Monitoring and Analysis of Chinese Chronic Myeloid Leukemia Patients Who Have Stopped Tyrosine Kinase Inhibitor Therapy

Abstract

Discontinuation of tyrosine kinase inhibitor (TKI) therapy after achieving a persistent deep molecular response (DMR) is an urgently needed treatment goal for chronic myeloid leukemia (CML) patients and has been included in the National Comprehensive Cancer Network (NCCN) guidelines (version 2.2017) for CML. Indeed, various studies have confirmed the feasibility of discontinuing TKI therapy. In this study, we analyzed data from 45 CML patients who had discontinued TKI therapy. Univariate analysis was performed to predict factors that were potentially related to treatment-free remission (TFR) and identify the differences between early relapse and late relapse. Out of the 45 patients, 20 exhibited molecular relapse after a median follow-up of 18 months (range, 1–54 months), and the estimated TFR at 24 months was 40%. The univariate analysis revealed that a high Sokal score and interruptions or dose reductions during TKI treatment were the only baseline factors associated with poor outcomes. Our results indicate that TKI discontinuation could be successfully put into practice in China.

Keywords

discontinuation / treatment-free remission / chronic myeloid leukemia / relapse

References

[1] Gambacorti-PasseriniC, AntoliniL, MahonFX, et al.. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst, 2011, 103(7): 553-561

[2] MughalTI, RadichJP, DeiningerMW, et al.. Chronic myeloid leukemia: reminiscences and dreams. Haematologica, 2016, 101(5): 541-558

[3] HehlmannR, MullerMC, LausekerM, et al.. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol, 2014, 32(5): 415-423

[4] CastagnettiF, GugliottaG, BrecciaM, et al.. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia, 2015, 29(9): 1823-1831

[5] MauroMJ. Striving to achieve safe, permanent treatment discontinuation in chronic myeloid leukemia. Leuk Res, 2013, 37(11): 1395-1403

[6] JiangQ, LiuZC, ZhangSX, et al.. Young age and high cost are associated with future preference for stopping tyrosine kinase inhibitor therapy in Chinese with chronic myeloid leukemia. J Cancer Res Clin Oncol, 2016, 142(7): 1539-1547

[7] JabbourE. Chronic myeloid leukemia: First-line drug of choice. Am J Hematol, 2016, 91(1): 59-66

[8] MahonFX. Discontinuation of tyrosine kinase therapy in CML. Ann Hematol, 2015, 94(2): S187-S193

[9] BrecciaM, ColafigliG, MolicaM, et al.. Timing and deepness of response to tyrosine kinase inhibitors as a measure of potential treatment discontinuation in chronic myeloid leukemia patients managed in the real-life. Am J Hematol, 2017, 92(12): E668-E670

[10] SausseleS, RichterJ, HochhausA, et al.. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia, 2016, 30(8): 1638-1647

[11] ReaD, MahonFX. How I manage relapse of chronic myeloid leukaemia after stopping tyrosine kinase inhibitor therapy. Br J Haematol, 2018, 180(1): 24-32

[12] BrownPA, ShahB, FathiA, et al.. NCCN Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2017. J Natl Compr Canc Netw, 2017, 15(9): 1091-1102

[13] BaccaraniM, DeiningerMW, RostiG, et al.. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood, 2013, 122(6): 872-884

[14] MahonFX, ReaD, GuilhotJ, et al.. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol, 2010, 11(11): 1029-1035

[15] RossDM, BranfordS, SeymourJF, et al.. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood, 2013, 122(4): 515-522

[16] LegrosL, NicoliniFE, EtienneG, et al.. Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia. Cancer, 2017, 123(22): 4403-4410

[17] EtienneG, GuilhotJ, ReaD, 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

[18] TakahashiN, KyoT, MaedaY, et al.. Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia. Haematologica, 2012, 97(6): 903-906

[19] ChomelJC, BonnetML, SorelN, et al.. Leukemic stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease. Blood, 2011, 118(13): 3657-3660

[20] WarfvingeR, GeironsonL, SommarinM, et al.. Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML. Blood, 2017, 129(17): 2384-2394

[21] LiQ, ZhongZ, ZengC, et al.. A clinical observation of Chinese chronic myelogenous leukemia patients after discontinuation of tyrosine kinase inhibitors. Oncotarget, 2016, 7(36): 58234-58243

[22] ChomelJC, BonnetML, SorelN, et al.. Leukemic stem cell persistence in chronic myeloid leukemia patients in deep molecular response induced by tyrosine kinase inhibitors and the impact of therapy discontinuation. Oncotarget, 2016, 7(23): 35293-35301

[23] BrecciaM, AlimenaG. Discontinuation of tyrosine kinase inhibitors and new approaches to target leukemic stem cells: treatment-free remission as a new goal in chronic myeloid leukemia. Cancer Lett, 2014, 347(1): 22-28

[24] LiF, HeB, MaX, et al.. Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1. Cell Stem Cell, 2017, 21(3): 359-373

[25] IlanderM, Olsson-StrombergU, SchlumsH, et al.. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia, 2017, 31(5): 1108-1116

[26] MustjokiS, RichterJ, BarbanyG, et al.. Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients. Leukemia, 2013, 27(7): 1520-1526