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Tumor Necrosis Factor and Lymphotoxin Alfa Genetic Polymorphisms and Outcome in Pediatric Patients With Non-Hodgkin’s Lymphoma: Results From Berlin-Frankfurt-Münster Trial NHL-BFM 95

From the Department of Pediatric Hematology and Oncology, Children's Hospital, Hannover Medical School, Hannover; and NHL-BFM Study Center, Department of Pediatric Hematology and Oncology, University Children's Hospital, Justus-Liebig-University Giessen, Germany

Address reprint requests to Kathrin Seidemann, MD, Department of Pediatric Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Str 1, D-30625 Hannover, Germany; e-mail: kseidemann{at}web.de

PURPOSE: To analyze the association of genetic variation within the tumor necrosis factor (TNF –308 [GA]) and lymphotoxin alfa (LT-a +252 [AG]) genes with outcome in non-Hodgkin's lymphoma of childhood and adolescence.

PATIENTS AND METHODS: Genotyping of the TNF –308 (GA) and LT-a +252 (AG) polymorphisms in patients (n = 488) enrolled onto the German-Austrian-Swiss multicenter trial NHL-BFM 95 from April 1996 to January 2000 was performed by polymerase chain reaction with subsequent restriction fragment length polymorphism analysis on DNA from tumor-free specimen.

RESULTS: In patients with Burkitt's lymphoma (BL) and B-cell acute lymphoblastic leukemia (B-ALL; n = 219, 211 eligible patients), patients carrying at least two variant alleles (high-producer haplotypes) had an increased risk of events: probability of event-free survival (pEFS) at 3 years was 81% (SE = 5%), compared with 91% (SE = 2%) in low-producer haplotypes (P = .018). In BL/B-ALL with high tumor load (lactate dehydrogenase [LDH] 500 U/L; n = 104), pEFS was 69% (SE = 8%) in high-producer versus 85% (SE = 4%) in low-producer haplotypes (P = .05). In multivariate analysis including risk factors for events (LDH 500 U/L, CNS involvement, methotrexate infusion regimen), TNF –308/LT- +252 haplotype kept prognostic relevance: patients with high-producer haplotypes had a 2.34-fold increase in risk of events (P = .048). The TNF –308 (GA) and LT- +252 (AG) polymorphisms were not associated with pEFS in lymphoblastic lymphoma (n = 101), anaplastic large-cell lymphoma (n = 67), or diffuse large B-cell lymphoma (n = 65), nor with therapy-related toxicity.

CONCLUSION: The TNF –308 (GA) and LT-a +252 (AG) polymorphisms were negative prognostic factors in pediatric BL/B-ALL. Among patients with serum LDH 500 U/L, haplotype analysis further determined patients at risk for events.

Supported by the Deutsche Krebshilfe, Bonn, Germany, Grant No. M 109/91/Re1, and the Verein zur Förderung der Behandlung krebskranker Kinder Hannover e.V.

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

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