Treatment free remission (TFR) after second-generation tyrosine kinase inhibitors (2G-TKIs) treatment in chronic myeloid leukemia (CML): from feasibility to safety

References

• Bower H, Björkholm 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):2851–2857. doi: 10.1200/JCO.2015.66.2866
   PubMed Web of Science ®Google Scholar
• Cohen MH, Williams G, Johnson JR, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002;8(5):935–942.
   PubMed Web of Science ®Google Scholar
• Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34(20):2333–2340. doi: 10.1200/JCO.2015.64.8899
   PubMed Web of Science ®Google Scholar
• Kantarjian HM, Hughes TP, Larson RA, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021;35(2):440–453. doi: 10.1038/s41375-020-01111-2
   PubMed Web of Science ®Google Scholar
• Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36(3):231–237. doi: 10.1200/JCO.2017.74.7162
   PubMed Web of Science ®Google Scholar
• Deininger MW, Shah NP, Altman JK, et al. Chronic myeloid leukemia, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020 [cited 2020 Oct 1];18(10):1385–1415. doi: 10.6004/jnccn.2020.0047
   PubMed Web of Science ®Google Scholar
• Efficace F, Baccarani M, Breccia M, et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood. 2011;118(17):4554–4560. doi: 10.1182/blood-2011-04-347575
   PubMed Web of Science ®Google Scholar
• Phillips KM, Pinilla-Ibarz J, Sotomayor E, et al. Quality of life outcomes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a controlled comparison. Support Care Cancer. 2013;21(4):1097–1103. doi: 10.1007/s00520-012-1630-5
   PubMed Web of Science ®Google Scholar
• Mahon F-X, Réa D, Guilhot J, 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. doi: 10.1016/S1470-2045(10)70233-3
   PubMed Web of Science ®Google Scholar
• Takahashi N, Tauchi T, Kitamura K, et al. Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study. Int J Hematol. 2018;107(2):185–193. doi: 10.1007/s12185-017-2334-x
   PubMed Web of Science ®Google Scholar
• 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):515–522. doi: 10.1182/blood-2013-02-483750
   PubMed Web of Science ®Google Scholar
• 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):424–430. doi: 10.1200/JCO.2012.48.5797
   PubMed Web of Science ®Google Scholar
• Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966–984. doi: 10.1038/s41375-020-0776-2
   PubMed Web of Science ®Google Scholar
• Atallah E, Schiffer CA. Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when and for whom? Haematologica. 2020 [cited 2020 Dec 1];105(12):2738–2745. doi: 10.3324/haematol.2019.242891
   PubMed Web of Science ®Google Scholar
• Shah NP, García-Gutiérrez V, Jiménez-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):650–659. doi: 10.1080/10428194.2019.1675879
   PubMed Web of Science ®Google Scholar
• Shah NP, García-Gutiérrez V, Jiménez-Velasco A, et al. Treatment-free remission after dasatinib in patients with chronic myeloid leukaemia in chronic phase with deep molecular response: final 5-year analysis of DASFREE. Br J Haematol. 2023;202(5):942–952. doi: 10.1111/bjh.18883
   PubMedGoogle Scholar
• Okada M, Imagawa J, Tanaka H, et al. Final 3-year results of the dasatinib discontinuation trial in patients with chronic myeloid leukemia who received dasatinib as a second-line treatment. Clin Lymphoma Myeloma Leuk. 2018;18(5):353–360.e1. doi: 10.1016/j.clml.2018.03.004
   PubMed Web of Science ®Google Scholar
• 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):182–192. doi: 10.1111/cas.13430
   PubMed Web of Science ®Google Scholar
• Kimura S, Imagawa J, Murai K, 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
   PubMed Web of Science ®Google Scholar
• Yoshida C, Yamaguchi H, Doki N, et al. Importance of TKI treatment duration in treatment-free remission of chronic myeloid leukemia: results of the D-FREE study. Int J Hematol. 2023;117(5):694–705. doi: 10.1007/s12185-023-03549-3
   PubMed Web of Science ®Google Scholar
• 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):1525–1531. doi: 10.1038/leu.2017.63
   PubMed Web of Science ®Google Scholar
• Ross DM, Masszi T, Gomez Casares MT, 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):945–954. doi: 10.1007/s00432-018-2604-x
   PubMed Web of Science ®Google Scholar
• Radich JP, Hochhaus A, Masszi T, et al. Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial. Leukemia. 2021;35(5):1344–1355. doi: 10.1038/s41375-021-01205-5
   PubMed Web of Science ®Google Scholar
• Hughes TP, Boquimpani C, Kim DW, et al. Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with second-line nilotinib (NIL): first results from the ENESTop study. JCO. 2016;34(15_suppl):7054–7054. doi: 10.1200/JCO.2016.34.15_suppl.7054
   Web of Science ®Google Scholar
• Hughes TP, Boquimpani C, Takahashi N, et al. ENESTop 192-week results: treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib (NIL). JCO. 2019;37(15_suppl):7005–7005. doi: 10.1200/JCO.2019.37.15_suppl.7005
   Web of Science ®Google Scholar
• Hughes TP, Clementino NCD, Fominykh M, et al. Long-term treatment-free remission in patients with chronic myeloid leukemia after second-line nilotinib: ENESTop 5-year update. Leukemia. 2021;35(6):1631–1642. doi: 10.1038/s41375-021-01260-y
   PubMed Web of Science ®Google Scholar
• 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):675–682. doi: 10.1007/s12185-019-02736-5
   PubMed Web of Science ®Google Scholar
• Takahashi N, Nishiwaki K, Nakaseko C, et al. Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan. Haematologica. 2018;103(11):1835–1842. doi: 10.3324/haematol.2018.194894
   PubMed Web of Science ®Google Scholar
• Rea D, Rosti G, Cross NC, et al. ENESTPath: treatment-free remission (TFR) after two different durations of nilotinib consolidation in patients with chronic myeloid leukemia (CML) previously treated with imatinib: enestpath study results. Blood. 2021;138(Supplement 1):635. doi: 10.1182/blood-2021-145611
   Google Scholar
• Ritchie EK, Catchatourian R, Klisovic RB, et al. Results from ENESTgoal: a phase 2 study of treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) who switched from imatinib to nilotinib. Blood. 2017;130(Supplement 1):2875.
   Google Scholar
• 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):747–757. doi: 10.1016/S1470-2045(18)30192-X
   PubMed Web of Science ®Google Scholar
• De Almeida M, Mayer J, Hjorth-Hansen H, et al. FINAL analysis of a PAN European STOP tyrosine kinase inhibitor trial in chronic myeloid leukemia: the EURO-SKI study. Blood. 2021;138(Supplement 1):633. doi: 10.1182/blood-2021-148369
   Google Scholar
• 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):846–854. doi: 10.1182/blood-2016-09-742205
   PubMed Web of Science ®Google Scholar
• Atallah E, Schiffer CA, Radich JP, et al. Assessment of outcomes after stopping tyrosine kinase inhibitors among patients with chronic myeloid leukemia: a nonrandomized clinical trial. JAMA Oncol. 2021;7(1):42–50. doi: 10.1001/jamaoncol.2020.5774
   PubMed Web of Science ®Google Scholar
• Inzoli E, Aroldi A, Piazza R, et al. Tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia: eligibility criteria and predictors of success. Am J Hematol. 2022;97(8):1075–1085. doi: 10.1002/ajh.26556
   PubMed Web of Science ®Google Scholar
• Jørgensen HG, Allan EK, Jordanides NE, et al. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood. 2007;109(9):4016–4019. doi: 10.1182/blood-2006-11-057521
   PubMed Web of Science ®Google Scholar
• Corbin AS, Agarwal A, Loriaux M, et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest. 2011;121(1):396–409. doi: 10.1172/JCI35721
   PubMed Web of Science ®Google Scholar
• Fassoni AC, Baldow C, Roeder I, et al. Reduced tyrosine kinase inhibitor dose is predicted to be as effective as standard dose in chronic myeloid leukemia: a simulation study based on phase III trial data. Haematologica. 2018;103(11):1825–1834. doi: 10.3324/haematol.2018.194522
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Iurlo A, Breccia M, Stagno F, et al. Full treatment-free remission outcome in patients with chronic myeloid leukemia in chronic phase following one year of nilotinib De-escalation: 96-week update of dante study. Blood. 2023;142(Supplement 1):4534. doi: 10.1182/blood-2023-180131
   Google Scholar
• Žácková D, Faber E, Stejskal L, et al. Half: a prospective multi-centre phase II clinical trial evaluating the efficacy and safety of tyrosine kinase inhibitors’ discontinuation after two-step dose reduction in patients with chronic myeloid leukemia in deep molecular remission. Blood. 2021;138(Supplement 1):3606. doi: 10.1182/blood-2021-146221
   Google Scholar
• Çiftçiler R, Akın MG, Erat Z, et al. A systematic review on second treatment-free remission (TFR) attempt in chronic myeloid leukemia (CML): can it be applied in clinical practice? Clin Lymphoma Myeloma Leuk. 2023;23(1):8–14. doi: 10.1016/j.clml.2022.09.004
   PubMed Web of Science ®Google Scholar
• Legros L, Nicolini FE, Etienne G, et al. Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia. Cancer. 2017;123(22):4403–4410. doi: 10.1002/cncr.30885
   PubMed Web of Science ®Google Scholar
• Perusini MA, Novitzky-Basso I, Atenafu EG, et al. Final report of TKI discontinuation trial with dasatinib for the second attempt of treatment-free remission after failing the first attempt with imatinib: treatment-free remission accomplished by dasatinib (TRAD) study. Br J Haematol. 2023;203(5):781–791. doi: 10.1111/bjh.19058
   PubMed Web of Science ®Google Scholar
• Dulucq S, Rigal-Huguet F, Nicolini FE, et al. Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: results of the French Nilo post-STIM study. Br J Haematol. 2023;201(6):1116–1124. doi: 10.1111/bjh.18796
   PubMed Web of Science ®Google Scholar
• Japan Registry of Clinical Trials. Reattempt of tyrosine kinase inhibitor discontinuation after maintenance therapy with ponatinib in patients with chronic myeloid leukemia in the chronic phase (JALSG CML RE-STOP219). [cited 2020 Feb 17]. Available from: https://jrct.niph.go.jp/en-latest-detail/jRCTs041190117
   Google Scholar
• Lino M, Yamamoto T, Sakamoto Y. Outcomes of unplanned tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia: retrospective analysis of real-world experience in a single institution. Hematology. 2019;24(1):355–361. doi: 10.1080/16078454.2019.1590964
   PubMed Web of Science ®Google Scholar
• Fava C, Rege-Cambrin G, Dogliotti I, et al. Observational study of chronic myeloid leukemia Italian patients who discontinued tyrosine kinase inhibitors in clinical practice. Haematologica. 2019;104(8):1589–1596. doi: 10.3324/haematol.2018.205054
   PubMed Web of Science ®Google Scholar
• Iurlo A, Cattaneo D, Consonni D, et al. Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: updated results from a campus CML real-life study. Front Pharmacol. 2023;14:1154377. doi: 10.3389/fphar.2023.1154377
   PubMed Web of Science ®Google Scholar
• Chen Y, Zhao H, Guo J, et al. Successful treatment discontinuation in CML patients with full-dose and low-dose TKI: results from real-world practice. Front Pharmacol. 2023;14:1101743. doi: 10.3389/fphar.2023.1101743
   PubMed Web of Science ®Google Scholar
• Ureshino H, Kamachi K, Nishioka A, et al. Subsequent attempt tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia; a single institute experience. Hematol Oncol. 2021;39(4):549–557. doi: 10.1002/hon.2896
   PubMed Web of Science ®Google Scholar
• 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):461–470. doi: 10.7326/M17-1094
   PubMed Web of Science ®Google Scholar
• Nicolini FE, Dulucq S, Boureau L, 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):6606–6613. doi: 10.1158/1078-0432.CCR-18-3373
   PubMed Web of Science ®Google Scholar
• Claudiani S, Metelli S, Kamvar R, et al. Introducing a predictive score for successful treatment free remission in chronic myeloid leukemia (CML). Blood. 2019;134(Supplement_1):26. doi: 10.1182/blood-2019-131500
   Google Scholar
• 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):1674–1682. doi: 10.1002/cncr.31977
   PubMed Web of Science ®Google Scholar
• 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):1368–1377. doi: 10.3324/haematol.2017.165001
   PubMed Web of Science ®Google Scholar
• Ilander M, Olsson-Strömberg 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):1108–1116. doi: 10.1038/leu.2016.360
   PubMed Web of Science ®Google Scholar
• 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;8:1–8. doi: 10.3389/fonc.2018.00194
   PubMed Web of Science ®Google Scholar
• 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):1613–1625. doi: 10.1038/s41375-019-0684-5
   PubMed Web of Science ®Google Scholar
• Laganà A, Pepe S, Scalzulli E, et al. One-month qRT-PCR BCR: ABL1 transcript threshold to predict early recurrence in chronic phase CML patients attempting first treatment free remission. Eur J Haematol. 2023;111(6):970–972. doi: 10.1111/ejh.14085
   PubMed Web of Science ®Google Scholar
• Di Giusto S, Toffoletti E, Bonifacio M, et al. BCR: ABL1 levels at first month after TKI discontinuation predict subsequent maintenance of treatment-free remission: a study from the “Gruppo Triveneto LMC”. Cancer Med. 2023;12(3):3180–3184. doi: 10.1002/cam4.5158
   PubMed Web of Science ®Google Scholar
• Rea D, Mahon FX. How I manage relapse of chronic myeloid leukaemia after stopping tyrosine kinase inhibitor therapy. Br J Haematol. 2018;180(1):24–32. doi: 10.1111/bjh.14973
   PubMed Web of Science ®Google Scholar
• Rea D. Handling challenging questions in the management of chronic myeloid leukemia: when is it safe to stop tyrosine kinase inhibitors? Hematology Am Soc Hematol Educ Program. 2020;2020(1):243–247. doi: 10.1182/hematology.2020002538
   PubMedGoogle Scholar
• Richter J, Soderlund S, Lübking A, et al. Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome? J Clin Oncol. 2014;32(25):2821–2823. doi: 10.1200/JCO.2014.55.6910
   PubMed Web of Science ®Google Scholar
• Murbach BA, Guidini VH, Palma LC, et al. Tyrosine kinase inhibitor withdrawal syndrome in chronic myeloid leukemia patients participants of two discontinuation clinical trials. Blood. 2023;142(Supplement 1):6368. doi: 10.1182/blood-2023-189925
   Google Scholar
• Claudiani S, Apperley JF, Deplano S, et al. Cognitive dysfunction after withdrawal of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia. Am J Hematol. 2016;91(11):E480–E481. doi: 10.1002/ajh.24495
   PubMed Web of Science ®Google Scholar
• Alfayez M, Richard-Carpentier G, Jabbour E, et al. Sudden blastic transformation in treatment-free remission chronic myeloid leukaemia. Br J Haematol. 2019;187(4):543–545. doi: 10.1111/bjh.16245
   PubMed Web of Science ®Google Scholar
• Dulucq S, Hayette S, Cayuela JM, et al. Onset of blast crisis in chronic myeloid leukemia patients in treatment-free remission. Haematologica. 2022;107(12):2944–2949. doi: 10.3324/haematol.2022.280740
   PubMed Web of Science ®Google Scholar
• Papalexandri A, Saloum R, Touloumenidou T, et al. Blast crisis of CML after TKI discontinuation in a patient with previous stable deep molecular response: is it safe to stop? Hemasphere. 2018;2(6):e157. doi: 10.1097/HS9.0000000000000157
   PubMed Web of Science ®Google Scholar
• Ernst T, Le Coutre P, Crysandt M, et al. S156: frontline asciminib combination in chronic phase chronic myeloid leukemia patients. the fascination trial. Hemasphere. 2023 [cited 2023 Aug 8];7(Suppl):e34543a6. doi: 10.1097/01.HS9.0000967536.34543.a6
   Google Scholar
• Mauro M, Visotcky A, Flynn KE, et al. Treatment free remission after combination therapy with asciminib (ABL001) plus imatinib in chronic phase chronic myeloid leukemia (CP-CML) patients who relapsed after a prior attempt at TKI discontinuation-H jean khoury cure CML consortium study. Blood. 2022;140(Supplement 1):6765–6766. doi: 10.1182/blood-2022-160138
   Google Scholar
• Lu L, Dang P, Hoow Kok C, et al. Highly sensitive droplet digital PCR to identify CML patients with a high probability of achieving treatment-free remission. Blood. 2021;138(Supplement 1):2559. doi: 10.1182/blood-2021-151966
   Google Scholar
• Zhu G, Yang Y, Wang H, et al. Monitoring treatment-free remission by droplet digital PCR in CML patients with deep molecular response to tyrosine kinase inhibitor: an analysis based on real-world data. Ann Clin Lab Sci. 2020;50(5):591–599.
   PubMed Web of Science ®Google Scholar