OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press7310.17650/1818-8346-2012-7-4-24-34HEMATOLOGIC MALIGNANCIES: DIAGNOSIS, TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ДИАГНОСТИКА, ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯInfluence of different chromosomal abnormalities in Ph-positive bone marrow cells on the chronic myeloid leukemia course during tyrosine kinase inhibitors therapyВлияние различных хромосомных аномалий в Ph-позитивных клетках костного мозга на течение хронического миелолейкоза при терапии ингибиторами тирозинкиназVinogradovaO. Yu.ВиноградоваО. Ю.
Russian Federation
olgavinz@mail.ruAseevaE. A.АсееваЕ. А.
Russian Federation
VorontsovaA. V.ВоронцоваА. В.
Russian Federation
TurkinaA. G.ТуркинаА. Г.
Russian Federation
NeverovaA. L.НевероваА. Л.
Russian Federation
LazarevaO. V.ЛазареваО. В.
Russian Federation
ChelyshevaE. Yu.ЧелышеваЕ. Ю.
Russian Federation
GusarovaG. A.ГусароваГ. А.
Russian Federation
KolosheinovaT. I.КолошейноваТ. И.
Russian Federation
KolosovaL. Yu.КолосоваЛ. Ю.
Russian Federation
GoryachevaS. R.ГорячеваС. Р.
Russian Federation
VakhrushevaM. V.ВахрушеваМ. В.
Russian Federation
KulikovS. M.КуликовС. М.
Russian Federation
TishchenkoI. A.ТищенкоИ. А.
Russian Federation
DyachenkoL. V.ДяченкоЛ. В.
Russian Federation
UdovichenkoA. I.УдовиченкоА. И.
Russian Federation
AlimovaG. A.АлимоваГ. А.
Russian Federation
KleinaE. V.КлеинаЕ. В.
Russian Federation
GrebenyukL. A.ГребенюкЛ. А.
Russian Federation
KonnovaM. L.КонноваМ. Л.
Russian Federation
SmirnovaS. Yu.СмирноваС. Ю.
Russian Federation
KhoroshkoN. D.ХорошкоН. Д.
Russian Federation
DomrachevaE. V.ДомрачеваЕ. В.
Russian Federation
Hematological Research Center, Ministry of Health of RussiaФГБУ «Гематологический научный центр» Минздрава России2311201274243423072014230720142012https://oncohematology.abvpress.ru/ongm/article/view/73

The additional molecular and chromosomal abnormalities (ACA) in Phositive cells usually considered as a genetic marker of chronic myeloid leukemia (CML) progression. 457 patients in different CML phases received tyrosine kinase inhibitors (1st and 2nd generation) were studied. During therapy 50 cases with additional chromosomal abnormalities in Ph+ clone (22 of them in chronic CML phase) were revealed (median follow-up from CML diagnosis – 117 months, median imatinib therapy – 62 months). 86 % of patients in chronic phase with Ph+- cell abnormalities were cytogenetic resistance, and their 5-years overall survival was 80 % which was significantly lower than in patients without ACA (p < 0.005). The treatment results depend on chromosomal abnormalities detected. In patients with additional chromosome 8 imatinib therapy is effective, although complete cytogenetic response (CCR) is achieved only in the later therapy stages. In patients with additional translocations CCR also achieved with imatinib or 2nd generation TKI. Only a third of patients with additional Ph-chromosome or BCR/ABL amplification achieved complete suppression of Ph+ clone using 2nd generation TKI. The presence of additional chromosome 7 abnormalities and complex karyotype disorders involving isochromosome i(17)(q10) are poor prognostic factors of TKI treatment failures.

chronic myeloid leukemiaadditional chromosomal abnormalitiesPh+-cellsхронический миелолейкоздополнительные хромосомные аномалии в Ph-позитивных клетках1. Cortes J., O’Dwyer M.E. Clonal evolution in chronic myelogenous leukemia. Hematol Oncol Clin N Am 2004;18(3):671–84.Cortes J., O’Dwyer M.E. Clonal evolution in chronic myelogenous leukemia. Hematol Oncol Clin N Am 2004;18(3):671–84.2. O'Hare T., Eide C.A., Deininger M.W. Bcr- Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007;110(7):2242–9.O'Hare T., Eide C.A., Deininger M.W. Bcr- Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007;110(7):2242–9.3. Sattler M., Verma S., Shrikhande G. et al. The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem 2000;275(32):24273–8.Sattler M., Verma S., Shrikhande G. et al. The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem 2000;275(32):24273–8.4. Branford S., Rudzki Z., Walsh S. et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003;102(1):276–83.Branford S., Rudzki Z., Walsh S. et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003;102(1):276–83.5. Willis S.G., Lange T., Demehri S. et al. Highsensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood 2005;106(6):2128–37.Willis S.G., Lange T., Demehri S. et al. Highsensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood 2005;106(6):2128–37.6. Quintás-Cardama A., Kantarjian H., Cortes J. et al. Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia. Cancer 2009;115(13):2912–21.Quintás-Cardama A., Kantarjian H., Cortes J. et al. Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia. Cancer 2009;115(13):2912–21.7. Koptyra M., Falinski R., Nowicki M.O. et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 2006;108(1):319–27.Koptyra M., Falinski R., Nowicki M.O. et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 2006;108(1):319–27.8. Nowicki M.O., Falinski R., Koptyra M. et al. BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen speciesdependent DNA double-strand breaks. Blood 2004;104(12):3746–53.Nowicki M.O., Falinski R., Koptyra M. et al. BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen speciesdependent DNA double-strand breaks. Blood 2004;104(12):3746–53.9. Dierov J., Sanchez P.V., Burke B.A. et al. BCR/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold. Leukemia 2009;23(2):279–86.Dierov J., Sanchez P.V., Burke B.A. et al. BCR/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold. Leukemia 2009;23(2):279–86.10. Skorski T. BCR/ABL, DNA damage and DNA repair: implications for new treatment concepts. Leuk Lymphoma 2008;49(4):610–4.Skorski T. BCR/ABL, DNA damage and DNA repair: implications for new treatment concepts. Leuk Lymphoma 2008;49(4):610–4.11. Cortes J.E., Talpaz M., Giles F. et al. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood 2003;101(10):3794–800.Cortes J.E., Talpaz M., Giles F. et al. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood 2003;101(10):3794–800.12. Calabretta B., Perotti D. The biology of CML blast crisis. Blood 2004;103:4010–22.Calabretta B., Perotti D. The biology of CML blast crisis. Blood 2004;103:4010–22.13. Clift R.A., Buckner C.D., Thomas E.D. et al. Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia. Blood 1994;84(12):4368–73.Clift R.A., Buckner C.D., Thomas E.D. et al. Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia. Blood 1994;84(12):4368–73.14. O’Dwyer M.E., Mauro M.J., Kurilik G. et al. The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 2002;100(5):1628–33.O’Dwyer M.E., Mauro M.J., Kurilik G. et al. The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 2002;100(5):1628–33.15. Круглов С.С. Резистентность к ингибитору тирозинкиназ BCR-ABL у пациентов в фазе акселерации хронического миелолейкоза. Автореф. дис. … канд. мед. наук. М., 2005.Круглов С.С. Резистентность к ингибитору тирозинкиназ BCR-ABL у пациентов в фазе акселерации хронического миелолейкоза. Автореф. дис. … канд. мед. наук. М., 2005.16. Круглов С.С., Туркина А.Г., Хорошко Н.Д. Резистентность при терапии гливеком у больных хроническим миелолейкозом в фазе акселерации. Гематол и трансфузиол 2005;50(4):17–24.Круглов С.С., Туркина А.Г., Хорошко Н.Д. Резистентность при терапии гливеком у больных хроническим миелолейкозом в фазе акселерации. Гематол и трансфузиол 2005;50(4):17–24.17. Baccarani M. // Chronic Myeloid Leukemia: An Update of Concepts and Management Recommendations of European Leukemia-net. // JCO, 2009, W. 27, № 35, P. 6041-51.Baccarani M. // Chronic Myeloid Leukemia: An Update of Concepts and Management Recommendations of European Leukemia-net. // JCO, 2009, W. 27, № 35, P. 6041-51.18. Домрачева Е.В., Захарова А.В., Асеева Е.А. Прогностическое значение дополнительных цитогенетических аномалий при хроническом миелолейкозе. Гематол и трансфузиол 2005;50(4):37–42.Домрачева Е.В., Захарова А.В., Асеева Е.А. Прогностическое значение дополнительных цитогенетических аномалий при хроническом миелолейкозе. Гематол и трансфузиол 2005;50(4):37–42.19. Мартынкевич И.С., Мартыненко Л.С., Иванова М.П. и др. Дополнительные хромосомные беррации у пациентов с хроническим миелолейкозом. Гематол и трансфузиол 2007;52(2):28–35.Мартынкевич И.С., Мартыненко Л.С., Иванова М.П. и др. Дополнительные хромосомные беррации у пациентов с хроническим миелолейкозом. Гематол и трансфузиол 2007;52(2):28–35.20. Куцев С.И., Морданов С.В., Зельцер А.Н. Прогностическое значение дополнительных хромосомных аномалий в Ph-позитивных клетках в терапии иматинибом хронического миелолейкоза. Мед ген 2009; 8(10):23–8.Куцев С.И., Морданов С.В., Зельцер А.Н. Прогностическое значение дополнительных хромосомных аномалий в Ph-позитивных клетках в терапии иматинибом хронического миелолейкоза. Мед ген 2009; 8(10):23–8.21. Hochhaus A., Kreil S., Corbin A.S. et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002;16(11):2190–6.Hochhaus A., Kreil S., Corbin A.S. et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002;16(11):2190–6.22. Marktel S., Marin D., Foot N. et al. Chronic myeloid leukemia in chronic phase responding to imatinib: the occurrence of additional cytogenetic abnormalities predicts disease progression. Haematologica 2003;88:260–7.Marktel S., Marin D., Foot N. et al. Chronic myeloid leukemia in chronic phase responding to imatinib: the occurrence of additional cytogenetic abnormalities predicts disease progression. Haematologica 2003;88:260–7.23. Baccarani M., Saglio G., Goldman J.M. et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European Leukemianet. Blood 2006;108:1809–20.Baccarani M., Saglio G., Goldman J.M. et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European Leukemianet. Blood 2006;108:1809–20.24. Fialkow P.J., Jacobson R.J., apayannopoulou T. Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am J Med 1997;63(1) :125–30.Fialkow P.J., Jacobson R.J., apayannopoulou T. Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am J Med 1997;63(1) :125–30.25. Hild F., Freund M., Fonatsch C. Chromosomal aberrations during interferon therapy for chronic myelogenous leukemia. N Engl J Med 1991;325:132.Hild F., Freund M., Fonatsch C. Chromosomal aberrations during interferon therapy for chronic myelogenous leukemia. N Engl J Med 1991;325:132.26. Heim S., Mitelman F. Cancer Cytogenetics. Chromosomal and molecular genetic aberrations of tumor cells. Wiley-Liss, New York, 1995.Heim S., Mitelman F. Cancer Cytogenetics. Chromosomal and molecular genetic aberrations of tumor cells. Wiley-Liss, New York, 1995.27. Levine A.J. p53, the cellular gatekeeper for growth and division. Cell 1997;88(3):323–31.Levine A.J. p53, the cellular gatekeeper for growth and division. Cell 1997;88(3):323–31.28. Wattel E., Preudhomme C., Hesquet B. et al. P53 are mutation associated with resistanse to chemotherapy and short survival in gematological malignancies. Blood 1994;84:3148–57.Wattel E., Preudhomme C., Hesquet B. et al. P53 are mutation associated with resistanse to chemotherapy and short survival in gematological malignancies. Blood 1994;84:3148–57.29. Ольшанская Ю.В., Домрачева Е.В. Хромосомные перестройки при острых лейкозах. М.: МЕДпресс-информ, 2006. С. 112.Ольшанская Ю.В., Домрачева Е.В. Хромосомные перестройки при острых лейкозах. М.: МЕДпресс-информ, 2006. С. 112.