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The detailed molecular and cellular mechanisms underpinning the clinical activity of most chemotherapies in cancers remain incompletely understood. Understanding how these drugs really act is a prerequisite for their rational therapeutic optimization.
Recent observations suggest that early molecular and cellular changes in cancer cells upon chemotherapy exposure may dictate their long-term fate.
We aim to address this question in previously untreated adult Acute Myeloid Leukemia (AML) patients treated with anthracycline/cytarabine association (either as free drugs, '7+3' regimen, or in liposomal formulation, CPX-351) by sequentially sampling peripheral blood during the first course of therapy, and by performing an early bone marrow reassessment. We will apply single cell RNA sequencing and multiparameter flow cytometry to correlate dynamic phenotypic landscapes with clinical outcomes (remission achievement and relapse-free survival).
The study will be carried in two phases. First, a feasibility phase will be carried in the first 20 patients irrespective of the genetic make-up of their leukemic cells to identify the optimal pre-analytical conditions for single-cell transcriptional profiling.
Second, an expansion phase will be carried focusing on two genetically subsets of patients chosen on the basis of their relative abundance and variability of clinical outcome, namely NPM1c-mutated AML (30% of patients, 60% cure rate) and NPM1-wildtype intermediate-risk AML (25% of patients, 40% cure rate), to correlate single-cell fates with remission and with long-term remission-free survival.
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Inclusion criteria
aged ≥18 years old,
have a newly diagnosed AML according to WHO criteria
o patients with AML related to prior chemotherapy or radiotherapy for another cancer will be eligible,
have signed the informed consent form of the e-THEMA observatory trial
have ≥10% blasts (blasts+myeloblasts) on the peripheral blood smear at screening,
have ≥20% blasts on the bone marrow smear at screening,
have not received any treatment for AML except for hydroxyurea and/or 6-mercaptopurine and steroids
o Patients having previous treatments for antecedent myeloid neoplasms including hypomethylating agents remain eligible,
Eligible to intensive chemotherapy, due to general health status,
ECOG performance status ≤ 2,
Patient is planned to receive anthracycline (daunorubicin [DNR] or idarubicine [IDA]) - cytarabine 7+3 with or without gemtuzumab ozogamycin (GO) or midostaurine, or CPX-351 as first induction course,
Weighing 50 kg or more (compliance to Loi Jardé for PB sampling),
Written informed consent obtained prior to any screening procedures,
Eligible for National Health Insurance in France.
Exclusion criteria
200 participants in 1 patient group
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Central trial contact
Raphael ITZYKSON; Matthieu Resche-Rigon
Data sourced from clinicaltrials.gov
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