Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial

Kimura, Shinya; Imagawa, Jun; Murai, Kazunori; Hino, Masayuki; Kitawaki, Toshio; Okada, Masaya; Tanaka, Hideo; Shindo, Motohiro; Kumagai, Toru; Ikezoe, Takayuki; Uoshima, Nobuhiko; Sato, Tsutomu; Watanabe, Reiko; Kowata, Shugo; Hayakawa, Masaya; Hosoki, Takaaki; Ikeda, Kazuhiko; Kobayashi, Tsutomu; Kakinoki, Yasutaka; Nishimoto, Tetsuo; Takezako, Naoki; Shibayama, Hirohiko; Takaori‐Kondo, Akifumi; Nakamae, Hirohisa; Kawaguchi, Atsushı; Ureshino, Hiroshi; Sakamoto, Junichi; Ishida, Yoshiteru

doi:10.1016/s2352-3026(19)30235-2

Cited by 79 publications

(73 citation statements)

References 31 publications

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“…Currently, as no head to head comparison between 2nd generation TKI has been done in the frontline setting, we hypothesized that the incidences of DMR would not significantly differ between 2nd and 3rd generation TKIs. In addition, discontinuation of 2nd generation TKIs as front-line or after IMA lead to similar rates of molecular recurrence-free remission [11,[47][48][49][50][51].…”

Section: Discussionmentioning

confidence: 99%

Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Étienne

Dulucq

Bauduer

et al. 2020

Cancers

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Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2–3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2–3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2–3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

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Section: Discussionmentioning

confidence: 99%

Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Étienne

Dulucq

Bauduer

et al. 2020

Cancers

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“…Previous studies have reported results supporting the notion that 2G-TKIs (mainly in second line) provide the same TFR curves as imatinib, and lead to similar or sometimes superior TFR outcomes. [14][15][16][17][18] In the Nilotinib Treatment-free Remission Study in CML Patients (ENESTfreedom) study, 190 patients entered the TFR phase. The median duration of nilotinib treatment before stopping was 43.5 months.…”

Section: Discussionmentioning

confidence: 99%

“…For the 58 patients who entered the maintenance phase and maintained a DMR for at least 1 year, the reported 6-month TFR rate was 55.2%. 18 Large national or international studies are needed to reach the statistical power to provide reliable answers to these questions. There is no doubt that the long-term follow-up analysis of the EURO-SKI study will provide robust and mature data in the field.…”

Section: Discussionmentioning

confidence: 99%

Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission

et al. 2020

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Abstract Treatment-free remission (TFR) is an opportunity for patients with chronic myeloid leukemia (CML). Reported cumulative incidence curves of molecular recurrence (MRec) arbor a 2-phase shape with mainly early events, but also some late events (late MRec [LMRec]). Having discontinued our first patient in 2004, we have access to a prolonged follow-up, enabling us to characterize these late events. Over 15 years, 128 patients from our institution were registered in the Stop Imatinib (STIM; A Study for Tyrosine Kinase Inhibitors Discontinuation [A-STIM]) trial. MRec was defined by the loss of major molecular response (BCR-ABL1IS >0.1%). At the first TFR attempt, patients had been taking a tyrosine kinase inhibitor for a median of 7.1 years and in BCR-ABL1IS ≤0.01% (MR4) for a median of 4 years. The median follow-up of patients in TFR was 6.5 years. The TFR rate was estimated to be 45.6% after 7 years. For 9/65 (14%) patients experiencing MRec, recurrence occurred after 2 years in TFR (median, 3.6 years). The residual rate of MRec after 2 years was estimated to be 18%. The probability of remaining in TFR was 65.4% for patients having experienced fluctuations of their minimal residual disease (MRD) (at least 2 consecutive measurements BCR-ABL1IS >0.0032% or loss of MR4), whereas it was 100% for those with stable MRD (P = .003). After 2 years in TFR, we observed an 18% residual rate of LMRec. These late events represent 14% of all MRec and occur in patients with fluctuating MRD measurements. A long-term molecular follow-up therefore remains mandatory for CML patients in TFR. The A-STIM study was registered at www.clinicaltrials.gov as #NCT02897245.

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“…[209][210][211][212][213] More recent studies have also confirmed the feasibility of TFR after discontinuation of dasatinib or nilotinib in patients with CP-CML who have achieved and maintained MR4.5 for 12 months after $2 years of TKI therapy in the first-line or second-line setting (TFR rates ranging from 44% to 54%; Table 7). [214][215][216][217][218][219][220] The feasibility of TFR after discontinuation of bosutinib or ponatinib has not yet been evaluated in clinical studies. In the EURO-SKI study that evaluated TFR after discontinuation of any first-line TKI therapy (imatinib, dasatinib, or nilotinib) in eligible patients, the type of first-line TKI therapy did not significantly affect molecular relapse-free survival.…”

Section: Discontinuation Of Tki Therapymentioning

confidence: 99%

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

Deininger

Shah

Altman³

et al. 2020

Journal of the National Comprehensive Cancer Network

193

210

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Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

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Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial

Cited by 79 publications

References 31 publications

Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

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