Early diagnosis and molecular-based treatment of very highly resistant acute lymphoblastic leukemia in childhood

Coordinator:    Prof. Dr. Martin Schrappe
Institution: Klinik für Allgemeine Pädiatrie
Childhood acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood and, nowadays - as a result of prolonged and well-organized research efforts - can be successfully treated in about 80% of patients. Treatment consists of intensive combination chemotherapy regimens, which in specific patient subgroups may need to be supplemented with radiation therapy and/or hematopoietic stem cell transplantation (HSCT). Unfortunately, childhood ALL refractory to current treatment approaches remains a challenging therapeutic problem in clinical pediatric oncology. During the last years, we conducted detailed investigations of the reduction of the leukemic cell burden in the body in response to the initially applied chemotherapy by a sensitive molecular technique called minimal residual disease (MRD) analysis. Through these studies, we are currently able to identify a group of childhood ALL patients (very high risk leukemia, VHRL) which is characterized by molecular persistance of leukemic cells on a high level throughout conventional treatment, even if intensified therapy is applied. Adding HSCT could not yet improve the poor prognosis of these VHRL patients. In the project presented here, we aim at 1) developing and establishing a scheme for early identification/diagnosis of these VHRL patients; 2) identification and characterization of individual treatment targets/pathways; 3) validation of these treatment strategies by using off-patient preclinical model systems; and 4), developing novel targeted treatment strategies for clinical application in VHRL patients. For several reasons, early identification of these patients is essential for the development of more efficacious therapies: 1) there is a large number of targeted therapies in clinical development but only a relatively small number of eligible patients could be identified so far; 2) one has to minimize unnecessary adjuvant therapy for those not in need of it; and 3) one should be able to utilize optimized therapy already in the first treatment cycles. Therefore, early identification of refractory ALL patients including their molecular characterization will allow timely introduction of specifically targeted treatment based on individual molecular characteristics of leukemic cells. More generally spoken, our project aims at translating comprehensive genome-wide collected molecular information into clinical application in order to generate valuable patient-oriented output for children with ALL.
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