De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial

Clark, Richard E.; Polydoros, Fotios; Apperley, Jane F.; Milojković, Dragana; Rothwell, K.; Pocock, Christopher; Byrne, Jennifer; Lavallade, Hugues de; Osborne, Wendy; Robinson, Lisa J.; O’Brien, Stephen G.; Read, Lucy; Foroni, Letizia; Copland, Mhairi

doi:10.1016/s2352-3026(19)30094-8

Cited by 148 publications

(182 citation statements)

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“…Informed consent was obtained in accordance with the Declaration of Helsinki and with approval from Greater Glasgow and Clyde NHS Trust Ethics Committee. BM samples from trial entry of the DESTINY clinical trial (NCT01804985) [19] were utilized to assess cell populations in patients with/without molecular recurrence on TKI discontinuation. Sample details are listed in Table S1.…”

Section: Human Samplesmentioning

confidence: 99%

“…BM samples of patients in MR4 (BCR-ABL1:ABL1 ratio of <0.01%), taken at entry into the DESTINY clinical trial (NCT01804985) [19], who either remained in MMR or better for at least 3 years (n = 4) or developed molecular recurrence (n = 4) after TKI discontinuation were thawed and cultured as previously described. Samples were sorted into LSC-CD93 − and LSC-CD93 + populations.…”

Section: Cd93 + But Not Cd93 − Cp-cml Cells Have Stem Cell Characmentioning

confidence: 99%

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CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

et al. 2020

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The introduction of BCR-ABL tyrosine kinase inhibitors has revolutionized the treatment of chronic myeloid leukemia (CML). A major clinical aim remains the identification and elimination of low-level disease persistence, termed "minimal residual disease". The phenomenon of disease persistence suggests that despite targeted therapeutic approaches, BCR-ABLindependent mechanisms exist which sustain the survival of leukemic stem cells (LSCs). Although other markers of a primitive CML LSC population have been identified in the preclinical setting, only CD26 appears to offer clinical utility. Here we demonstrate consistent and selective expression of CD93 on a lin − CD34 + CD38 − CD90 + CML LSC population and show in vitro and in vivo data to suggest increased stem cell characteristics, as well as robust engraftment in patient-derived xenograft models in comparison with a CD93 − CML stem/progenitor cell population, which fails to engraft. Through bulk and single-cell analyses of selected stem cell and cell survival-specific genes, we confirmed the quiescent character and demonstrate their persistence in a population of CML patient samples who demonstrate molecular relapse on TKI withdrawal. Taken together, our results identify that CD93 is consistently and selectively expressed on a lin − CD34 + CD38 − CD90 + CML LSC population with stem cell characteristics and may be an important indicator in determining poor TKI responders.

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Section: Human Samplesmentioning

confidence: 99%

Section: Cd93 + But Not Cd93 − Cp-cml Cells Have Stem Cell Characmentioning

confidence: 99%

CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

et al. 2020

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“…Since April 2019, two new studies have been published (Clark et al , ; Devos et al , ). We did not access the full text of one of them.…”

Section: Discussionmentioning

confidence: 99%

“…The other one tested de‐escalation of TKI therapy before treatment discontinuation. This strategy seems to improve MRFS up to 72% in patients in MR4 (Clark et al , ).…”

Section: Discussionmentioning

confidence: 99%

Risk of molecular recurrence after tyrosine kinase inhibitor discontinuation in chronic myeloid leukaemia patients: a systematic review of literature with a meta‐analysis of studies over the last ten years

et al. 2020

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More than 10 years ago, the first pilot observational study of imatinib discontinuation was reported in chronic myeloid leukaemia (CML) patients in deep molecular response (DMR). Several studies have been published since then, in patients treated with frontline imatinib, or second-generation tyrosine kinase inhibitors (TKI) in first or second line but also on second attempt of TKI discontinuation. Our objective was to estimate, through meta-analyses of the literature data, the probability of molecular recurrence (MolRec) in the time periods of 0-6, 6-12, 12-18 and 18-24 months after a first and second TKI discontinuation and the probability of re-acquisition of DMR after MolRec. The Medline and Scopus databases were searched up to April 2019. The studies were selected by three independent reviewers. Random-effect meta-analyses were conducted using the MetaXL software. The probability of MolRec in the time periods 0-6, 6-12, 12-18 and 18-24 months after the first attempt was respectively 35%, 8%, 3% and 3%, whereas the probability of MolRec in the time periods 0-6, 6-12 and 12-18 after the second attempt was 48%, 27% and 12% respectively. Re-acquisition of a DMR was observed in 90% of patients. Most of the MolRec occur during the first six months in case of a first attempt, whereas the second MolRec occurs over a larger window of time.Keywords: meta-analysis, chronic myeloid leukemia, tyrosine kinase inhibitors discontinuation, first and second attempt. Recently, second attempts to discontinue TKI in patients who relapsed have been reported (Legros et al.

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“…Furthermore, in those patients who have switched TKI due to intolerance, TFR rates are comparable to those patients who received only a single agent, provided criteria regarding molecular response and other features are met and are superior to those patients previously experiencing resistance to their first-line TKI [16]. A further intriguing development is the de-escalation of TKI prior to cessation, recently demonstrated to improve the success of TFR protocols though the mechanism of this benefit is not yet clear [22].…”

Section: Discussionmentioning

confidence: 99%

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

Langabeer

Faryal

O’Dwyer

et al. 2020

Case Reports in Hematology

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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.

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De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial

Cited by 148 publications

References 21 publications

CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy

Risk of molecular recurrence after tyrosine kinase inhibitor discontinuation in chronic myeloid leukaemia patients: a systematic review of literature with a meta‐analysis of studies over the last ten years

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

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