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Patient-Initiated Discontinuation of Tyrosine Kinase Inhibitor for Chronic Myeloid Leukemia.

ABSTRACT: The introduction of tyrosine kinase inhibitors (TKI) has revolutionised the management of patients with chronic myeloid leukemia (CML) over the last twenty years, but despite significant improvements in survival, patients exhibit long-term side effects that impact on quality of life. A major advance in CML management has been the ability to discontinue TKI therapy achieving a treatment-free remission (TFR), yet this option is only available to eligible patients who present with low-risk disease and who subsequently attain deep and sustained molecular responses. A case is described of a patient with CML who self-initiated stopping of TKI therapy when in a less than optimal molecular remission. Despite this action, the patient continues to experience a TFR with prospective close molecular monitoring performed. It is emphasized that this approach may lead to ineffective treatment discontinuation, molecular relapse, and increased patient anxiety. As TFR for patients with CML moves from clinical trials into routine clinical practice, emphasis is placed on adherence to (evolving) guidelines critical to ensure optimal counselling, selection, monitoring, and continued management of patients whether TFR is successful or not.

SUBMITTER: Langabeer SE

PROVIDER: S-EPMC7125505 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Patient-Initiated Discontinuation of Tyrosine Kinase Inhibitor for Chronic Myeloid Leukemia.

Langabeer Stephen E SE Faryal Rehman R O'Dwyer Michael M Loingsigh Sorcha Ní SN

Case reports in hematology 20200323

The introduction of tyrosine kinase inhibitors (TKI) has revolutionised the management of patients with chronic myeloid leukemia (CML) over the last twenty years, but despite significant improvements in survival, patients exhibit long-term side effects that impact on quality of life. A major advance in CML management has been the ability to discontinue TKI therapy achieving a treatment-free remission (TFR), yet this option is only available to eligible patients who present with low-risk disease ...[more]

PMID: 32274226

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Project description:Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional evaluation of intraindividual EVI1-high cells. Introduction of CML into Evi1-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) knock-in mice, a versatile HSC-reporter strain, enables us to separate Evi1-high CML cells from the individual. Evi1-IRES-GFP allele models of CML in chronic phase (CML-CP), by retroviral overexpression of BCR-ABL and by crossing BCR-ABL transgenic mice, revealed that Evi1 is predominantly enriched in the stem cell fraction and associated with an enhanced proliferative as well as a leukemia-initiating capacity and that Evi1-high CML-CP cells exhibit resistance to TKIs. Overexpressing BCR-ABL and NUP98-HOXA9 in Evi1-IRES-GFP knock-in mice to model CML in blast crisis (CML-BC), in which Evi1-high cells turned to be a major population as opposed to a minor population in CML-CP models, showed that Evi1-high CML-BC cells have a greater potential to recapitulate the disease and appear resistant to TKIs. Furthermore, given that Evi1 heterozygosity ameliorates CML-CP and CML-BC development and that the combination of Evi1 and BCR-ABL causes acute myeloid leukemia resembling CML-BC, Evi1 could regulate CML development as a potent driver. In addition, in human CML-CP cases, we show that EVI1 is highly expressed in stem cell-enriched CD34+CD38-CD90+ fraction at single-cell level. This is the first report to clarify directly that Evi1-high leukemic cells themselves possess the superior potential to Evi1-low cells in oncogenic self-renewal, which highlights the role of Evi1 as a valuable and a functional marker of CML stem cells.

Dataset Information

Patient-Initiated Discontinuation of Tyrosine Kinase Inhibitor for Chronic Myeloid Leukemia.

Publications

Patient-Initiated Discontinuation of Tyrosine Kinase Inhibitor for Chronic Myeloid Leukemia.

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