Benefits of the Intermittent Use of 6-Mercaptopurine and Methotrexate in Maintenance Treatment for Low-Risk Acute Lymphoblastic Leukemia in Children: Randomized Trial From the Brazilian Childhood Cooperative Group—Protocol ALL-99

Abstract

PURPOSE To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. PATIENTS AND METHODS Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MTX (200 mg/m(2) every 3 weeks; group 2, n = 272). RESULTS The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P = .28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2). CONCLUSION The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.

The magnitude and predictors of abandonment of therapy in paediatric acute leukaemia in middle-income countries: A systematic review and meta-analysis

“…Nine studies defined abandonment, ranging from 4 to 12 weeks of missed therapy. 17,[19][20][21][22][23][24][25][26] Only two studies actively followed up cases of abandonment to minimise misclassification. 21,22…”

Childhood cancer mortality trends in Brazil, 1979 – 2008

“…SOBOPE has established cooperative groups with planned clinical trials, which may potentially impact survival and mortality rates. The Brazilian Cooperative Group for Treatment of Childhood Acute Lymphocytic Leukemia (ALL) reported a 5-year overall survival of 92.5% among 544 children with low-risk ALL in several Brazilian centers (22). A recent study from the Osteosarcoma Brazilian Group indicated an overall survival of 60% for patients with nonmetastatic disease; a large tumor size was observed in 43% of the cases and was not associated with longer lag time (23).…”

Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia

“…One-hundred and one patients were treated according to Brazilian Group for Treatment of Childhood Leukaemia (GBTLI-99), while 37 were treated according to the ALL-Berlin-Frankfurt-Munster (BFM) protocols backbone strategies, as described elsewhere [16,17]. …”