KM Abdulkadyrov, VA Shuvaev, IS Martynkevich, MS Fominykh, NA Potikhonova, II Zotova, VYu Udal’eva, RA Golovchenko, NV Shakhvorostova, DI Shikhbabaeva, MN Zenina, SA Tiranova, SA Kudryashova, LS Martynenko, MP Ivanova, NYu Tsybakova, EV Petrova, LB Polushkina, EV Kleina
Russian Scientific Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024
For correspondence: Vasilii Anatol’evich Shuvaev, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(921)636-54-72; e-mail: email@example.com
For citation: Abdulkadyrov KM, Shuvaev VA, Martynkevich IS, et al. Chronic Myeloid Leukemia: Long-Term Experience of Target Therapy. Clinical oncohematology. 2016;9(1):54–60 (In Russ).
Background & Aims. Interpretation of key aspects of pathogenesis of chronic myeloid leukemia (CML) and development and introduction of target therapy have changed the prognosis of this once fatal disease dramatically. Results of numerous clinical trials demonstrated substantial superiority of tyrosine kinase inhibitors over previous therapy techniques. At the same time, clinical trials had limitations in patient enrollment, as well as treatment conditions and duration. The analysis of our clinical experience in CML target therapy (over the period from 2003 till 2015) is an important argument for introduction of novel drugs into routine clinical practice. The aim of the study is to analyze our own experience in CML target therapy and to compare our results with clinical trials data.
Methods. Outpatient’s cards and case histories of CML patients treated in the Russian Scientific Research Institute of Hematology and Transfusiology over last 12 years were analyzed in this work. Published results of multi-center clinical trials evaluating the use of tyrosine kinase inhibitors in CML were used for a comparative analysis. The primary morbidity rate and the prevalence of CML, results of first and subsequent treatment lines were studied with assessment of survival rates, adverse events, and the nature of the response (hematologic, cytogenetic and molecular).
Results. The experience in treatment of 208 CML patients was analyzed. The use of imatinib led to clinical and hematological remission (complete hematologic response) was achieved in 95 % of patients. The frequency of complete cytogenetic responses (CCyR) was 69 %, and that of major molecular responses (MMR) was 58 %. The overall 5-year survival (OS) was 86.4 %, the 10-years OS was 67.5 %. The use of nilotinib during the second line permitted to achieve CCyR in 61 % of patients, and the MMR in 55 % of cases. The two-year OS was 96 % and the 5-year OS was 68 %. CCyR and MMR were achieved in 50 % patients treated with dasatinib during the second line. As for the third line, CCyR was achieved in 50 % of patients and MMR in 25 %. In case of previous imatinib and nilotinib resistance, CCyR was observed only in 36 % of patients and MMR in 18 % of cases. During second-line dasatinib treatment, the 2-year OS was 85 %, and the 5-year OS was 51 %; as for the third line, the results were 75 % and 50 %, respectively. The range and rates of adverse events of the therapy, in general, corresponded to results of clinical trials.
Conclusion. The use of tyrosine kinase inhibitors in treatment of CML permits to prolong patient’s life span and quality of life significantly. The use of nilotinib and dazatinib (in case of nilotinib intolerance and/or resistance) could be effective in most patients.
Keywords: chronic myeloid leukemia, target therapy, tyrosine kinase inhibitors, imatinib, nilotinib, dasatinib, clinical practice.
Received: September 10, 2015
Accepted: October 20, 2015Read in PDF (RUS)
- Salesse S, Verfaillie CM. BCR/ABL: from molecular mechanisms of leukemia induction to treatment of chronic myelogenous leukemia. Oncogene. 2002;21:8547–59. doi: 10.1038/sj.onc.1206082.
- Goldman JM, Melo JV. Targeting the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia. N Engl J Med. 2001;344(14):1084–6. doi: 10.1056/ nejm200104053441409.
- Абдулкадыров К.М., Абдуллаев А.О., Авдеева Л.Б. и др. Федеральные клинические рекомендации по диагностике и терапии хронического мие- лолейкоза. Вестник гематологии. 2013;9(3):4–40. [Abdulkadyrov KM, Abdullaev AO, Avdeeva LB, et al. Federal clinical recommendations for diagnosis and treatment of chronic myeloid leukemia. Vestnik gematologii. 2013;9(3):4–40. (In Russ)]
- Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84. doi: 10.1182/blood-2013-05-501569.
- NCCN Guidelines Chronic Myelogenous Leukemia. Version 1.2015. Available from: www.nccn.org/cml.pdf. (accessed 14.05.2015).
- Шуваев В.А., Абдулкадырова А.С., Мартынкевич И.С. и др. Опыт лечения хронического миелолейкоза в Санкт-Петербурге. Вестник гема- тологии. 2011;7(1):43. [Shuvaev VA, Abdulkadyrova AS, Martynkevich IS, et al. Experience in treatment of chronic myeloid leukemia in Saint-Petersburg. Vestnik gematologii. 2011;7(1):43. (In Russ)]
- Стахина О.В., Туркина А.Г., Гусарова Г.А. и др. Отдаленные резуль- таты выживаемости больных в поздней хронической фазе Ph+ хрониче- ского миелолейкоза при лечении иматиниб мезилатом (Гливек®). Вестник гематологии. 2009;5(2):42. [Stakhina OV, Turkina AG, Gusarova GA, et al. Long-term results of survival rates of patients in late chronic phase of Ph+ chronic myeloid leukemia treated with imatinib mesylate (Glivec®). Vestnik gematologii. 2009;5(2):42. (In Russ)]
- Cortes J, Rousselot P, Kim D-W, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109(8):3207–13. doi: 10.1182/blood-2006-09-046888.
- Cortes J, Saglio G, Baccarani M, et al. Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA180-056). 56th Annual Meeting and Exposition, San Francisco, CA December 6–9, 2014. Blood. 2014;21: Abstract 152.
- Deininger M, O’Brien SG, Guilhot F, et al. International Randomized Study of Interferon Vs STI571 (IRIS) 8-Year Follow up: Sustained Survival and Low Risk for Progression or Events in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. Blood (ASH Annual Meeting Abstracts). 2009;114(22): Abstract 1126.
- Giles FJ, Rosti G, Beris P, et al. Nilotinib is superior to imatinib as first-line therapy of chronic myeloid leukemia: the ENESTnd study. Expert Rev Hematol. 2010;3(6):665–73. doi: 10.1586/ehm.10.61.
- Hochhaus A, Shah NP, Cortes JE. Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): DASISION 3-year follow-up. Program and abstracts of the 2012 Annual Meeting of the American Society of Clinical Oncology, Chicago, Illinois, June 1–5, 2012. Abstract 6504.
- Hoglund M, Sandin F, Simonsson B. Epidemiology of chronic myeloid leukaemia: an update. Ann Hematol. 2015;94(2):241–7. doi: 10.1007/s00277- 015-2314-2.
- Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119(5):1123–9. doi: 10.1182/ blood-2011-08-376087.
- Powell BL, Khoury HJ, Lipton JH, et al. Nilotinib Responses and Tolerability Confirmed in North American Patients with Chronic Myeloid Leukemia (CML) From ENACT (Expanding Nilotinib Access in Clinical Trials). Blood. 2009;114(22):3295.
- Saglio G, LeCoutre PD, Pasquini R, et al. Nilotinib Versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-Month (mo) Follow-up. Blood. 2011;118(21):452.
- Куликов С.М., Виноградова О.Ю., Челышева Е.Ю. и др. Заболе- ваемость хроническим миелолейкозом в 6 регионах России по данным популяционного исследования 2009–2012 гг. Терапевтический архив. 2014;7:24–30. [Kulikov SM, Vinogradova OYu, Tchelysheva EYu, et al. Incidence of chronic myeloid leukemia in 6 regions of Russia, according to a population-based study over the period from 2009 to 2012. Terapevticheskii arkhiv. 2014;7:24–30. (In Russ)]
- Лазарева О.В., Туркина А.Г., Гусарова Г.А. и др. Итоги 12-летней те- рапии ингибиторами тирозинкиназ больных в поздней хронической фазе хронического миелолейкоза после неудачи лечения ИФН-α. Сибирский научный медицинский журнал. Бюллетень СО РАМН. 2015;35(1):90–7. [Lazareva OV, Turkina AG, Gusarova GA, et al. Results of 12-year therapy with tyrosine kinase inhibitors in patients with late chronic phase of chronic myeloid leukemia after IFN-a treatment failure. Sibirkii meditcinskiy jurnal. Bulleten’ SO RAMN. 2015;35(1):90–7. (In Russ)]
- Zdenek R, Belohlavkova P, Cetkovsky P, et al. Comparison of Glucose and Lipid Metabolism Abnormality during Nilotinib, Imatinib and Dasatinib Therapy – Results of Enigma 2 Study. Blood. 2014;124(21):1813.
- Nicolini FE, Turkina A, Shen Z-X, et al. Expanding Nilotinib Access in Clinical Trials (ENACT). Cancer. 2012;118(1):118–26. doi: 10.1002/cncr.26249.
- Hughes TP, le Coutre PD, Jootar S, et al. ENESTnd 5-year follow-up: continued benefit of frontline nilotinib (NIL) compared with imatinib (IM) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP). Haematologica. 2014;99(Suppl 1):236–7.
- Shah NP, Kantarjian HM, Kim D-W, et al. Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia. J Clin Oncol. 2008;26(19):3204–12. doi: 10.1200/jco.2007.14.9260.
- Jabbour E, Makenbaeva D, Lingohr-Smith M, et al. Evaluation of Comorbidities Relevant to Tyrosine Kinase Inhibitor Treatment Among Patients with Chronic Myelogenous Leukemia in the US. Managed Care Setting. Blood. 2014;124(21):4550.