Actively Recruiting
Dynamics of Resistance Emergence to Azacitidine-based Therapies in Acute Myeloid Leukemia
Led by Assistance Publique - Hôpitaux de Paris · Updated on 2024-05-29
120
Participants Needed
1
Research Sites
178 weeks
Total Duration
On this page
AI-Summary
What this Trial Is About
Acute myeloid leukemia (AML) is a malignancy of aging endowed with poor prognosis. The combination of the hypomethylating agent azacitidine (AZA) with the BCL-2 inhibitor venetoclax (VEN) is the first-line treatment of older AML patients but is endowed with substantial resistance. The project leverages functional precision oncology, single-cell studies and mouse experiments to dissect the mechanisms of primary and adaptive resistance to AZA/VEN. The primary objective is to prospectively validate an ex vivo drug sensitivity testing (DST) assay as predictor of primary resistance to first-line AZA/VEN in 100 unfit AML patients. The study will also explore whether newer DST assays with enhanced niche mimicry can improve on the standard assay. By serially interrogating the short-term fate of both leukemic and immune cells upon AZA/VEN exposure in patients primed towards refractoriness, transient or prolonged remission, the aim is to dissect the cell-intrinsic and immune-mediated mechanisms of primary versus adaptive resistance. A parallel flow cytometry study will interrogate the role of senescence in AZA/VEN activity. These translational studies will be mirrored by experiments in a transplantable AML model derived from syngeneic mice harboring the age-related Tet2-/- leukemia-predisposing genotype. Lineage tracing single-cell experiments will backtrack AZA/VEN resistance to determine whether it is driven by selection or adaptation. The actionable stress sensor Pml will be invalidated in the same model to determine whether Pml-driven senescence contributes to AZA/VEN anti-leukemic activity in vivo. The project will pave the way to the clinical implementation of functional precision oncology in a high-risk malignancy. By simultaneously interrogating cell-intrinsic and immune-mediated drug resistance in vivo in a prospective patient cohort mirrored by controlled mice experiments, the project will provide a framework for the integrative analysis of drug resistance in cancers.
CONDITIONS
Official Title
Dynamics of Resistance Emergence to Azacitidine-based Therapies in Acute Myeloid Leukemia
Who Can Participate
Eligibility Criteria
You may qualify if you...
- Be 18 years old or older
- Have a newly diagnosed acute myeloid leukemia (AML) according to ICC 2022 criteria
- Patients with AML related to prior chemotherapy or radiotherapy for another cancer are eligible
- Patients with MDS/AML according to ICC 2022 criteria are eligible
- Have signed the informed consent form of the eTHEMA observatory trial
- Have at least 10% blasts in bone marrow smear at screening
- Have not received any treatment for AML except for hydroxyurea and/or steroids
- Be eligible for azacitidine and venetoclax (AZA/VEN) or azacitidine and ivosidenib (AZA/IVO) therapy based on general health
- Have an ECOG performance status of 2 or less
- Be planned to receive AZA/VEN or AZA/IVO as frontline therapy
- Weigh at least 40 kg
- Have provided written informed consent before any screening procedures
You will not qualify if you...
- Have suspected or proven acute promyelocytic leukemia (APL) including non-PML::RARA rearrangements
- Have suspected or proven AML with t(9;22)(q34.1;q11.2)/BCR::ABL1
- Have myeloid sarcoma
- Have failed to perform bone marrow aspiration at screening
- Have received previous AML therapy with investigational agents or cytotoxic drugs within 28 days before treatment (except hydroxyurea)
- Are pregnant or breastfeeding (for women)
- Have any severe or uncontrolled medical condition that could affect study participation
- Are enrolled in another clinical trial that could affect participation
AI-Screening
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Trial Site Locations
Total: 1 location
1
Hôpital Saint Louis
Paris, France
Actively Recruiting
Research Team
R
Raphael Itzykson, Pr
CONTACT
J
Jérôme Lambert, Pr
CONTACT
How is the study designed?
Study Type
OBSERVATIONAL
Masking
N/A
Allocation
N/A
Model
N/A
Primary Purpose
N/A
Number of Arms
1
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