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Вопросы гематологии/онкологии и иммунопатологии в педиатрии

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Перспективы таргетной терапии острого лейкоза у детей

https://doi.org/10.24287/1726-1708-2017-16-2-62-74

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Аннотация

Острые лейкозы (ОЛЛ и ОМЛ) составляют более трети онкологических заболеваний у детей. У 20% детей с ОЛЛ (больные групп высокого риска и рецидивы) и у 40% детей с ОМЛ (резистентные больные и рецидивы) результаты лечения химиопрепаратами остаются неутешительными, несмотря на то что трансплантация гемопоэтических стволовых клеток (ТГСК) способна улучшить прогноз у 40-50% резистентных и рецидивных пациентов. Новые данные об аберрантной активации сигнальных путей и эпигенетических расстройствах, сопровождающих лейкемогенез, привели к разработке новых препаратов, точечно воздействующих на механизм трансформации. В представленном обзоре коротко описаны основные виды таргетной терапии острых лейкозов у детей, дана оценка эффективности ферментных препаратов и их модификаций, показаны возможности ингибирования тирозинкиназ, протеасом, эпигенетических регуляторов экспрессии генов, гистондеацетилазы, дисраптора теломерной передачи сигнала-1, моноклональных антител и конъюгированных иммунотоксинов, биспецифических активирующих Т-клетки антител и Т-клеток с модифицированным химерным антигенным рецептором.

Об авторе

А. Г. Румянцев
ФГБУ «Национальный научно-практический центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России, Москва
Россия


Список литературы

1. Карачунский А.И., Румянцева Ю.В., Румянцев А.Г. Эволюция лечения ОЛЛ у детей: критическое использование мирового опыта в России // Вопросы гематологии/онкологии и иммунологии в педиатрии, 2011; 10 (2): 15-32.

2. Румянцев А.Г. Эволюция лечения острого лимфобластного лейкоза у детей // Педиатрия, 2016; 4: 7-14.

3. De Rooij J.D.E., Zwan C.M., van den Heuvel-Eibrink M. Pediatric AML: From biology to Clinical management. J Clin Med 2015; 4: 127-49.

4. Saletta F., Wadham C., Ziegler D.S., Marshall G.M., Haber M., Mc Cowage G., et al. Molecular profiling of childhood cancer: Biomarkers and novel therapies. BBA clinical 2014; 1: 59-77.

5. Махонова Л.А., Маякова С.А., Румянцев А.Г. Применение L-аспарагиназы у детей с острым лейкозом при повторных обострениях заболевания // Проблемы гематологии и переливания крови, 1973; 1: 53-55.

6. Горошкова М.Ю., Румянцева Ю.В., Алейникова О.В. и др. Оптимизация терапии нативной E. coli-аспарагиназой в протоколе ALL-МВ 2002 у детей с острым лимфобластным лейкозом стандартной группы риска // Онкогематология, 2008; 3: 25-33.

7. Пшонкин А.В., Румянцева Ю.В., Литвинов Д.В. и др. Лечение ОЛЛ у подростков и молодых взрослых: опыт Москва - Берлин // Российский журнал детской гематологии и онкологии, 2016; 3 (1): 35-43.

8. Jaccard A., Petit B., Girault S., et al. L-asparaginase-based treatment of 15 western patients with extranodal NK/T-cell lymphoma and leukemia and a review of the literature. Ann Oncol 2009; 20 (1): 110-6.

9. Reinert R.B., Oberle L.M., Wek S.A., et al. Role of glutamine depletion in directing tissue-specific nutrient stress responses to L-asparaginase. J Biol Chem 2006; 281: 3122-33.

10. Steiner M., Attarbaschi A., Kastner U., et al. Distinct fluctuations of ammonia levels during asparaginase therapy for childhood acute leukemia. Pediatr Blood Cancer 2007; 9 (5): 640-2.

11. Avramis V.I., Tiwari P.N. Asparaginase (native ASNase or pegylated ASNase) in the treatment of acute lymphoblastic leukemia. Int J Nanomed 2006; 1 (3): 241-54.

12. Покровский В.С., Трещалина Е.М. Ферментные препараты в онкогематологии: актуальные направления экспериментальных исследований и перспективы клинического применения // Клиническая онкогематология, 2014; 7 (1): 28-38.

13. Delage B., Luong P., Maharaj L., O’Riain C., Syed N., Crook T., et al. Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis. Cell Death Dis 2012; 3: e342.

14. Ita M., Halicka H.D., Tanaka T., Kurose A., Ardelt B., Shogen K., Darzynkiewicz Z. Remarkable enhancement of cyto-toxicity of onconase and cepharanthine when used in combination on various tumor cell lines. Cancer Biol Ther 2008; 7: 1104-8.

15. Schultz K.R., Carroll A., Heerema N.A., Bowman W., Aledo A., Slayton W., et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031. Leukemia 2014; 28 (7): 1467-71.

16. Soverini S., Benedittis C., Papayannidis C., Paolini S., Venturi C., Jacobucci I., et al. Drug resistence and BCR-ABL Kinase domain mutations in Rh+ ALL imatinib to the second-generation tyrosine Kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement. Cancer 2014; 120: 1002-9.

17. Chang B., Willis S., Stork L., Hunger S., Carro W., Camitta B., et al. Imatinib resistant BCR-ABL1 mutations at relapse in children with Ph+AL: a Children’s Oncology Group (COG) study. Br J Haematol 2012; 157: 507-10.

18. Porkka K., Koskenvesa P., Lundan T., Rimpilainen J., Mustjoki S., Smykla R., et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Ph+ALL. Blood 112: 1005-12.

19. Sekimizu M., Yamashita V., Ueki H., Akita N., Hattory H., Maeda N., et al. Nilotinib monotherapy induced complete remission in pediatric Ph+ALL resistant to imatinib and dasatinib. Leukemia Lymphoma 2013; 55: 1652-3.

20. Cortes J., Kim D., Pinilla-Ibazz J., le Coutre, Paquette R., Chuah C., et al. A phase 2 trial of Ph+ALL. N Engl J Med 2013; 369: 1783-96.

21. Annesley C.E., Brown P. Novel agents for the treatment of childhood acute leukemia. Ther Adv Hematol 2015: 6 (2): 61-79.

22. DaverN., Cortes J. Molecular targeted thepapy in AML. Hematology 2012; 17 (Suppl. I): 59-63.

23. Mullighan C., Zhang J., Harvey R. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc. Nate Acad Sci USA 2009; 106: 9414-8.

24. Maude S., Tasian S., Vincent T., Hall J., Sheen C., Roberts K., et al. Targeting JAK 1/2 and mTOR in murin Xenograft models of Ph+like ALL. Blood 201; 120: 3510-8.

25. Roberts K., Li Y., Payne-Turner D., Harvej R., Jang J., Pei D., et al. Targetable kinase- activating lesions in Ph-likeALL. N Engl J Med 2014; 371 (11): 1005-15.

26. Weisberg E., Liu Q., Nelson E., Kung A., Christie A., Bronson R., et al. Using combination therapy to override stromal-mediated chemoresistance in mutant FLT-positive AML: synergism between FLT-3 inhibitors dasatinib/multy-targeted inhibitors and JAK inhibitors. Leukemia 2012; 26: 2233-44.

27. Attar E., De Angelo D., Supko J., D'Amato F., Zahrieh D., Sirulnik A., et al. Phase I and pharmacokinetic study of bortezomib in combination with idarubicin and cytarabine in patients with AML. Clin Cancer Res 2008; 14: 1446-54.

28. Messinger Y., Gaynon P., Sposto B., van der Giessen J., Eckroth E., Malvar J., et al. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study Blood 2012; 120: 285-90.

29. Yang J., Wang Z., Fang Y., Jiang J., Zhao F., Wong H., et al. Pharmacokinetics, pharmacodynamics metabolism, distribu-tion and excretion of carfilzomib in rats. Drug Metab Disposition 2011; 3a: 1873-82.

30. Jayanthan A., Ruan Y., Hagerty M., Shah R., Truong T., Lewis V., et al. In Vitro Growth Inhibition, Target Modulation and Drug Synergy In Pediatric Leukemia By The Novel Proteasome Inhibitor Carfilzomib. Blood 2013; 122: 2673-81.

31. Armstrong S., Staunton J., Silverman L., Pieters R., den Boer M.L., Minden M.D., et al. MLL-translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Gen 2002; 30: 41-7.

32. Meshinchi S., Alonzo T.A., Stirewalt D.L., Zwaan M., Zimmerman M., Reinhardt D., et al: Clinical implications of FLT3 mutation in pediatric AML. Blood 2006; 108: 3654-61.

33. Levis М., Perl A., Dombret H., Döhner H., Steffen B., Rousselot P., et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3- ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. ASH Annual Meeting Abstracts 2012, 120 (21): 673.

34. Fischer T., Stone R., Deangelo D., Galinsky I., Estey E., Lanza C., et al. Phase IIB trial of oral Midostaurin, the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 2010; 28: 4339-46.

35. Cooper T., Malvar J., Cassar J., Eckroth E., Malvar J., Gaynon P., et al. A phase I study of A Phase I study of Quizartinib in combined with cytarabine anf etoposide inrelapsed/refractory childhood ALL anf AML: a therapeutic advances in Childhood Leukemia & lymphoma (TACL) Study. Blood 2013; 122: 624-34.

36. Ravandi F., Cortes J., Jones D., Faderl S., Garcia-Manero G., Jabbour E., Konopleva M., et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 2010; 28 (11): 1856-62.

37. Pulsipher M., Langholz B., Wall D., Schultz K.R., Bunin N., Carroll W.L., et al. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children’s Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood 2014; 124: 2017-25.

38. Gore S., Baylin S., Sugar E., Carraway H., Miller C.B., Carducci M., et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 2006; 66 (12): 6361-9.

39. Попа А.В., Немировченко В.С., Флейшман Е.В., Сокова О.И., Субботина Н.Н., Серебрякова И.Н. и др. Ингибиторы гистондеацетилазы и ДНК-метилтрансферазы в лечении детей, больных острым миелобластным лейкозом, их эффективность и место в терапии // Российский журнал детской гематологии и онкологии, 2016; 3 (4): 48-54.

40. Bhatla T., Wang J., Morrison D., Raetz E.A., Burke M.J., Brown P., et al. Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. Blood 2012; 119: 5201-10.

41. Stumpel D., Schneider P., Seslija L., Osaki H., Williams O., Pieters R., et al. Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia. Leukemia 2012; 26: 682-92.

42. Garcia-Manero G., Assouline S., Cortes J., Estrov Z., Kantarjian H., Yang H., et al. Phase I study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 2008; 112 (4): 981-9.

43. Fouladi M., Park J., Stewart C., Gilbertson R.J., Schaiquevich P., Sun J., et al. Pediatric phase I trial and pharmacokinetic study of vorinostat: a COG phase I consortium report. J Clin Oncol 2010; 28: 3623-9.

44. Krivtsov A., Feng Z., Lemieux M., et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 2008; 14 (5): 355-68.

45. Yokoyama A., Lin M., Naresh A., Faber J., Vempati S., Sinha A., et al. A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell 2010; 17: 198-212.

46. Daigle S., Olhava E., Therkelsen C., Majer C., Sneeringer C., Song J., et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 2011; 20 (1): 53-65.

47. Deshpande A., Chen L., Fazio M., Sinha A.U., Bernt K.M., Banka D., et al. Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l. Blood 2013; 28; 121 (13): 2533-4.

48. Sievers E., Larson R., Stadfmauer E., Estey E, Löwenberg B, Dombret H., et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001; 19 (13): 3244-54.

49. Aplenc R., Alonzo T., Sung L., Meshin-chi S., Gerbing R., Raimondi S., et al. Gemtuzumab Ozogamicin (GO) in children with de novo AML improves EFS by reducing relapse risk-results from the randomized phase III CO G trial AAML0531. Blood 2013; 122: 355-65.

50. Hasle H., Abrahamsson J., Forestier E., Ha S., Heldrup J., Jahnukainen K., et al. Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 2004. Blood 2012; 120: 978-84.

51. Castaigne S., Pantas C., Terre C., Raffoux E, Bordessoule D., Bastie J.N., et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 2012; 379 (9825): 1508-16.

52. Satwani P., Bhatia M., Garvin J., George D., Dela Cruz H., Le Gall J., et al. A phase I study of gemtuzumab ozogamicin (GO) in combination with busulfan and cyclophosphamide and allogeneic stem cell transplantation in children with poor-risk CD33+ AML: a new targeted immunochemotherapy myeloablative conditioning (MAC) regimen. Biol Blood Marrow Transplant 2012; 18 (2): 324-9.

53. Ravandi F., Estey E., Appelbaum F., Lo-Coco F, Schiffer C.A., Larson R.A., et al. Gemtuzumab ozogamicin: time of resurrect. J Clin Oncol 2012; 30 (32): 3921-3.

54. Raetz E., Cairi M., Borowitz M., Lu X., Devidas M., Reid J., et al. Reinduction chemoimmunotherapy with epratuzumab in relapsed acute lymphoblastic leukemia (ALL) in children, adolescents and young adults: results from children's oncology group (COG) study ADVL04P2. Blood 2011; 118 (21): 573.

55. Fayad L., Offner F., Smith M., Verhoef G., Johnson P., Kaufman J.L., et al. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol 2013; 31: 573-83.

56. Kantarjian H., Thomas D., Jorgensen J., Kebriaei P., Jabbour E., Rytting M., et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer 2013; 119 (15): 2728-36.

57. Rytting M., Triche L., Thomas D. O'Brien S., Kantarjian H., et al. Initial experience with inotuzumab ozogamicin in pediatric patients with relapsed B-cell acute lymphoblastic leukemia. Blood Cancer 2014; 61 (2): 369-72.

58. Mussai F., Campana D., Bhojwani D., Stetler-Stevenson M., Steinberg S.M., Wayne A.S., et al. Cytotoxicity of the anti-CD22 immunotoxin HA22 (CAT-8015) against paediatric acute lymphoblastic leukaemia. Br J Haematol 2010; 150: 352-8.

59. Waine A., Btojwani D., Silverman L., Richards K., Stetler-Stevenson M., Shah N., et al. A novel anti-CD22 immunotoxin, moxetumomab pasudotox: phase I study in pediatric acute lymphoblastic leukemia (ALL). Ann Meeting Abstracts 2011; 118 (21).

60. Карачунский А.И., Румянцева Ю.В., фон Штакельберг А. Анти-СД19 моноклональные антитела при острой лимфобластной лейкемии у детей // Российский журнал детской гематологии и онкологии, 2016; 3 (4): 60-72.

61. Topp M., Gokburget N., Zugmaier G., Degenhard E., Goebeler M.E., Klinger M., et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood 2012; 120: 5185-7.

62. Klinger M., Brande C., Zugmaier G., Hijazi Y., Bargou R.C., Topp M.S., et al Immunopharmacology response of pati-ents with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood 2012; 119 (26): 6226-33.

63. Handgretinger R., Zugmaier G., Henze G., Kreyenberg H., Lang P., von Stackel-berg A., et al. Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia. Leucemia 2011; 25 (1): 181-4.

64. Zugmaier G., Handgretinger R., Locatelly F., Rizzari C., Trippett T., Borkhardt A., et al. A phase 1/2 study of blinatumomab in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood 2013; 122 (21): 70-5.

65. Barrett D., Singh N., Porter D., Grupp S.A., June C.H. Chimeric antigen receptor therapy for cancer. Ann Rev Med 2014; 65: 333-47.

66. Kalos M., Levine B., Porter D., Katz S., Grupp S., Bagg A., et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011; 3: 95-7.

67. Grupp S., Kalos M., Barrett D., Aplenc R., Porter D.L., Rheingold SR., et al. Chimeric antigen receptor-modified T -cells for ALL. N Engl J Med 2013; 368:1509-18.

68. Frey N., Aplenc R., Barret D., Chew A., Kalos M., Levine B., et al. T-cell engineered with a chimeric antigen receptor (CAR) targeting CD19 produce significant in vivo proliferation, complete responses an long-term persistence with out GVHD in children and adults with relapsed refractory ALL. Blood 2013; 122: 67-77.

69. Haso W., Lee D., Shah N., Stetler-Stevenson M., Yuan C.M., Pastan I.H., et al. Anti-CD22-chimeric antigen recep-tors targeting B-cell precursor ALL. Blood 2013; 12: 1165-74.


Для цитирования:


Румянцев А.Г. Перспективы таргетной терапии острого лейкоза у детей. Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2017;16(2):62-74. https://doi.org/10.24287/1726-1708-2017-16-2-62-74

For citation:


Rumyantsev A.G. Prospects of targeted therapy of acute leukemias in children. Pediatric Hematology/Oncology and Immunopathology. 2017;16(2):62-74. (In Russ.) https://doi.org/10.24287/1726-1708-2017-16-2-62-74

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