Новые перспективы в лечении пациентов с миелодиспластическим синдромом промежуточного-2 и высокого риска
https://doi.org/10.17650/1818-8346-2022-17-4-106-117
Аннотация
В настоящее время терапевтическая тактика у пациентов с миелодиспластическим синдромом основана на проведении риск-адаптированной терапии с последующей аллогенной трансплантацией гемопоэтических стволовых клеток, которая остается единственным радикальным методом лечения. Для пациентов, которым невозможно проведение трансплантации, остается актуальной проблема поиска новых методов лечения. Современные знания о патогенезе заболевания позволяют получить представления о ключевых путях, связанных с онкогенезом, и разработать новые эпигенетические методы лечения.
В обзоре рассмотрены терапевтические подходы, применяемые в настоящее время при лечении пациентов с миелодиспластическим синдромом групп низкого и высокого риска, а также продемонстрирована актуальность поиска новых методов таргетной и иммунотерапии. Освещены достижения в области таргетной терапии, в частности изучение биологии молекулы TIM3 и ее лигандов, новые данные клинических испытаний моноклональных антител против TIM3.
Об авторах
Е. В. МорозоваРоссия
197022 Санкт-Петербург, ул. Льва Толстого, 6–8
Н. Ю. Цветков
Россия
197022 Санкт-Петербург, ул. Льва Толстого, 6–8
М. В. Барабанщикова
Россия
197022 Санкт-Петербург, ул. Льва Толстого, 6–8
К. С. Юровская
Россия
197022 Санкт-Петербург, ул. Льва Толстого, 6–8
И. С. Моисеев
Россия
197022 Санкт-Петербург, ул. Льва Толстого, 6–8
Список литературы
1. Афанасьев Б.В., Зубаровская Л.С. Миелодиспластический синдром у детей. Российский журнал детской гематологии и онкологии 2018;5(3):23–35. DOI: 10.17650/231112672018532335
2. Greenberg P. The myelodysplastic syndromes. In: Hematology: Basic Principles and Practice. Eds.: R. Hoffman, E. Benz, S. Shattil et al. New York, NY: Churchill Livingstone, 2000. Pp. 1106–1129.
3. Gattermann N. Iron overload in myelodysplastic syndromes (MDS). Int J Hematol 2018;107(1):55–63. DOI: 10.1007/s1218501723671
4. Vinchi F., Muckenthaler M.U., Da Silva M.C. et al. Atherogenesis and iron: from epidemiology to cellular level. Front Pharmacol 2014;5:94. DOI: 10.3389/fphar.2014.00094
5. Duffy S.J., Biegelsen E.S., Holbrook M. et al. Iron chelation improves endothelial function in patients with coronary artery disease. Circulation 2001;103(23):2799–804. DOI: 10.1161/01. cir.103.23.2799
6. Dayyani F., Conley A.P., Stromet S.S. et al. Cause of death in patients with lowerrisk myelodysplastic syndrome. Cancer 2010;116(9):2174–9. DOI: 10.1002/cncr.24984
7. Steensma D.P. Graphical representation of clinical outcomes for patients with myelodysplastic syndromes. Leuk Lymphoma 2016;57(1):17–20. DOI: 10.3109/10428194.2015.1061191
8. Савченко В.Г., Паровичникова Е.Н., Кохно А.В. и др. Национальные клинические рекомендации по диагностике и лечению миелодиспластических синдромов взрослых. Гематология и трансфузиология 2016;61(1–S4):1–32.
9. GarciaManero G., Shan J., Faderl S. et al. A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia 2008;22(3):538–43. DOI: 10.1038/sj.leu.2405070
10. Itzykson R., Crouch S., Travaglino E. et al. Early platelet count kinetics has prognostic value in lowerrisk myelodysplastic syndromes. Blood Adv 2018;2(16):2079–89. DOI: 10.1182/ bloodadvances.2018020495
11. Mittelman M., Zeidman A. Platelet function in the myelodysplastic syndromes. Int J Hematol 2000;71(2):95–8.
12. HellstromLindberg E., Gulbrandsen N., Lindberg G. et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colonystimulating factor: significant effects on quality of life. Br J Haematol 2003;120(6):1037–46. DOI: 10.1046/j.13652141.2003.04153.x
13. List A., Kurtin S., Roe D.J. et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005;352(6):549–57. DOI: 10.1056/NEJMoa041668
14. List A., Bennett J., Giagounidis A. et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006;355(14):1456–65. DOI: 10.1056/NEJMoa061292
15. Steensma D.P. Hematopoietic growth factors in myelodysplastic syndromes. Semin Oncol 2011;38:635–47. DOI: 10.1053/j. seminoncol.2011.04.014
16. Brierley C.K., Steensma D.P. Thrombopoiesisstimulating agents and myelodysplastic syndromes. Br J Haematol 2015;169(3):309–23. DOI: 10.1111/bjh.13285
17. Mittelman M., Platzbecker U., Afanasyev B. et al. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebocontrolled, phase 2 trial. Lancet Haematol 2018;5(1):e34– 43. DOI: 10.1016/S23523026(17)302284
18. Oliva E.N, Alati C., Santini V. et al. Eltrombopag versus placebo for lowrisk myelodysplastic syndromes with thrombocytopenia (EQoLMDS): phase 1 results of a singleblind, randomised, controlled, phase 2 superiority trial. Lancet Haematol 2017;4(3):e127–36. DOI: 10.1016/S23523026(17)300121
19. Shastri A., Verma A.K. Eltrombopag reduces clinically relevant thrombocytopenic events in higher risk MDS and AML. Lancet Haematol 2018;5(1):e6–7. DOI: 10.1016/S23523026(17)302296
20. Villar S., Robin M. Allogeneic stem cell transplantation for MDS. Hematol 2021;2(3):545–55. DOI: 10.3390/hemato2030034
21. Greenberg P., Cox C., LeBeau M.M. et al. International scoring system for evaluating prognosis in myelodysplastic syndromes [published correction appears in Blood 1998;91(3):1100]. Blood 1997;89(6):2079–88.
22. Cataldo V.D., Cortes J., QuintásCardama A. Azacitidine for the treatment of myelodysplastic syndrome. Expert Rev Anticancer Ther 2009;9(7):875–84. DOI: 10.1586/era.09.61
23. Berg T., Guo Y., Abdelkarim M. et al. Reversal of p15/INK4b hypermethylation in AML1/ETOpositive and negative myeloid leukemia cell lines. Leuk Res 2007;31(4):497–506. DOI: 10.1016/ j.leukres.2006.08.008
24. Kimura S., Kuramoto K., Homan J. et al. Antiproliferative and antitumor effects of azacitidine against the human myelodysplastic syndrome cell line SKM1. Anticancer Res 2012;32(3):795–8.
25. Stresemann C., Bokelmann I., Mahlknecht U., Lyko F. Azacytidine causes complex DNA methylation responses in myeloid leukemia. Mol Cancer Ther 2008;7(9):2998–3005. DOI: 10.1158/15357163. MCT080411
26. Fabiani E., Leone G., Giachelia M. et al. Analysis of genomewide methylation and gene expression induced by 5aza2deoxycytidine identifies BCL2L10 as a frequent methylation target in acute myeloid leukemia. Leuk Lymphoma 2010;51(12):2275–84. DOI: 10.3109/10428194.2010.528093
27. Khan C., Pathe N., Fazal S. et al. Azacitidine in the management of patients with myelodysplastic syndromes. Ther Adv Hematol 2012;3(6):355–73. DOI: 10.1177/2040620712464882
28. Fenaux P., Mufti G.J., HellstromLindberg E. et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higherrisk myelodysplastic syndromes: a randomised, openlabel, phase III study. Lancet Oncol 2009;10(3):223–32. DOI: 10.1016/S14702045(09)700038
29. Gurion R., Vidal L., GafterGvili A. et al. 5azacitidine prolongs overall survival in patients with myelodysplastic syndrome – a systematic review and metaanalysis. Haematologica 2010;95(2):303–10. DOI: 10.3324/haematol.2009.010611
30. Cheson B.D., Jasperse D.M., Simon R. et al. A critical appraisal of lowdose cytosine arabinoside in patients with acute nonlymphocytic leukemia and myelodysplastic syndromes. J Clin Oncol 1986;4(12):1857–64. DOI: 10.1200/JCO.1986.4.12.1857
31. Fenaux P., Haase D., Sanz G.F. et al. Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and followup. Ann Oncol 2014;25(Suppl 3):iii57–69. DOI: 10.1093/annonc/mdu180
32. Kantarjian H., O’brien S., Cortes J. et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or highrisk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 2006;106(5):1090–8. DOI: 10.1002/cncr.21723
33. Schmid C., Wreede L., Biezen A. et al. Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of the European Society of Blood and Marrow Transplantation. Haematologica 2018;103(2):237–45. DOI: 10.3324/haematol.2017.168716
34. Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12(4):252–64. DOI: 10.1038/nrc3239
35. Riva A., Chokshi S. Immune checkpoint receptors: homeostatic regulators of immunity. Hepatol Int 2018;12(3):223–36. DOI: 10.1007/s1207201898679
36. Darvin P., Toor S.M., Sasidharan N.V. et al. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 2018;50(12):1–11. DOI: 10.1038/s1227601801911
37. Havel J.J., Chowell D., Chan T.A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 2019;19(3):133–50. DOI: 10.1038/s415680190116x
38. Pagliuca S., Gurnari C., Visconte V. Molecular targeted therapy in myelodysplastic syndromes: new options for tailored treatments. Cancers 2021;13(4):784. DOI: 10.3390/cancers13040784
39. Boddu P., Kantarjian H., GarciaManero G. et al. The emerging role of immune checkpoint based approaches in AML and MDS. Leuk Lymphoma 2018;59(4):790–802. DOI: 10.1080/10428194.201 7.1344905
40. Zeidan A.M., Knaus H.A., Robinson T.M. et al. A multicenter phase I trial of ipilimumab in patients with myelodysplastic syndromes following hypomethylating agent failure. Clin Cancer Res 2018;24(15):3519–27. DOI: 10.1158/10780432.CCR173763
41. Wendelbo O., Nesthus I., Sjo M. et al. Functional characterization of T lymphocytes derived from patients with acute myelogenous leukemia and chemotherapyinduced leukopenia. Cancer Immunol Immunother 2004;53(8):740–7. DOI: 10.1007/s0026200405050
42. GarciaManero G., Sasaki K., MontalbanBravo G. et al. A phase II study of nivolumab or ipilimumab with or without azacitidine for patients with myelodysplastic syndrome (MDS). Blood 2018;132.
43. GarciaManero G., Tallman M.S., Martinell I.G. et al. Pembrolizumab, a PD1 inhibitor, in patients with myelodysplastic syndrome (MDS) after failure of hypomethylating agent treatment. Blood 2016;128. DOI: 10.1182/blood.V128.22.345.345
44. Davids M.S., Kim H.T., Bachireddy P. et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med 2016;375(2):143–53. DOI: 10.1056/NEJMoa1601202
45. Daver N., Boddu P., GarciaManero G. et al. Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia 2018;32(5):1094–105. DOI: 10.1038/s4137501800708
46. Khaznadar Z., Henry G., Setterblad N. et al. Acute myeloid leukemia impairs natural killer cells through the formation of a deficient cytotoxic immunological synapse. Eur J Immunol 2014;44(10):3068–80. DOI: 10.1002/eji.201444500
47. Bewersdorf J.P., Shallis R.M., Zeidan A.M. Immune checkpoint inhibition in myeloid malignancies: moving beyond the PD1/PDL1 and CTLA4 pathways. Blood Rev 2021;45:100709. DOI: 10.1016/j.blre.2020.100709.
48. Chiba S., Baghdadi M., Akiba H. et al. Tumorinfiltrating DCs suppress nucleic acidmediated innate immune responses through interactions between the receptor TIM3 and the alarmin HMGB1. Nat Immunol 2012;13(9):832–42. DOI: 10.1038/ni.2376
49. Huang Y.H., Zhu C., Kondo Y. et al. CEACAM1 regulates TIM3mediated tolerance and exhaustion. Nature 2015;517(7534):386–90. DOI: 10.1038/nature13848
50. Kikushige Y., Miyamoto T., Yuda J. et al. A TIM3/Gal9 autocrine stimulatory loop drives selfrenewal of human myeloid leukemia stem cells and leukemic progression. Cell Stem Cell 2015;17(3):341–52.
51. De Kruyff R.H., Bu X., Ballesteros A. et al. T cell/transmembrane, Ig, and mucin3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol 2010;184(4):1918–30. DOI: 10.4049/jimmunol.0903059
52. Zhu C., Anderson A.C., Schubart A. et al. The TIM3 ligand galectin9 negatively regulates T helper type 1 immunity. Nat Immunol 2005;6(12):1245–52. DOI: 10.1038/ni1271
53. Monney L., Sabatos C.A., Gaglia J.L. et al. Th1specific cell surface protein TIM3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002;415(6871):536–41. DOI: 10.1038/415536a
54. Wolf Y., Anderson A.C., Kuchroo V.K. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol 2020;20(3):173–85. DOI: 10.1038/s4157701902246
55. Wang Y., Zhao E., Zhang Z. et al. Association between Tim3 and Gal9 expression and gastric cancer prognosis. Oncol Rep 2018;40(4):2115–26. DOI: 10.3892/or.2018.6627
56. Gonçalves Silva I., Yasinska I.M., Sakhnevych S.S. et al. The TIM3galectin9 secretory pathway is involved in the immune escape of human acute myeloid leukemia cells. EBioMedicine 2017;22: 44–57. DOI: 10.1016/j.ebiom.2017.07.018
57. Li H., Wu K., Tao K. et al. TIM3/galectin9 signaling pathway mediates Tcell dysfunction and predicts poor prognosis in patients with hepatitis B virusassociated hepatocellular carcinoma. Hepatology 2012;56(4):1342–51. DOI: 10.1002/hep.25777
58. Cao E., Zang X., Ramagopal U.A. et al. T cell immunoglobulin mucin3 crystal structure reveals a galectin9independent ligandbinding surface. Immunity 2007;26(3):311–21. DOI: 10.1016/j.immuni.2007.01.016
59. Kang C.W., Dutta A., Chang L.Y. et al. Apoptosis of tumor infiltrating effector TIM3+CD8+ T cells in colon cancer. Sci Rep 2015;5:15659. DOI: 10.1038/srep15659
60. Kikushige Y., Shima T., Takayanagi S. et al. TIM3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 2010;7(6):708–17. DOI: 10.1016/j.stem.2010.11.014
61. Kikushige Y., Miyamoto T. TIM3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells. Int J Hematol 2013;98(6):627–33. DOI: 10.1007/s1218501314336
62. Asayama T., Tamura H., Ishibashi M. et al. Functional expression of TIM3 on blasts and clinical impact of its ligand galectin9 in myelodysplastic syndromes. Oncotarget 2017;8(51):88904–17. DOI: 10.18632/oncotarget.21492
63. Dama P., Tang M., Fulton N. et al. Gal9/TIM3 expression level is higher in AML patients who fail chemotherapy. J Immunother Cancer 2019;7(1):175. DOI: 10.1186/s4042501906113
64. Kong Y., Zhang J., Claxton D.F. et al. PD1(hi)TIM3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation. Blood Cancer J 2015;5(7):e330. DOI: 10.1038/bcj.2015.58
65. Gonçalves Silva I., Rüegg L., Gibbs B.F. et al. The immune receptor TIM3 acts as a trafficker in a TIM3/galectin9 autocrine loop in human myeloid leukemia cells. Oncoimmunology 2016;5(7):e1195535. DOI: 10.1080/2162402X.2016.1195535
66. Acharya N., SabatosPeyton C., Anderson A.C. TIM3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer 2020;8(1):e000911. DOI: 10.1136/jitc20200091
67. Dardalhon V., Anderson A.C., Karman J. et al. TIM3/galectin9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly–6G+ myeloid cells. J Immunol 2010;185(3):1383– 92. DOI: 10.4049/jimmunol.0903275
68. Gao X., Zhu Y., Li G. et al. TIM3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One 2012;7(2):e30676. DOI: 10.1371/journal.pone.0030676
69. Jones R.B., Ndhlovu L.C., Barbour J.D. et al. TIM3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV1 infection. J Exp Med 2008;205(12):2763–79. DOI: 10.1084/jem.20081398
70. Fourcade J., Sun Z., Benallaoua M. et al. Upregulation of TIM3 and PD1 expression is associated with tumor antigenspecific CD8+ T cell dysfunction in melanoma patients. J Exp Med 2010;207(10):2175–86. DOI: 10.1084/jem.20100637
71. Sakuishi K., Apetoh L., Sullivan J.M. et al. Targeting TIM3 and PD1 pathways to reverse T cell exhaustion and restore antitumor immunity. J Exp Med 2010;207(10):2187–94. DOI: 10.1084/jem.20100643
72. Yang Z.Z., Grote D.M., Ziesmer S.C. et al. IL12 upregulates TIM3 expression and induces T cell exhaustion in patients with follicular B cell nonHodgkin lymphoma. J Clin Invest 2012;122(4):1271–82. DOI: 10.1172/JCI59806
73. Liu J., Zhang S., Hu Y. et al. Targeting PD1 and TIM3 pathways to reverse CD8 Tcell exhaustion and enhance ex vivo Tcell responses to autologous dendritic/tumor vaccines. J Immunother 2016;39(4):171–80. DOI: 10.1097/CJI.0000000000000122
74. Borate U., Esteve J., Porkka K. et al. AntiTIM3 antibody MBG453 in combination with hypomethylating agents in patients with highrisk myelodysplastic syndrome and acute myeloid leukemia: a phase 1 study. Paper presented at: 25th EHA Congress. June 11–21, 2020 [abstract S185].
Рецензия
Для цитирования:
Морозова Е.В., Цветков Н.Ю., Барабанщикова М.В., Юровская К.С., Моисеев И.С. Новые перспективы в лечении пациентов с миелодиспластическим синдромом промежуточного-2 и высокого риска. Онкогематология. 2022;17(4):106-117. https://doi.org/10.17650/1818-8346-2022-17-4-106-117
For citation:
Morozova E.V., Tsvetkov N.Yu., Barabanshchikova M.V., Yurovskaya K.S., Moiseev I.S. New perspectives in the treatment of patients with intermediate-2 and high-risk myelodysplastic syndrome. Oncohematology. 2022;17(4):106-117. (In Russ.) https://doi.org/10.17650/1818-8346-2022-17-4-106-117