Biological Mechanisms of Sustaining Deep Molecular Response in Chronic Myeloid Leukemia Upon Withdrawal of Tyrosine Kinase Inhibitors

The feasibility of treatment-free follow-up in chronic myeloid leukemia (CML) patients is an important issue in the era of tyrosine kinase inhibitors (TKI). The clinical trials of TKI withdrawal in case of a stable deep molecular response prove the probability of sustaining molecular remission in 40–60 % of patients. Treatment-free remission (TFR), even under persistence of residual leukemia cells, suggests that there are special biologically determined mechanisms of tumor cell proliferation control, which are independent of BCR-ABL kinase activity. The search for factors determining differences in residual leukemia clone kinetics upon TKI withdrawal is an objective which is crucial for understanding TFR as a new biological phenomenon. The review provides worldwide evidence dealing with the study of immunological, genetic, and other biological mechanisms underlying the control of minimal residual disease upon TKI discontinuation in CML patients.

• Ekaterina Yurevna Chelysheva National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• M.A. Guryanova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167
• A.G. Turkina National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167

1. 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
2. Cross NCP, White HE, Colomer D, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015;29(5):999–1003. doi: 10.1038/leu.2015.29. DOI: https://doi.org/10.1038/leu.2015.29
3. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966–84. doi: 10.1038/s41375-020-0776-2. DOI: https://doi.org/10.1038/s41375-020-0776-2
4. 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
5. Castagnetti F, Gugliotta G, Breccia M, et al. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia. 2015;29(9):1823–31. doi: 10.1038/leu.2015.152. DOI: https://doi.org/10.1038/leu.2015.152
6. Claudiani S, Gatenby A, Szydlo R, et al. MR4 sustained for 12 months is associated with stable deep molecular responses in chronic myeloid leukemia. Haematologica. 2019;104(11):2206–14. doi: 10.3324/haematol.2018.214809. DOI: https://doi.org/10.3324/haematol.2018.214809
7. Hehlmann R, Muller MC, Lauseker M, 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):415–23. doi: 10.1200/JCO.2013.49.9020. DOI: https://doi.org/10.1200/JCO.2013.49.9020
8. Туркина А.Г., Новицкая Н.В., Голенков А.К. и др. Регистр больных хроническим миелолейкозом в Российской Федерации: от наблюдательного исследования к оценке эффективности терапии в клинической практике. Клиническая онкогематология. 2017;10(3):390–401. doi: 10.21320/2500-2139-2017-10-3-390-401. DOI: https://doi.org/10.21320/2500-2139-2017-10-3-390-401
9. [Turkina AG, Novitskaya NV, Golenkov AK, et al. Chronic Myeloid Leukemia Patient Registry in the Russian Federation: From Observational Studies to the Efficacy Evaluation in Clinical Practice. Clinical oncohematology. 2017;10(3):390–401. doi: 10.21320/2500-2139-2017-10-3-390-401. (In Russ)] DOI: https://doi.org/10.21320/2500-2139-2017-10-3-390-401
10. Graham SM, Jorgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99(1):319–25. doi: 10.1182/blood.v99.1.319. DOI: https://doi.org/10.1182/blood.V99.1.319
11. Copland M, Hamilton A, Elrick LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood. 2006;107(11):4532–9. doi: 10.1182/blood-2005-07-2947. DOI: https://doi.org/10.1182/blood-2005-07-2947
12. Goldman J, Gordon M. Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: does it really matter? Leuk Lymphoma. 2006;47(1):1–7. doi: 10.1080/10428190500407996. DOI: https://doi.org/10.1080/10428190500407996
13. Goldman JM. Chronic myeloid leukemia: molecular targeting as a basis for therapy. Rev Clin Exp Hematol. 2004;7(1):64–72.
14. Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood. 2017;129(12):1595–606. doi: 10.1182/blood-2016-09-696013. DOI: https://doi.org/10.1182/blood-2016-09-696013
15. Zhou H, Xu R. Leukemia stem cells: the root of chronic myeloid leukemia. Protein Cell. 2015;6(6):403–12. doi: 10.1007/s13238-015-0143-7. DOI: https://doi.org/10.1007/s13238-015-0143-7
16. Melo JV, Ross DM. Minimal residual disease and discontinuation of therapy in chronic myeloid leukemia: can we aim at a cure? Hematology Am Soc Hematol Educ Program. 2011;2011(1):136–42. doi: 10.1182/asheducation-2011.1.136. DOI: https://doi.org/10.1182/asheducation-2011.1.136
17. Tang M, Gonen M, Quintas-Cardama A, et al. Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells. Blood. 2011;118(6):1622–31. doi: 10.1182/blood-2011-02-339267. DOI: https://doi.org/10.1182/blood-2011-02-339267
18. Roeder I, Horn M, Glauche I, et al. Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nat Med. 2006;12(10):1181–4. doi: 10.1038/nm1487. DOI: https://doi.org/10.1038/nm1487
19. Branford S, Seymour JF, Grigg A, et al. BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res. 2007;13(23):7080–5. doi: 10.1158/1078-0432.CCR-07-0844. DOI: https://doi.org/10.1158/1078-0432.CCR-07-0844
20. Mughal T, Goldman J. Chronic myeloid leukemia: current status and controversies. Oncology. 2004;18(7):837–44.
21. 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
22. Pagani IS, Shanmuganathan N, Kok CH, et al. Long-term treatment-free remission of chronic myeloid leukemia with falling levels of residual leukemic cells. Leukemia. 2018;32(12):2572–9. doi: 10.1038/s41375-018-0264-0. DOI: https://doi.org/10.1038/s41375-018-0264-0
23. Петрова А.Н., Челышева Е.Ю., Туркина А.Г. Ремиссия без лечения у больных хроническим миелолейкозом: обзор литературы. Онкогематология. 2019;14(3):12–22. doi: 10.17650/1818-8346-2019-14-3-12-22. DOI: https://doi.org/10.17650/1818-8346-2019-14-3-12-22
24. [Petrova AN, Chelysheva EYu, Turkina AG. Treatment-free remission in patients with chronic myeloid leukemia: literature review. Onkogematologiya. 2019;14(3):12–22. doi: 10.17650/1818-8346-2019-14-3-12-22. (In Russ)] DOI: https://doi.org/10.17650/1818-8346-2019-14-3-12-22
25. Туркина А.Г., Петрова А.Н., Челышева Е.Ю. и др. Результаты проспективного исследования по наблюдению больных хроническим миелолейкозом после прекращения терапии ингибиторами тирозинкиназ. Гематология и трансфузиология. 2020;65(4):370–85. doi: 10.35754/0234-5730-2020-65-4-370-385. DOI: https://doi.org/10.35754/0234-5730-2020-65-4-370-385
26. [Turkina AG, Petrova AN, Chelysheva EYu, et al. A prospective study of the monitoring of patients with chronic myeloid leukemia upon withdrawal of tyrosine kinase inhibitor therapy. Gematologiya i transfuziologiya. 2020;65(4):370–85. doi: 10.35754/0234-5730-2020-65-4-370-385. (In Russ)] DOI: https://doi.org/10.35754/0234-5730-2020-65-4-370-385
27. Шухов О.А., Петрова А.Н., Челышева Е.Ю. и др. Факторы сохранения молекулярной ремиссии после прекращения терапии ингибиторами тирозинкиназ у пациентов с хроническим миелолейкозом: результаты нерандомизированного проспективного клинического исследования. Клиническая онкогематология. 2021;14(1):1–12. doi: 10.21320/2500-2139-2021-14-1-1-12. DOI: https://doi.org/10.21320/2500-2139-2021-14-1-1-12
28. [Shukhov OA, Petrova AN, Chelysheva EYu, et al. Factors for Sustaining Molecular Remission after Discontinuation of Tyrosine Kinase Inhibitors Therapy in Chronic Myeloid Leukemia: Results of Non-Randomized Prospective Clinical Trial. Clinical oncohematology. 2021;14(1):1–12. doi: 10.21320/2500-2139-2021-14-1-1-12. (In Russ)] DOI: https://doi.org/10.21320/2500-2139-2021-14-1-1-12
29. Rousselot P, Charbonnier A, Cony-Makhoul P, et al. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014;32(5):424–30. doi: 10.1200/JCO.2012.48.5797. DOI: https://doi.org/10.1200/JCO.2012.48.5797
30. Ross DM, Branford S, Seymour JF, et al. Patients with chronic myeloid leukaemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukaemia by DNA PCR. Leukemia. 2010;24(10):1719–24. doi: 10.1038/leu.2010.185. DOI: https://doi.org/10.1038/leu.2010.185
31. Rousselot P, Loiseau C, Delord M, et al. A report on 114 patients who experienced treatment free remission in a single institution during a 15 years period: long term follow-up, late molecular relapses and second attempts. Blood. 2019;134(1):27. doi: 10.1182/blood-2019-129919. DOI: https://doi.org/10.1182/blood-2019-129919
32. Imagawa J, Tanaka H, Okada M, et al. DADI Trial Group. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015;2(12):528–35. doi: 10.1016/S2352-3026(15)00196-9. DOI: https://doi.org/10.1016/S2352-3026(15)00196-9
33. Takahashi N, Nishiwaki K, Nakaseko Ch, et al. Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan. 2018;103(11):1835–42. doi: 10.3324/haematol.2018.194894. DOI: https://doi.org/10.3324/haematol.2018.194894
34. Ilander M, Olsson-Stromberg U, Schlums H, et al. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia. 2017;31(5):1108–16. doi: 10.1038/leu.2016.360. DOI: https://doi.org/10.1038/leu.2016.360
35. Rea D, Henry G, Khaznadar Z, et al. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study. Haematologica. 2017;102(8):1368–77. doi: 10.3324/haematol.2017.165001. DOI: https://doi.org/10.3324/haematol.2017.165001
36. Borg C, Terme M, Taieb J, et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J Clin Invest. 2004;114(4):379–88. doi: 10.1172/JCI21102. DOI: https://doi.org/10.1172/JCI200421102
37. Yoshimoto T, Mizoguchi I, Katagiri S, et al. Immunosurveillance markers may predict patients who can discontinue imatinib therapy without relapse. OncoImmunology. 2014;3(5):28861. doi: 10.4161/onci.28861. DOI: https://doi.org/10.4161/onci.28861
38. Mizoguchi I, Yoshimoto T, Katagiri S, et al. Sustained upregulation of effector natural killer cells in chronic myeloid leukemia after discontinuation of imatinib. Cancer Sci. 2013;201(104):1146–53. doi: 10.1111/cas.12216. DOI: https://doi.org/10.1111/cas.12216
39. Ohyashiki K, Katagiri S, Tauchi T, et al. Increased natural killer cells and decreased CD3+CD8 +CD62L+ T cells in CML patients who sustained complete molecular remission after discontinuation of imatinib. Br J Haematol. 2012;157(2):254–6. doi: 10.1111/j.1365-2141.2011.08939.x. DOI: https://doi.org/10.1111/j.1365-2141.2011.08939.x
40. Blake SJ, Lyons AB, Hughes TP. Nilotinib inhibits the Src-family kinase LCK and T-cell function in vitro. J Cell Mol Med. 2009;13(3):599–601. doi: 10.1111/j.1582-4934.2009.00500_1.x. DOI: https://doi.org/10.1111/j.1582-4934.2009.00500_1.x
41. Schade AE, Schieven GL, Townsend R, et al. Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood. 2008;111(3):1366–77. doi: 10.1182/blood-2007-04-084814. DOI: https://doi.org/10.1182/blood-2007-04-084814
42. Mustjoki S, Ekblom M, Arstila TP, et al. Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia. 2009;23(8):1398–405. doi: 10.1038/leu.2009.46. DOI: https://doi.org/10.1038/leu.2009.46
43. Molldrem JJ, Lee PP, Wang C, et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med. 2000;6(9):1018–23. doi: 10.1038/79526. DOI: https://doi.org/10.1038/79526
44. Ross DM, Branford S, Seymour JF, 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):515–22. doi: 10.1182/blood-2013-02-483750. DOI: https://doi.org/10.1182/blood-2013-02-483750
45. 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
46. Burchert A, Wolfl S, Schmidt M, et al. Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia. Blood. 2003;101(1):259–64. PMID: 12393722. DOI: https://doi.org/10.1182/blood-2002-02-0659
47. Essers MA, Offner S, Blanco-Bose WE, et al. IFN alpha activates dormant haematopoietic stem cells in vivo. Nature. 2009;458(7240):904–8. doi: 10.1038/nature07815. DOI: https://doi.org/10.1038/nature07815
48. Burchert A, Muller MC, Kostrewa P, et al. Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia. J Clin Oncol. 2010;28(8):1429–35. doi: 10.1200/JCO.2009.25.5075. DOI: https://doi.org/10.1200/JCO.2009.25.5075
49. Hochhaus A, Burchert A, Saussele S, et al. Nilotinib vs nilotinib plus pegylated interferon α (Peg-IFN) induction and nilotinib or Peg-IFN maintenance therapy for newly diagnosed BCR-ABL1 positive chronic myeloid leukemia patients in chronic phase (TIGER study): the addition of Peg-IFN is associated with higher rates of deep molecular response. Blood. 2019;134(1):495. doi: 10.1182/blood-2019-130043. DOI: https://doi.org/10.1182/blood-2019-130043
50. Nicolini FE, Etienne G, Huguet F, et al. The combination of nilotinib + pegylated IFN alpha 2a provides somewhat higher cumulative incidence rates of MR4.5 at M36 versus nilotinib alone in newly diagnosed CP CML patients. Updated results of the Petals phase III national study. Blood. 2019;134(1):494. doi: 10.1182/blood-2019-123674. DOI: https://doi.org/10.1182/blood-2019-123674
51. Schutz C, Inselmann S, Sausslele S, et al. Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. Leukemia. 2017;31(4):829–36. doi: 10.1038/leu.2017.9. DOI: https://doi.org/10.1038/leu.2017.9
52. Ross DM, Hughes TP, Melo JV. Do we have to kill the last CML cell? Leukemia. 2011;25(2):193–200. doi: 10.1038/leu.2010.197. DOI: https://doi.org/10.1038/leu.2010.197
53. Ilaria S, Pagani IS, Dang P, et al. Lineage of measurable residual disease in patients with chronic myeloid leukemia in treatment-free remission. Leukemia. 2020;34(4):1052–61. doi: 10.1038/s41375-019-0647-x. DOI: https://doi.org/10.1038/s41375-019-0647-x
54. Herrmann H, Sadovnik I, Cerny-Reiterer S, et al. Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood. 2014;123(25):3951–62. doi: 10.1182/blood-2013-10-536078. DOI: https://doi.org/10.1182/blood-2013-10-536078
55. Raspadori D, Pacelli P, Sicuranza A, et al. Flow cytometry assessment of CD26+ leukemic stem cells in peripheral blood: a simple and rapid new diagnostic tool for chronic myeloid leukemia. Cytometry B Clin Cytom. 2019;96(4):294–9. doi: 10.1002/cyto.b.21764. DOI: https://doi.org/10.1002/cyto.b.21764
56. Valent P, Sadovnik I, Racil Z, et al. DPPIV (CD26) as a novel stem cell marker in Ph+ chronic myeloid leukaemia. Eur J Clin Invest. 2014;44(12):1239–45. doi: 10.1111/eci.12368. DOI: https://doi.org/10.1111/eci.12368
57. Blatt K, Menzl I, Eisenwort G, et al. Phenotyping and target expression profiling of CD34+/CD38– and CD34+/CD38+ stem- and progenitor cells in acute lymphoblastic leukemia. Neoplazia. 2018;20(6):632–42. doi: 10.1016/j.neo.2018.04.004. DOI: https://doi.org/10.1016/j.neo.2018.04.004
58. Cui J, Zhu Z, Liu S, et al. Monitoring of leukemia stem cells in chronic myeloid leukemia patients. Leuk Lymphoma. 2018;59(9):2264–6. doi: 10.1080/10428194.2017.1421755. DOI: https://doi.org/10.1080/10428194.2017.1421755
59. Bocchia M, Sicuranza A, Abruzzese E, et al. Residual peripheral blood CD26+ leukemic stem cells in chronic myeloid leukemia patients during TKI therapy and during treatment-free remission. Front Oncol. 2018;8:194. doi: 10.3389/fonc.2018.00194. DOI: https://doi.org/10.3389/fonc.2018.00194
60. Iwasaki M, Liedtke M, Gentles A, et al. Cleary. CD93 marks a non-quiescent human Leukemia Stem Cell population and is required for development of MLL-rearranged acute myeloid leukemia. Cell Stem Cell. 2015;17(4):412–21. doi: 10.1016/j.stem.2015.08.008. DOI: https://doi.org/10.1016/j.stem.2015.08.008
61. Kinstrie R, Horne GA, Morrison H, et al. CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population, which persists after tyrosine kinase inhibitor therapy. Leukemia. 2020;34(6):1613–25. doi: 10.1038/s41375-019-0684-5. DOI: https://doi.org/10.1038/s41375-019-0684-5
62. Agarwal P, Bhatia R. Influence of bone marrow microenvironment on leukemic stem cells: breaking up an intimate relationship. Adv Cancer Res. 2015;127:227–52. doi: 10.1016/bs.acr.2015.04.007. DOI: https://doi.org/10.1016/bs.acr.2015.04.007
63. Park M, Park C.J, Cho YW, et al. Alterations in the bone marrow microenvironment may elicit defective hematopoiesis: a comparison of aplastic anemia, chronic myeloid leukemia, and normal bone marrow. Exp Hematol. 2017;45:56–63. doi: 10.1016/j.exphem.2016.09.009. DOI: https://doi.org/10.1016/j.exphem.2016.09.009
64. Schepers K, Pietras EM, Reynaud D, et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self reinforcing leukemic niche. Cell Stem Cell. 2013;13(3):285–99. doi: 10.1016/j.stem.2013.06.009. DOI: https://doi.org/10.1016/j.stem.2013.06.009
65. Schepers K, Campbell TB, Passegue E. Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell. 2015;16(3):254–67. doi: 10.1016/j.stem.2015.02.014. DOI: https://doi.org/10.1016/j.stem.2015.02.014
66. Петинати Н.А., Шипунова И.Н., Бигильдеев А.Е. и др. Изменения в клетках-предшественницах стромального микроокружения костного мозга больных хроническим миелолейкозом в дебюте заболевания и в ходе лечения. Гематология и трансфузиология. 2019;64(4):424–35. doi: 10.35754/0234-5730-2019-64-4-424-435. DOI: https://doi.org/10.1016/j.denabs.2019.08.041
67. [Petinati NA, Shipunova IN, Bigildeev AE, et al. Changes in stromal progenitor cells derived from bone marrow in patients with chronic myelogenous leukaemia at the onset of the disease and during treatment. Gematologiya i transfuziologiya. 2019;64(4):424–35. doi: 10.35754/0234-5730-2019-64-4-424-435. (In Russ)] DOI: https://doi.org/10.35754/0234-5730-2019-64-4-424-435
68. Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial. Lancet Haematol. 2019;6(7):e375–e383. doi: 10.1016/S2352-3026(19)30094-8. DOI: https://doi.org/10.1016/S2352-3026(19)30094-8
69. Claudiani S, Apperley JF, Gale RP, et al. E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy. Haematologica. 2017;102(8):e297–e299. doi: 10.3324/haematol.2017.168740. DOI: https://doi.org/10.3324/haematol.2017.168740
70. D’Adda M, Farina M, Schieppati F, et al. The e13a2 BCR-ABL transcript negatively affects sustained deep molecular response and the achievement of treatment-free remission in patients with chronic myeloid leukemia who receive tyrosine kinase inhibitors. Cancer. 2019;125(10):1674–82. doi: 10.1002/cncr.31977. DOI: https://doi.org/10.1002/cncr.31977
71. Lucas CM, Harris RJ, Giannoudis A, et al. Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript. Haematologica. 2009;94(10):1362–7. doi: 10.3324/haematol.2009.009134. DOI: https://doi.org/10.3324/haematol.2009.009134
72. Lee SE, Choi SY, Song HY, et al. Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study. Haematologica. 2016;101(6):717–23. doi: 10.3324/haematol.2015.139899. DOI: https://doi.org/10.3324/haematol.2015.139899
73. Schmidt M, Hochhaus A, Konig-Merediz SA, et al. Expression of interferon regulatory factor 4 in chronic myeloid leukemia: correlation with response to interferon alfa therapy. J Clin Oncol. 2000;18(19):3331–8. doi: 10.1200/JCO.2000.18.19.3331. DOI: https://doi.org/10.1200/JCO.2000.18.19.3331
74. Schmidt M, Hochhaus A, Nitsche A, et al. Expression of nuclear transcription factor interferon consensus sequence binding protein in chronic myeloid leukemia correlates with pretreatment risk features and cytogenetic response to interferon-alpha. Blood. 2001;97(11):3648–50. doi: 10.1182/blood.v97.11.3648. DOI: https://doi.org/10.1182/blood.V97.11.3648
75. La Nasa G, Caocci G, Littera R, et al. Homozygosity for killer immunoglobin-like receptor haplotype A predicts complete molecular response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia patients. Exp Hematol. 2013;41(5):424–31. doi: 10.1016/j.exphem.2013.01.008. DOI: https://doi.org/10.1016/j.exphem.2013.01.008
76. Caocci G, Martino B, Greco M, et al. Killer immunoglobulin-like receptors can predict TKI treatment-free remission in chronic myeloid leukemia patients. Exp Hematol. 2015;43(12):1015–8. doi: 10.1016/j.exphem.2015.08.004. DOI: https://doi.org/10.1016/j.exphem.2015.08.004
77. Caocci G, Greco M, Delogu G, et al. Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients. J Hematol Oncol. 2016;9(1):63. doi: 10.1186/s13045-016-0293-y. DOI: https://doi.org/10.1186/s13045-016-0293-y
78. Смирнихина С.А., Лавров А.В., Адильгереева Э.П. и др. Клиническое значение полноэкзомных исследований миелоидных опухолей методом секвенирования следующего поколения. Клиническая онкогематология. 2013;6(1):11–9. DOI: https://doi.org/10.21320/2500-2139-2013-6-1-12-19
79. [Smirnikhina SA, Lavrov AV, Adilgereeva EP, et al. Clinical significance of the whole-exome studies in myeloid neoplasms using next­generation sequencing. Klinicheskaya onkogematologiya. 2013;6(1):11–9. (In Russ)]
80. Smirnikhina S, Chelysheva E, Lavrov A, et al. Genetic markers of stable molecular remission in chronic myeloid leukemia after targeted therapy discontinuation. Leuk Lymphoma. 2018;59(10):2512–5. doi: 10.1080/10428194.2018.1434880. DOI: https://doi.org/10.1080/10428194.2018.1434880
81. Mori S, Vagge E, le Coutre P, et al. Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study. Am J Hematol. 2015;90(10):910–4. doi: 10.1002/ajh.24120. DOI: https://doi.org/10.1002/ajh.24120
82. Nicolini FE, Dulucq S, Boureau P, et al. Evaluation of residual disease and TKI duration are critical predictive factors for molecular recurrence after stopping imatinib first-line in chronic phase CML patients. Clin Cancer Res. 2019;25(22):6606–13. doi: 10.1158/1078-0432.CCR-18-3373. DOI: https://doi.org/10.1158/1078-0432.CCR-18-3373
83. 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
84. Ross DM, Masszi T, Gomez Casares TM, et al. Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study. J Cancer Res Clin Oncol. 2018;144(5):945–54. doi: 10.1007/s00432-018-2604-x. DOI: https://doi.org/10.1007/s00432-018-2604-x
85. Kimura S, Imagawa J, Kazunori M, et al. Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2020;7(3):e218–e225. doi: 10.1016/S2352-3026(19)30235-2. DOI: https://doi.org/10.1016/S2352-3026(19)30235-2
86. Kumagai T, Nakaseko C, Nishiwaki K, et al. Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation. Cancer Sci. 2018;109(1):182–92. doi: 10.1111/cas.13430. DOI: https://doi.org/10.1111/cas.13430
87. Shah NP, Garcia-Gutierrez V, Jimenez-Velasco A, et al. Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study. Leuk Lymphoma. 2020;61(3):650–9. doi: 10.1080/10428194.2019.1675879. DOI: https://doi.org/10.1080/10428194.2019.1675879
88. 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
89. Nagafuji K, Matsumura I, Shimose T, et al. Cessation of nilotinib in patients with chronic myelogenous leukemia who have maintained deep molecular responses for 2 years: a multicenter phase 2 trial, stop nilotinib (NILSt). Int J Hematol. 2019;110(6):675–82. doi: 10.1007/s12185-019-02736-5. DOI: https://doi.org/10.1007/s12185-019-02736-5