mRNA expression profile of multidrug resistance genes in childhood acute lymphoblastic leukemia. Low expression levels associated with a higher risk of toxic death.

BACKGROUND: Increased activity of multidrug resistance (MDR) genes has been associated with treatment failure in acute leukemias, although with controversial reports. The objective of the present study was to assess the expression profile of the genes related to MDR: ABCB1, ABCC1, ABCC3, ABCG2, and LRP/MVP in terms of the clinical and biological variable and the survival of children with acute lymphoblastic leukemia (ALL). PROCEDURE: The levels of mRNA expression of the drug resistance genes ABCB1, ABCC1, ABCC3, ABCG2, and LRP/MVP were analyzed by quantitative real-time PCR using the median values as cut-off points, in consecutive samples from 140 children with ALL at diagnosis. RESULTS: Expression levels of the ABCG2 gene in the patient group as a whole (P = 0.05) and of the ABCG2 and ABCC1 genes in patients classified as being at high risk were associated with higher rates of 5-year event-free survival (EFS) (P = 0.04 and P = 0.01). Expression levels of the ABCG2 gene below the median were associated with a greater chance of death related to treatment toxicity for the patient group as a whole (P = 0.009) and expression levels below the median of the ABCG2 and ABCC1 genes were associated with a greater chance of death due to treatment toxicity for the high-risk group (P = 0.02 and P = 0.03, respectively). CONCLUSION: The present data suggest a low participation of the drug efflux genes in treatment failure in patients with childhood ALL. However, the low expression of some of these genes may be associated with a higher death risk related to treatment toxicity.

Shorter Maintenance Therapy in Childhood Acute Lymphoblastic Leukemia: The Experience of the Prospective, Randomized Brazilian GBTLI ALL-93 Protocol.

AIM: Maintenance therapy is an important phase of the childhood ALL treatment, requiring 2-year long therapy adherence of the patients and families. Weekly methotrexate with daily 6-mercaptopurine (6MP) constitutes the backbone of maintenance therapy. Reduction in the maintenance therapy could overweight problems related with poverty of children with ALL living in limited-income countries (LIC). OBJECTIVE: To compare, prospectively, the EFS rates of children with ALL treated according to two maintenance regimens: 18 vs. 24 months duration. MATERIALS AND METHODS: From October 1993 to September 1999, 867 consecutive untreated ALL patients <18 years of age were treated according to the Brazilian Cooperative Group for Childhood ALL Treatment (GBTLI) ALL-93 protocol. Risk classification was based exclusively on patient's age and leukocyte count (NCI risk group) and clinical extra medullary involvement of the disease. Data were analyzed by the intention-to-treat approach. RESULTS: Fourteen patients (1.6%) were excluded: wrong diagnosis (n = 7) and previous corticosteroid (n = 7). Of the 853 eligible patients, 421 were randomly allocated, at study enrollment, to receive 18-month (group 1) and 432 to receive 24-month (group 2) maintenance therapy. Complete remission rate was achieved in 96% of the patients (817/853). Twenty-eight patients (3.4%) died during the induction phase. Thirty-four patients (4.0%) were lost to follow-up. The overall EFS was 66.1 ± 1.7% at 15 years. No difference was seen according to maintenance: EFS15y was 65.8 ± 2.3% (group 1) and 66.3 ± 2.3% (group 2; p = 0.79). No difference between regimens was detected after stratifying the analyses according to factors associated with adverse prognosis in this study (age group <1 year or >10 years and high WBC at diagnosis). Overall death in remission rate was 6.85% (56 patients). Deaths during maintenance were 13 in group 1 and 12 in group 2, all due to infection. Over 15 years of follow-up, two patients both from group 2 presented a second malignancy (Hodgkin's disease and thyroid carcinoma) after 8.3 and 11 years off therapy, respectively. CONCLUSION: Six-month reduction of maintenance therapy in ALL children treated according to the GBTLI ALL-93 protocol provided the same overall outcome as 2-year duration regimen.

Instituição de protocolo de tratamento padronizado pelo Grupo Cooperativo Brasileiro de Síndrome Mielodisplástica em Pediatria / The development and institution of a therapeutic program by the Brazilian Pediatric Myelodysplastic Syndrome Co-operative Group

O tratamento da Síndrome Mielodisplásica (SMD) na criança ainda é assunto de debate e controvérsias. O atrelamento histórico da doença na infância com a SMD do adulto levou a um retrocesso em diversas áreas do conhecimento desta patologia, sendo talvez as questões relativas ao tratamento as mais afetadas. Dado a origem clonal da doença, postula-se que ela seja virtualmente incurável com as terapias convencionais. Muito se tem estudado a respeito do transplante de células-tronco hematopoéticas, nas suas mais diversas fontes e possibilidades, com alguns resultados promissores. O Grupo Cooperativo Brasileiro de Síndrome Mielodisplásica em Pediatria (GCB-SMD-PED) foi criado em 1997, com o objetivo de estudar esta doença na população brasileira, em seus mais diversos aspectos, quer sejam clínicos, epidemiológicos, citológicos, patológicos, citogenéticos ou moleculares. Após cinco anos de atividades, o Grupo Cooperativo iniciou discussões afim de propor protocolo terapêutico para suas crianças. Para tanto, como passo inicial, fez-se ampla revisão de literatura sobre o assunto, a qual é aqui discutida. Ainda com este fim, o grupo analisou a sobrevida dos pacientes matriculados no GCB-SMD-PED, os diagnósticos realizados na instituição de origem e as mais diversas abordagens terapêuticas seguidas, as quais variaram desde tratamento conservador, medidas de suporte, transfusões sangüíneas à transplante de medula óssea. Os autores descrevem as mais diferentes abordagens utilizadas para o tratamento da SMD em crianças, bem como o racional do emprego de cada modalidade terapêutica e os estudos pertinentes na área.

The management of Myelodysplastic Syndrome (MDS) in childhood is still a matter of debate and controversy. The historic relationship of this illness in children with MDS in adulthood delayed development in different areas, where perhaps knowledge related to treatment was the most affected. Due to the clonal origin of this illness, it is thought that it is virtually incurable with conventional therapies. There have been plenty of studies related to hematopoetic stem-cell transplantation with some promising results.The Brazilian Pediatric Myelodysplastic Cooperative Group (GCB-SMD-PED) was created in 1997, with the aim of studying this disease in the Brazilian population and its different aspects, whether clinical, epidemiological, cytological, pathological, cytogenetical or molecular. After five years of activities, the Co-operative Group has initiated discussions to propose therapeutic protocols for children. For this, as an initial step, a review of publications was performed about this subject, which is discussed in this article. The group also analysed the overall survival of patients referred to the Bra-PMD-CG and the different diagnostic and treatment schedules employed in each institution, varying from simply conservative treatment, palliative measures, blood transfusions to bone marrow transplantation.The authors describe the different ways used for MDS treatment in childhood, as well as the rationale employed of each therapeutic modality and the studies related to this area.