Treatment-Free Remission Outcome in Patients with Chronic Myeloid Leukemia in Chronic Phase Following One Year of Nilotinib De-Escalation: 96-Week Update of Dante Study

Stagno, Fabio; Abruzzese, Elisabetta; Iurlo, Alessandra; Pane, Fabrizio; Attolico, Imma; Sportoletti, Paolo; Pregno, Patrizia; Galimberti, Sara; Scappini, Barbara; Miglino, Maurizio; Siragusa, Sergio; Capodanno, Isabella; Valsecchi, Diletta; Nardozza, Aurelio Pio; Coco, Paola; Rosti, Gianantonio; Saglio, Giuseppe; Breccia, Massimo

doi:10.1182/blood-2022-157700

Cited by 7 publications

(6 citation statements)

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“…The RFS was 36% (95% CI, and 72% (95% CI, 64-80) in the MMR and MR4 groups respectively. These results appear to be more favourable than those reported in the EURO-SKI trial, where the RFS was 50% (95% CI, [46][47][48][49][50][51][52][53][54] for patients achieving and maintaining MR4 with half of the standard TKI dose before discontinuation. 9 Support for the rationale of TKI deescalation after achieving stable remission comes from a mathematical model based on patient cohorts enrolled in the clinical trials IRIS and CML-IV Study.…”

Section: Dose Optimization Strategiesmentioning

confidence: 65%

“…The Italian DANTE trial is currently evaluating the effect of de-escalation of nilotinib on TFR. 54 In this study, 113 CML-CP patients are initially treated with nilotinib 300 mg BID for ≥3 years. During the consolidation phase, 107 patients are switched to nilotinib 300 mg QD and 40 patients with sustained DMR attempt TFR.…”

Section: Dose Optimization Strategiesmentioning

confidence: 99%

“…The Italian DANTE trial is currently evaluating the effect of de‐escalation of nilotinib on TFR 54 . In this study, 113 CML‐CP patients are initially treated with nilotinib 300 mg BID for ≥3 years.…”

Section: Strategies To Enhance Tfr Eligibilitymentioning

confidence: 99%

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How to improve treatment‐free remission eligibility in chronic myeloid leukaemia?

Costa,

Breccia

2023

Br J Haematol

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SummaryThe achievement of treatment‐free remission (TFR) has become a significant clinical end‐point in the management of patients with chronic myeloid leukaemia (CML), providing an opportunity to discontinue therapy with tyrosine kinase inhibitors (TKIs) while maintaining deep molecular response (DMR). Early studies, such as the French STIM trial, have demonstrated that a portion of patients can maintain DMR after treatment cessation, with rates ranging from 40% to 50%, and most relapses occurring within the first 6 months. Key prognostic factors for successful TFR, including treatment duration, duration of DMR, risk scores, and transcript type, have been identified. Optimal patient selection for TFR remains a challenge, but recent research provides insights into potential strategies to increase TFR eligibility. Evidence suggests that early intervention switching to achieve optimal response, treatment combinations, proactive switch in the case of absence of DMR, dose‐optimization and induction‐maintenance approach can improve molecular responses and, consequently, enhance TFR eligibility. In this review, we report and discuss all the potential therapeutic strategies that may enhance eligibility for a first attempt at TFR, with a particular emphasis on potential future approaches.

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Section: Dose Optimization Strategiesmentioning

confidence: 65%

Section: Dose Optimization Strategiesmentioning

confidence: 99%

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How to improve treatment‐free remission eligibility in chronic myeloid leukaemia?

Costa,

Breccia

2023

Br J Haematol

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“…More recently, the prospective, multicenter phase II DANTE study (NCT03874858) aimed to evaluate the safety of first-line nilotinib de-escalation and its impact on TFR success in Italian CML-chronic phase subjects. While in a previously interim analysis 1 year of nilotinib de-escalation prior to TFR in patients with stable DMR was shown to be safe and effective ( Breccia et al, 2021 ), a molecular recurrence rate of approximately 32% 1 year after stopping nilotinib was reported, thus demonstrating that de-escalation of this drug before attempting TFR may be a successful dose optimization strategy ( Stagno et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study

et al. 2023

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TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.

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“…Bosutinib side-effects can be mitigated with a dose-escalation schedule: 100 mg daily x 1-2 weeks, then 200 mg daily x 2–4 weeks, then 300 mg daily x 1 month, then adjust the dose to 400 mg daily (approved dose in frontline therapy) or a lower or higher dose (500 mg daily; approved in subsequent-line therapies) depending on the response, CML status (frontline or later lines) and side-effects [ 82 , 83 ]. Nilotinib can be de-escalated safely from 300–400 mg BID to 150–200 mg BID, or even 200 mg daily, if side-effects occur, or if there are safety concerns in patients who have responded optimally [ 84 , 85 ]. Recent studies have also shown that dose-adjusted ponatinib schedules (e.g.…”

Section: Management Of CML Post-tki Toxicitiesmentioning

confidence: 99%

Management of chronic myeloid leukemia in 2023 – common ground and common sense

et al. 2023

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With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient’s comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results.

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Treatment-Free Remission Outcome in Patients with Chronic Myeloid Leukemia in Chronic Phase Following One Year of Nilotinib De-Escalation: 96-Week Update of Dante Study

Cited by 7 publications

References 0 publications

How to improve treatment‐free remission eligibility in chronic myeloid leukaemia?

How to improve treatment‐free remission eligibility in chronic myeloid leukaemia?

Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study

Management of chronic myeloid leukemia in 2023 – common ground and common sense

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