Project Details
Projekt
Defining outcome signatures of ALL across age groups and genetic subtypes
Subject Area
Hematology, Oncology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 444949889
Cure rates in children and adolescents suffering from acute lymphoblastic leukemia (ALL) have continuously improved over the last five decades based on the optimization of risk-adapted multi-agent treatment. However, about 10-15% of pediatric patients suffer ALL relapse. Prognosis of patients with relapsed ALL remains limited especially if relapses occur early, and highly intensive chemotherapy is associated with severe toxicity and long-term sequelae. Therefore, further improvement of risk-adapted treatment by optimizing risk stratification as well as modification of therapy considering innovative treatment modalities are required. In contrast, prognosis of adults suffering from ALL has historically been poor with cure rates less than 40% if treated with multi-agent chemotherapy. In recent years, advances in the molecular characterization of ALL, the identification of activated signaling pathways opening the possibility for targeted treatment and the exploration of immunotherapeutic approaches including Chimeric Antigen Receptor T cell (CAR T) therapies lead to an increased rate of molecular remission and improved cure rates in pediatric and adult ALL. To advance our knowledge on the pathogenesis of treatment failure and to identify additional targetable signaling pathways as well as high-risk prognostic markers we will use the unique opportunity of this consortium to investigate high-risk ALL as defined by minimal residual disease (MRD) persistence in adults and children in a joint effort. This project focuses on the characterization of leukemic-intrinsic as well as extrinsic determinants of MRD persistence by defining molecular subtypes and driver alterations of MRD poor responders and by the identification of subtype and treatment response-related immune-signatures in pediatric and adult patients. We will endorse the molecular characterization of adult and pediatric high-risk BCP-ALL to reveal key leukemic alterations across age groups. In-depth investigation of age-dependency and prognosis by analyzing the molecular portrait on the genomic, transcriptomic and epigenomic levels in KMT2A-rearranged ALL including immune signatures, in vivo and in vitro drug response as well as clinical parameters and treatment will be applied. Our findings will be validated in large independent uniformly treated ALL patients’ cohorts and functional validation of potential novel targeted approaches will be explored in PDX models. The definition of new molecular and immunological outcome signatures will allow the upfront identification of high-risk patients and unravel potential targets for age-overriding as well as age-dependent therapeutic interventions including immunotherapies to be integrated in prospective treatment decisions in clinical trials as well as in our clinical translation platform (Z).
DFG Programme
Clinical Research Units
Subproject of
KFO 5010:
CATCH ALL Towards a Cure for Adults and Children with Acute Lymphoblastic Leukemia (ALL)
International Connection
Switzerland
Cooperation Partners
Privatdozent Dr. Beat Bornhauser; Professor Dr. Jean-Pierre Bourquin
