Cegal Protocol : Evaluation of the Feasibility of a Chemogenomic Approach to Identify Personalized Therapy for Relapse or Refractory AML Patients

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.1401-1401
• Main Authors: Vey, Norbert, Hospital, Marie Anne, Collignon, Aude, Collette, Yves, Birnbaum, Daniel, Charbonnier, Aude, Mohty, Bilal, D'Incan, Evelyne, Rey, Jerome, Castellano, Remy, Montersino, Camille, Chaffanet, Max, Carbuccia, Nadine, Adelaide, Jose, Bouchacourt, Benjamin, Guille, Arnaud
• Format: Article
• Language: English
• Subjects: Life Sciences
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-119263

Introduction : Significant improvements of leukemia free survival have been obtained over the last 30 years in AML. This progress has resulted from optimization of the same chemotherapy-based “one-size-fits-all” approach. However, even though the majority of patients eligible for intensive chemotherapy achieve complete remission (60% to 80%), the majority still relapse and ultimately die (5-year overall survival being around 20%). Recent genomic studies have revealed the heterogeneity of AML at the molecular level, stressing the need for personalized therapeutic approaches. The fundamental idea in genomic medicine is that somatic genetic alterations can be identified and matched with drugs targeting those abnormalities for a patient's benefit. However, there are not that many potent, tolerated targeted agents in the clinic that can induce significant clinical responses. Interestingly, the majority of the most effective drugs do not function by exploiting genetic mutations in individual tumors. Thus, additional functional approaches are needed to identify new drugs and assign existing drugs to larger numbers of patients with AML.From this perspective, the“chemogenomic” approach realizes an integratedanalysis of the molecular clonal abnormalities for the leukemic patients, and compares it to a functional drug sensitivity testing (DST) which can test simultaneously dozens of drugsex vivo. This approach aims to identify correlations between genomic changes and sensibilities increased in certain categories of drugs. The CEGAL project is a prospectivemonocentric study aiming to evaluate the feasibility of this personalized approach for relapse or refractory AML patientsby determining the proportion of patients whosechemogenomic results are available in less than 21 days. Methods : Patients with relapsed and/or refractory AML were eligible if no alternative therapy was available. Written consent was obtained from all patients (Study CeGAL-IPC 2014-012, EUDRACT 2014-A01209-38). Ex vivo sensitivity profiling was performed on freshly isolated AML blasts derived from patient bone marrow aspirates and peripheral blood with a panel of 78 drugs representative of the main therapeutic classeskwown to be active in AML. After 48h of incubation, cellular viability was measured with the CellTiter-Glo© Luminescent cell viability assay (Promega) kit to obtain one EC50. Next generation sequencing (NGS) was performed on a 200 genes panel with Mi-Seq (Illumina) and genomic profils