EPIgenetics and in Vivo Resistance of Chronic Myeloid Leukemia Stem Cells to Tyrosine Kinase Inhibitors

Chronic Myeloid Leukemia (CML) Clinical Trial

— EPIK  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03481868
• Other study ID #: CHU-376
• Secondary ID: 2017-A01332-51
• Status: Recruiting
• Phase: N/A
• Start date: February 1, 2018
• Est. completion date: February 1, 2026

Study information

• Verified date: April 2024
• Source: University Hospital, Clermont-Ferrand
• Contact: Patrick LACARIN
• Phone: 04 73 75 11 95
• Email: placarin[@]chu-clermontferrand.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: February 1, 2026
• Est. primary completion date: May 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Exclusion Criteria:

• Contra-indication to the use of TKI

• Probability of poor compliance during treatment

• Patients already treated for CML

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia (CML)
• Chronic Phase
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Biological:
• 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

Locations

Country	Name	City	State
France	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-Étienne
France	CHU Versailles	Versailles

Sponsors (16)

Lead Sponsor

Collaborator

University Hospital, Clermont-Ferrand

AP-HP Hôpital Henri-Mondor, hematology department, AP-HP, hematology department, Centre Leon Berard, CH Annecy Genevois, CHRU Lille, hematology department, CHU Caen, hematology department, CHU Lyon, hematology department, CHU Nancy, hematology department, CHU Nice, hematology department, CHU Saint-Etienne, hematology department, Institut Bergonié Bordeaux, hematology department, Institut Paoli-Calmettes, Institut Universitaire du Cancer de Toulouse - Oncopole, hematology department, University Hospital, Grenoble, Versailles Hospital

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Epigenetic dysregulations of in vivo TKI-resisting CML cells	Epigenetic and/or gene expression anomalies in in vivo TKI-selected CML cells for 3 months in comparison with anomalies identified at D0	at Day 0 and Month3
Secondary	relationship between epigenetic/gene expression profile and CML burden (M3)	Ratio BCR-ABL/ABL in bone marrow	at Month 3
Secondary	relationship between epigenetic/gene expression profile and the characteristics of patients	Sokal / EUTOS	at Day 0 and Month 3
Secondary	early new biomarkers	To identify in primary CML clones the shared epigenetic marks and/or deregulated genes of 3 months TKI-resistant cells and their relationship with CML burden at M3	at Day 0 and Month 3