SAN FRANCISCO -- Dexamethasone and prednisone were equally effective as induction therapy for children with newly diagnosed acute lymphocytic leukemia in terms of five-year event-free survival, according to a second interim analysis of EORTC Trial 58951.
But some important differences were observed between the two drugs. Although dexamethasone decreased the five-year incidence rate of central nervous system (CNS) leukemia by 2%, a 1.5% increase was seen in the incidence of non-CNS leukemia in the dexamethasone group compared with the prednisone group. Also, the death rate was increased by 0.6% in patients who achieved complete response in the dexamethasone group. Further, dexamethasone induction had a higher infection rate during consolidation, particularly when L-asparaginase was used throughout consolidation.
"Although this is only an interim analysis, results were robust," said Yves Bertrand, MD, from the department of pediatric hematology, CHU Lyon and Universit Claude Bernard in Lyon, France.
The doses used in the EORTC Trial 58951 were dexamethasone 6 mg/m2/d and prednisone 60 mg/m2/d (conventional dose). Dr. Bertrand pointed out that other studies using different doses of these two drugs had better results with dexamethasone.
"The optimal dose of either drug remains to be determined for better efficacy without increased toxicity," he said.
EORTC 58951 was a randomized phase III trial with a 2 x 2 factorial design. The first randomization compared dexamethasone versus conventional dose prednisone as induction therapy. The second randomization compared prolonged versus conventional L-asparaginase during consolidation and late intensification for non-very high risk patients only. Average risk patients (n = 384) were also randomized for continuation therapy with additional pulses of vincristine plus the same drug assigned for induction (either dexamethasone or prednisone) during initial randomization (abstract #8).
Patients were treated with a type of Berlin Frankfurt Munster (BFM) regimen, commonly used in Europe. No radiation was given, even for patients with initial CNS leukemia. Whenever feasible, patients were randomized on day 1 of the prephase; if they were randomized on day 8, prednisone was administered before day 8.
The trial enrolled 1,853 children up to the age of 18 years with newly diagnosed ALL. At the second pre-planned interim analysis, 1,703 patients were evaluable for event-free survival (the primary end point) and overall toxicity and survival (secondary end points).
At a median follow-up of 4.3 years, the five-year overall event-free survival rate was 82.1% for the dexamethasone arm and 82.4% for the prednisone arm. No significant difference in five-year event-free survival was observed between the two induction treatments in either the B-lineage or the T-lineage ALL groups. CNS crude relapse rates were 1% with dexamethasone versus 1.6% with prednisone for precursor-B ALL patients, and 1% with dexamethasone versus 2.2% with prednisone for precursor-T ALL.
The five-year CNS leukemia incidence rate was 2.9% versus 4.9%, respectively, and the non-CNS leukemia incidence was10.9% versus 9.4%, respectively. The five-year death rate in patients who achieved CR was 2.7% for dexamethasone versus 2.1% for prednisone.
The incidence of grade 3 and 4 infection was similar in both arms during induction. However, during post-induction consolidation, the rate of grade 3 and 4 infections was higher in the dexamethasone arm: 23.5% versus 21.1% with prednisone. Patients who were randomized to prolonged exposure to L-asparaginase plus dexamethasone were particularly vulnerable to grade 3 and 4 infection compared with prednisone: 29.1% versus 21.8%, respectively.
EORTC Trial 58951 outcomes dovetailed with results from the Trial AIEOP-BFM ALL 2000 in which dexamethasone in the induction phase of chemotherapy led to a one-third reduction in the risk of relapse, compared with standard treatment. Once again, the drug was also associated with a greater risk of serious side effects, including invasive infections.