Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment

Okada, Masaya; Imagawa, Jun; Tanaka, Hideo; Nakamae, Hirohisa; Hino, Masayuki; Murai, Kazunori; Ishida, Yoshiteru; Kumagai, Toru; Sato, Seiichi; Ohashi, Kazuteru; Sakamaki, Hisashi; Wakita, Hisashi; Uoshima, Nobuhiko; Nakagawa, Yasunori; Minami, Yosuke; Ogasawara, M.; Takeoka, Tomoharu; Akasaka, Hiroshi; Utsumi, Takahiko; Uike, Naokuni; Sato, Tsutomu; Ando, Sachiko; Usuki, Kensuke; Mizuta, Syuichi; Hashino, Satoshi; Nomura, Takanobu; Shikami, Masato; Fukutani, H; Ohe, Yokiko; Kosugi, Hiroshi; Shibayama, Hirohiko; Maeda, Yasuhiro; Fukushima, Toshihiro; Yamazaki, Hirohito; Tsubaki, Kazuo; Kukita, Toshimasa; Adachi, Yoko; Nataduka, Toshiki; Sakoda, Hiroto; Yokoyama, Hisayuki; Okamoto, Takahiro; Shirasugi, Yukari; Onishi, Yasushi; Nohgawa, Masaharu; Yoshihara, Satoshi; Morita, Satoshi; Sakamoto, Junichi; Kimura, Shinya

doi:10.1016/j.clml.2018.03.004

Cited by 95 publications

(114 citation statements)

References 21 publications

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“…However, TFR data with second‐generation TKIs are emerging, and several of these discontinuation trials are currently ongoing. Clinical trial data regarding dasatinib and nilotinib discontinuation, including key elements of each study, TFR eligibility, line of therapy, and relapse rate, are shown in Table …”

Section: Outcomes With First‐ and Second‐generation Tki Discontinuationmentioning

confidence: 99%

Treatment‐free remission with first‐ and second‐generation tyrosine kinase inhibitors

2018

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Chronic myeloid leukemia (CML) has become a chronic disease, for which the chronic phase is manageable with tyrosine kinase inhibitor (TKI) therapy. Patients with optimal responses to TKIs have achieved long‐term survival, and treatment‐free remission (TFR) has since become an additional treatment goal in CML. In this review, we discuss important factors to consider prior to stopping treatment. In addition, published and presented data with the first‐generation TKI imatinib, as well as current clinical trials evaluating TFR with the second‐generation TKIs dasatinib and nilotinib, are examined. Results obtained outside of clinical trials have been included as well. Because successful TKI discontinuation depends upon accurate BCR‐ABL1 monitoring, emerging technologies are also discussed. Clinical data obtained to date indicate that for many patients who achieve deep molecular response (DMR) on TKI therapy, TFR is a safe treatment goal, and, if the response is lost, patients can expect to regain their responses immediately upon reinitiation of TKI. It is also clear that there remains much room for improvement to make TFR a successful reality for most patients. Data from ongoing trials should help refine decisions as to which patients are the best candidates to attempt TKI discontinuation with safe monitoring in place.

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Section: Outcomes With First‐ and Second‐generation Tki Discontinuationmentioning

confidence: 99%

Treatment‐free remission with first‐ and second‐generation tyrosine kinase inhibitors

2018

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“…Since the first pilot study (Rousselot et al , ), two pioneers studies confirmed that treatment discontinuation is feasible and safe (Mahon et al , ; Ross et al , ) and numerous clinical trials and observational studies have been published thereafter to refine the criteria for stopping and molecular recurrence (MolRec), not only after imatinib treatment (Rousselot et al , ; Mori et al , ; Lee et al , ; Ferrero et al , ; Cerveira et al , ; Hernández‐Boluda et al , ; Saussele et al , ; Takahashi et al , , ; Chamoun et al , ; Fava et al , ; Fujisawa et al , ; Iino et al , ; Nicolini et al , ) but also after second‐generation TKIs whether used in first or second line (Rea et al , ; Cerveira et al , ; Hernández‐Boluda et al , ; Kumagai et al , ; Mahon et al , ; Okada et al , ; Saussele et al , ; Ross et al , ; Takahashi et al , ; Iino et al , ).…”

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confidence: 99%

“…Recently, second attempts to discontinue TKI in patients who relapsed have been reported (Legros et al , , ; Rea et al , ; Ross et al , ). Although the predictors of MolRec are not fully identified, criteria such as duration of treatment or duration of molecular response before discontinuation or initial response to TKI have been found to be associated with MolRec in several studies (Takahashi et al , ; Imagawa et al , ; Etienne et al , ; Legros et al , ; Rea et al , ; Cerveira et al , ; Hernández‐Boluda et al , ; Okada et al , ; Saussele et al , ; Chamoun et al , ; Fava et al , ; Fujisawa et al , ; Iino et al , ; Nicolini et al , ). Recommendations on the selection of patients with a higher probability of successfully attempting to discontinue TKI have been proposed by Australian and French experts (Hughes & Ross, ; Rea et al , ).…”

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confidence: 99%

Risk of molecular recurrence after tyrosine kinase inhibitor discontinuation in chronic myeloid leukaemia patients: a systematic review of literature with a meta‐analysis of studies over the last ten years

et al. 2020

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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.Keywords: meta-analysis, chronic myeloid leukemia, tyrosine kinase inhibitors discontinuation, first and second attempt. Recently, second attempts to discontinue TKI in patients who relapsed have been reported (Legros et al.

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“…Different studies independently confirmed that about half of the patients show a molecular recurrence, while the others stay in sustained treatment-free remission (TFR) after TKI stop. Consistently, most patients present with a recurrence within 6 months, while only a few cases are observed thereafter (11)(12)(13)(14)(15). The overall good response of those patients after restarting treatment with the previously administered TKI indicates that clonal transformation and resistance occurrence is not a primary problem in CML.…”

Section: Introductionmentioning

confidence: 75%

Inferring immunological control mechanisms from TKI dose alterations in CML patients

Haehnel

Baldow

Fassoni

et al. 2019

Preprint

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Recent clinical findings in chronic myeloid leukemia (CML) patients suggest that the risk of molecular recurrence after stopping tyrosine kinase inhibitors (TKI) treatment substantially depend on an individual, leukemia-specific immune response. However, it is still not possible to prospectively identify patients that will most likely remain in a long-term treatment free remission (TFR). Here, we use a mathematical model for CML, which explicitly includes an anti-leukemic (presumably immunological) effect and apply it to a set of patients (n=60) for whom BCR-ABL/ABL time courses had been quantified before and after TKI stop. We demonstrate that such a feedback control is conceptually necessary to explain long-term remission as observed in about half of the patients. Based on simulation results we classify the patient data sets into three different groups according to their predicted immune system configuration. While one class of patients requires a complete CML eradication to achieve TFR, other patients are able to control the leukemia after treatment cessation. Among them, we identified a third class of patients, which only maintains TFR if an optimal balance between leukemia abundance and immunological activation is achieved before treatment cessation. Further, we demonstrate that the immune response classification of the patients cannot be obtained solely from BCR-ABL measurements before treatment cessation. However, our results strongly suggest that changes in the BCR-ABL dynamics arising after system perturbations, such as TKI dose reduction, holds the information to predict the individual outcome after treatment cessation.

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Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment

Abstract: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.

Cited by 95 publications

References 21 publications

Treatment‐free remission with first‐ and second‐generation tyrosine kinase inhibitors

Treatment‐free remission with first‐ and second‐generation tyrosine kinase inhibitors

Risk of molecular recurrence after tyrosine kinase inhibitor discontinuation in chronic myeloid leukaemia patients: a systematic review of literature with a meta‐analysis of studies over the last ten years

Inferring immunological control mechanisms from TKI dose alterations in CML patients

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