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      Feasibility of the imatinib stop study in the Japanese clinical setting: delightedly overcome CML expert stop TKI trial (DOMEST Trial)

      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , , 27

      International Journal of Clinical Oncology

      Springer Singapore

      Chronic myelogenous leukemia, Treatment-free remission, Imatinib, Deep molecular response, Molecular recurrence-free survival

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs).

          Methods

          A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib.

          Results

          Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy ( p = 0.0002) and long duration of imatinib therapy ( p = 0.0029) predicted a favorable prognosis.

          Conclusions

          This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.

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          Most cited references 21

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          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.

          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. 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. 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. 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. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study.

            Most patients with chronic myeloid leukemia (CML) treated with imatinib will relapse if treatment is withdrawn. We conducted a prospective clinical trial of imatinib withdrawal in 40 chronic-phase CML patients who had sustained undetectable minimal residual disease (UMRD) by conventional quantitative polymerase chain reaction (PCR) on imatinib for at least 2 years. Patients stopped imatinib and were monitored frequently for molecular relapse. At 24 months, the actuarial estimate of stable treatment-free remission was 47.1%. Most relapses occurred within 4 months of stopping imatinib, and no relapses beyond 27 months were seen. In the 21 patients treated with interferon before imatinib, a shorter duration of interferon treatment before imatinib was significantly associated with relapse risk, as was slower achievement of UMRD after switching to imatinib. Highly sensitive patient-specific BCR-ABL DNA PCR showed persistence of the original CML clone in all patients with stable UMRD, even several years after imatinib withdrawal. No patients with molecular relapse after discontinuation have progressed or developed BCR-ABL mutations (median follow-up, 42 months). All patients who relapsed remained sensitive to imatinib re-treatment. These results confirm the safety and efficacy of a trial of imatinib withdrawal in stable UMRD with frequent, sensitive molecular monitoring and early rescue of molecular relapse.
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              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

              In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54% 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR4.5; BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.
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                Author and article information

                Contributors
                +81-952-34-2353 , shkimu@cc.saga-u.ac.jp
                Journal
                Int J Clin Oncol
                Int. J. Clin. Oncol
                International Journal of Clinical Oncology
                Springer Singapore (Singapore )
                1341-9625
                1437-7772
                12 November 2018
                12 November 2018
                2019
                : 24
                : 4
                : 445-453
                Affiliations
                [1 ]ISNI 0000 0004 0467 212X, GRID grid.413045.7, Department of Hematology, , Yokohama City University Medical Center, ; Yokohama, Japan
                [2 ]ISNI 0000 0001 0688 6269, GRID grid.415565.6, Department of Hematology/Oncology, , Kurashiki Central Hospital, ; Kurashiki, Japan
                [3 ]GRID grid.414992.3, Department of Hematology, , NTT Medical Center, ; Tokyo, Japan
                [4 ]ISNI 0000 0004 0471 5871, GRID grid.416691.d, Department of Hematology, , Obihiro Kosei Hospital, ; Obihiro, Japan
                [5 ]ISNI 0000 0001 1302 4472, GRID grid.261356.5, Department of General Medicine, , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, ; Okayama, Japan
                [6 ]GRID grid.415479.a, Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, , Komagome Hospital, ; Tokyo, Japan
                [7 ]ISNI 0000 0004 1764 9308, GRID grid.416948.6, Department of Hematology, , Osaka City General Hospital, ; Osaka, Japan
                [8 ]ISNI 0000000123090000, GRID grid.410804.9, Department of Hematology, Saitama Medical Center, , Jichi Medical University, ; Saitama, Japan
                [9 ]GRID grid.416627.0, Department of Hematology, , Numazu City Hospital, ; Numazu, Japan
                [10 ]ISNI 0000 0004 1772 7492, GRID grid.416762.0, Department of Hematology, , Ogaki Municipal Hospital, ; Ogaki, Japan
                [11 ]ISNI 0000 0004 1764 8671, GRID grid.416773.0, Department of Hematology, , Ome Municipal General Hospital, ; Ome, Japan
                [12 ]ISNI 0000 0004 1764 9041, GRID grid.412808.7, Division of Hematology, Department of Medicine, , Showa University Fujigaoka Hospital, ; Yokohama, Japan
                [13 ]GRID grid.413416.5, Department of Hematology, , Daiyukai General Hospital, ; Ichinomiya, Japan
                [14 ]ISNI 0000 0004 0595 994X, GRID grid.471868.4, Department of Hematology, , National Hospital Organization Osaka Minami Medical Center, ; Osaka, Japan
                [15 ]GRID grid.416616.2, Department of Hematology, , Saiseikai Maebashi Hospital, ; Maebashi, Japan
                [16 ]ISNI 0000 0001 2173 8328, GRID grid.410821.e, Department of Hematology, , Nippon Medical School, ; Tokyo, Japan
                [17 ]Department of Hematology, Fujioka General Hospital, Fujioka, Japan
                [18 ]ISNI 0000 0004 1772 7425, GRID grid.414413.7, Department of Hematology, , Ehime Prefectural Central Hospital, ; Matsuyama, Japan
                [19 ]ISNI 0000 0004 0642 244X, GRID grid.415262.6, Department of Hematology, , Sapporo Hokuyu Hospital, ; Sapporo, Japan
                [20 ]ISNI 0000000123090000, GRID grid.410804.9, Division of Hematology, Saitama Medical Center, , Jichi Medical University, ; Saitama, Japan
                [21 ]ISNI 0000 0004 0378 6088, GRID grid.412167.7, Department of Hematology, , Hokkaido University Hospital, ; Sapporo, Japan
                [22 ]GRID grid.410845.c, Department of Hematology, , National Hospital Organization Mito Medical Center, ; Mito, Japan
                [23 ]Department of Gastroenterology and Hematology/Clinical Oncology, Steel Muroran Memorial Hospital, Muroran, Japan
                [24 ]ISNI 0000 0004 1762 2738, GRID grid.258269.2, Department of Next Generation Hematology Laboratory Medicine, , Juntendo University Faculty of Medicine, ; Tokyo, Japan
                [25 ]ISNI 0000 0004 0631 9477, GRID grid.412342.2, Department of Hematology and Oncology, , Okayama University Hospital, ; Okayama, Japan
                [26 ]Department of Internal Medicine, Okayama Municipal Hospital, Okayama, Japan
                [27 ]ISNI 0000 0001 1172 4459, GRID grid.412339.e, Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, , Saga University, ; Saga, Japan
                [28 ]ISNI 0000 0004 0372 2033, GRID grid.258799.8, Department of Biomedical Statistics and Bioinformatics, , Kyoto University Graduate School of Medicine, ; Kyoto, Japan
                [29 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Division of Biomedical Statistics, Department of Integrated Medicine, Graduate School of Medicine, , Osaka University, ; Osaka, Japan
                [30 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Division of Biomedical Statistics, Department of Integrated Medicine, Graduate School of Medicine, , Osaka University, ; Osaka, Japan
                [31 ]ISNI 0000 0004 1771 7518, GRID grid.460103.0, Tokai Central Hospital, ; Kakamigahara, Japan
                Article
                1368
                10.1007/s10147-018-1368-2
                6438937
                30421023
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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                © Japan Society of Clinical Oncology 2019

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