Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV

Saußele, Susanne; Hehlmann, Rüdiger; Fabarius, Alice; Jeromin, Sabine; Proetel, Ulrike; Rinaldetti, Sébastien; Kohlbrenner, Katharina; Einsele, Hermann; Falge, Christiane; Kanz, Lothar; Neubauer, Andreas; Kneba, Michael; Stegelmann, Frank; Pfreundschuh, Michael; Waller, Christiane; Leibundgut, Elisabeth Oppliger; Heim, Dominik; Krause, Stefan W.; Hofmann, Wolf‐Karsten; Hasford, Joerg; Pfirrmann, Markus; Müller, Martin C.; Hochhaus, Andreas; Lauseker, Michael

doi:10.1038/s41375-018-0055-7

Cited by 24 publications

(14 citation statements)

References 28 publications

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“…The landmark time point of 2.5 years to achieve MMR showed the largest difference between those with or without MMR with regard to progression-free survival. 57 A specific time to achieve DMR for progression-free survival was not detected. The updated ELN recommendations now state a change of treatment may be considered if MMR is not reached by 36-48 months.…”

Section: Introductionmentioning

confidence: 95%

“…A recent analysis of the German CML-Study IV confirmed the optimal response time to achieve 1% BCRABL1 at about 12 to 15 months for progression-free survival, with progression being development of accelerated phase, blast crisis or death. 57 The study also investigated when it is necessary to regard lack of MMR as treatment failure, indicating that a switch of therapy is warranted. The landmark time point of 2.5 years to achieve MMR showed the largest difference between those with or without MMR with regard to progression-free survival.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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

Branford

2020

haematol

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“…Achieving major molecular response (MMR), defined as BCR::ABL1/ ABL1 ≤ 0.1% on the international scale (IS), with BCR::ABL1 tyrosine kinase inhibitors (TKIs), is a major milestone in patients with chronic myeloid leukemia (CML). It is associated with lower chances of progression to advanced phase disease [1][2][3][4] as well as higher chances of deep and durable molecular responses and treatmentfree remission (TFR). [5][6][7] Hence, the European LeukemiaNet (ELN) recommendations define optimal response as achieving and maintaining MMR within 12 months after initiating tyrosine kinase inhibitor (TKI) therapy.…”

Section: Introductionmentioning

confidence: 99%

Chronic myeloid leukemia without major molecular response after 2 years of treatment with tyrosine kinase inhibitor

et al. 2023

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Achieving major molecular response (MMR) with BCR::ABL1 tyrosine kinase inhibitors (TKIs) is associated with lower chances of progression to advanced phase disease and higher chances of treatment‐free remission (TFR) in patients with chronic myeloid leukemia (CML). Failure to achieve this molecular milestone after 1 year has been highlighted as “suboptimal” or “warning” sign of treatment failure in CML guidelines and recommendations and implied to predict a poor long‐term outcome. In this analysis, we report the long‐term outcome of 131 patients who did not achieve MMR within the first 2 years of TKI therapy. Patients who achieved a major cytogenetic response (MCyR; roughly equivalent to BCR::ABL1 transcript levels on the International Scale [IS] <10%) had good long‐term overall survival (OS) (10‐year OS of 88%) and CML‐related overall survival (CML‐OS) (10‐year CML‐OS of 95%). The achievement of MCyR within the first 2 years of treatment predicted a better OS (HR = 0.43, p = .03). The value of MMR was even less pronounced among patients aged 60 years or older at diagnosis, in whom mortality was primarily due to comorbidities unrelated to CML (10‐year OS of 55% vs. 10‐year CML‐OS of 100%). In conclusion, achievement of MCyR within 2 years is a reasonable milestone in CML, and these patients can still have good outcomes even when MMR is not achieved.

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“…Thus, there is an ongoing research regarding the appropriate management of patients having BCR-ABL1 IS between 1 and 0.1% in the long run. This issue has been recently tackled by the German CML Study IV group, which showed evidence suggesting that the optimal waiting time for patients to achieve MMR is about 2.5 years (67), after which a change in the treatment should be considered.…”

Section: The Role Of Bcr-abl1 Is In Monitoring CMLmentioning

confidence: 99%

Assessing Measurable Residual Disease in Chronic Myeloid Leukemia. BCR-ABL1 IS in the Avant-Garde of Molecular Hematology

et al. 2019

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Chronic myelogenous leukemia (CML) is a malignancy of the myeloid cell lineage characterized by a recurrent chromosomal abnormality: the Philadelphia chromosome, which results from the reciprocal translocation of the chromosomes 9 and 22. The Philadelphia chromosome contains a fusion gene called BCR-ABL1. The BCR-ABL1 codes for an aberrantly functioning tyrosine kinase that drives the malignant proliferation of the founding clone. The advent of tyrosine kinase inhibitors (TKI) represents a landmark in the treatment of CML, that has led to tremendous improvement in the remission and survival rates. Since the introduction of imatinib, the first TKI, several other TKI have been approved that further broadened the arsenal against CML. Patients treated with TKIs require sensitive monitoring of BCR-ABL1 transcripts with quantitative real-time polymerase chain reaction (qRT-PCT), which has become an essential part of managing patients with CML. In this review, we discuss the importance of the BCR-ABL1 assay, and we highlight the growing importance of BCR-ABL1 dynamics. We also introduce a mathematical correction for the BCR-ABL1 assay that could help homogenizing the use of the ABL1 as a control gene. Finally, we discuss the growing body of evidence concerning treatment-free remission. Along with the continuous improvement in the therapeutic arsenal against CML, the molecular monitoring of CML represents the avant-garde in the struggle to make CML a curable disease.

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Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV

Cited by 24 publications

References 28 publications

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

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

Chronic myeloid leukemia without major molecular response after 2 years of treatment with tyrosine kinase inhibitor

Assessing Measurable Residual Disease in Chronic Myeloid Leukemia. BCR-ABL1 IS in the Avant-Garde of Molecular Hematology

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