Clinical trial NCT03481868: EPIgenetics and in Vivo Resistance of Chronic Myeloid Leukemia Stem Cells to Tyrosine Kinase Inhibitors
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Chronic Myeloid Leukemia (CML)
Chronic Phase
Keywords: chronic myeloid leukemia
epigenetic
leukemic stem cell
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
Collaborators: name: Institut Paoli-Calmettes
name: CHRU Lille, hematology department
name: CH Annecy Genevois
name: Institut Bergonié Bordeaux, hematology department
name: Central Hospital, Nancy, France
name: CHU Saint-Etienne, hematology department
name: Institut Universitaire du Cancer de Toulouse
name: CHU Caen, hematology department
name: CHU Nice, hematology department
name: Hospices Civils de Lyon
name: AP-HP, hematology department
name: AP-HP Hôpital Henri-Mondor, hematology department
name: Versailles Hospital
name: Centre Leon Berard
name: University Hospital, Grenoble
First posted: 2018-03-29
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief 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

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Epigenetic dysregulations of in vivo TKI-resisting CML cells
timeFrame: at Day 0 and Month3
Secondary outcomes:
measure: relationship between epigenetic/gene expression profile and CML burden (M3)
timeFrame: at Month 3
measure: relationship between epigenetic/gene expression profile and the characteristics of patients
timeFrame: at Day 0 and Month 3
measure: early new biomarkers
timeFrame: at Day 0 and Month 3
Other outcomes:
Locations:
city: Annecy
country: France
facility: CHU Annecy-Genevois
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: CHU Caen
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
city: Grenoble
country: France
facility: CHU Grenoble Alpes
city: Lille
country: France
facility: CHU Lille
city: Lyon
country: France
facility: Centre Léon Bérard
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Nancy
country: France
facility: CHU Nancy
city: Nice
country: France
facility: CHU Nice
city: Paris
country: France
facility: Hôpital Bicêtre
city: Paris
country: France
facility: Hôpital Henri Mondor
city: Paris
country: France
facility: Hôpital Paul Brousse
city: Paris
country: France
facility: Hôpital Saint Louis
city: Saint-Étienne
country: France
facility: CHU Saint-Etienne
city: Versailles
country: France
facility: CHU Versailles
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Marc BERGER
role: PRINCIPAL_INVESTIGATOR
References: