OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press66610.17650/1818-8346-2008-0-1-2-31-33HEMATOLOGIC MALIGNANCIES: DIAGNOSIS, TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ДИАГНОСТИКА, ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯThe case of successful therapy with Nilotinib in patients with Ph-positive chronic myelogenous leukemia of chronic phase resistant to Interferon and GleevecПример успешной терапии нилотинибом пациентки с PH-позитивным хроническим миелолейкозом в хронической фазе с резистентностью к интерферону и ГливекуAfanasyevaN. A.АфанасьеваН. А.
Russian Federation

Moscow

Москва

GusarovaG. A.ГусароваГ. А.
Russian Federation

Moscow

Москва

Research Center for Hematology of Russian Academy of Medical Sciences, department of chemotherapy for leukemia and pathology of erythronГематологический научный центр РАМН, отделение химиотерапии лейкозов и патологии эритрона230520081-2313323112022231120222008https://oncohematology.abvpress.ru/ongm/article/view/666

In spite of striking successes achieved in the treatment of chronic leukemia with Gleevec, some patients remain resistant to the drug. Risk for development of resistance to Gleevec increases with the duration of chronic phase of disease and, more evidently, with onset of acceleration phase and blast crisis. Besides, other patients can not tolerate Gleevec. Nilotinib (tasigna, Novartis Pharma) which is a new highly selective inhibitor of bcr/abl tyrosine-kinase has been introduced into clinical practice after the mechanisms of resistance to drug became clear. Clinical trials of phase I and II demonstrated high activity of Nilotinib in patients with resistance to Gleevec, low toxicity profile and absence of cross toxicity with Gleevec. The clinical case of successful therapy with Nilotinib in patient with cytogenetically proved resistance to Gleevec is reported in the article. The major cytogenetic response was achieved after a short period of time (6 months) with acceptable tolerability of treatment.

Несмотря на впечатляющие успехи в лечении хронического миелолейкоза гливеком, часть больных остаются резистентными к данному препарату. Риск развития резистентности возрастает с увеличением длительности хронической фазы заболевания и тем более, с развитием фазы акселерации и бластного криза. Кроме того, у небольшой части пациентов имеется непереносимость гливека. Раскрытие некоторых механизмов развития резистентности привело к появлению в клинической практике нового высокоселективного ингибитора bcr/abl-тирозинкиназы — нилотиниба (тасигна, «Новартис Фарма»). В ходе 1-й и 2-й фазы клинических испытаний препарат показал высокую активность при резистентности к гливеку, низкий профиль токсичности, отсутствие перекрестной токсичности с гливеком.В статье приводится клинический случай успешной терапии нилотинибом пациентки с цитогенетической резистентностью к гливеку. Показано быстрое (через 6 мес терапии) достижение большого цитогенетического ответа при хорошей переносимости препарата.

chronic myeloleukemiaGleevecresistanceNilotinibхронический миелолейкозгливекрезистентностьнилотиниб1. Hochhaus A., Drucker B.J., Larson R.A. IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. Blood 2007;110(11):25.Hochhaus A., Drucker B.J., Larson R.A. IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. Blood 2007;110(11):25.2. Silver R.T., Talpaz M., Sawyers C.L. et al. Four Years of Follow-Up of 1027 Patients with Late Chronic Phase (L-CP), Accelerated Phase (AP), or Blast Crisis (BC) Chronic Myeloid Leukemia (CML) Treated with Imatinib in Three Large Phase II Trials. Blood 2004;104(11):23.Silver R.T., Talpaz M., Sawyers C.L. et al. Four Years of Follow-Up of 1027 Patients with Late Chronic Phase (L-CP), Accelerated Phase (AP), or Blast Crisis (BC) Chronic Myeloid Leukemia (CML) Treated with Imatinib in Three Large Phase II Trials. Blood 2004;104(11):23.3. O,Brien S.G., Gulihot F., Larson R.A. et al. IRIS nvestigetors. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic myeloid leukemia. N Engl J Med 2003;348(11):994—1004.O,Brien S.G., Gulihot F., Larson R.A. et al. IRIS nvestigetors. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic myeloid leukemia. N Engl J Med 2003;348(11):994—1004.4. Kantarjian H., Sawyers C., Hochhaus A. et al; International STI 571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346(9):645—52.Kantarjian H., Sawyers C., Hochhaus A. et al; International STI 571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346(9):645—52.5. Hochhaus A., La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leucemia 2004;18(8):1321—31.Hochhaus A., La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leucemia 2004;18(8):1321—31.6. Kantarjian H.M., Larson R.A., Gulihot F. Declining rates of adverse events (AEs), rare occurrence of serios AEs (SAEs), and unexpected long-term side effects at 5 years in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) initially treated with imatinib in the internationalrandomised study of interferon vs STI571(IRIS). Poster, ASH 2006.Kantarjian H.M., Larson R.A., Gulihot F. Declining rates of adverse events (AEs), rare occurrence of serios AEs (SAEs), and unexpected long-term side effects at 5 years in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) initially treated with imatinib in the internationalrandomised study of interferon vs STI571(IRIS). Poster, ASH 2006.7. Hochhaus A., Kreil S., Corbin A.S. et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI 571) therapy. Leucemia 2002;16(11):2190—6.Hochhaus A., Kreil S., Corbin A.S. et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI 571) therapy. Leucemia 2002;16(11):2190—6.8. Brandford S., Hughes T. Detection of BCR-ABL mutations and resistance to imatinib mesylate. Methods Mol Med 2006;125:93—106.Brandford S., Hughes T. Detection of BCR-ABL mutations and resistance to imatinib mesylate. Methods Mol Med 2006;125:93—106.9. Jiang X., Zhao Y., Smith C. et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leucemia 2007;21:926—35.Jiang X., Zhao Y., Smith C. et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leucemia 2007;21:926—35.10. Soverini S., Martinell G., Rosti G. et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid leukemia. J Clin Oncol 2005;23(18):4100—9.Soverini S., Martinell G., Rosti G. et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid leukemia. J Clin Oncol 2005;23(18):4100—9.11. Weisberg E., Manley P.W., Breitenstein W. et al. Characterization of AMN 107,a selective inhibitors of wild-type and mutant BCR-ABL. Cancer Cell 2005;7:129—41.Weisberg E., Manley P.W., Breitenstein W. et al. Characterization of AMN 107,a selective inhibitors of wild-type and mutant BCR-ABL. Cancer Cell 2005;7:129—41.12. Nagar B., Bornman W.G., Pellicena P. et al. Crystal structures of the kinase domain c-abl in complex with the small molecule ingibitors PD 173955 and imatinib (STI-571). Cancer Res 2002;62(15):4236—43.Nagar B., Bornman W.G., Pellicena P. et al. Crystal structures of the kinase domain c-abl in complex with the small molecule ingibitors PD 173955 and imatinib (STI-571). Cancer Res 2002;62(15):4236—43.13. Kantarjian H.M., Hochhaus A., Cortes J. et al. Nilotinib Is Highly Active and Safe in Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Patients with Imatinib-Resistance or Intolerance. Blood 2007;110(11):226a (abstr 735).Kantarjian H.M., Hochhaus A., Cortes J. et al. Nilotinib Is Highly Active and Safe in Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Patients with Imatinib-Resistance or Intolerance. Blood 2007;110(11):226a (abstr 735).14. Cortes J., Jabbour E., Hochhaus A. et al. Nilotinib Is Associated with minimal cross intolerance to imatinib in patients with imatinib-intolerant Philadelphia-positive (Ph+) chronic myelogenous leukemia (CML) in either chronic phase (CP) or accelerated phase (AP). Blood 2007;110(11):315a (abstr 1040).Cortes J., Jabbour E., Hochhaus A. et al. Nilotinib Is Associated with minimal cross intolerance to imatinib in patients with imatinib-intolerant Philadelphia-positive (Ph+) chronic myelogenous leukemia (CML) in either chronic phase (CP) or accelerated phase (AP). Blood 2007;110(11):315a (abstr 1040).