Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results

Hughes, Timothy P.; Leber, Brian; Cervantes, Francisco; Spector, Nelson; Pasqüini, Ricardo; Clementino, Nelma Cristina D.; Schwarer, Anthony P.; Dorlhíac-Llacer, Pedro Enrique; Fx, Mahon; Réa, Delphine; Guerci‐Bresler, Agnès; Kamel‐Reid, Suzanne; Bendit, Israel; Acharya, Sandip; Glynos, Tara; Dalal, Darshan; Branford, Susan; Lipton, Jeff H.

doi:10.1038/leu.2017.247

Cited by 39 publications

(35 citation statements)

References 11 publications

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“…The ENESTcmr trial [132,133] provides some relevant information, however. In what was termed "persistent molecular disease", those patients who had achieved CCyR were randomized to continuing imatinib or switching to nilotinib 400 mg twice daily.…”

Section: Discussionmentioning

confidence: 99%

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

et al. 2020

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The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available firstline). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

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Section: Discussionmentioning

confidence: 99%

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

et al. 2020

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“…This approach also applies to patients on second generation TKIs, because, as mentioned earlier, early switching has not yet shown to influence long‐term outcome . Another study randomized patients in CCyR on imatinib for at least 2 years to continue imatinib or switch to nilotinib . Switching to nilotinib induced deeper molecular responses, but did not translate into an improvement in progression‐free survival or in other meaningful outcomes.…”

Section: Monitoring Treatment Response: Surrogate Endpoints and Milesmentioning

confidence: 99%

Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring

2018

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CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL1 oncoprotein. Frontline therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; this has not translated into improved long-term survival, because of the availability of effective salvage therapies. Salvage therapy: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Second and third generation TKIs, although potent and selective, exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least 2 TKIs, and for all patients in CML advanced phases.

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“…In the case of nonoptimal response, the change from a TKI to another TKI is optional, if it is believed that it may help to achieve a deeper molecular response and to bring the patient to TFR. There are some data, 20,26,32,43 and there is some experience, of switching from imatinib to a 2GTKI, not from a 2GTKI to another TKI. All studies suggest that such a switch may increase the rate of deep molecular response (DMR), hence the number of patients eligible for treatment discontinuation and TFR, but, regrettably, all of these studies are single-arm and do not allow for calculation of the benefit of a switching policy against the risk of increased toxicity.…”

Section: The Switch From First-linementioning

confidence: 99%

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP

et al. 2019

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Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 >10% at 3 and 6 months, >1% at 12 months, and >0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR.

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Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results

Cited by 39 publications

References 11 publications

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP

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