Treatment of Chronic Myeloid Leukemia According to Current Guidelines: The Results of the Pilot Prospective Study “Early Induction Therapy and Monitoring” (РИТМ)

Background. Current clinical guidelines on diagnosis and treatment of chronic myeloid leukemia (CML) define indications for substitution of first-line tyrosine kinase inhibitor (TKI) at therapy failure during different phases of disease progression.

Aim. To assess the efficacy of CML treatment with implementing the protocol of timely monitoring and switching to another TKI.

Materials & Methods. Patients were included into pilot prospective study РИТМ during 5 years. Data on 100 CML patients were analyzed. Therapy and monitoring were conducted according to the Federal clinical guidelines on CML diagnosis and therapy, 2013.

Results. Median follow-up after initiation of treatment was 46 months (range 12–74). Imatinib mesylate was administered as first-line therapy to 91 (91 %) patients, 9 (9 %) patients received 2nd generation TKI (TKI2). Therapy failure was registered in 31 (31 %) patients; 26 (84 %) of them were switched to TKI2. At the time of analysis 95 (95 %) patients were followed-up. Cumulative incidence of CML-associated mortality was 2 %. By the fifth year of follow-up cumulative probability of complete cytogenetic, major and deep molecular responses was 93 %, 88 % and 66 %, respectively.

Conclusion. CML treatment according to current guidelines yields the results comparable with those achieved by first-line TKI2 therapy. This approach reduces CML treatment costs and lowers the risk of TKI2-associated adverse events. Due to a high rate of deep molecular response the proportion of CML patients in remission without treatment can be increased in the future.

• Oleg Aleksandrovich Shukhov National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167
• A.G. Turkina National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167
• E.Yu. Chelysheva National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167
• A.V. Bykova National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167
• A.N. Petrova National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167
• G.A. Gusarova National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167
• I.S. Nemchenko National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167
• A.O. Abdullaev National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167
• T.N. Obukhova National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167
• A.B. Sudarikov National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4а, Москва, Российская Федерация, 125167

1. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994–1004. doi: 10.1056/NEJMoa022457. DOI: https://doi.org/10.1056/NEJMoa022457
2. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl Med. 2017;376(10):917–27. doi: 10.1056/NEJMoa1609324. DOI: https://doi.org/10.1056/NEJMoa1609324
3. Bower H, Bjorkholm M, Dickman PW, et al. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34(24):2851–7. doi: 10.1200/JCO.2015.66.2866. DOI: https://doi.org/10.1200/JCO.2015.66.2866
4. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–54. doi: 10.1038/leu.2016.5. DOI: https://doi.org/10.1038/leu.2016.5
5. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34(20):2333–40. doi: 10.1200/JCO.2015.64.8899. DOI: https://doi.org/10.1200/JCO.2015.64.8899
6. Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118(17):4567–76. doi: 10.1182/blood-2011-05-355594. DOI: https://doi.org/10.1182/blood-2011-05-355594
7. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393–404. doi: 10.1182/blood-2016-09-739086. DOI: https://doi.org/10.1182/blood-2016-09-739086
8. Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol. 2012;30(3):232–8. doi: 10.1200/JCO.2011.38.6565. DOI: https://doi.org/10.1016/j.yonc.2012.07.031
9. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014;123(4):494–500. doi: 10.1182/blood-2013-06-511592. DOI: https://doi.org/10.1182/blood-2013-06-511592
10. Saglio G, Snedecor SJ, Xiang J, et al. Early molecular response (EMR) with frontline treatment is a significant predictor of long-term BCR-ABL transcript levels in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in chronic phase. Blood. 2015;126(23):1579, DOI: https://doi.org/10.1182/blood.V126.23.1579.1579
11. Dulucq S, Mahon FX. Deep molecular responses for treatment-free remission in chronic myeloid leukemia. Cancer Med. 2016;5(9):2398–411. doi: 10.1002/cam4.801. DOI: https://doi.org/10.1002/cam4.801
12. 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. DOI: https://doi.org/10.1182/blood-2013-05-501569
13. National Comprehensive Cancer Network. Chronic myeloid leukemia. Version 1.2019. Available from: https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. (accessed 3.12.2018).
14. Абдулкадыров К.М., Абдуллаев А.О., Авдеева Л.Б. и др. Федеральные клинические рекомендации по диагностике и терапии хронического миелолейкоза. Вестник гематологии. 2013;9(3):4–41.
15. [Abdulkadyrov KM, Abdullaev AO, Avdeeva LB, et al. Federal clinical guidelines for diagnosis and treatment of chronic myeloid leukemia. Vestnik gematologii. 2013;9(3):4–41. (In Russ)]
16. Туркина А.Г., Зарицкий А.Ю., Шуваев В.А. и др. Клинические рекомендации по диагностике и лечению хронического миелолейкоза. Клиническая онкогематология. 2017;10(3):294–316. doi: 21320/2500-2139-2017-10-3-294-316. DOI: https://doi.org/10.21320/2500-2139-2017-10-3-294-316
17. [Turkina AG, Zaritskii AYu, Shuvaev VA, et al. Clinical Recommendations for the Diagnosis and Treatment of Chronic Myeloid Leukemia. Clinical oncohematology. 2017;10(3):294–316. doi: 10.21320/2500-2139-2017-10-3-294-316. (In Russ)] DOI: https://doi.org/10.21320/2500-2139-2017-10-3-294-316
18. Klil-Drori AJ, Yin H, Azoulay L, et al. Early switch to second-line tyrosine kinase inhibitor in chronic myeloid leukemia patients failing to achieve early molecular response. Am J Hematol. 2017;92(10):E602–4. doi: 10.1002/ajh.24838. DOI: https://doi.org/10.1002/ajh.24838
19. Milojkovic D, Clarck RE, Byrne JL, et al. The Target UK study: Real-world evidence of molecular response to tyrosine kinase inhibitors supports European LeukemiaNet 2013 recommendations for the management of chronic myeloid leukaemia. Blood. 2017;130(1):2892, abstract.
20. Yeung DT, Osborn MP, White DL, et al. TIDEL-II: first-use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015;125(6):915–23. doi: 10.1182/blood-2014-07-590315. DOI: https://doi.org/10.1182/blood-2014-07-590315
21. Mahon FX. Discontinuation of tyrosine kinase therapy in CML. Ann Hematol. 2015;94(Suppl 2):187–93. doi: 10.1007/s00277-015-2320-4. DOI: https://doi.org/10.1007/s00277-015-2320-4
22. Hochhaus A, Masszi T, Giles FJ, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7):1525–31. doi: 10.1038/leu.2017.63. DOI: https://doi.org/10.1038/leu.2017.63
23. Mahon FX, Boquimpani C, Kim DW, et al. Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, phase 2, open-label study. Ann Intern Med. 2018;168(7):461–70. doi: 10.7326/M17-1094. DOI: https://doi.org/10.7326/M17-1094
24. Etienne G, Guilhot J, Rea D, et al. Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. J Clin Oncol. 2017;35(3):298–305. doi: 10.1200/JCO.2016.68.2914. DOI: https://doi.org/10.1200/JCO.2016.68.2914
25. Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19(6):747–57. doi: 10.1016/S1470-2045(18)30192-X. DOI: https://doi.org/10.1016/S1470-2045(18)30192-X
26. Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016;128(1):17–23. doi: 10.1182/blood-2016-01-694265. DOI: https://doi.org/10.1182/blood-2016-01-694265
27. Тасигна® (инструкция по медицинскому применению). Швейцария: Novartis pharma, AG. Доступно по: https://www.vidal.ru/drugs/tasigna__42603. Ссылка активна на12.2018.
28. [Tasigna® (package insert). Switzerland: Novartis pharma, AG. Available from: https://www.vidal.ru/drugs/tasigna__42603. (accessed 3.12.2018) (In Russ)]
29. Rea D, Nicolini FE, Tulliez M, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2017;129(7):846–54. doi: 10.1182/blood-2016-09-742205. DOI: https://doi.org/10.1182/blood-2016-09-742205
30. ТуркинаА.Г., Челышева Е.Ю., Шуваев В.А. и др. Результаты наблюдения больных хроническим миелолейкозом с глубоким молекулярным ответом без терапии ингибиторами тирозинкиназ. Терапевтический архив. 2017;89(12):86–96. doi: 10.17116/terarkh2017891286-96. DOI: https://doi.org/10.17116/terarkh2017891286-96
31. [Turkina AG, Chelysheva EYu, Shuvaev VA, et al. Results of following up patients with chronic myeloid leukemia and a deep molecular response without tyrosine kinase inhibitor therapy. Terapevticheskii arkhiv. 2017;89(12):86–96. doi: 10.17116/terarkh2017891286-96. (In Russ)] DOI: https://doi.org/10.17116/terarkh2017891286-96
32. Туркина А.Г., Челышева Е.Ю. Стратегия терапии хронического миелолейкоза: возможности и перспективы. Терапевтический архив. 2013;85(7):4–9.
33. [Turkina AG, Chelysheva EYu. Therapeutic strategy for chronic myeloid leukemia: possibilities and prospects. Terapevticheskii arkhiv. 2013;85(7):4–9. (In Russ)]
34. Шуваев В.А., Абдулкадыров К.М., Туркина А.Г. и др. Фармакоэкономический анализ ремиссии хронического миелолейкоза без лечения. Гематология и трансфузиология. 2015;60(4):14–20.
35. [Shuvaev VA, Abdulkadyrov KM, Turkina AG, et al. Pharmacoeconomic analysis of chronic myeloid leukemia remission without treatment. Gematologiya i transfuziologiya. 2015;60(4):14–20. (In Russ)]