EPIgenetics and in Vivo Resistance of Chronic Myeloid Leukemia Stem Cells to Tyrosine Kinase Inhibitors
NCT ID: NCT03481868
Last Updated: 2024-04-09
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
NA
160 participants
INTERVENTIONAL
2018-02-01
2026-02-01
Brief Summary
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Detailed Description
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* A detectable residual disease in the majority of cases, and after treatment for several years.
* The relapse of about half of patients after stopping TKI; these relapses are the proof of the in vivo persistence of LSC, even when CML clone is particularly sensitive to TKI.
* Cases of unexplained TKI resistance (no BCR-ABL mutation etc…)
The mechanisms involved in in vivo survival of LSC remain largely unknown. Mechanisms independent of BCR-ABL TK activity could be responsible of LSC survival. However, the fact that CML is the consequence of t(9; 22) if it appears in a HSC, suggests that a stem cell specific biological status should play a role in the emergence of the disease and probably the special feature of this cell subset. Several studies showed the essential role of epigenetic factors in stem cell behavior (quiescence, self-renewal, or differentiation process). Epigenetic dysregulation of some gene expression was observed in CML cells and changes in DNA methylation are involved in CML progression towards accelerated or blast phase, more resistant to TKIs. These observations led to clinical trial combining TKI with epigenetic drugs which results confirmed the in vivo involvement of epigenetic mechanisms during CML progression. However, the role of epigenetics in the early resistance of a chronic phase CML cell subset remains unknown.
The hypothesis is that epigenetic features could participate in TKI resistance of CML LSC and their survival in bone marrow.
In order to identify new mechanisms and/or new targets involved in LSC resistance, investigator choose a global approach of DNA methylation profile with an HM450K microarray. Investigator analyzed the sorted CML CD34+ CD15- cell subset (n=6) in comparison with: 1) CD34+ CD15- cells from healthy donors (hematopoietic grafts), in order to eliminate specificities of normal hematopoietic hierarchy, 2) the CD34-CD15+ sub-clone from the CML clone before any treatment in order to eliminate characteristic of CML mature compartment. The CD34+CD15- cells showed a specific DNA methylation profile, from diagnosis and from this level of cell hierarchy ((Bourgne et al., oral communication, SFH meeting 2017, manuscript submitted). In order to identify biomarkers specific to CML cells, investigator removed abnormally methylated regions that are differently methylated during hematopoietic differentiation. After this step, 825, 2210 and 1461 probes identified regions specifically dysmethylated in CD34-CD15+, CD34+ CD15- CML cells and both respectively. Investigator also observed changes in expression of epigenetic actors. These results validate our hypothesis. With the recent data published in literature, they strongly argue in favor of the involvement of epigenetic dysregulation in native intra-clonal heterogeneity, and justify this original translational research project.
Conditions
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Study Design
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NA
SINGLE_GROUP
OTHER
NONE
Study Groups
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Chronic Myeloid Leukemia
Patients newly diagnosed for Chronic Myeloid Leukemia, according to inclusion and exclusion criteria
Collection of blood and bone marrow
Collection of blood and bone marrow in order to identify epigenetic abnormalities and their consequences in surviving CML cells after 3 months of TKI treatment
Interventions
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Collection of blood and bone marrow
Collection of blood and bone marrow in order to identify epigenetic abnormalities and their consequences in surviving CML cells after 3 months of TKI treatment
Eligibility Criteria
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Inclusion Criteria
* Patient older than 18 years old
* Patient who received no treatment for CML at the time of sampling on D0
* Intention of prescription with first-line treatment with TKI only
* Choice of first-line CML treatment by TKI only
* Patient having signed an informed consent
* Patient with a social security system
Exclusion Criteria
* Probability of poor compliance during treatment
* Patients already treated for CML
18 Years
ALL
No
Sponsors
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Institut Paoli-Calmettes
OTHER
CHRU Lille, hematology department
UNKNOWN
CH Annecy Genevois
OTHER
Institut Bergonié Bordeaux, hematology department
UNKNOWN
Central Hospital, Nancy, France
OTHER
CHU Saint-Etienne, hematology department
UNKNOWN
Institut Universitaire du Cancer de Toulouse
OTHER
CHU Caen, hematology department
UNKNOWN
CHU Nice, hematology department
UNKNOWN
Hospices Civils de Lyon
OTHER
AP-HP, hematology department
UNKNOWN
AP-HP Hôpital Henri-Mondor, hematology department
UNKNOWN
Versailles Hospital
OTHER
Centre Leon Berard
OTHER
University Hospital, Grenoble
OTHER
University Hospital, Clermont-Ferrand
OTHER
Responsible Party
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Principal Investigators
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Marc BERGER
Role: PRINCIPAL_INVESTIGATOR
University Hospital, Clermont-Ferrand
Locations
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CHU Annecy-Genevois
Annecy, , France
Institut Bergonié
Bordeaux, , France
CHU Caen
Caen, , France
CHU Clermont-Ferrand
Clermont-Ferrand, , France
CHU Grenoble Alpes
Grenoble, , France
CHU Lille
Lille, , France
Centre Léon Bérard
Lyon, , France
Hospices Civils de Lyon
Lyon, , France
CHU Nancy
Nancy, , France
CHU Nice
Nice, , France
Hôpital Bicêtre
Paris, , France
Hôpital Henri Mondor
Paris, , France
Hôpital Paul Brousse
Paris, , France
Hôpital Saint Louis
Paris, , France
CHU Saint-Etienne
Saint-Etienne, , France
CHU Versailles
Versailles, , France
Countries
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Central Contacts
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Facility Contacts
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Other Identifiers
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2017-A01332-51
Identifier Type: OTHER
Identifier Source: secondary_id
CHU-376
Identifier Type: -
Identifier Source: org_study_id
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