The IGF-system and the prediction of event risk in children with acute lymphoblastic leukemia.

P Vorwerk MD^a, K Mohnike MD PhD^a, H Wex PhD^a, FR Röhl PhD^b, M Zimmermann PhD^c, WF Blum MD PhD^d, U Mittler MD PhD^a

^aDept. Pediatric Oncology, University Otto von Guericke, Magdeburg, Germany, ^bInstitute of Biometrics and Medical Informatics, University Otto von Guericke, Magdeburg, Germany, ^cDept. Pediatric Oncology, Hannover Medical School, Germany, ^dLilly Germany GmbH, Bad Homburg, Germany

AIM Investigation of the predictive value of components of the IGF-system for the identification of risk groups for relapse or fatal outcome in childhood acute lymphoblastic leukemia. METHODS Serum levels of IGF-I, -II, and IGFBP-1 to -3 were measured at diagnosis in 162 children with ALL treated by the BFM study protocols ALL-BFM 90 and 95. The patients were followed up to ten years after diagnosis and Cox-regression was used to test, if the different components of the IGF-system are influencing the EFS. Stepwise multivariate discrimination analysis was used to investigate if these components had independent effects on EFS compared to conventional risk factors, i.e. age immunophenotype, initial leukocyte and platelet count, blast count at day 8 and hemoglobin. RESULTS At diagnosis highly elevated IGFBP-2 ( 3.01 ± 2.34 SDS), low IGFBP-3 (-1,26 ± 1.9 SDS) and IGF-I ( -2.47 ± 1.65 SDS) serum levels were found. High IGFBP-2 and low IGFBP-3 at diagnosis correlate with higher event risk. IGFBP-2 was identified as independent risk factor, which gives additional benefit (sensitivity 55.2%, specificity 80.4%) to the conventional prediction model (sensitivity 48.2%, specificity 81.2%). Correlation analyses of IGF to IGFBP in the group of patients with event and in the group of patients in complete clinical remission demonstrate a shift from the importance of the main carrier of IGF in the circulation IGFBP-3 to IGFBP-2 in patients with events. Since similar observations were made in patients with colon carcinoma and brain tumors we hypothesize an active involvement of IGFBP-2 in the pathophysiology of ALL. CONCLUSIONS Our results show that components of the IGF-system are linked to the outcome of ALL in children. Furthermore we demonstrate an additional benefit of IGFBP-2 to the prognostic prediction model of ALL. However, since only a weak correlation between the group of conventional risk factors and components of the IGF-system was found, we conclude that the biological background of both complexes must be different. This encourage for the search of additional factors, which may be the link between both complexes and will give us additional information for the treatment of our patients.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 798 (Growth factors & signalling).