Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment‐free remission

Erba, Harry P.

doi:10.1002/ajh.23902

Cited by 12 publications

(9 citation statements)

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“…Persistence of LSCs during treatment prevents cure of CML by TKIs in the majority of patients, and permits accumulation of additional mutations leading to overt drug resistance or BC [ 4 , 6 – 8 ]. Our previous studies suggested resistance to Fas-induced apoptosis might contribute to this effect [ 12 – 14 ].…”

Section: Discussionmentioning

confidence: 99%

Decreased calpain activity in chronic myeloid leukemia impairs apoptosis by increasing survivin in myeloid progenitors and xiap1 in differentiating granulocytes

et al. 2017

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Chronic Myeloid Leukemia (CML) is characterized by translocations between chromosomes 9 and 22, resulting in expression of Bcr-abl oncogenes. Although the clinical course of CML was revolutionized by development of Bcr-abl-directed tyrosine kinase inhibitors (TKIs), CML is not cured by these agents. Specifically, the majority of subjects relapsed in clinical trials attempting TKI discontinuation, suggesting persistence of leukemia stem cells (LSCs) even in molecular remission. Identifying mechanisms of CML-LSC persistence may suggest rationale therapeutic targets to augment TKI efficacy and lead to cure. Apoptosis resistance is one proposed mechanism. In prior studies, we identified increased expression of Growth Arrest Specific 2 (Gas2; a Calpain inhibitor) in Bcr-abl+ bone marrow progenitor cells. A number of previously described Calpain substrates might influence apoptosis in CML, including βcatenin and the X-linked Inhibitor of Apoptosis Protein 1 (Xiap1). We previously found Gas2/Calpain dependent stabilization of βcatenin in CML, and increased expression of βcatenin target genes, including Survivin (also an IAP). In the current work, we investigate contributions of Survivin and Xiap1 to Fas-resistance in Bcr-abl+ bone marrow cells. Inhibitors of these proteins are currently in clinical trials for other malignancies, but a role for either IAP in CML-LSC persistence is unknown.

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Section: Discussionmentioning

confidence: 99%

Decreased calpain activity in chronic myeloid leukemia impairs apoptosis by increasing survivin in myeloid progenitors and xiap1 in differentiating granulocytes

et al. 2017

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“…Successful TKI therapy has the potential to reduce the disease burden of CML below the threshold of detection of hematologic and cytogenetic testing, and there is evidence that the early achievement of reduced disease burden predicts favorable long-term outcomes. [10][11][12] Molecular monitoring, which measures BCR-ABL1 transcript level using quantitative real-time polymerase chain reaction (qPCR) on the International Scale (IS), allows the detection of low levels of residual leukemia cells and provides important prognostic information for CML patients receiving TKI. 13 Molecular monitoring helps determine whether a patient is responding optimally to treatment, helps identify those at risk of progression, and provides evidence regarding the need to reassess treatment or initiate second-line therapy.…”

Section: Study Design and Sample Selectionmentioning

confidence: 99%

Health Care Resource Utilization and Costs in Patients with Chronic Myeloid Leukemia with Better Adherence to Tyrosine Kinase Inhibitors and Increased Molecular Monitoring Frequency

Latrémouille-Viau¹,

Guérin²,

Gagnon-Sanschagrin³

et al. 2017

JMCP

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This study was funded by Novartis Pharmaceuticals, which was involved in all stages of the study and in the decision to submit the report for publication. Latremouille-Viau, Guerin, Gagnon-Sanschagrin, and Dea are employees of Analysis Group, which received consulting fees from Novartis Pharmaceuticals for work on this study. Joseph is an employee of Novartis Pharmaceuticals and owns stock in Amgen and Pfizer. Cohen was an employee of Novartis Pharmaceuticals at the time of this study. Portions of this study were presented online (beginning May 20, 2016) as part of the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, on June 3-7, 2016, and as a poster at the American Society of Hematology (ASH) Annual Meeting in San Diego, California, on December 3-6, 2016. Study concept and design were contributed by Latremouille-Viau and Guerin, along with the other authors. Gagnon-Sanschagrin and Dea took the lead in data collection, assisted by the other authors, and data interpretation was performed by Cohen and Joseph, along with the other authors. The manuscript was written by Latremouille-Viau, along with the other authors, and revised by Joseph, along with the other authors.

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“…ELN and NCCN guidelines provide definitions of optimal responses to TKIs and recommendations for molecular monitoring . However, what constitutes a CMR may not be an absolute, as more sensitive techniques are validated for future use …”

Section: Discussionmentioning

confidence: 99%

Dasatinib dose management for the treatment of chronic myeloid leukemia

Talpaz

Saglio

Atallah

et al. 2018

Cancer

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Chronic myeloid leukemia (CML) has evolved into a chronic disease that is managed with tyrosine kinase inhibitor therapy. Now that long‐term survival has been achieved in patients with CML, the focus of treatment has shifted to dose optimization, with the goal of maintaining response while improving quality of life. In this review, the authors discuss optimizing the dose of the second‐generation tyrosine kinase inhibitor dasatinib. Once‐daily dosing regimens for dasatinib in the first and later lines of treatment were established through long‐term (5‐year and 7‐year) trials. Recently published data have indicated that further dose optimization may maintain efficacy while minimizing adverse events. Results obtained from dose optimization and discontinuation trials currently in progress will help practitioners determine the best dose and duration of dasatinib for patients with CML, because treatment decisions will be made through continued discussions between physicians and patients. Cancer 2018;124:1660‐72. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment‐free remission

Cited by 12 publications

References 64 publications

Decreased calpain activity in chronic myeloid leukemia impairs apoptosis by increasing survivin in myeloid progenitors and xiap1 in differentiating granulocytes

Decreased calpain activity in chronic myeloid leukemia impairs apoptosis by increasing survivin in myeloid progenitors and xiap1 in differentiating granulocytes

Health Care Resource Utilization and Costs in Patients with Chronic Myeloid Leukemia with Better Adherence to Tyrosine Kinase Inhibitors and Increased Molecular Monitoring Frequency

Dasatinib dose management for the treatment of chronic myeloid leukemia

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