Considerations for Successful Treatment-free Remission in Chronic Myeloid Leukemia

Open AccessPublished:November 29, 2017DOI:https://doi.org/10.1016/j.clml.2017.11.006

      Abstract

      BCR-ABL1 tyrosine kinase inhibitors have dramatically improved outcomes for patients with chronic myeloid leukemia, and current studies are investigating whether some patients may be able to suspend therapy yet maintain response in a state known as “treatment-free remission” (TFR). Results from ongoing studies suggest that ≈ 40% to 60% of patients in sustained (generally ≥ 2 years) deep molecular response (defined as a 4-log or deeper reduction in BCR-ABL1 transcripts, depending on the study) who attempt TFR may successfully remain off treatment. Results from TFR clinical trials, patient considerations for attempting TFR, and potential predictive factors associated with successful TFR are reviewed herein.

      Keywords

      Introduction

      The management of Philadelphia chromosome–positive chronic myeloid leukemia (CML) has undergone remarkable advancement over the past 15 years with the availability of 5 BCR-ABL1 tyrosine kinase inhibitors (TKIs; imatinib, nilotinib, dasatinib, bosutinib, and ponatinib), in addition to the non-TKI therapies omacetaxine mepesuccinate and pegylated interferon (IFN) alfa.
      • Baccarani M.
      • Deininger M.W.
      • Rosti G.
      • et al.
      European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia. V1.2018.
      Imatinib, nilotinib, and dasatinib are indicated for frontline treatment of patients with CML in chronic phase (CML-CP)
      • Baccarani M.
      • Deininger M.W.
      • Rosti G.
      • et al.
      European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia. V1.2018.
      ; with these options, ≈ 70% to 80% of patients in clinical trials achieved complete cytogenetic responses by 12 months,
      • Baccarani M.
      • Deininger M.W.
      • Rosti G.
      • et al.
      European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
      and > 90% can expect to survive > 5 years beyond diagnosis.
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • 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.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • et al.
      Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial.
      Response to TKI therapy is assessed by hematologic, cytogenetic, and molecular testing and is benchmarked against time-based milestones to guide treatment decisions.
      • Baccarani M.
      • Deininger M.W.
      • Rosti G.
      • et al.
      European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia. V1.2018.
      Molecular testing involves real-time quantitative polymerase chain reaction (RQ-PCR) and can be used to evaluate the full range of CML responses (from untreated levels to the deepest established molecular milestones). Because there are many technical factors that cause variability in RQ-PCR results,
      • Mattarucchi E.
      • Pallotti F.
      • Casalone R.
      Technical issues behind molecular monitoring in chronic myeloid leukemia.
      the International Scale (BCR-ABL1IS) was developed to improve the standardization of BCR-ABL1 quantification.
      • Baccarani M.
      • Deininger M.W.
      • Rosti G.
      • et al.
      European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia. V1.2018.
      Defined molecular milestones include early molecular response (BCR-ABL1IS ≤ 10% at 3 months), major molecular response (MMR; BCR-ABL1IS ≤ 0.1%), and deeper responses, such as MR4 (BCR-ABL1IS ≤ 0.01%) and MR4.5 (BCR-ABL1IS ≤ 0.0032%). Responses beyond MR4.5 are often undetectable by conventional RQ-PCR. Patients are more likely to achieve, and to achieve more rapidly, each milestone with second-generation TKIs than with imatinib, but the clinical benefit of achieving more rapid responses is undetermined.
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • 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.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • et al.
      Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial.
      With multiple potent therapies available, more patients may be able to achieve sustained deep MR (MR4 or better).
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • et al.
      Impact of treatment with frontline nilotinib (NIL) vs imatinib (IM) on sustained deep molecular response (MR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP).
      This has led to the natural hypothesis that some patients, with time, might be able to safely discontinue TKIs and remain in treatment-free remission (TFR).
      • Mahon F.X.
      • Rea D.
      • Guilhot J.
      • et al.
      on behalf of the Intergroupe Francais des Leucemies Myeloides Chroniques (FILMC)
      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.
      Successful TFR may represent a “functional cure,” in which the risk of clinical relapse is low or absent, although BCR-ABL1 transcripts may be detectable. To date, the majority of evidence regarding TFR is based on patients who received long-term therapy with imatinib
      • Rousselot P.
      • Huguet F.
      • Rea D.
      • et al.
      Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years.
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • et al.
      Long-term follow-up of the French Stop Imatinib study (STIM1) in chronic myeloid leukemia patients.
      • Mahon F.X.
      • Nicolini F.E.
      • Noël M.
      • et al.
      Preliminary report of the STIM2 study: a multicenter Stop Imatinib Trial for chronic phase chronic myeloid leukemia de novo patients on imatinib.
      • 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.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      • Lee S.E.
      • Choi S.Y.
      • Song H.Y.
      • 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.
      • Mori S.
      • Le Coutre P.
      • Abruzzese E.
      • et al.
      Late relapses, up to 45 months after imatinib discontinuation: results from the ISAV study.
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      ; however, TFR is also being investigated in patients treated with nilotinib and dasatinib.
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      • Rea D.
      • Nicolini F.E.
      • Tulliez M.
      • et al.
      France Intergroupe des Leucemies Myeloides Chroniques. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      • Rousselot P.
      • Etienne G.
      • Coiteux V.
      • et al.
      Attempt to early discontinue dasatinib first line in chronic phase CML patients in early molecular response and included in the prospective OPTIM-dasatinib trial.
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Hughes T.P.
      • Boquimpani C.
      • Takahashi N.
      • et al.
      Results from ENESTop: treatment-free remission following switch to nilotinib in patients with chronic myeloid leukemia in chronic phase.
      • Takahashi N.
      • Nishiwaki K.
      • Nakaseko C.
      • et al.
      Successful treatment free remission in CML after 2 year consolidation with nilotinib of an MR4.5 response level achieved original with imatinib treatment: first report from STAT2 trial in Japan.
      • Kadowaki N.
      • Kawaguchi T.
      • Kuroda J.
      • et al.
      Discontinuation of nilotinib in patients with chronic myeloid leukemia who have maintained deep molecular responses for at least 2 years: a multicenter phase 2 Stop Nilotinib (NILSt) trial.
      • Shah N.P.
      • Paquette R.
      • Müller M.C.
      • et al.
      Treatment-free remission (TFR) in patients with chronic phase chronic myeloid leukemia (CML-CP) and in stable deep molecular response (DMR) to dasatinib - the DASFREE Study.
      • Kumagai T.
      • Nakaseko C.
      • Nishiwaki K.
      • et al.
      Discontinuation of dasatinib after deep molecular response for over 2 years in patients with chronic myelogenous leukemia and the unique profiles of lymphocyte subsets for successful discontinuation: a prospective, multicenter Japanese trial (D-STOP Trial).
      • Mahon F.X.
      • Baccarani M.
      • Mauro M.J.
      • et al.
      Treatment-free remission (TFR) following nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom, ENESTop, ENESTgoal, and ENESTpath.

      Increasing the Rates of Deep MR to Permit TFR

      Obtaining a deep MR is a prerequisite for attempting TFR.
      • Hughes T.P.
      • Ross D.M.
      Moving treatment-free remission into mainstream clinical practice in CML.
      Although many patients achieve deep MR with imatinib, faster and higher rates have been observed in patients treated with frontline nilotinib or dasatinib (Table 1).
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • 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.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • et al.
      Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial.
      In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, 56% of patients treated with nilotinib 300 mg twice daily achieved MR4.5 by 6 years compared with 33% of patients treated with imatinib 400 mg once daily.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • et al.
      Efficacy and safety of nilotinib vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase: 6-year follow-up of ENESTnd.
      In the Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients (DASISION), more patients achieved MR4.5 by 5 years with dasatinib 100 mg once daily (42%) than with imatinib 400 mg once daily (33%).
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • et al.
      Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial.
      Deep MR has been associated with increased long-term survival rates
      • Hehlmann R.
      • Müller M.C.
      • 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.
      ; however, survival rates are high with all frontline TKIs, and no survival advantage has been observed with nilotinib or dasatinib compared with imatinib at the approved doses.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • et al.
      Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • et al.
      Efficacy and safety of nilotinib vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase: 6-year follow-up of ENESTnd.
      Table 1Long-term Efficacy of Frontline BCR-ABL1 TKIs in Patients With CML-CP
      Cumulative MMR by 5 Years, %Cumulative MR4.5 by 5 Years, %Estimated PFS at 5 Years, %
      Progressions reported on study treatment or after treatment discontinuation.
      Estimated OS at 5 Years, %
      ENESTnd
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • 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.
       Nilotinib 300 mg twice daily (n = 282)77549294
      P versus imatinib<.0001<.0001.6879.4881
       Nilotinib 400 mg twice daily (n = 281)77529696
      P versus imatinib<.0001<.0001.0204.0266
       Imatinib 400 mg once daily (n = 283)60319192
      DASISION
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • et al.
      Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial.
       Dasatinib 100 mg once daily (n = 259)76428591
      P versus imatinib.0022.0251.7934.9800
       Imatinib 400 mg once daily (n = 260)64338690
      Abbreviations: CML-CP = chronic myeloid leukemia in chronic phase; DASISION = Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients; ENESTnd = Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients; IS = International Scale; MMR = major molecular response; MR4.5 = BCR-ABL1IS ≤ 0.0032%; OS = overall survival; PFS = progression-free survival; TKI = tyrosine kinase inhibitors.
      a Progressions reported on study treatment or after treatment discontinuation.
      Dose optimization of frontline imatinib, or switching from imatinib to a second-generation TKI, may also improve deep MR rates compared with standard-dose imatinib. In CML-Study IV, higher rates of MR4.5 by 6 years were observed with high-dose imatinib (800 mg/day; 66%) than with standard-dose imatinib (400 mg/day; 56%).
      • Hehlmann R.
      • Müller M.C.
      • 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.
      The Therapeutic Intensification in De novo Leukaemia (TIDEL)-I and TIDEL-II studies evaluated whether imatinib dose escalation and/or switch to nilotinib could improve responses in patients who missed early response targets on frontline imatinib 600 mg/day.
      • Hughes T.P.
      • Branford S.
      • White D.L.
      • et al.
      Australasian Leukaemia and Lymphoma Group
      Impact of early dose intensity on cytogenetic and molecular responses in chronic-phase CML patients receiving 600 mg/day of imatinib as initial therapy.
      • Yeung D.T.
      • Osborn M.P.
      • White D.L.
      • et al.
      TIDEL-II: frontline use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets.
      Although limited by stringent escalation requirements and single-arm design, the TIDEL studies demonstrated improved responses in individual patients following dose escalation or switch and overall response rates exceeding historical rates with standard-dose imatinib and comparable to second-generation TKIs.
      • Baccarani M.
      • Deininger M.W.
      • Rosti G.
      • et al.
      European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
      In a trial of patients with detectable minimal residual disease after ≥ 2 years of imatinib (ENEST–Complete Molecular Response [ENESTcmr]), patients who switched to nilotinib 400 mg twice daily achieved higher rates of MR4.5 by 4 years (52%) compared with patients randomized to continue imatinib (28%, excluding responses achieved after crossover).
      • Hughes T.P.
      • Leber B.
      • Cervantes F.
      • et al.
      Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results.
      Although TKI therapy is generally well-tolerated,
      • Baccarani M.
      • Deininger M.W.
      • Rosti G.
      • et al.
      European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia. V1.2018.
      second- and third-generation TKIs have been associated with higher rates of potentially serious adverse events (AEs), including cardiovascular, peripheral vascular, and cerebrovascular occlusive events
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • 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.
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • et al.
      PACE Investigators
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
      • Gambacorti-Passerini C.
      • Cortes J.E.
      • Lipton J.H.
      • et al.
      Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia.
      and pleural effusion.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • et al.
      Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial.
      Whether such risks can be offset by a greater proportion of patients achieving a deeper MR, making TFR attempts more feasible or successful, remains to be determined.

      Studies Investigating TFR

      Several studies have investigated TFR following long-term imatinib therapy.
      • Rousselot P.
      • Huguet F.
      • Rea D.
      • et al.
      Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years.
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • et al.
      Long-term follow-up of the French Stop Imatinib study (STIM1) in chronic myeloid leukemia patients.
      • Mahon F.X.
      • Nicolini F.E.
      • Noël M.
      • et al.
      Preliminary report of the STIM2 study: a multicenter Stop Imatinib Trial for chronic phase chronic myeloid leukemia de novo patients on imatinib.
      • 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.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      • Lee S.E.
      • Choi S.Y.
      • Song H.Y.
      • 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.
      • Mori S.
      • Le Coutre P.
      • Abruzzese E.
      • et al.
      Late relapses, up to 45 months after imatinib discontinuation: results from the ISAV study.
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      Among the first large TFR studies were Stop Imatinib (STIM1) and TWISTER, which enrolled patients with ≥ 3 years of prior imatinib therapy and ≥ 2 years of sustained undetectable BCR-ABL1 (confirmed in a central laboratory with sensitivity to > 5-log [STIM1] or ≥ 4.5-log [TWISTER] reductions in BCR-ABL1).
      • Mahon F.X.
      • Rea D.
      • Guilhot J.
      • et al.
      on behalf of the Intergroupe Francais des Leucemies Myeloides Chroniques (FILMC)
      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.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      In both studies, patients with detectable BCR-ABL1 transcripts confirmed in a second test (or loss of MMR in a single assessment) were considered to have molecular relapse, triggering retreatment. Approximately 40% of patients in each study were able to maintain TFR for > 3 years, and the majority of molecular relapses occurred during the first 6 months after imatinib was suspended.
      • Mahon F.X.
      • Rea D.
      • Guilhot J.
      • et al.
      on behalf of the Intergroupe Francais des Leucemies Myeloides Chroniques (FILMC)
      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.
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • et al.
      Long-term follow-up of the French Stop Imatinib study (STIM1) in chronic myeloid leukemia patients.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      Subsequent investigations “moved the bar” by documenting that undetectable BCR-ABL1 is not required for successful TFR.
      • 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.
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      The According to STIM (A-STIM) trial enrolled patients with ≥ 3 years of imatinib treatment and ≥ 2 years of either undetectable BCR-ABL1 (≥ 40,000 ABL1 copies) or occasional positive transcripts (BCR-ABL1IS < 0.1%).
      • 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.
      Of great significance was the fact that the authors found no difference in the 12-month molecular relapse rate between patients with stable undetectable BCR-ABL1 and those with occasional positivity. An important distinction of and paradigm shift initiated by A-STIM relative to earlier TFR trials is that, in A-STIM, molecular relapse was redefined as loss of MMR rather than re-emergence of BCR-ABL1. By 2 years, the cumulative rate of molecular relapse was 36%, whereas the cumulative rate of loss of undetectable BCR-ABL1 (molecular relapse as defined in STIM1) was 54%. The A-STIM study suggested that loss of MMR could be a safe and pragmatic definition of molecular relapse. Of the 31 patients in A-STIM who reinitiated treatment after loss of MMR, all regained MMR, and 23 regained undetectable BCR-ABL1 with 17 months' median retreatment. In the more recent European Stop Tyrosine Kinase Inhibitor (EURO-SKI) trial, patients with ≥ 3 years of TKI treatment and MR4 sustained for ≥ 1 year were eligible.
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      Of 717 evaluable patients in EURO-SKI (with a median follow-up of 10 months), the rate of molecular relapse–free survival (no loss of MMR) was 62% at 6 months and 56% at 12 months.
      Discontinuation studies with nilotinib and dasatinib, which aim to capitalize on the higher rates of MR compared with imatinib,
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • et al.
      Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial.
      • Hughes T.P.
      • Larson R.A.
      • Kim D.W.
      • et al.
      Efficacy and safety of nilotinib vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase: 6-year follow-up of ENESTnd.
      are ongoing. Results from some of these studies have been reported (Table 2).
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      • Rea D.
      • Nicolini F.E.
      • Tulliez M.
      • et al.
      France Intergroupe des Leucemies Myeloides Chroniques. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      • Rousselot P.
      • Etienne G.
      • Coiteux V.
      • et al.
      Attempt to early discontinue dasatinib first line in chronic phase CML patients in early molecular response and included in the prospective OPTIM-dasatinib trial.
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Hughes T.P.
      • Boquimpani C.
      • Takahashi N.
      • et al.
      Results from ENESTop: treatment-free remission following switch to nilotinib in patients with chronic myeloid leukemia in chronic phase.
      • Takahashi N.
      • Nishiwaki K.
      • Nakaseko C.
      • et al.
      Successful treatment free remission in CML after 2 year consolidation with nilotinib of an MR4.5 response level achieved original with imatinib treatment: first report from STAT2 trial in Japan.
      • Kadowaki N.
      • Kawaguchi T.
      • Kuroda J.
      • et al.
      Discontinuation of nilotinib in patients with chronic myeloid leukemia who have maintained deep molecular responses for at least 2 years: a multicenter phase 2 Stop Nilotinib (NILSt) trial.
      • Shah N.P.
      • Paquette R.
      • Müller M.C.
      • et al.
      Treatment-free remission (TFR) in patients with chronic phase chronic myeloid leukemia (CML-CP) and in stable deep molecular response (DMR) to dasatinib - the DASFREE Study.
      • Kumagai T.
      • Nakaseko C.
      • Nishiwaki K.
      • et al.
      Discontinuation of dasatinib after deep molecular response for over 2 years in patients with chronic myelogenous leukemia and the unique profiles of lymphocyte subsets for successful discontinuation: a prospective, multicenter Japanese trial (D-STOP Trial).
      • Clark R.E.
      • Polydoros F.
      • Apperley J.F.
      • et al.
      De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial.
      • Clark R.
      • Polydoros F.
      • Apperley J.
      • et al.
      Initial reduction of therapy before complete withdrawal improves the chance of successful treatment discontinuation in chronic myeloid leukaemia (CML): year 2 results in the British DESTINY study.
      • Ritchie E.K.
      • Catchatourian R.
      • Klisovic R.B.
      • et al.
      ENESTgoal treatment-free remission study: updated preliminary results and digital polymerase chain reaction analysis in patients with chronic myeloid leukemia in chronic phase who switched from imatinib to nilotinib.
      • Kim D.D.H.
      • Bence-Bruckler I.
      • Forrest D.L.
      • et al.
      Treatment-Free Remission Accomplished By Dasatinib (TRAD): preliminary results of the pan-Canadian tyrosine kinase inhibitor discontinuation trial.
      The Stop Second-Generation TKI (STOP 2G-TKI) study enrolled patients with CML-CP receiving nilotinib or dasatinib (frontline or subsequent) who had received ≥ 3 years of TKI treatment and maintained undetectable MR4.5 for ≥ 2 years.
      • Rea D.
      • Nicolini F.E.
      • Tulliez M.
      • et al.
      France Intergroupe des Leucemies Myeloides Chroniques. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.
      Among 60 patients, the majority received nilotinib or dasatinib following imatinib intolerance (65%) or suboptimal response or resistance to imatinib (22%), whereas only 13% received frontline nilotinib or dasatinib. With 12 months' minimum follow-up, 26 patients (43%) had molecular relapse; the median time to molecular relapse was 4 months. Perhaps expectedly, patients with prior suboptimal response or resistance to TKI therapy had a significantly lower 48-month probability of successful TFR than other patients (23% vs. 62%; P = .0029). Successful TFR did not appear to be associated with gender, age, Sokal risk, prior IFN exposure, second-generation TKI type, undetectable MR4.5 duration, or treatment duration.
      Table 2TFR Trials in Patients Treated With Second-generation TKIs
      EURO-SKI is not included because most patients received IM prior to TFR.15
      AgentStudy, N = Total EnrollmentTKI Treatment Prior to Enrollment (TKI Treatment on Study)BCR-ABL1 Level (Duration) Required to Attempt TFRMolecular Relapse DefinitionRate of Sustained DMR in the Consolidation Phase and Entry to TFR Phase, % (Duration of Consolidation)Reported 1-Year TFR Rate (95% CI), %
      Ongoing studies with results
       NIL or DASSTOP 2G-TKI
      • Rea D.
      • Nicolini F.E.
      • Tulliez M.
      • et al.
      France Intergroupe des Leucemies Myeloides Chroniques. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.


      N = 60
      ≥3 y TKI therapy, currently on DAS or NIL as frontline therapy or following IMUndetectable MR4.5 (≥2 y)Loss of MMRNA63 (51-76)
       DASDADI (UMIN000005130)
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.


      N = 88
      DAS following IM, other prior treatments allowed (1 y DAS)BCR-ABL1IS < 0.0069% (≥1 y)BCR-ABL1IS ≥ 0.0069% in 1 assessment72 (1 y)48 (35-59)
       DASOPTIM-dasatinib

      (NCT01916785)
      • Rousselot P.
      • Etienne G.
      • Coiteux V.
      • et al.
      Attempt to early discontinue dasatinib first line in chronic phase CML patients in early molecular response and included in the prospective OPTIM-dasatinib trial.


      N = 20
      (≥3 y frontline DAS)MR4.5 (2 y)Loss of MMRNA41 (18-66)
       NILENESTfreedom (NCT01784068)
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.


      N = 215
      ≥2 y frontline NIL (1 y NIL)MR4.5 (≥1 y)Loss of MMR88 (1 y)52 (44-59)
      TFR rate at 48 weeks.
       NILENESTop (NCT01698905)
      • Hughes T.P.
      • Boquimpani C.
      • Takahashi N.
      • et al.
      Results from ENESTop: treatment-free remission following switch to nilotinib in patients with chronic myeloid leukemia in chronic phase.


      N = 163
      ≥3 y TKI therapy, including > 4 wk frontline IM and ≥2 y second-line NIL (1 y NIL)MR4.5 (≥1 y)Loss of MMR or confirmed loss of MR477 (1 y)58 (49-67)
      TFR rate at 48 weeks.
       NILSTAT2

      (UMIN000005904)
      • Takahashi N.
      • Nishiwaki K.
      • Nakaseko C.
      • et al.
      Successful treatment free remission in CML after 2 year consolidation with nilotinib of an MR4.5 response level achieved original with imatinib treatment: first report from STAT2 trial in Japan.


      N = 96
      IM (2 y NIL)MR4.5 (≥2 y)Confirmed loss of MR4.578 (2 y)69 (NR)
       NILNILSt

      (UMIN000007141)
      • Kadowaki N.
      • Kawaguchi T.
      • Kuroda J.
      • et al.
      Discontinuation of nilotinib in patients with chronic myeloid leukemia who have maintained deep molecular responses for at least 2 years: a multicenter phase 2 Stop Nilotinib (NILSt) trial.


      N = 112
      IM or NIL (2 y NIL)MR4.5 (≥2 y)Loss of MR4.578 (2 y)59 (NR)
       DASDASFREE (NCT01850004)
      • Shah N.P.
      • Paquette R.
      • Müller M.C.
      • et al.
      Treatment-free remission (TFR) in patients with chronic phase chronic myeloid leukemia (CML-CP) and in stable deep molecular response (DMR) to dasatinib - the DASFREE Study.


      N = 71
      ≥2 y DASMR4.5 (≥1 y)Loss of MMRNA63 (44-78)
      Rate of event-free survival, defined as no loss of MMR.
       DASD-STOP (NCT01627132)
      • Kumagai T.
      • Nakaseko C.
      • Nishiwaki K.
      • et al.
      Discontinuation of dasatinib after deep molecular response for over 2 years in patients with chronic myelogenous leukemia and the unique profiles of lymphocyte subsets for successful discontinuation: a prospective, multicenter Japanese trial (D-STOP Trial).


      N = 65
      Not specified (2 y DAS)Undetectable MR4 (≥2 y)Confirmed loss of undetectable BCR-ABL183 (2 y)63 (NR)
      Estimated rate of treatment-free survival.
       IM, NIL, DASDESTINY (NCT01804985)
      • Clark R.E.
      • Polydoros F.
      • Apperley J.F.
      • et al.
      De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial.
      • Clark R.
      • Polydoros F.
      • Apperley J.
      • et al.
      Initial reduction of therapy before complete withdrawal improves the chance of successful treatment discontinuation in chronic myeloid leukaemia (CML): year 2 results in the British DESTINY study.


      N = 174
      ≥3 y IM, NIL, or DAS (1 y same TKI at half-standard dose)MMR or MR4 (≥2 y)Confirmed loss of MMRMMR but not MR4: 73% (1 y)

      MR4: 94% (1 y)
      NR
      Of a total of 174 patients enrolled in the study, 49 entered the stable MMR cohort (maintained MMR but not MR4), and 125 entered the stable MR4 cohort. Among 49 patients in the MMR cohort, 36 entered the discontinuation phase, and of these, 20 had molecular relapse during the first year after discontinuing treatment. Among 125 patients in the MR4 cohort, 117 entered the discontinuation phase, and of these, 26 had molecular relapse during the first year after discontinuing treatment.
      Ongoing studies without results
       NILENESTgoal (NCT01744665)
      • Ritchie E.K.
      • Catchatourian R.
      • Klisovic R.B.
      • et al.
      ENESTgoal treatment-free remission study: updated preliminary results and digital polymerase chain reaction analysis in patients with chronic myeloid leukemia in chronic phase who switched from imatinib to nilotinib.


      N = 59
      ≥1 y IM (2-4 y NIL)MR4 (2 y)
      After achieving MR4.5 on NIL, patients without confirmed loss of MR4 during 2 years of NIL consolidation therapy will be eligible to attempt TFR.
      Confirmed loss of MMR
       NILENESTpath (NCT01743989)
      • Mahon F.X.
      • Baccarani M.
      • Mauro M.J.
      • et al.
      Treatment-free remission (TFR) following nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom, ENESTop, ENESTgoal, and ENESTpath.


      N = 1058
      ≥2 y IM (2-3 y NIL)MR4 (≥1 y)Loss of MMR or confirmed loss of MR4
       NILNilo Post-STIM (NCT01774630)

      N = 70
      2 y NIL as retreatment following molecular relapse in a post-IM TFR study
      Patients originally enrolled in STIM1, STIM2, or EURO-SKI.
      CMR (2 y)BCR-ABL1 positive on 2 occasions
       IM, DASTRAD (NCT02268370)
      • Kim D.D.H.
      • Bence-Bruckler I.
      • Forrest D.L.
      • et al.
      Treatment-Free Remission Accomplished By Dasatinib (TRAD): preliminary results of the pan-Canadian tyrosine kinase inhibitor discontinuation trial.


      N = 135
      First TFR: ≥3 y frontline

      (second TFR, following molecular relapse in first TFR: 2 y second-line DAS)
      First TFR: ≥MR4.5 (≥2 y)

      Second TFR: not reported (≥1 y)
      Loss of MMR or confirmed loss of MR4
       NIL + peg-IFN alfa-2bTIGER (NCT01657604)

      N = 717
      (NIL or NIL + peg-IFN alfa-2b)MR4Loss of MMR
      Abbreviations: CMR = complete molecular response; D-STOP = dasatinib stop; DADI = dasatinib discontinuation; DAS = dasatinib; DASFREE = Open-Label Study Evaluating Dasatinib Therapy Discontinuation in Patients With Chronic Phase Chronic Myeloid Leukemia With Stable Complete Molecular Response; DESTINY = De-Escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel; DMR = deep molecular response; ENEST = Evaluating Nilotinib Efficacy and Safety in Clinical Trials; EURO-SKI = European Stop Tyrosine Kinase Inhibitor; IM = imatinib; IS = International Scale; MMR = major molecular response; MR = molecular response; MR4 = BCR-ABL1IS ≤ 0.01%; MR4.5 = BCR-ABL1IS ≤ 0.0032%; NA = not applicable; NIL = nilotinib; NILSt = Stop Nilotinib; NR = not reported; OPTIM-dasatinib = Optimized Tyrosine Kinase Inhibitors Monotherapy; peg-IFN alfa-2b = pegylated interferon alfa-2b; STAT2 = Stop Tasigna 2; STIM = Stop Imatinib; STOP 2G-TKI = Stop Second-Generation TKI; TFR = treatment-free remission; TIGER = Tasigna and Interferon Alpha Evaluation Initiated by the German CML Study Group; TKI = tyrosine kinase inhibitor; TRAD = Treatment-Free Remission Accomplished With Dasatinib.
      –Indicates data have not yet been reported for the study.
      a EURO-SKI is not included because most patients received IM prior to TFR.
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      b TFR rate at 48 weeks.
      c Rate of event-free survival, defined as no loss of MMR.
      d Estimated rate of treatment-free survival.
      e Of a total of 174 patients enrolled in the study, 49 entered the stable MMR cohort (maintained MMR but not MR4), and 125 entered the stable MR4 cohort. Among 49 patients in the MMR cohort, 36 entered the discontinuation phase, and of these, 20 had molecular relapse during the first year after discontinuing treatment. Among 125 patients in the MR4 cohort, 117 entered the discontinuation phase, and of these, 26 had molecular relapse during the first year after discontinuing treatment.
      f After achieving MR4.5 on NIL, patients without confirmed loss of MR4 during 2 years of NIL consolidation therapy will be eligible to attempt TFR.
      g Patients originally enrolled in STIM1, STIM2, or EURO-SKI.
      In several of the ongoing second-generation TFR studies, patients do not immediately discontinue TKI treatment upon enrollment but instead enter a treatment consolidation phase during which they continue to receive TKI therapy with specific and often centralized monitoring; only patients who maintain a deep MR (as defined in each individual study) throughout the consolidation phase are eligible to discontinue treatment and enter the study's TFR phase.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Hughes T.P.
      • Boquimpani C.
      • Takahashi N.
      • et al.
      Results from ENESTop: treatment-free remission following switch to nilotinib in patients with chronic myeloid leukemia in chronic phase.
      • Takahashi N.
      • Nishiwaki K.
      • Nakaseko C.
      • et al.
      Successful treatment free remission in CML after 2 year consolidation with nilotinib of an MR4.5 response level achieved original with imatinib treatment: first report from STAT2 trial in Japan.
      • Kadowaki N.
      • Kawaguchi T.
      • Kuroda J.
      • et al.
      Discontinuation of nilotinib in patients with chronic myeloid leukemia who have maintained deep molecular responses for at least 2 years: a multicenter phase 2 Stop Nilotinib (NILSt) trial.
      • Kumagai T.
      • Nakaseko C.
      • Nishiwaki K.
      • et al.
      Discontinuation of dasatinib after deep molecular response for over 2 years in patients with chronic myelogenous leukemia and the unique profiles of lymphocyte subsets for successful discontinuation: a prospective, multicenter Japanese trial (D-STOP Trial).
      For example, ENESTfreedom enrolled patients who had received ≥ 2 years of frontline nilotinib therapy and had achieved MR4.5 prior to study entry; before attempting TFR, enrolled patients had to maintain their deep MR throughout 1 year of consolidation therapy with RQ-PCR assessments every 12 weeks. Of the 190 patients who completed the consolidation phase and attempted TFR in ENESTfreedom, 52% had not lost MMR by week 48 of the TFR phase, and 49% had not lost MMR by week 96. Eighty-seven of 88 patients who received retreatment regained MMR by the 96-week data cutoff (1 patient discontinued study participation).
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Ross D.
      • Masszi T.
      • Gómez Casares M.T.
      • et al.
      Durable treatment-free remission (TFR) following frontline nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom 96-wk update.
      Similarly, ENESTop investigated TFR in patients who achieved MR4.5 with nilotinib after switching from imatinib and then maintained the response through a 1-year nilotinib consolidation phase. A total of 126 patients completed the consolidation phase and discontinued nilotinib in ENESTop; 58% remained off therapy at week 48 and 53% continued to remain off therapy at week 96 of the TFR phase. Fifty-two of 56 patients who required retreatment regained at least MR4 by the 96-week data cutoff.
      • Hughes T.P.
      • Boquimpani C.
      • Takahashi N.
      • et al.
      Results from ENESTop: treatment-free remission following switch to nilotinib in patients with chronic myeloid leukemia in chronic phase.
      • Hughes T.
      • Boquimpani C.
      • Takahashi N.
      • et al.
      Durable treatment-free remission (TFR) after stopping second-line nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTop 96-wk update.
      In the Stop Tasigna 2 (STAT2) study, patients with MR4.5 on imatinib were switched to nilotinib for 2 years of consolidation therapy. Of the 75 patients who then attempted nilotinib discontinuation, 69% remained in TFR without molecular relapse (confirmed loss of MR4.5).
      • Takahashi N.
      • Nishiwaki K.
      • Nakaseko C.
      • et al.
      Successful treatment free remission in CML after 2 year consolidation with nilotinib of an MR4.5 response level achieved original with imatinib treatment: first report from STAT2 trial in Japan.
      In the Dasatinib Discontinuation (DADI) study, patients with CML-CP who received dasatinib following resistance to or intolerance of imatinib and had BCR-ABL1IS < 0.0069% for ≥ 1 year were eligible to attempt TFR.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      Molecular relapse was defined as BCR-ABL1IS ≥ 0.0069% in a single assessment, more stringent than other contemporary studies.
      • Mahon F.X.
      • Baccarani M.
      • Mauro M.J.
      • et al.
      Treatment-free remission (TFR) following nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom, ENESTop, ENESTgoal, and ENESTpath.
      • Hughes T.P.
      • Ross D.M.
      Moving treatment-free remission into mainstream clinical practice in CML.
      Among 63 patients who discontinued dasatinib, the estimated rates of TFR were 49% at 6 months and 44% at 36 months.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      • Nakamae H.
      • Imagawa J.
      • Tanaka H.
      • et al.
      Final study results of discontinuation of dasatinib in patients with CML who maintained deep molecular response for longer than one year (DADI trial) after three years of follow-up.
      In the Optimized Tyrosine Kinase Inhibitors Monotherapy (OPTIM)–dasatinib study, TFR was evaluated in 20 patients who received dasatinib for ≥ 3 years with MR4.5 for 2 years; at 12 months, 41% remained free of molecular relapse (no loss of MMR).
      • Rousselot P.
      • Etienne G.
      • Coiteux V.
      • et al.
      Attempt to early discontinue dasatinib first line in chronic phase CML patients in early molecular response and included in the prospective OPTIM-dasatinib trial.

      Considerations for Cessation of TKI Therapy

       Patient Preferences in TFR

      Patients' levels of understanding of the risks and benefits of TFR have been queried in surveys.
      • Breccia M.
      • Efficace F.
      • Sica S.
      • et al.
      Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia. A patient-based survey on 1133 patients.
      • Boquimpani C.M.
      • Szczudlo T.
      • Mendelson E.
      • Benjamin K.
      • Masszi T.
      Attitudes and perceptions of patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) toward treatment-free remission (TFR).
      • Goldberg S.
      • Hamarman S.
      Patients with chronic myelogenous leukemia may not want to discontinue tyrosine kinase inhibitor therapy.
      • Sanford D.
      • Kyle R.
      • Lazo-Langner A.
      • et al.
      Patient preferences for stopping tyrosine kinase inhibitors in chronic myeloid leukemia.
      • Jiang Q.
      • Liu Z.C.
      • Zhang S.X.
      • Gale R.P.
      Young age and high cost are associated with future preference for stopping tyrosine kinase inhibitor therapy in Chinese with chronic myeloid leukemia.
      A significant proportion of patients (42%-71%) have expressed a cautious willingness to attempt TFR.
      • Breccia M.
      • Efficace F.
      • Sica S.
      • et al.
      Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia. A patient-based survey on 1133 patients.
      • Boquimpani C.M.
      • Szczudlo T.
      • Mendelson E.
      • Benjamin K.
      • Masszi T.
      Attitudes and perceptions of patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) toward treatment-free remission (TFR).
      • Goldberg S.
      • Hamarman S.
      Patients with chronic myelogenous leukemia may not want to discontinue tyrosine kinase inhibitor therapy.
      • Sanford D.
      • Kyle R.
      • Lazo-Langner A.
      • et al.
      Patient preferences for stopping tyrosine kinase inhibitors in chronic myeloid leukemia.
      However, in a survey of 1133 Italian patients, 49% indicated they would not interrupt treatment if they achieved a “perfect and long-lasting response” owing to fear of relapse.
      • Breccia M.
      • Efficace F.
      • Sica S.
      • et al.
      Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia. A patient-based survey on 1133 patients.
      In another survey, patients' willingness to stop TKI therapy was found to be inversely related to the expected risk of relapse
      • Sanford D.
      • Kyle R.
      • Lazo-Langner A.
      • et al.
      Patient preferences for stopping tyrosine kinase inhibitors in chronic myeloid leukemia.
      ; safety concerns surrounding TFR have been repeatedly identified in other surveys.
      • Boquimpani C.M.
      • Szczudlo T.
      • Mendelson E.
      • Benjamin K.
      • Masszi T.
      Attitudes and perceptions of patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) toward treatment-free remission (TFR).
      • Goldberg S.
      • Hamarman S.
      Patients with chronic myelogenous leukemia may not want to discontinue tyrosine kinase inhibitor therapy.
      Motivators for attempting TFR may include relief from toxicities, quality-of-life improvements, or economic considerations.
      • Boquimpani C.M.
      • Szczudlo T.
      • Mendelson E.
      • Benjamin K.
      • Masszi T.
      Attitudes and perceptions of patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) toward treatment-free remission (TFR).
      • Goldberg S.
      • Hamarman S.
      Patients with chronic myelogenous leukemia may not want to discontinue tyrosine kinase inhibitor therapy.
      • Jiang Q.
      • Liu Z.C.
      • Zhang S.X.
      • Gale R.P.
      Young age and high cost are associated with future preference for stopping tyrosine kinase inhibitor therapy in Chinese with chronic myeloid leukemia.
      Unfortunately, many patients who experience chronic toxicities may be unable to achieve the deep MR needed to qualify for TFR studies
      • Efficace F.
      • Rosti G.
      • Cottone F.
      • et al.
      Profiling chronic myeloid leukemia patients reporting intentional and unintentional non-adherence to lifelong therapy with tyrosine kinase inhibitors.
      • Marin D.
      • Bazeos A.
      • Mahon F.X.
      • et al.
      Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib.
      ; however, the potential to minimize the ongoing risk of developing new toxicities during long-term TKI therapy, including cardiovascular events or other serious AEs, is a potential benefit of TFR. Although quality-of-life improvements (such as lessening of fatigue) have been observed following TKI withdrawal,
      • Mori S.
      • Le Coutre P.
      • Abruzzese E.
      • et al.
      Imatinib suspension and validation study: results at 24 months.
      the effect on toxicities may not be unidirectional; new or worsening AEs (including musculoskeletal pain, pruritus, and/or exacerbation of preexisting inflammatory diseases) have also been reported following TKI cessation, although these may be temporary.
      • Lee S.E.
      • Choi S.Y.
      • Song H.Y.
      • 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.
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Richter J.
      • Söderlund S.
      • Lübking A.
      • et al.
      Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome?.
      • Rousselot P.
      • Charbonnier A.
      • Cony-Makhoul P.
      • et al.
      Reply to J. Richter et al.
      • Park J.S.
      • Lee S.E.
      • Jeong S.H.
      • et al.
      Change of health-related profiles after imatinib cessation in chronic phase chronic myeloid leukemia patients.
      Although surveyed patients noted financial considerations related to TFR,
      • Boquimpani C.M.
      • Szczudlo T.
      • Mendelson E.
      • Benjamin K.
      • Masszi T.
      Attitudes and perceptions of patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) toward treatment-free remission (TFR).
      • Goldberg S.
      • Hamarman S.
      Patients with chronic myelogenous leukemia may not want to discontinue tyrosine kinase inhibitor therapy.
      • Sanford D.
      • Kyle R.
      • Lazo-Langner A.
      • et al.
      Patient preferences for stopping tyrosine kinase inhibitors in chronic myeloid leukemia.
      • Jiang Q.
      • Liu Z.C.
      • Zhang S.X.
      • Li J.
      • Gale R.P.
      Age and cost are associated with patient preference for stopping tyrosine kinase inhibitor therapy in chronic myeloid leukemia.
      little information is available on the financial impact of TFR. An analysis from STIM1 estimated a total savings of €5.5 million for the 100 patients attempting TFR.
      • Mahon F.X.
      • Rea D.
      • Guilhot J.
      • et al.
      Long term follow-up after imatinib cessation for patients in deep molecular response: the update results of the STIM1 study.
      A single-institution retrospective analysis of 29 patients who discontinued therapy estimated a net savings of > $3 million, largely from decreased medication costs, despite increased costs associated with intensified molecular monitoring.
      • McCloskey J.K.
      • Koprivnikar J.L.
      • Goldberg S.L.
      • et al.
      A single institution respective study of tyrosine kinase inhibitor cessation in patients with chronic phase CML in MMR.
      Similarly, a Brazilian report noted substantial projected healthcare savings resulting from TFR.
      • Burin M.M.
      • da Silva E.G.
      • Vanelli T.
      • et al.
      Economic impact of imatinib mesylate withdraw: as option for third world countries?.
      Owing to the more rapid achievement of deep MR with second-generation TKIs,
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • 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.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • et al.
      Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial.
      the potential economic impact of TFR may be greater for patients treated with nilotinib or dasatinib than with imatinib. Conversely, the availability of generic imatinib may lessen therapy costs and, in turn, affect any cost-value assessment of second-generation TKIs in the frontline setting.

       Monitoring

      Frequent, highly sensitive molecular monitoring of BCR-ABL1 levels is key for ensuring the safety of patients attempting TFR, particularly during the first year of TFR, and during retreatment if needed.
      • Hughes T.P.
      • Ross D.M.
      Moving treatment-free remission into mainstream clinical practice in CML.
      The majority of molecular relapses have been observed within 6 months of TKI cessation,
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • et al.
      Long-term follow-up of the French Stop Imatinib study (STIM1) in chronic myeloid leukemia patients.
      • Mahon F.X.
      • Nicolini F.E.
      • Noël M.
      • et al.
      Preliminary report of the STIM2 study: a multicenter Stop Imatinib Trial for chronic phase chronic myeloid leukemia de novo patients on imatinib.
      • 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.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      • Rea D.
      • Nicolini F.E.
      • Tulliez M.
      • et al.
      France Intergroupe des Leucemies Myeloides Chroniques. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      and nearly all patients regained MR with retreatment.
      • Mahon F.X.
      • Rea D.
      • Guilhot J.
      • et al.
      on behalf of the Intergroupe Francais des Leucemies Myeloides Chroniques (FILMC)
      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.
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • et al.
      Long-term follow-up of the French Stop Imatinib study (STIM1) in chronic myeloid leukemia patients.
      • 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.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      • Mahon F.X.
      • Rea D.
      • Guilhot J.
      • et al.
      Long term follow-up after imatinib cessation for patients in deep molecular response: the update results of the STIM1 study.
      Of 16 TFR studies reporting data with ≥ 6 months of follow-up, only 1 case of progression following TFR has been reported among > 2000 patients attempting TFR
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • et al.
      Long-term follow-up of the French Stop Imatinib study (STIM1) in chronic myeloid leukemia patients.
      • 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.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      • Lee S.E.
      • Choi S.Y.
      • Song H.Y.
      • 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.
      • Mori S.
      • Le Coutre P.
      • Abruzzese E.
      • et al.
      Late relapses, up to 45 months after imatinib discontinuation: results from the ISAV study.
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      • Rea D.
      • Nicolini F.E.
      • Tulliez M.
      • et al.
      France Intergroupe des Leucemies Myeloides Chroniques. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      • Rousselot P.
      • Etienne G.
      • Coiteux V.
      • et al.
      Attempt to early discontinue dasatinib first line in chronic phase CML patients in early molecular response and included in the prospective OPTIM-dasatinib trial.
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Hughes T.P.
      • Boquimpani C.
      • Takahashi N.
      • et al.
      Results from ENESTop: treatment-free remission following switch to nilotinib in patients with chronic myeloid leukemia in chronic phase.
      • Kadowaki N.
      • Kawaguchi T.
      • Kuroda J.
      • et al.
      Discontinuation of nilotinib in patients with chronic myeloid leukemia who have maintained deep molecular responses for at least 2 years: a multicenter phase 2 Stop Nilotinib (NILSt) trial.
      • Shah N.P.
      • Paquette R.
      • Müller M.C.
      • et al.
      Treatment-free remission (TFR) in patients with chronic phase chronic myeloid leukemia (CML-CP) and in stable deep molecular response (DMR) to dasatinib - the DASFREE Study.
      • Kumagai T.
      • Nakaseko C.
      • Nishiwaki K.
      • et al.
      Discontinuation of dasatinib after deep molecular response for over 2 years in patients with chronic myelogenous leukemia and the unique profiles of lymphocyte subsets for successful discontinuation: a prospective, multicenter Japanese trial (D-STOP Trial).
      • Clark R.E.
      • Polydoros F.
      • Apperley J.F.
      • et al.
      De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial.
      • Clark R.
      • Polydoros F.
      • Apperley J.
      • et al.
      Initial reduction of therapy before complete withdrawal improves the chance of successful treatment discontinuation in chronic myeloid leukaemia (CML): year 2 results in the British DESTINY study.
      • Ross D.
      • Masszi T.
      • Gómez Casares M.T.
      • et al.
      Durable treatment-free remission (TFR) following frontline nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom 96-wk update.
      • Hughes T.
      • Boquimpani C.
      • Takahashi N.
      • et al.
      Durable treatment-free remission (TFR) after stopping second-line nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTop 96-wk update.
      • Nakamae H.
      • Imagawa J.
      • Tanaka H.
      • et al.
      Final study results of discontinuation of dasatinib in patients with CML who maintained deep molecular response for longer than one year (DADI trial) after three years of follow-up.
      • Mori S.
      • Vagge E.
      • le Coutre P.
      • et al.
      Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study.
      • Takahashi N.
      • Nakaseko C.
      • Nishiwaki K.
      • Wakita H.
      Two-year consolidation by nilotinib is associated with successful treatment free remission in chronic myeloid leukemia with MR: subgroup analysis from STAT2 trial in Japan.
      : a patient from A-STIM who progressed after responding to imatinib retreatment following molecular relapse.
      • 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.
      Following relapse, this patient received allogeneic hematopoietic stem cell transplant in July 2011 and was alive at last follow-up.
      • 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.
      Ongoing studies (including Life After Stopping Tyrosine Kinase Inhibitors [LAST; NCT02269267] and the Imatinib Suspension and Validation [ISAV]
      • Mori S.
      • Le Coutre P.
      • Abruzzese E.
      • et al.
      Late relapses, up to 45 months after imatinib discontinuation: results from the ISAV study.
      studies) are assessing the clinical potential of digital PCR, a highly sensitive technique that can monitor transcripts in patients with undetectable BCR-ABL1 by conventional RQ-PCR. Strategies such as digital PCR may allow for better understanding of minimal residual disease and its dynamics under TFR conditions and potentially permit earlier identification of patients who will experience molecular relapse. Although the majority of relapses occur rapidly, 2 late relapses (30.5 and 45.5 months following discontinuation) were reported in the ISAV study.
      • Mori S.
      • Le Coutre P.
      • Abruzzese E.
      • et al.
      Late relapses, up to 45 months after imatinib discontinuation: results from the ISAV study.
      A concern for patients considering treatment cessation is the risk of relapse and a fear that their CML may not remain responsive to therapy following relapse. However, across all TFR studies to date, > 450 patients have reinitiated treatment following molecular relapse during a treatment-free period; among these patients, only a single case of progression and only 2 reports of patients who did not regain MMR after restarting therapy have been reported. In TFR studies that assessed deep molecular responses after treatment was restarted because of molecular relapse, only 28 patients did not regain a deep response as defined in the study (as of the latest report from each study).
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • et al.
      Long-term follow-up of the French Stop Imatinib study (STIM1) in chronic myeloid leukemia patients.
      • 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.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      • Lee S.E.
      • Choi S.Y.
      • Song H.Y.
      • 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.
      • Mori S.
      • Le Coutre P.
      • Abruzzese E.
      • et al.
      Late relapses, up to 45 months after imatinib discontinuation: results from the ISAV study.
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      • Rea D.
      • Nicolini F.E.
      • Tulliez M.
      • et al.
      France Intergroupe des Leucemies Myeloides Chroniques. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      • Rousselot P.
      • Etienne G.
      • Coiteux V.
      • et al.
      Attempt to early discontinue dasatinib first line in chronic phase CML patients in early molecular response and included in the prospective OPTIM-dasatinib trial.
      • Hochhaus A.
      • Masszi T.
      • Giles F.J.
      • et al.
      Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.
      • Hughes T.P.
      • Boquimpani C.
      • Takahashi N.
      • et al.
      Results from ENESTop: treatment-free remission following switch to nilotinib in patients with chronic myeloid leukemia in chronic phase.
      • Kadowaki N.
      • Kawaguchi T.
      • Kuroda J.
      • et al.
      Discontinuation of nilotinib in patients with chronic myeloid leukemia who have maintained deep molecular responses for at least 2 years: a multicenter phase 2 Stop Nilotinib (NILSt) trial.
      • Shah N.P.
      • Paquette R.
      • Müller M.C.
      • et al.
      Treatment-free remission (TFR) in patients with chronic phase chronic myeloid leukemia (CML-CP) and in stable deep molecular response (DMR) to dasatinib - the DASFREE Study.
      • Kumagai T.
      • Nakaseko C.
      • Nishiwaki K.
      • et al.
      Discontinuation of dasatinib after deep molecular response for over 2 years in patients with chronic myelogenous leukemia and the unique profiles of lymphocyte subsets for successful discontinuation: a prospective, multicenter Japanese trial (D-STOP Trial).
      • Clark R.E.
      • Polydoros F.
      • Apperley J.F.
      • et al.
      De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial.
      • Clark R.
      • Polydoros F.
      • Apperley J.
      • et al.
      Initial reduction of therapy before complete withdrawal improves the chance of successful treatment discontinuation in chronic myeloid leukaemia (CML): year 2 results in the British DESTINY study.
      • Ross D.
      • Masszi T.
      • Gómez Casares M.T.
      • et al.
      Durable treatment-free remission (TFR) following frontline nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom 96-wk update.
      • Hughes T.
      • Boquimpani C.
      • Takahashi N.
      • et al.
      Durable treatment-free remission (TFR) after stopping second-line nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTop 96-wk update.
      • Nakamae H.
      • Imagawa J.
      • Tanaka H.
      • et al.
      Final study results of discontinuation of dasatinib in patients with CML who maintained deep molecular response for longer than one year (DADI trial) after three years of follow-up.
      • Mori S.
      • Vagge E.
      • le Coutre P.
      • et al.
      Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study.
      • Takahashi N.
      • Nakaseko C.
      • Nishiwaki K.
      • Wakita H.
      Two-year consolidation by nilotinib is associated with successful treatment free remission in chronic myeloid leukemia with MR: subgroup analysis from STAT2 trial in Japan.
      The potential risks of not regaining a molecular response or progressing to advanced disease will continue to be clarified as data from additional studies accumulate.

       Predictors of Successful TFR

      A variety of factors have been identified as potentially predictive of successful TFR.
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • et al.
      Long-term follow-up of the French Stop Imatinib study (STIM1) in chronic myeloid leukemia patients.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      • Lee S.E.
      • Choi S.Y.
      • Song H.Y.
      • 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.
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      • Rea D.
      • Nicolini F.E.
      • Tulliez M.
      • et al.
      France Intergroupe des Leucemies Myeloides Chroniques. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      • Mori S.
      • Le Coutre P.
      • Abruzzese E.
      • et al.
      Imatinib suspension and validation study: results at 24 months.
      • Lee S.E.
      • Choi S.Y.
      • Bang J.H.
      • et al.
      Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib.
      • Takahashi N.
      • Kyo T.
      • Maeda Y.
      • et al.
      Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia.
      • Caocci G.
      • Greco M.
      • Delogu G.
      • et al.
      Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients.
      In STIM1, patients with low/intermediate Sokal risk and those with a longer duration of imatinib therapy were more likely to maintain TFR.
      • Etienne G.
      • Guilhot J.
      • Rea D.
      • et al.
      Long-term follow-up of the French Stop Imatinib study (STIM1) in chronic myeloid leukemia patients.
      Similarly in EURO-SKI, treatment and MR4 durations were predictive of TFR success.
      • Richter J.
      • Mahon F.X.
      • Guilhot J.
      • et al.
      Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial.
      In the Korean Imatinib Discontinuation (KID) study, which required > 3 years of imatinib treatment and undetectable BCR-ABL1 for ≥ 2 years, longer (≥ 62 months) duration of TKI therapy and development of an imatinib withdrawal syndrome (including musculoskeletal pain and/or pruritus),
      • Lee S.E.
      • Choi S.Y.
      • Song H.Y.
      • 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.
      as well as prior allogeneic hematopoietic stem cell transplant,
      • Lee S.E.
      • Choi S.Y.
      • Bang J.H.
      • et al.
      Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib.
      were favorable for TFR. In the ISAV study, younger age and detectable BCR-ABL1 by digital PCR at study entry were both unfavorable: no patient aged < 45 years with baseline digital PCR positivity remained in TFR by 24 months.
      • Mori S.
      • Le Coutre P.
      • Abruzzese E.
      • et al.
      Imatinib suspension and validation study: results at 24 months.
      In DADI, no association was found between duration of prior TKI therapy and successful TFR, although higher rates of TFR at 12 months were observed in patients who demonstrated (by immune profiling) an increased number of natural killer (NK) cells in the peripheral blood during the consolidation phase prior to discontinuation.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      Shortening of telomere length has also been associated with higher rates of successful TFR and may be a predictor for response.
      • Caocci G.
      • Greco M.
      • Delogu G.
      • et al.
      Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients.
      Trends for higher rates of successful TFR among patients with prior IFN therapy have been repeatedly noted,
      • Mahon F.X.
      • Rea D.
      • Guilhot J.
      • et al.
      on behalf of the Intergroupe Francais des Leucemies Myeloides Chroniques (FILMC)
      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.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      • Takahashi N.
      • Kyo T.
      • Maeda Y.
      • et al.
      Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia.
      although this trend could be partially owing to a selection bias for long treatment duration and low biological risk among patients with prior IFN.
      • Hughes T.P.
      • Ross D.M.
      Moving treatment-free remission into mainstream clinical practice in CML.
      In a retrospective analysis from Japan, patients who remained in TFR at 12 months after suspending treatment were significantly more likely to have received prior IFN (20 of 26 patients remaining in TFR at 12 months had prior IFN) than those who relapsed by 12 months (5 of 14 patients had prior IFN; P = .0102).
      • Takahashi N.
      • Kyo T.
      • Maeda Y.
      • et al.
      Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia.
      In TWISTER, patients who received IFN therapy prior to imatinib had an estimated 3-year TFR rate of 52% compared with 34% in patients without prior IFN (P > .05).
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      In patients with CML, IFN impacts CML and other cells through multiple pathways, although the most crucial mechanisms of IFN therapy are poorly understood.
      • Talpaz M.
      • Hehlmann R.
      • Quintas-Cardama A.
      • Mercer J.
      • Cortes J.
      Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia.
      IFN has been shown to promote the activation of immune effector cells in patients with CML.
      • Talpaz M.
      • Hehlmann R.
      • Quintas-Cardama A.
      • Mercer J.
      • Cortes J.
      Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia.
      Thus, a role for the immune system, and in particular, NK cell number, phenotype, and activation status, has been suggested in maintaining deep MR and TFR.
      • Imagawa J.
      • Tanaka H.
      • Okada M.
      • et al.
      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.
      • 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.
      • 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.
      • Yoshimoto T.
      • Mizoguchi I.
      • Katagiri S.
      • et al.
      Immunosurveillance markers may predict patients who can discontinue imatinib therapy without relapse.
      A significant association between NK cell killer-cell immunoglobulin-like receptor haplotype A homozygosity and improved likelihood of successfully maintaining TFR has been reported.
      • Caocci G.
      • Martino B.
      • Greco M.
      • et al.
      Killer immunoglobulin-like receptors can predict TKI treatment-free remission in chronic myeloid leukemia patients.
      Markers of active immunosurveillance may be useful for identifying patients with a higher or lower likelihood of achieving TFR.
      • Yoshimoto T.
      • Mizoguchi I.
      • Katagiri S.
      • et al.
      Immunosurveillance markers may predict patients who can discontinue imatinib therapy without relapse.
      TFR following treatment with nilotinib and IFN is being investigated (Table 2).
      Other factors have been cited as cautionary for selection of appropriate TFR candidates. Intuitively, patients with atypical BCR-ABL1 transcripts not easily measured with RQ-PCR may be difficult to monitor effectively while off TKI therapy. Additionally, there is limited experience with discontinuation among patients with BCR-ABL1 mutations or a history of TKI resistance or advanced CML. Additionally, TKI discontinuation in pediatric CML has not been fully explored.
      • Hughes T.P.
      • Ross D.M.
      Moving treatment-free remission into mainstream clinical practice in CML.

      Conclusions and Future Directions

      Approximately 40% to 60% of patients with CML-CP who achieve sustained (≥ 2 years) deep MR with TKI therapy can achieve TFR. Molecular relapses typically occurred within 6 months, and patients quickly regained their prior depth of MR upon retreatment with the same TKI.
      • Hughes T.P.
      • Ross D.M.
      Moving treatment-free remission into mainstream clinical practice in CML.
      As such, many TFR trials require monthly RQ-PCR monitoring for the first 6 to 12 months, with a gradual reduction in frequency thereafter.
      • Mahon F.X.
      • Rea D.
      • Guilhot J.
      • et al.
      on behalf of the Intergroupe Francais des Leucemies Myeloides Chroniques (FILMC)
      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.
      • 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.
      • Ross D.M.
      • Branford S.
      • Seymour J.F.
      • et al.
      Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER Study.
      • Rea D.
      • Nicolini F.E.
      • Tulliez M.
      • et al.
      France Intergroupe des Leucemies Myeloides Chroniques. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.
      Clinical progression of CML related to participation in a TFR study has been observed only once,
      • 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.
      although fear of progression could limit patient participation in trials.
      As data from TFR studies continue to mature, questions remain about longer-term outcomes as well as the proper selection and molecular monitoring of patients. Novel treatment approaches that may enable more patients to achieve TFR include TKI dose optimization, treatment combinations or sequencing, and incorporation of immunotherapy agents.
      • Talpaz M.
      • Hehlmann R.
      • Quintas-Cardama A.
      • Mercer J.
      • Cortes J.
      Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia.
      • Burchert A.
      • Inselmann S.
      • Saussele S.
      • et al.
      Frequency of CTLA-4 receptor ligand (CD86, B7.2)-positive plasmacytoid dendritic cells predicts risk of disease recurrence after tyrosine-kinase inhibitor discontinuation in chronic myeloid leukemia: results from a prospective substudy of the EUROSKI trial.
      • Gugliotta G.
      • Castagnetti F.
      • Breccia M.
      • et al.
      GIMEMA CML Working Party
      Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia.
      One area of research ripe for future development would be strategies to permit subsequent TFR attempts after failure of the first attempt.
      • Hughes T.P.
      • Ross D.M.
      Moving treatment-free remission into mainstream clinical practice in CML.
      • Pagliardini T.
      • Nicolini F.E.
      • Giraudier S.
      • et al.
      Second TKI discontinuation in CML patients that failed first discontinuation and subsequently regained deep molecular response after TKI re-challenge.
      Although it is debatable whether available data are sufficient to support TFR in routine clinical practice, United States guidelines have recently incorporated ground rules for this endeavor.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia. V1.2018.
      • Hughes T.P.
      • Ross D.M.
      Moving treatment-free remission into mainstream clinical practice in CML.
      Currently, the decision to pursue TFR is complex and highly individualized. It is not considered a safe approach for patients with CML with a history of accelerated phase or blast crisis, and controversy exists regarding attempting TFR in patients with a history of resistance to therapy within chronic phase.
      • Hughes T.P.
      • Ross D.M.
      Moving treatment-free remission into mainstream clinical practice in CML.
      Patients may be more likely to consider TFR because of extenuating health circumstances; desire for TFR also has overlap with desire to achieve pregnancy, although these circumstances are strikingly different, as reinitiation of TKI therapy in the case of relapse may not be immediately addressable during active pregnancy.
      • Baccarani M.
      • Deininger M.W.
      • Rosti G.
      • et al.
      European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia. V1.2018.
      • Lee S.E.
      • Choi S.Y.
      • Song H.Y.
      • 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.
      • Jiang Q.
      • Liu Z.C.
      • Zhang S.X.
      • Li J.
      • Gale R.P.
      Age and cost are associated with patient preference for stopping tyrosine kinase inhibitor therapy in chronic myeloid leukemia.
      • Takahashi N.
      • Kyo T.
      • Maeda Y.
      • et al.
      Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia.
      Potential economic benefits and reduction of treatment complications (including cardiovascular events or pleural effusions
      • Hochhaus A.
      • Saglio G.
      • Hughes T.P.
      • 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.
      • Cortes J.E.
      • Saglio G.
      • Kantarjian H.M.
      • et al.
      Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial.
      • Cortes J.E.
      • Kim D.W.
      • Pinilla-Ibarz J.
      • et al.
      PACE Investigators
      A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
      • Gambacorti-Passerini C.
      • Cortes J.E.
      • Lipton J.H.
      • et al.
      Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia.
      ) will require long-term comparisons between continuous/lifelong TKI use and finite TKI treatment and subsequent TFR. Irrespective of whether TFR is ready for routine use in clinical practice, it has become a natural extension of our approach to definitive treatment of patients with CML-CP and is a promising next chapter in the progress for patients with CML.

      Disclosure

      S.L.G. reports non-financial support from Novartis and personal fees from Ariad, Bristol-Myers Squibb, Novartis, and Pfizer. M.S. reports grants from Astex, Incyte, Sunesis, Takeda, and TG Therapeutics and personal fees from Amgen, Astex, Celgene, Gilead, and Karyopharm. M.J.M. reports other support (institutional research funding) from Novartis Oncology.

      Acknowledgments

      The authors thank Karen Kaluza, PhD, of ArticulateScience LLC, for medical editorial assistance with this manuscript. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.

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