Dexamethasone(DEX)(6mg/sm/d) and Prednisolone(PRED)(60mg/sm/d) in Induction Therapy of Childhood ALL Are Equally Effective: Results of the 2nd Interim Analysis of EORTC Trial 58951

Abstract

Background: there is some biologic and clinical evidence that DEX is more efficient than PRED at similarly anti-inflammatory doses in the treatment of childhood ALL. Previous trials have called for PRED doses (40 mg/sm/d) lower than those of PRED traditionally used in EORTC trials. In order to check whether the claimed superiority of DEX might be dose-dependent, we conducted a randomized phase III trial comparing DEX (6 mg/sm/d) to PRED (60 mg/sm/d) (conventional dose) in induction therapy.Methods: the trial was opened in 12/1998 to all newly diagnosed children with ALL up to 18 y. of age. After the opening of the Interfant trial in 1999, children <1 y. old were registered in the latter. Ph1 pts recruited in this 58951 trial were kept in the present analysis because the switch to the EsPhALL was only after induction. The treatment regimen was of BFM type, without CNS radiation even in case of initial CNS leukemia. Randomization was done either on day 1 of the prephase (whenever feasible) or on day 8. In the latter case, PRED was administered before day 8. Non-very high risk pts were further randomized to prolong versus conventional duration of L-asparaginase courses during consolidation and late intensification. Part of average risk pts were also randomized (N=384) for the addition of pulses of VCR + glucocorticoid (same as that assigned for induction) in continuation therapy. Randomization was done centrally, stratification factors being disease, WBC, age, sex, timing of randomization and center. The main endpoint was EFS; secondary endpoints were OS and toxicity. Two interim analyses were foreseen in the protocol. Intent-to-treat analysis was used.Results: between 12/1998 and 2/2008, a total of 1853 ALL pts were randomized; as of 2/2008, 1703 pts were evaluable for EFS analysis. At a median follow up of 4.3 y., the 5 y. EFS rate was 82.1% (SE 1.5%) for the pts in the DEX arm and 82.4% (SE 1.5%) in the PRED arm (hazard ratio (HR) = 0.99, 98.8% CI 0.72–1.36, p=0.94); the futility boundary was crossed. In precursor-B ALL pts, the 5 y. EFS rate was 84.2% (DEX) vs 84.1% (PRED) (HR=0.95, p=0.75) and in precursor-T ALL the 5y. EFS rate was 70.7% vs 72.0% (HR=1.06, p=0.83). Isolated and combined CNS relapse crude rates were 1.1% each (DEX) vs 1.6% and 2.2% (PRED) respectively (resp.). The 5-y CNS incidence rate was 2.9% (DEX) vs 4.9% (PRED), the non-CNS incidence rate was 10.9% (DEX) vs 9.4% (PRED), and the 5-yr death in CR incidence rate was 2.7% (DEX) vs 2.1% (PRED). During induction the incidence of grade 3–4 infection was very similar in the two arms. During post-induction consolidation (“protocol IB”), it was higher in the DEX arm (23.5% vs 21.1%), in particular in pts randomized to prolonged L-asparaginase arm: 29.1% (DEX) vs 21.8% (PRED).Conclusion: DEX and PRED, used at the doses of resp. 6 and 60 mg/sm/d during induction, had equal efficacy. DEX decreased by 2.0% the 5-yr CNS incidence rate but increased by 1.5% the non-CNS incidence rate and by 0.6% the death in CR incidence rate. DEX in induction entails a higher infection rate during the consolidation, particularly when L-asparaginase is pursued throughout this phase. The optimal dosage of either glucocorticoid, compatible with acceptable toxicity, remains to be determined.