Клинические и генетические особенности острого миелоидного лейкоза с t(8;21) у детей и результаты терапии по протоколу ОМЛ-ММ-2000

У детей с ОМЛ транслокация t(8;21) встречается наиболее часто. Пациентов с данной генетической аномалией традиционно относят к группе благоприятного прогноза с вероятностью выздоровления до 80 %. При ОМЛ с t(8;21) известны дополнительные цитогенетические аномалии, не влияющие на прогноз заболевания. К ним относят потерю одной из половых хромосом, del(9q). Роль дополнительных аномалий с вовлечением 7-й и 11-й хромосом у пациентов с t(8;21) неизвестна. Целью данного исследования служил цитогенетический анализ дополнительных аномалий, встречающихся у больных с t(8;21), и их влияния на прогноз заболевания. За исследовательский период 173 ребенка с ОМЛ получили терапию по протоколу ОМЛ-ММ-2000 в России и Беларуси. Из них у 33 детей (11 девочек и 22 мальчика, медиана возраста 10,5 лет) обнаружена транслокация t(8;21) при проведении хромосомного или молекулярно-генетического исследования. В группе пациентов с наличием t(8;21) нейролейкоз обнаружен у 8 детей, экстрамедуллярное поражение — у 8 пациентов. У 4 больных нейролейкоз сочетался с наличием экстрамедуллярных очагов. Данные характеристики не отразились на результатах терапии. Общая выживаемость больных ОМЛ с t(8;21) составила 0,67 ± 0,08 по сравнению с 0,44 ± 0,04 пациентов с ОМЛ без данной аномалии (p = 0,04). Особую подгруппу составили 5 пациентов, у которых помимо t(8;21) были выявлены хромосомные аномалии, затрагивающие 7-ю и 11-ю хромосомы, что явилось неблагоприятным прогностическим фактором. Бессобытийная выживаемость в этой подгруппе пациентов (n = 5) составила 0,0 ± 0,0, тогда как пациентов с t(8;21) без дополнительных аномалий (n = 28) — 0,34 ± 0,16 (p = 0,027).

1. Pui C.H., Schrappe M., Ribeiro R.C. et al. Childhood and adolescent lymphoid and myeloid leukemia. Hematology Am Soc Hematol Educ Program 2004:118–45.

2. Kaspers G.J., Creutzig U. Pediatric acute myeloid leukemia: international progress and future directions. Leukemia 2005 Dec;19(12):2025–9.

3. Creutzig U., Zimmermann M., Ritter J. et al. Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials. Leukemia 2005 Dec;19(12):2030–42.

4. Gibson B.E., Wheatley K., Hann I.M. et al. Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia 2005 Dec;19(12):2130–8.

5. Rowley J.D. Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet 1973;16:109–12.

6. Ferrara F., Del Vecchio L. Acute myeloid leukemia with t(8;21)/AML1/ETO: a distinct biological and clinical entity. Haematologica 2002;87:306–19.

7. Strout M.P., Marcucci G., Caligiuri M.A., Bloomfield C.D. Core-binding factor (CBF) and MLL-associated primary acute myeloid leukemia: biology and clinical implications. Ann Hematol 1999;78:251–64.

8. Marcucci G., Caligiuri M.A., Bloomfield C.D. Molecular and clinical advances in core binding factor primary acute myeloid leukemia: a paradigm for translational research in malignant hematology. Cancer Invest 2000; 18:768–80.

9. Raimondi S.C., Chang M.N., Ravindranath Y., Behm F.G., Gresik M.V., Steuber C.P. et al. Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study — POG 8821. Blood 1999;94:3707–16.

10. Hiddemann W., Büchner T., Ritter J. et al. Acute Leukemias IX. Basic research, experimentalapproaches and novel therapies.

11. Andrieu V., Radford-Weiss I., Troussard X., Chane C., Valensi F., Guesnu M. et al. Molecular detection of t(8;21)/AML1-ETO n AML M1/M2: correlation with cytogenetics, morphology and immunophenotype. Br J Haematol 1996;92:855–65.

12. Hurwitz C.A., Raimondi S.C., Head D., Krance R., Mirro J. Jr, Kalwinsky D.K. et al. Distinctive immunophenotypic features of t(8;21)(q22;q22) acute myeloblastic leukemia in children. Blood 1992;80:3182–8.

13. Kita K., Nakase K., Miwa H., Masuya M., Nishii K., Morita N. et al. Phenotypical characteristics of acute myelocytic leukemia associated with the t(8;21)(q22;q22) chromosomal abnormality: frequent expression of immature B cell antigen CD19 together with the stem cell antigen CD34. Blood 1992;80:470–7.

14. Kita K., Shirakawa S., Kamada N. Cellular characteristics of acute myeloblastic leukemia associated with t(8;21)(q22;22). The Japanese Cooperative Group of Leukemia/Lymphoma. Leuk Lymphoma 1994;13:229–34.

15. Dusenbery K.E., Howells W.B., Arthur D.C. et al. Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the Children's Cancer Group. J Pediatr Hematol Oncol. 2003 Oct;25(10):760–8.

16. Kobayashi R., Tawa A., Hanada R. et al. Extramedullary infiltration at diagnosis and prognosis in children with acute myelogenous leukemia. Pediatr Blood Cancer 2007 Apr;48(4):393–8.

17. Schwyzer R., Sherman G.G., Cohn R.J. et al. Granulocytic sarcoma in children with acute myeloblastic leukemia and t(8;21). Med Pediatr Oncol 1998 Sep;31(3):144–9.

18. Tallman M.S., Hakimian D., Shaw J.M., Lissner G.S., Russell E.J., Variakojis D. Granulocytic sarcoma is associated with the 8;21 translocation in acute myeloid leukemia. J Clin Oncol 1993;11:690–7.

19. Byrd J.C., Weiss R.B., Arthur D.C., Lawrence D., Baer M.R., Davey F. et al. Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22; q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol 1997;15:466–75.

20. Grimwade D., Walker H., Oliver F. et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998;92:2322–33.

21. Marcucci G., Mrozek K., Ruppert A.S. et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol 2005;23:5705–17.

22. Heim S., Mitelman F. Quantitative acute leukemia cytogenetics. Cancer cytogenetics. Second ed. Chichester et al. Wiley-Liss; 1995.

23. Lin P., Chen L., Luthra R., Konoplev S.N., Wang X., Medeiros L.J. Acute myeloid leukemia harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations. Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77003, USA. peilin@mdanderson.org.

24. Slovak M.L., Kopecky K.J., Cassileth P.A. et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000 Dec 15;96(13):4075–83.

25. Schoch C., Haase D., Haferlach T. et al. Fifty-one patients with acute myeloid leukemia and translocation t(8;21)(q22;q22): an additional deletion in 9q is an adverse prognostic factor. Leukemia 1996;10:1288–95.

26. Sarriera J.E., Albitar M., Estrov Z. et al. Comparison of outcome in acute myelogenous leukemia patients with translocation (8;21) found by standard cytogenetic analysis and patients with AML1/ETO fusion transcript found only by PCR testing. Leukemia 2001 Jan;15(1):57–61.

27. Kiyoi H., Naoe T. Biology, clinical relevance, and molecularly targeted therapy in acute leukemia with FLT3 mutation. Int J Hematol 2006 May;83(4):301–8.

28. Doepfner K.T., Boller D., Arcaro A. Targeting receptor tyrosine kinase signaling in acute myeloid leukemia. Crit Rev Oncol Hematol 2007 Sep;63(3):215–30. Epub 2007 Jul 19.

29. Testa U., Riccioni R. Deregulation of apoptosis in acute myeloid leukemia. Haematologica 2007 Jan;92(1):81–94.

30. Kondo M., Horibe K., Takahashi Y. et al. Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med Pediatr Oncol 1999 Dec;33(6):525–9.

31. Meshinchi S., Alonzo T.A., Stirewalt D.L. et al. Clinical implications of FLT3 mutations in pediatric AML. Blood 2006 Dec;108(12):3654–61. Epub 2006 Aug 15.

32. Zwaan C.M., Meshinchi S., Radich J.P. et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood 2003 Oct;102(7):2387–94.

33. Heibert S.W., Lutterbach B., Durst K. et al. Mechanisms of transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)-encoded fusion proteins. Cancer Chemother Pharmacol 2001 Aug;48 Suppl 1:31–4.

34. Boissel N., Leroy H., Brethon B. et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 2006 Jun;20(6):965–70.

35. Paschka P., Marcucci G., Ruppert A.S., Mro´zek K. et al. Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study. J Clin Oncol 2006 Aug;24:3904–11.

36. Shimada A., Taki T., Tabuchi K. et al. KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. BLOOD March 2006:107,5:1805–9.

37. Nucifora G., Larson R.A., Rowley J.D. Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission. Blood 1993;82:712–5.

38. Saunders M.J., Tobal K., Yin J.A. Detection of t(8;21) by reverse transcriptase polymerase chain reaction in patients in remission of acute myeloid leukemia type M2 after chemotherapy or bone marrow transplantation. Leuk Res 1994;18:891–5.

39. Miyamoto T., Nagafuji K., Akashi K. et al. Persistence of multipotent progenitors expressingAML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia. Blood 1996;87:4789–96.

40. Tobal K., Newton J., Macheta M., Chang J. et al. Molecular quantitation of minimal residual disease in acute myeloid leukemia with t(8;21) can identify patients in durable remission and predict clinical relapse. Blood 2000;95:815–9.

41. Morschhauser F., Cayuela J.M., Martini S., Baruchel A. et al. Evaluation of Minimal Residual Disease Using Reverse- Transcription Polymerase Chain Reaction in t(8;21) Acute Myeloid Leukemia: A Multicenter Study of 51 Patients. J Clin Oncol 2000;18:788–94. 2000 by American Society of Clinical Oncology.

42. Swerdlow S.H., Campo E., Yarris N.L. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (4th Ed.).International Agency for Research on Cancer. Lyon, 2008; p. 439.

43. Bennett J.M., Catovsky D., Daniel M.T. et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) cooperative group. Br J Haematol 1976 Aug;33(4):451–8.

44. Kaspers G.J.L., Zwaan C.M. Pediatric acute myeloid leukemia: towards high-quality cure of all patients. Haematologica/the hematology journal 2007;92(11):1519–32.

45. Kaspers G.J.L., Zimmermann M., Reinhardt D., Tamminga R., Maschan A. et al. Clinical relevance of early treatment response in pediatric relapsed acute myeloid leukemia (AML): study relapsed AML 2001/01. Annals of Hematology;Vol 87 (Suppl 1) February 2008.