Summary
More than 10 years ago, the first pilot observational study of imatinib discontinuation was reported in chronic myeloid leukaemia (CML) patients in deep molecular response (DMR). Several ...studies have been published since then, in patients treated with frontline imatinib, or second‐generation tyrosine kinase inhibitors (TKI) in first or second line but also on second attempt of TKI discontinuation. Our objective was to estimate, through meta‐analyses of the literature data, the probability of molecular recurrence (MolRec) in the time periods of 0–6, 6–12, 12–18 and 18–24 months after a first and second TKI discontinuation and the probability of re‐acquisition of DMR after MolRec. The Medline and Scopus databases were searched up to April 2019. The studies were selected by three independent reviewers. Random‐effect meta‐analyses were conducted using the MetaXL software. The probability of MolRec in the time periods 0–6, 6–12, 12–18 and 18–24 months after the first attempt was respectively 35%, 8%, 3% and 3%, whereas the probability of MolRec in the time periods 0‐6, 6‐12 and 12‐18 after the second attempt was 48%, 27% and 12% respectively. Re‐acquisition of a DMR was observed in 90% of patients. Most of the MolRec occur during the first six months in case of a first attempt, whereas the second MolRec occurs over a larger window of time.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
STOP second generation (2G)–tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving ...first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval CI, 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy.
•First-line or subsequent dasatinib or nilotinib can be safely stopped in CML patients with deep and long-lasting molecular responses.•A suboptimal response or resistance prior to dasatinib or nilotinib is associated with significantly worse treatment-free remission.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic myeloid leukemia (CML) is caused by formation of the BCR-ABL1 fusion protein. Tyrosine kinase inhibitors (TKI) that target BCR-ABL1 are now the standard of care for patients with CML. ...Molecular monitoring of residual BCR-ABL1 mRNA transcripts, typically performed using real-time quantitative PCR, has improved treatment management, particularly for patients with CML in chronic phase. Major molecular response (MMR; i.e., a ≥3-log reduction in BCR-ABL1 transcript levels) is used in current treatment guidelines to assess prognosis. Recent evidence suggests that deeper molecular responses (≥4-log reductions in BCR-ABL1 transcript levels), particularly when attained early during treatment, may have even better correlation with long-term outcomes, including survival and disease progression. Furthermore, achieving deep molecular response is a requirement for entering trials evaluating treatment-free remission (TFR). In this review, we discuss the evolving definition of minimal residual disease and the various levels of molecular response under evaluation in current clinical studies. In addition, the available clinical data on achieving MMR and deeper levels of molecular response with TKI therapy, the prognostic value of deep molecular response, and factors that may predict a patient's ability to achieve and sustain a deep molecular response on TKI therapy are also discussed. Available data from TFR studies are addressed. We discuss current knowledge of the ideal conditions for attempting treatment discontinuation, factors predictive of molecular relapse, when TKI therapy should be restarted, and which therapeutic strategies (when administered in the first-line setting and beyond) are expected to best enable successful TFR.
Summary
During the last 10 years, clinical trials formally demonstrated that about 50% of patients with chronic phase (CP) chronic myeloid leukaemia (CML) who achieve and maintain deep molecular ...responses for a prolonged period of time during treatment with imatinib or new generation tyrosine kinase inhibitors (TKIs) may successfully stop their anti‐leukaemic therapy. Based on the accumulated knowledge from abundant clinical trial experience, TKI discontinuation is becoming an important goal to achieve and is about to enter clinical practice. This review focuses on relapse definition, laboratory tests to identify relapse and relapse management after TKI discontinuation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary Background Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the ...long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib. Methods In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR–ABL and ABL levels and undetectable transcripts on quantitative RT-PCR). Patients who had undergone immunomodulatory treatment (apart from interferon α), treatment for other malignancies, or allogeneic haemopoietic stem-cell transplantation were not included. Patients were enrolled at 19 participating institutions in France. In this interim analysis, rate of relapse was assessed by use of RT-PCR for patients with at least 12 months of follow-up. Imatinib was reintroduced in patients who had molecular relapse. This study is registered with ClinicalTrials.gov , number NCT00478985. Findings 100 patients were enrolled between July 9, 2007, and Dec 17, 2009. Median follow-up was 17 months (range 1–30), and 69 patients had at least 12 months follow-up (median 24 months, range 13–30). 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29–52). All patients who relapsed responded to reintroduction of imatinib: 16 of the 42 patients who relapsed showed decreases in their BCR–ABL levels, and 26 achieved CMR that was sustained after imatinib rechallenge. Interpretation Imatinib can be safely discontinued in patients with a CMR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitors. Funding French Ministry of Health (Programme Hospitalier de Recherche 2006 grants), Institut National du Cancer (INCA).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final ...results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. Results The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months. Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. Conclusion With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR.
Abstract Stopping tyrosine kinase inhibitor (TKI) therapy after achieving a sustained deep molecular response is an emerging treatment goal for patients with chronic myeloid leukaemia in chronic ...phase (CML-CP). Indeed, the feasibility of stopping TKI therapy has been confirmed in various studies. The Stop Imatinib 1 (STIM1) study has shown a consistent follow-up which allowed defining a new criterion of clinical outcome evaluation, the treatment free remission (TFR). However, announcing a definitive cure remains a challenge owing to the discovery that TKIs spare quiescent leukaemic stem cells (LSC). It is definitely known that even a patient in long-term TFR has persistent LSCs. For this reason, a ‘Functional” Cure has been defined and proposed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
More than half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated ...loss of major molecular response (MMR) as a criterion for resuming therapy.
A multicenter observational study (A-STIM According to Stop Imatinib) evaluating MMR persistence was conducted in 80 patients with CP-CML who had stopped imatinib after prolonged CMR.
Median time from imatinib initiation to discontinuation was 79 months (range, 30 to 145 months);median duration of CMR before imatinib discontinuation was 41 months (range, 24 to 96 months); median follow-up after discontinuation was 31 months (range, 8 to 92 months). Twenty-nine patients (36%) lost MMR after a median of 4 months off therapy (range, 2 to 17 months). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25% to 46%) at 12 months and 36% (95% CI, 26% to 47%) at 24 months, whereas probability of losing CMR was higher. Fluctuation of BCR-ABL transcript levels below the MMR threshold (≥ two consecutive positive values) was observed in 31% of patients after imatinib discontinuation. Treatment-free remission was estimated as 64% (95% CI, 54% to 75%) at 12 and 24 months and 61% (95% CI, 51% to 73%) at 36 months. Median to time to second CMR was estimated as 7.3 months in re-treated patients.
Loss of MMR is a practical and safe criterion for restarting therapy in patients with CML with prolonged CMR.
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