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      Brazilian chronic myeloid leukemia working group recommendations for discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia in clinical practice

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          Abstract

          Introduction

          Treatment-free remission (TFR) is a new goal of chronic myeloid leukemia (CML) therapy. TFR is feasible when the patient has achieved a deep and stable molecular response and met the criteria required to ensure its success. Treatment discontinuation should not be proposed to the CML patient if minimum conditions are not met. In Brazil, for example, molecular tests ( BCR::ABL1) are not broadly available, making it difficult to monitor the patients adequately.

          Objective

          In this sense, providing TFR recommendations for Brazilian physicians are therefore necessary. These recommendations include the main criteria checklist to start the TKIs treatment discontinuing process in patients diagnosed with CML and the population-eligible characteristics for treatment discontinuation.

          Method

          Age, risk score at diagnosis, TKI treatment duration, BCR::ABL1 transcripts type, depth of the molecular response for treatment discontinuation, treatment adherence, patient monitoring and withdrawal syndrome are essential factors to consider in TFR. After TKI discontinuation, BCR::ABL1 transcripts monitoring should be more frequent. When a major molecular response loss is observed during the monitoring of a patient in TFR, the TKI treatment should be resumed.

          Conclusion

          These recommendations should serve as a basis for medical professionals interested in proposing TKI discontinuation for CML patients in clinical practice. It is important to highlight that, despite the benefits of TFR for the patients and the health system, it should only be feasible following the minimum standards proposed in this recommendation.

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          Most cited references71

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          European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

          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 first-line). 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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            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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                Author and article information

                Contributors
                Journal
                Hematol Transfus Cell Ther
                Hematol Transfus Cell Ther
                Hematology, Transfusion and Cell Therapy
                Sociedade Brasileira de Hematologia e Hemoterapia
                2531-1379
                2531-1387
                03 May 2022
                Jul-Sep 2022
                03 May 2022
                : 44
                : 3
                : 402-409
                Affiliations
                [a ]Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO), Rio de Janeiro, RJ, Brazil
                [b ]ONCOCLÏNICA CTO, Rio de Janeiro, RJ, Brazil
                [c ]Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, (HC FM USP), São Paulo, SP, Brazil
                [d ]Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, SP, Brazil
                [e ]Hospital das Clínicas da Universidade Federal de Minas Gerais (HC UFMG), Belo Horizonte, MG, Brazil
                [f ]Instituto COI, Rio de Janeiro, RJ, Brazil
                [g ]Centro de Pesquisas Oncológicas (CEPON), Itacurubi, Florianópolis, SC, Brazil
                [h ]Centro de Hematologia e Hemoterapia, Universidade Estadual de Campinas, (Hemocentro Unicamp), Campinas, SP, Brazil
                [i ]Instituto Hemomed de Oncologia e Hematologia, São Paulo, SP, Brazil
                [j ]Complexo Hospital de Clínicas, Universidade Federal do Paraná (CHC-UFPR), Curitiba, PR, Brazil
                Author notes
                [* ]Corresponding author at: Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO), Rua Frei Caneca 8, Centro, CEP 20211-030 Rio de Janeiro, RJ, Brazil. carla.boquimpani@ 123456icloud.com
                Article
                S2531-1379(22)00050-5
                10.1016/j.htct.2022.04.002
                9477780
                35654721
                5ff9047a-e0cd-4b0a-a553-212c48ea1d22
                © 2022 Published by Elsevier España, S.L.U. on behalf of Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 28 September 2021
                : 1 April 2022
                Categories
                Review Article

                practice guideline,leukemia myelogenous chronic,bcr-abl positive,therapeutics

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