Detail Article

Informations générales (source: ClinicalTrials.gov)

Numéro NCT

NCT03481868 Statut inconnu

Titre

Collection of Biological Resources During Medical Care of Patients With Chronic Myeloid Leukemia (CML) in Chronic Phase for an Epigenetic Study of Leukemic Stem Cells

Type

Interventional

Pathologie

Leucémies
Leucémie myéloïde
Leucémie myéloïde chronique BCR-ABL positive

Phase

N/A

Promoteur

University Hospital, Clermont-Ferrand (Voir sur ClinicalTrials)

Date de début

février 2018

Date de fin

février 2026

Dernière mise à jour

30 avril 2026

Résumé

Primary objective : To identify epigenetic dysregulations of in vivo TKI-resisting CML cells Hypothesis : An epigenetic dysregulation is involved in the in vivo survival of a CML cell subclone despite the use of TKIs

Détail

Voir le détail Chronic myeloid leukemia (CML) is a model of leukemogenesis because the malignant transformation of a hematopoietic stem cell is considered as the consequence of a unique major event: the translocation t(9;22) which is able to produce the BCR-ABL chimeric protein. The treatment of CML has made considerable progress with the development of tyrosine kinase inhibitors (TKI) targeting the BCR-ABL protein activity. Despite the efficacy of these drugs, several studies showed the existence of intra-clonal heterogeneity and the in vivo survival of a leukemic stem cell (LSC) subset by: - 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. Fermer le détail

Etablissements

Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données
AP-HP - Hôpital Henri Mondor-Albert Chenevier		En recrutement IDF	Contact (sur clinicalTrials)
AP-HP - Hôpital Paul Brousse		En recrutement IDF	Contact (sur clinicalTrials)
CH DE VERSAILLES SITE ANDRE MIGNOT		En recrutement IDF	Contact (sur clinicalTrials)
Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données
Centre Léon Bérard - Lyon - France		En recrutement	Contact (sur clinicalTrials)
CHU Annecy-Genevois - Annecy - France		En recrutement	Contact (sur clinicalTrials)
CHU Caen - Caen - France		En recrutement	Contact (sur clinicalTrials)
CHU Clermont-Ferrand - 63003 - Clermont-Ferrand - France	Patrick LACARIN	En recrutement	Contact (sur clinicalTrials)
CHU Grenoble Alpes - Grenoble - France		En recrutement	Contact (sur clinicalTrials)
CHU Lille - Lille - France		En recrutement	Contact (sur clinicalTrials)
CHU Nancy - Nancy - France		En recrutement	Contact (sur clinicalTrials)
CHU Nice - Nice - France		En recrutement	Contact (sur clinicalTrials)
CHU Saint-Etienne - Saint-Étienne - France		En recrutement	Contact (sur clinicalTrials)
Hôpital Bicêtre - Paris - France		En recrutement	Contact (sur clinicalTrials)
Hôpital Saint Louis - Paris - France		En recrutement	Contact (sur clinicalTrials)
Hospices Civils de Lyon - Lyon - France		En recrutement	Contact (sur clinicalTrials)
Institut Bergonié - Bordeaux - France		En recrutement	Contact (sur clinicalTrials)

Critères

Genre

Tous

Nombre d'inclusion

Critère d'inclusion

Inclusion Criteria:

- Patient newly diagnosed for Chronic Myeloid Leukemia in chronic phase

- 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

Critère de non inclusion

- Contra-indication to the use of TKI

- Probability of poor compliance during treatment

- Patients already treated for CML

NCT03481868 - Collection of Biological Resources During Medical Care of Patients With Chronic Myeloid Leukemia (CML) in Chronic Phase for an Epigenetic Study of Leukemic Stem Cells

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