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Dynamics of Resistance Emergence to Azacitidine-based Therapies in Acute Myeloid Leukemia

NCT06225128 · Status: RECRUITING · Type: OBSERVATIONAL · Enrollment: 120

Last updated 2024-05-29

No results posted yet for this study

Summary

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

Interventions

OTHER

Biobanking blood

Additional volume of 30mL (EDTA) At Screening, pre-Cycle 1 Day 1,Day 1 H8, Day 2, Day of post-cycle 1 and post-cycle 6 evaluation.

OTHER

Bone marrow specimens

Additional volume of 2mL (EDTA) * at screening for correlative studies,at Day 7 for smears and for correlative studies. * Post-cycle 1 and post-cycle 6 evaluations for correlative studies. Optionnal : Trephine biopsy at screening and at post-cycle 1 and 6 evaluations (performed at the same time as aspiration)

Sponsors & Collaborators

  • Assistance Publique - Hôpitaux de Paris

    lead OTHER

Eligibility

Min Age
18 Years
Max Age
100 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2024-01-16
Primary Completion
2027-06-19
Completion
2027-06-19

Countries

  • France

Study Locations

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Entities

Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT06225128 on ClinicalTrials.gov