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High Interleukin-15 Expression Characterizes Childhood Acute Lymphoblastic Leukemia With Involvement of the CNS

Gunnar Cario, Shai Izraeli, Anja Teichert, Peter Rhein, Julia Skokowa, Anja Möricke, Martin Zimmermann, Andre Schrauder, Leonid Karawajew, Wolf-Dieter Ludwig, Karl Welte, Holger J. Schünemann, Brigitte Schlegelberger, Martin Schrappe, Martin Stanulla

From the Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel; Department of Pediatric Hematology/Oncology and Institute for Cell and Molecular Pathology, Hannover Medical School, Hannover; Department of Hematology, Oncology, and Tumor Immunology, Robert-Rössle-Clinic at the HELIOS Klinikum Berlin-Buch, Charité Medical School, Berlin, Germany; Department of Pediatric Hematology/Oncology, Sackler School of Medicine, Chaim Sheba Medical Center, Ramat Gan, Israel; and Clinical Research and Information Translation Unit, SC Epidemiology, Italian National Cancer Institute Regina Elena, Rome, Italy

Address reprint requests to Martin Stanulla, MD, MSc, Department of Pediatric Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany; e-mail: stanulla.martin{at}mh-hannover.de

Purpose Applying current diagnostic methods, overt CNS involvement is a rare event in childhood acute lymphoblastic leukemia (ALL). In contrast, CNS-directed therapy is essential for all patients with ALL because without it, the majority of patients eventually will experience relapse. To approach this discrepancy and to explore potential distinct biologic properties of leukemic cells that migrate into the CNS, we compared gene expression profiles of childhood ALL patients with initial CNS involvement with the profiles of CNS-negative patients.

Patients and Methods We evaluated leukemic gene expression profiles from the bone marrow of 17 CNS-positive patients and 26 CNS-negative patients who were frequency matched for risk factors associated with CNS involvement. Results were confirmed by real-time quantitative polymerase chain reaction analysis and validated using independent patient samples.

Results Interleukin-15 (IL-15) expression was consistently upregulated in leukemic cells of CNS-positive patients compared with CNS-negative patients. In multivariate analysis, IL-15 expression levels greater than the median were associated with CNS involvement compared with expression equal to or less than the median (odds ratio [OR] = 10.70; 95% CI, 2.95 to 38.81). Diagnostic likelihood ratios for CNS positivity were 0.09 (95% CI, 0.01 to 0.65) for the first and 6.93 (95% CI, 2.55 to 18.83) for the fourth IL-15 expression quartiles. In patients who were CNS negative at diagnosis, IL-15 levels greater than the median were associated with subsequent CNS relapse compared with expression equal to or less than the median (OR = 13.80; 95% CI, 3.38 to 56.31).

Conclusion Quantification of leukemic IL-15 expression at diagnosis predicts CNS status and could be a new tool to further tailor CNS-directed therapy in childhood ALL.

Supported by the Madeleine-Schickedanz-Kinderkrebsstiftung, Verein zur Förderung der Behandlung krebskranker Kinder Hannover eV, Deutsche Krebshilfe, and the Bundesministerium für Bildung und Forschung.

Presented in part at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL.

The Hannover Medical School, Germany, has filed a patent application associated with the findings reported in this article.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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