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
Improvement of treatment in children and adolescents with acute lymphoblastic leukemia (ALL) by optimizing risk-adapted chemotherapy as the key to success has reached its limits. This is due to the fact that further treatment intensification is accompanied by an unacceptable increase in toxicity. Moreover, 10–15% of pediatric patients suffer from ALL relapse, and intensive chemotherapy and allogeneic stem cell transplantation are associated with severe toxicity and long-term sequelae. The prognosis of adult patients with ALL treated with pediatric-inspired chemotherapy had been poor, with cure rates less than 40%. This was only in part explained by a lower chemotherapy tolerance and a different subtype distribution between childhood and adult ALL. Meanwhile, immunotherapeutic approaches significantly improved outcomes. Treatment response as assessed by measurable residual disease (MRD) constitutes the strongest predictor of outcome with MRD persistence being associated with high relapse rates in adult and childhood ALL. However, the clinical course of ALL remains heterogeneous even within molecular subtypes and seems to be associated with other factors like mutational burden in oncogenic pathways. Moreover, pharmacogenomics highlights age-related disparities in ALL subtypes across age. Thus, improvement of risk-adapted treatment in pediatric and adult ALL by modifying therapy including innovative, specific, and leukemia-targeting modalities is required. During the first funding period of CATCH ALL in Project P1 we have aggregated the largest age-overriding RNA-Seq data set available and have specifically explored KMT2A-rearranged (KMT2A-r) ALL as a high-risk molecular subtype in infants, children, and adults. Multi-level data integration-based sub-clustering of KMT2A-r B-ALL revealed that not age per se, but the interplay of developmental cell stage, fusion partners, and age contributed to inter-subtype heterogeneity and correlated with drug response and MRD. Here, we successfully established a framework for multi-level data integration in KMT2A-r B-ALL, which enables quantitative analysis of each factor’s contribution to the clinical phenotype and the development of predictive models that integrate molecular and clinical features. This follow-up project will leverage our knowledge of cell-intrinsic and extrinsic determinants of MRD persistence by considering different contributing factors like molecular genetics features, cell of origin/cell of arrest, and lineage involvement within and across additional genetic ALL subtypes of pediatric and adult patients. Exploration of multilevel molecular insights — gained in the first funding period in KMT2A-r ALL— will now be applied to the overall ALL cohort. We will continuously deepen our knowledge and use the unique opportunity of the CATCH ALL consortium to investigate high-risk ALL across age in a joint effort. This will — via molecular-guided therapy – eventually improve treatment outcomes.
DFG Programme
Clinical Research Units
