Discontinuation of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia: a Review of the Biological Factors Associated with Treatment-Free Remission

Stuckey, Ruth; Rodríguez, Juan Francisco López; Gómez‐Casares, María Teresa

doi:10.1007/s11912-022-01228-w

Cited by 8 publications

(6 citation statements)

References 95 publications

(98 reference statements)

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“…1 However, ongoing lifelong treatment with TKIs can significantly reduce quality of life, lead to offtarget effects, such as life-threatening cardiovascular TherapeuTic advances in hematology or liver toxicity, and represent a significant financial burden. 2,3 Therefore, successful treatmentfree remission (TFR) has become a new therapeutic goal, and large, prospective data has shown encouraging results. In the Stop Imatinib (STIM) study, molecular recurrence-free survival (RFS) at 60 months was 38% [95% confidence interval (CI): 29-47%] with no disease progression among patients in whom BCR::ABL1 transcripts were not detected for >2 years.…”

Section: Introductionmentioning

confidence: 99%

Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor

Park,

Kim,

Sohn

et al. 2023

Therapeutic Advances in Hematology

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Background: Droplet digital polymerase chain reaction (ddPCR) is an exact method of measurement. Objectives: We conducted this study to identify the prognostic factors for successful treatment-free remission in patients with chronic-phase chronic myeloid leukemia who discontinued tyrosine kinase inhibitors (TKIs). We also aimed to validate ddPCR for predicting molecular relapse. Design: This is a prospective, multicenter study. Methods: We enrolled patients treated with TKIs for at least 3 years with a confirmed sustained deep molecular response (DMR) for at least 1 year. TKI was re-administered in patients who experienced the loss of major molecular response (MMR). Results: A total of 66 patients from five institutions in South Korea were enrolled. During a median follow-up period of 16.5 months, 29/66 (43.9%) patients experienced molecular relapse; the probability of molecular relapse-free survival (RFS) at 6 or 12 months after TKI discontinuation was 65.6% or 57.8%, respectively, with most molecular relapses occurring within the first 7 months. All patients who lost MMR were re-treated with TKI, and all re-achieved MMR at a median of 2.8 months. E14a2 transcript type ( p = 0.005) and longer DMR duration (⩾48 months) prior to TKI discontinuation ( p = 0.002) were associated with prolonged molecular RFS and with sustained DMR. Patients with both e13a2 transcript type and detectable BCR::ABL1 (⩾MR5.0) by ddPCR at the time of TKI discontinuation showed shorter duration of molecular RFS ( p = 0.015). Conclusion: Our data suggest that transcript type and BCR::ABL1 transcript levels on ddPCR should be taken into consideration when deciding whether to discontinue TKI therapy.

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Section: Introductionmentioning

confidence: 99%

Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor

Park,

Kim,

Sohn

et al. 2023

Therapeutic Advances in Hematology

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“…51,136,137 Other possible markers include regulatory T cells, cytotoxic CD8+ T lymphocyte (CTL), and somatic mutations. 134,[138][139][140] Type of BCR-ABL1 transcript also has a role; in a study by D'Adda et al, TFR maintenance was observed to be higher in CML patients with e14a2 transcript when compared with e13a2 transcripts. 141 However, all of these biomarkers are not readily available for routine clinical use, and thus, clinical parameters remain the most widely used or accessible parameters for TFR.…”

Section: Predictors and Biomarkers For Tfrmentioning

confidence: 99%

Chronic Myeloid Leukemia, from Pathophysiology to Treatment-Free Remission: A Narrative Literature Review

Rinaldi¹,

Winston²

2023

JBM

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Chronic myeloid leukemia (CML) is one of the most common leukemias occurring in the adult population. The course of CML is divided into three phases: the chronic phase, the acceleration phase, and the blast phase. Pathophysiology of CML revolves around Philadelphia chromosome that constitutively activate tyrosine kinase through BCR-ABL1 oncoprotein. In the era of tyrosine kinase inhibitors (TKIs), CML patients now have a similar life expectancy to people without CML, and it is now very rare for CML patients to progress to the blast phase. Only a small proportion of CML patients have resistance to TKI, caused by BCR-ABL1 point mutations. CML patients with TKI resistance should be treated with second or third generation TKI, depending on the BCR-ABL1 mutation. Recently, many studies have shown that it is possible for CML patients who achieve a long-term deep molecular response to stop TKIs treatment and maintain remission. This review aimed to provide an overview of CML, including its pathophysiology, clinical manifestations, the role of stem cells, CML treatments, and treatment-free remission.

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“…These hallmarks may be useful as prognostic biomarkers of longer TFR [ 67 ]. Further clinical trials are needed to test these predicting biomarkers for TFR [ 69 ]. Moreover, the memory-like NK cells, characterized as CD3 − CD56 dim CD57 + NKG2A − NKG2C + , were increased in patients with TFR success [ 70 ].…”

Section: Dasatinib-mediated Immunomodulatory Effects In CMLmentioning

confidence: 99%

Immunomodulatory Activity of the Tyrosine Kinase Inhibitor Dasatinib to Elicit NK Cytotoxicity against Cancer, HIV Infection and Aging

et al. 2023

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Tyrosine kinase inhibitors (TKIs) have been extensively used as a treatment for chronic myeloid leukemia (CML). Dasatinib is a broad-spectrum TKI with off-target effects that give it an immunomodulatory capacity resulting in increased innate immune responses against cancerous cells and viral infected cells. Several studies reported that dasatinib expanded memory-like natural killer (NK) cells and γδ T cells that have been related with increased control of CML after treatment withdrawal. In the HIV infection setting, these innate cells are associated with virus control and protection, suggesting that dasatinib could have a potential role in improving both the CML and HIV outcomes. Moreover, dasatinib could also directly induce apoptosis of senescence cells, being a new potential senolytic drug. Here, we review in depth the current knowledge of virological and immunogenetic factors associated with the development of powerful cytotoxic responses associated with this drug. Besides, we will discuss the potential therapeutic role against CML, HIV infection and aging.

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Discontinuation of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia: a Review of the Biological Factors Associated with Treatment-Free Remission

Cited by 8 publications

References 95 publications

Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor

Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor

Chronic Myeloid Leukemia, from Pathophysiology to Treatment-Free Remission: A Narrative Literature Review

Immunomodulatory Activity of the Tyrosine Kinase Inhibitor Dasatinib to Elicit NK Cytotoxicity against Cancer, HIV Infection and Aging

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