Short summary

Central nervous system (CNS) involvement in leukemia and non-Hodgkins's lymphoma among children and young adults remains a therapeutic challenge. This research project aims to develop better methods for detection of malignant cells in the spinal fluid and to improve the biological understanding of CNS disease. Such advances would in the future make it possible to stratify CNS-directed treatment according to risk of relapse and to develop less toxic CNS-directed treatments.

Rationale

Owing to treatment advances survival of children and adolescents with acute lymphoblastic lymphoma (ALL) and non-Hodgkin lymphoma (NHL) now exceeds 80%. However, involvement of the central nervous system (CNS) represents a major therapeutic challenge, and patients who develop CNS relapse have a very poor prognosis. Current methods cannot reliably identify patients with CNS involvement or patients at high risk of CNS relapse. Therefore, all children with ALL and NHL receive CNS-directed treatment. This approach is problematic for two reasons: Firstly, in many cases this neurotoxic treatment is unwarranted and the resulting late-effects avoidable. Secondly, despite aggressive CNS-directed treatment 5-10% of patients still relapse in the CNS, suggesting that current treatment is inadequate. The overall aims of the present project are to 1) reduce the rate of CNS relapse in childhood ALL and NHL and 2) reduce CNS-directed treatment in ALL and NHL patients with low risk of CNS relapse. This can be accomplished by devising novel approaches to improve both diagnosis of CNS involvement and CNS-directed treatment. Specifically, in a series of related studies in we will: 1) Assess the prevalence and prognostic significance of CNS involvement determined by CSF flow cytometry 2) Investigate the presence of cell-free circulating tumor DNA (ctDNA) in CSF 3) Identify gene expression and CSF proteome signatures associated with CNS dissemination 4) Study the molecular mechanisms employed by malignant cells for invading the CNS and surviving within the CNS niche 5) Determine the concentration of the monoclonal antibody rituximab in the CSF of NHL patients

Description of the cohort

Children and young adults with ALL (0-45 years) and NHL (0-18 years)

Data and biological material

Biological material: Blood samples and spinal fluid samples. Data categories: Data from clinical trial data registries and patient journal regarding demographics, diagnosis and baseline characteristics, treament response.

Collaborating researchers and departments

Department of Pediatric Hematology and Oncology, H.C. Andersen Children's Hospital, Odense University Hospital, Odense, Denmark

• Peder Wehner

Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark

• Birgitte Klug Albertsen

Section of Pediatric Hematology and Oncology, Aalborg University Hospital, Aalborg, Denmark

• Marianne Olsen

University Hospital Gothenburg, Gothenburg, Sweden

• Karin Mellgren

University Children's Hospital Münster, Münster, Germany

• Birgit Burkhardt

Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

• Christina Halsey

Publications associated with the project

Thastrup M, Marquart HV, Levinsen M, Grell K, Abrahamsson J, Albertsen BK, Frandsen TL, Harila-Saari A, Lähteenmäki PM, Niinimäki R, Pronk CJ, Ulvmoen A, Vaitkevičienė G, Taskinen M and Schmiegelow K on behalf of the Nordic Society of Pediatric Hematology and Oncology (NOPHO). Flow cytometric detection of leukemic blasts in cerebrospinal fluid predicts risk of relapse in childhood acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology study. Leukemia 2020;34(2):336-346. PMID: 31534171.