From the ALFA group
In two recent studies conducted in older and younger AML patients, respectively, and through the integration of more patient/disease-related annotations in the decision-making (including the mutational profiles), the ALFA group proposes significant refinements in the indications of allogeneic HSCT in first remission.
Currently, HSCT indications are based on the European LeukemiaNet (ELN) risk classification, which includes conventional cytogenetics and mutations in the six following genes: NPM1, CEBPA, FLT3, ASXL1, RUNX1 et TP53. In the favorable AML subtypes, like core binding factor (CBF) AML or AML with NPM1 gene mutation, measurable residual disease (MRD) levels after induction and/or consolidation might also be taken into account for this important clinical decision: transplant or not transplant?
In a first paper published in May 2020 in Blood Advances, C. Gardin and coll. studied the incidence and prognostic impact of so-called “secondary AML-like (sAML-like)” mutations, as described by R. Coleman Lindsley and coll. These mutations include not only the ASXL1 gene, but also SRSF2, SF3B1, U2AF1, ZRSR2, EZH2, BCOR et STAG2. Interestingly, this molecular definition allowed classifying as "having a secondary AML” almost half of older AML patients aged 60 years old or more included in the prospective ALFA-1200 study (48% of the entire cohort, 38% of intermediate ELN-risk AML patients), even if only 15% had prior clinically identified hematological disorders. In the intermediate ELN-risk group, the presence of sAML-like gene mutations allowed discriminating a subset of patients almost similar to adverse-risk AML patients in terms of outcome, while those without these mutations had an event-free survival close to that observed in favorable-risk AML patients (Figure A). In terms of overall survival, allogeneic transplantation in first remission benefited to the former subgroup (adverse + intermediate sAML+), while not to the latter subgroup (favorable + intermediate sAML-).
In a more recent publication (Blood Jan 2021) based on the younger AML ALFA-0702 study, L. Fenwarth, R. Itzykson and coll. enriched the ELN-2017 classification through the integration of items from a Knowledge Bank (KB), as published by M. Gerstund and coll. in 2017, as well as NPM1-MRD levels in the subset of patients with NPM1-mutated AML. The important result of this study was that this integration allowed substantially improving the prognostic value of the ELN-2017 classification. The combination of these two scores (ELN-2017 + KB) was associated with an impressive prediction of the effect of allogeneic HSCT in first remission. Even if this new approach requires validation in other future prospective studies, it is amazing to see how transplantation might benefit to 50% of the patients, while being detrimental in the other 50% (Figure B).
The newly created institute Carnot OPALE gathers the most important research and development French teams working in the field of leukemia and related disorders. This makes OPALE the reference partner for all companies developing innovate diagnostic, therapeutic and follow-up tools for patients with these diseases.
Leukemias and related disorders are the more devastating blood cancers. Their incidence is increasing, with 2.3 million people currently suffering from these diseases. They also represent the most frequent childhood cancers.
The institute Carnot OPALE (Organization for Partnership Research in Leukemia) structures all the preclinical and clinical French research forces, with the aim to present a comprehensive R&D offer to industrial companies interested in this medical field. OPALE belongs to the 39 institutes Carnot labeled in February 2020 by the French Ministry for Higher Education, Research and Innovation for a 4-year period of time.
The institute, member of the Institute Carnot Association and the FINDMED consortium, a research partner for medicinal product SME, gathers 17 research teams, 7 cooperative groups and 4 R&D platforms,1 covering the entire R&D chain as well as the medical and industrial valorization processes.
Basic, translational and clinical research fields of OPALE include:
• New therapeutic target discovery
• Innovative drug development, including cell and gene therapies
• Hospital diagnosis and care
• Clinical trials
• Real-world and long-term follow-up
• Startup incubation
With approximately 700 full-time equivalent employees and an annual 7.2 M€ budget of partnership research, the ultimate goal of OPALE is to define new curative, ambulatory, less toxic and financially sustainable treatment options for all patients with leukemia and related disorders during the next 10-year period.
- Cooperative groups for clinical research:
• The Organization for Partnerships in Leukemia (OPALE)
• Acute Leukemia French Association (ALFA),
• Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL),
• French Innovative Leukemia Organization, (FILO),
• Groupe Francophone des Myélodysplasies (GFM),
• French Intergroup Myeloproliferative Disorders (FIM),
• Société Française de Lutte contre les Cancers et Leucémies de l’Enfant et de l'Adolescent (SFCE),
- Research teams:
• Centre National de Médecine de Précision sur les Leucémies THEMA (UMR-944, UMR-1131, UMR-1160, UMR-976, EA-3518, Institut de Recherche Saint-Louis, Université de Paris),
• Centre de Recherche en Cancérologie de Marseille (UMR-1068 ; Institut Paoli-Calmettes, Université Aix-Marseille),
• Centre de Recherche en Cancérologie de Toulouse (UMR-1037 ; Oncopôle, Université de Toulouse III),
• Université de Bourgogne Franche-Comté (UMR-1098 ; Besançon),
• Institut de Radiobiologie Cellulaire et Moléculaire (UMR-1274, CEA Fontenay-aux-Roses),
• Institut IDMIT (UMR-1184 ; CEA Fontenay-aux-Roses),
• Institut Cochin (UMR-1016 ; Université de Paris),
• Gustave Roussy (UMR-1170 ; Université Paris Saclay)
• Centre de Recherche Saint-Antoine (UMR-938 ; Sorbonne Université),
• Centre de Recherche Jean-Pierre Aubert (UMR-1172 ; Université de Lille),
• Centre Méditérranéen de Médecine Moléculaire (INSERM-1065 ; Université Nice Cote d’Azur),
• Université de Bordeaux (UMR-1035),
• Université de Tours (ERL7501 LNOX),
- R&D platforms:
• Plateforme Meary de Thérapie Cellulaire et Génique / CIC-BT (Paris Saint-Louis),
• Plateforme de Thérapie Cellulaire et Génique / CIC-BT (Marseille IPC),
• Plateforme Meary de R&D Génomique et Bioinformatique (Paris Saint-Louis),
Hervé Dombret, M.D./ Professor of Hematology, Institut de Recherche Saint-Louis, Hôpital Saint-Louis (AP-HP), OPALE Chairman
Pascal Deschaseaux, M.D./ OPALE General Director / email@example.com