. Oncoimmunology. 2014;3(1):е28101. Doi: 10.4161/onci.28101.

55. Ansell S.M., Lesokhin A.M., Borrello I., et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–19. Doi: 10.1056/NEJMoa1411087.

56. Armand F., Engert A., Younes A., et al. Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J Clin Oncol. 2018;36(14):1428–39.

57. Ramchandren R., Fanale M.A., Rueda A., et al. Nivolumab for Newly Diagnosed Advanced-Stage Classical Hodgkin lymphoma (cHL): Results from the Phase 2 Checkmate 205 Study. Blood. 2017;130(Suppl. 1):651.

58. Mahoney K.M., Freeman G.J., McDermott D.F. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther. 2015;37:764–82. Doi: 10.1016/j.clinthera.2015.02.018.

59. Armand P., Shipp M.A., Ribrag V., et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016;34(31):3733–39. Doi: 10.1200/JCO.2016.67.3467.

60. Chen R.W., Zinzani P.L., Fanale M.A., et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol. 2017;35(19):2125–32.

61. Moskowitz C.H., Zinzani P., Fanale M., et al. Pembrolizumab in Relapsed/Refractory Classical Hodgkin Lymphoma: Primary End Point Analysis of the Phase 2 Keynote-087 Study. Blood. 2016;128:1107.

62. Kwong Y.L., Lopes D., Khong P.L. Low-dose pembrolizumab induced remission in patients with refractory classical Hodgkin lymphoma. Br J Haematol. 2017;176:131–43. Doi: 10.1111/bjh.13920.

63. Chan T.S.Y., Luk T.H., Lau J.S.M., et al. Low-dose pembrolizumab for relapsed/refractory Hodgkin lymphoma: high efficacy with minimal toxicity. Ann Hematol. 2017;96:647–51. Doi: 10.1007/s00277-017-2931-z.

64. Merryman R.W., Kim H.T., Zinzani P.L., et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood. 2017;129(10):1380–88. Doi: 10.1182/blood-2016-09-738385.

65. Herbaux C., Gauthier J., Brice P., et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. Blood. 2017;129(18):2471–78. Doi: 10.1182/blood-2016-11-749556.

66. Haverkos B.M., Abbott D., Hamadani M., et al. PD-1 blockade for relapsed lymphoma post–allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. 2017;130:221–28. Doi: 10.1182/blood-2017-01-761346.

67. Bashey A., Medina B., Corringham S., et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell ransplantation. Blood. 2009;113(7):1581–88. Doi: 10.1182/blood-2008-07-168468.

68. Davids M.S., Kim H.T., Bachireddy P., et al. Leukemia and Lymphoma Society Blood Cancer Research Partnership. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375(2):143–53. Doi: 10.1056/NEJMoa1601202.

69. Younes A., Santoro A., Shipp M., et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet. Oncol. 2016;17(9):1283–94. Doi: 10.1016/S1470-2045(16)30167-X.

70. Chen R., Zinzani P.L., Fanale M.A., et al. KEYNOTE-087. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017;35(19):2125–32.


Об авторах / Для корреспонденции


Автор для связи: Л.В. Филатова, д.м.н., ведущий науч. сотр. научного отдела инновационных методов терапевтической онкологии и реабилитации, НМИЦ онкологии им. Н.Н. Петрова; доцент кафедры онкологии, СЗГМУ им. И.И. Мечникова, Санкт-Петербург, Россия; e-mail: Larisa_Filatova@list.ru, ORCID: https://orcid.org/0000-0002-0728-4582
Адрес: 197758, Россия, Санкт-Петербург, пос. Песочный, ул. Ленинградская, 68


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