CASE REPORTS
Treatment of B Non-Hodgkin's Lymphoma in children: the experience of multicentre studies and Brazilian National Cancer Institute's experience
Claudete Klumb
Pediatric lymphomas are the third most common neoplasm in children and adolescents. Unlike lymphomas in adults, childhood non-Hodgkin's lymphomas (NHL) are diffuse, aggressive neoplasms with a tendency to widespread dissemination. The outcome in childhood lymphoma non-Hodgkin's (NHL) has improved steadily over the past decade through the incremental development of multiagent chemotherapeutics regimens. At present, 80-90% of children are cured with intensive risk-adapted chemotherapy. The most recent era advance is chemotherapy directed toward both stage and histology, an approach that has been validated in randomized multicenter clinical trials. Nevertheless, in developing countries there are many obstacles to treatment of childhood lymphomas. The most important are late diagnosis, low socioeconomic status and under-nourishment . In developing countries patients with these conditions may be at increased risk for therapy-related toxicity, including life-threatening infections.
In more recently trials, Patte et al. and Reiter et al., reported higher long term EFS in children with advanced stages of B-NHL using short intensive multiagent chemotherapy. However, the application of these regimens in developing countries may result in severe and life-threatening toxicity. Previously, our group reported 86.7% (SE=0.87) and 64% (SE=0.78) pEFS for children with early and advanced stage of non-lymphoblastic lymphoma, respectively. At that time, our results confirmed that a short duration therapy was effective to treat most children with non-lymphoblastic lymphoma in Brazil. Our following objective was to treat non-Hodgkin's B cell lymphoma in children with manageable toxicity-related morbidity without detriment of survival results. Between January 1998 to April 2003, 53 consecutive patients (age < 16 years), from National Cancer Institute, Brazil were stratified by risk factors (Stage and LDH level) and treated with BFM 86/90 (Berlin-Frankfurt-Münster) based protocol with reduction of metotrexate dose from 5 mg/m2 to 2mg/m2. The mean age of patients was 6 years (range: 1 to 16 years). Seventy 2% of patients had lymphomas classified as Burkitt type; 11% as diffuse large cell lymphoma, 6% as Burkitt-like lymphoma, and 11% were not classified. At a median follow-up time of 35 months 44 patients (83%) survive in complete remission. The event free survival for all patients was 78% (SE= 0.07), 100% (SE=0.0) for stage I/II patients, and 74% (SE= 0.08) for stage III/IV disease. Six patients suffered from initial treatment failure, 1 patient relapsed, all of whom died. There was only one death for sepsis related to treatment. This strategy was very effective for the treatment of B-NHL in setting of a developing country. Our results were comparable to BFM 90 study and other contemporary groups and represent an advance of the cure rates in childhood B-NHL from Brazil. However, despite dramatic improvements in the treatment of childhood NHL, approximately 20% of patients either do not achieve a complete remission, or develop recurrent disease. The identification of clinical and biologic features that are predictive of treatment failure may help in the development of more effective therapeutic strategies.
The TP53 gene encodes a nuclear protein implicated in the regulation of the cell cycle, DNA repair, and apoptosis. TP53 mutations and other alterations have been described in numerous types of tumors, and some of these have been associated with poor prognosis. Some reports in the literature have indicated a relationship between TP53 status and prognosis especially in non-small-cell lung cancer, breast cancer and NHL.
In order to characterize these molecular abnormalities and their clinical significance in prognosis, we also have analyzed the possible correlation between mutations in TP53 gene, clinical findings, response to chemotherapy and survival in 49 children of our series. The mutations of TP53 gene were analyzed by single-strand conformation polymorphism analysis (SSCP) of exons 5 through 9 and direct sequencing. Mutations of TP53 were detected in 11 of 49 (22.5%) patients and more specifically in 20% of Burkitt's lymphoma. No significant correlation was found regarding age, gender, clinical stage and LDH level and TP53 gene mutations. The comparison of EFS curves using the Log-Rank test were also not significant. However, the analysis of the effects of mutations on the core p53 structure identified biological and biochemical mutants with phenotypes probably related to different response to chemotherapy. Our data suggest that some types of mutants can alter the protein distinctly and may be associated with a more aggressive phenotype.
Publication Dates
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Publication in this collection
06 Jan 2006 -
Date of issue
Oct 2005
