Long‐term impact of molecular response fluctuations in chronic myeloid leukaemia patients treated with imatinib

Molica, Matteo; Breccia, Massimo; Colafigli, Gioia; Massaro, Fulvio; Quattrocchi, Luisa; Mancini, Marco; Diverio, Daniela; Latagliata, Roberto; Foà, Robin

doi:10.1111/bjh.14560

Cited by 3 publications

(5 citation statements)

References 5 publications

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“…None of the patients who achieved a stable MR4.5 developed resistance with an EFS of 100%, whereas the EFS in the cohort who never achieved a stable MR4.5 was 81% ( p = 0.01). Indeed, as previously reported, fluctuations of the molecular residual disease at the level of MR4.5 did not influence EFS or OS [ 12 ]. None of the patients who reached a stable MR4.5 progressed to blast phase, whereas 6 patients who did not reach a stable MR4.5 (4.4%) did progress ( p = 0.001).…”

Section: Resultssupporting

confidence: 61%

Prognostic factors associated with a stable MR4.5 achievement in chronic myeloid leukemia patients treated with imatinib

et al. 2017

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Deep molecular response in chronic myeloid leukemia (CML) patients treated with imatinib is a prerequisite for possible discontinuation. We identify clinico-biologic features linked with the probability of reaching MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS) as a stable response (confirmed on two or more consecutive determinations). In a series of 208 patients treated with imatinib first-line outside clinical trials, after a median follow-up of 7 years the incidence of stable MR4.5 was 34.6%, obtained in median time of 5.4 years. In univariate analysis, female gender (p = 0.02), lower median age (56.4 vs 58.6, p = 0.03), Sokal risk stratification (p = 0.01) and e14a2 type of transcript (43% vs 31%, p = 0.02) are associated to achievement of a stable MR4.5. In multivariate regression analysis, female gender (HR 1.6, 95% CI: 1.1–2.6; P = 0.022), Sokal risk (HR 1.4, 95% CI: 1.1–2.3; p = 0.03), type of transcript (e14a2 vs e13a2 type, HR 1.6, 95% CI: 1.3–2.9; P = 0.03) and achievement of an early molecular response (EMR) at 3 months (HR 1.5, 95% CI: 1.2–2.8; P = 0.01), retained statistical significance. These clinical and biologic features associated with the achievement of a stable deep molecular response should be taken into account at a time when treatment-free remission strategies are being actively pursued in the management of CML.

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Section: Resultssupporting

confidence: 61%

Prognostic factors associated with a stable MR4.5 achievement in chronic myeloid leukemia patients treated with imatinib

et al. 2017

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“…A study of 208 patients treated with imatinib as their first-line therapy investigated the outcome of patients with fluctuating BCR-ABL1 values according to the level of response achieved. 63 A stable molecular response was defined as persistence of the same molecular response (MMR, MR4 or MR4.5) at three consecutive assessments. A fluctuation was the achievement of the molecular response and its subsequent loss.…”

Section: How Stable Is Deep Molecular Response?mentioning

confidence: 99%

“…This study demonstrated that unstable MMR was associated with an increased risk of imatinib resistance, whereas fluctuations of deeper molecular responses did not influence outcome. 63 Data suggest that when a DMR is achieved it is relatively stable and the risk of TKI resistance is low. However, vigilance and long-term molecular monitoring are recommended, even for patients with stable DMR.…”

Section: How Stable Is Deep Molecular Response?mentioning

confidence: 99%

Why is it critical to achieve a deep molecular response in chronic myeloid leukemia?

Branford

2020

haematol

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The primary goal of tyrosine kinase inhibitor (TKI) therapy for patients with chronic myeloid leukemia is survival, which is achieved by the vast majority of patients. The initial response to therapy provides a sensitive measure of future clinical outcome. Measurement of BCR-ABL1 transcript levels using real-time quantitative polymerase chain reaction standardized to the international reporting scale is now the principal recommended monitoring strategy. The method is used to assess early milestone responses and provides a guide for therapeutic intervention. When patients successfully traverse the critical first 12 months of TKI therapy, most will head towards another milestone response, deep molecular response (DMR, BCR-ABL1 ≤0.01%). DMR is essential for patients aiming to achieve treatment-free remission and a prerequisite for a trial of TKI discontinuation. The success of discontinuation trials has led to new treatment strategies in order for more patients to reach this milestone response. DMR has been incorporated into endpoints of clinical trials and is considered by some expert groups as the optimal treatment response. But is DMR a stable response and does it provide the ultimate protection against TKI resistance and death? Do we need to increase the sensitivity of detection of BCR-ABL1 to better identify the patients who would likely remain in treatment-free remission after TKI discontinuation? Is it necessary to switch current TKI therapy to a more potent inhibitor if the goal is to achieve DMR? These are issues that I will explore in this review.

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“…After 12 months, 83.1% achieved CCyR, and 62% achieved MR3, while after a seven-year follow-up, 64.4% reached MR3. The cumulative incidence of MR4 was 51%, and that of MR4.5 was 34.6% after a median time of 3.8 and 5.4 years [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…A Brazilian working group has also provided recommendations for discontinuing tyrosine kinase inhibitors. In Molica et al, 17 out of 208 patients showed fluctuations in BCR::ABL1 quantification, of which just 2 exhibited a mutation of the ABL1 kinase domain (E255K and M351T) [ 48 ]. In a report with 125 imatinib-resistant CML patients, 28 (22.4%) showed a BCR::ABL1 kinase domain mutation, from which 7.2% had T315I and 3.2% had E255K [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular BCR::ABL1 Quantification and ABL1 Mutation Detection as Essential Tools for the Clinical Management of Chronic Myeloid Leukemia Patients: Results from a Brazilian Single-Center Study

Marin,

Wosniaki,

Sanchuki

et al. 2023

IJMS

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Chronic myeloid leukemia (CML) is a well-characterized oncological disease in which virtually all patients possess a translocation (9;22) that generates the tyrosine kinase BCR::ABL1 protein. This translocation represents one of the milestones in molecular oncology in terms of both diagnostic and prognostic evaluations. The molecular detection of the BCR::ABL1 transcription is a required factor for CML diagnosis, and its molecular quantification is essential for assessing treatment options and clinical approaches. In the CML molecular context, point mutations on the ABL1 gene are also a challenge for clinical guidelines because several mutations are responsible for tyrosine kinase inhibitor resistance, indicating that a change may be necessary in the treatment protocol. So far, the European LeukemiaNet and the National Comprehensive Cancer Network (NCCN) have presented international guidelines on CML molecular approaches, especially those related to BCR::ABL1 expression. In this study, we show almost three years’ worth of data regarding the clinical treatment of CML patients at the Erasto Gaertner Hospital, Curitiba, Brazil. These data primarily comprise 155 patients and 532 clinical samples. BCR::ABL1 quantification by a duplex-one-step RT-qPCR and ABL1 mutations detection were conducted. Furthermore, digital PCR for both BCR::ABL1 expression and ABL1 mutations were conducted in a sub-cohort. This manuscript describes and discusses the clinical importance and relevance of molecular biology testing in Brazilian CML patients, demonstrating its cost-effectiveness.

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Long‐term impact of molecular response fluctuations in chronic myeloid leukaemia patients treated with imatinib

Cited by 3 publications

References 5 publications

Prognostic factors associated with a stable MR4.5 achievement in chronic myeloid leukemia patients treated with imatinib

Prognostic factors associated with a stable MR4.5 achievement in chronic myeloid leukemia patients treated with imatinib

Why is it critical to achieve a deep molecular response in chronic myeloid leukemia?

Molecular BCR::ABL1 Quantification and ABL1 Mutation Detection as Essential Tools for the Clinical Management of Chronic Myeloid Leukemia Patients: Results from a Brazilian Single-Center Study

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