Key Points• Dexamethasone vs prednisone in induction of pediatric ALL led to significant relapse reduction and increased treatment-related mortality.• No overall survival benefit was achieved with dexamethasone except in the subset of patients with T-cell ALL and good early treatment response.Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and BerlinFrankfurt-Münster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m 2 per day) or prednisone (60 mg/m 2 per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (6 standard error) was 10.8 6 0.7% in the dexamethasone and 15.6 6 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P 5 .00013), resulting in 5-year event-free survival rates of 83.9 6 0.9% for dexamethasone and 80.8 6 0.9% for prednisone (P 5 .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 6 0.7%; prednisone, 90.5 6 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 6 2.4%; prednisone, 82.6 6 3.2%; P 5 .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov

Improved risk stratification enabled decreased therapy intensity for selected patients without compromising survival. Intensified chemotherapy with EVAIA did not improve outcome of localized high-risk rhabdomyosarcoma.