Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000

Abstract

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

Osteonecrosis in children with acute lymphoblastic leukemia

“…Notwithstanding that the overall incidence of osteonecrosis was substantially higher (4.7%) 35 and exceeded that reported in the trial NOPHO ALL-2008 (3.1%), 36 and EORTC-CLG 58951 (2.5%), 37 it still remained lower than that of CCG, 38,39 35 14.5% 10-15 years; DFCI-ALL 00-01 41 14% 10-18 years). However, a factor which remained consistent throughout all the studies was that older children and adolescents are at a much higher risk of developing osteonecrosis.…”

“…51 ASP treatment leads to increased plasma concentrations of dexamethasone, 6,51,52 whereas ASP allergy is associated with decreased systemic exposure to ASP and with decreased risk of osteonecrosis. 53 These effects might further be influenced by the different preparations of ASP used and, to some extent, explain the above-mentioned conflicting results regarding the risk of osteonecrosis in older patients, with the administration of dexamethasone compared to prednisone in trial ALL-BFM 2000 (native asparaginase) 35 and AALL0232 (pegylated asparaginase). 38 High-dose MTX can damage the growth plate and primary bone, and the long-term use of MTX can reduce primary bone formation, likely due to decreased osteoblast function as well as increased osteoclast formation and function.…”

Relevance of ID3-TCF3-CCND3 pathway mutations in pediatric aggressive B-cell lymphoma treated according to the non-Hodgkin Lymphoma Berlin-Frankfurt-Münster protocols

“…All patients had previously been diagnosed between 2000 and 2006 and were treated according to the ALL-BFM 2000 protocol. 25 More detailed clinical characteristics of the analyzed patients can be found in the online supplement ( Online Supplementary Methods ).…”

Glucocorticoid selection for pediatric ALL

“…Over 3500 children and adolescents with ALL received a 7-day prednisone prophase, and then were randomized to receive either 21 days of dexamethasone or prednisone for the remainder of the first month of therapy. 1 The results are impressive and add important new data for ALL clinical researchers to consider. Substituting dexamethasone for prednisone, one glucocorticoid for another, for 3 weeks in the context of 2 years of multiagent chemotherapy reduced the relapse risk by one-third (see figure).…”