Effect of dexamethasone (DEX) dose modification on osteonecrosis (ON) risk associated with intensified therapies for standard risk acute lymphoblastic leukemia (SR-ALL): A report from the Children’s Oncology Group (COG) study AALL0331.

Abstract

10002 Background: ON is a known toxicity of childhood ALL therapy, particularly in patients (pts) >9 years (y). Intensified use of DEX, methotrexate (MTX), and asparaginase (ASNase) may increase the risk of developing ON among B-precursor NCI SR-ALL pts despite their younger age. Methods: Newly diagnosed SR-ALL pts 1-9y enrolled on AALL0331 between 4/05 and 5/10 were prospectively monitored for symptomatic ON within three treatment cohorts risk-stratified by clinical, cytogenetic, and early response criteria. ON sites were confirmed by imaging. SR-Low (SRL) pts were randomized to standard therapy +/- 4 additional doses of PEG-ASNase. SR-Average (SRA) pts were randomized (2x2) to standard therapy +/- an intensive consolidation (IC) +/- an augmented interim maintenance/delayed intensification (AIM/ADI). SR-High (SRH) pts all received IC and two AIM/ADI phases. After 6/08, alternate week DEX (AWD, days 1-7/15-21) replaced continuous DEX (days 1-21) during DI, and escalating-dose MTX replaced oral MTX during IM. All pts received DEX days 1-28 during induction and 5-day pulses every 4 weeks during maintenance. Results: Overall ON cumulative incidence (CI) at 5y was 2.7% (133/5261), correlating with sex (F 3.7%, M 1.9%, p<0.0001), age (1-2y 0.8%, 3-4y 2.0%, 5-6y 3.3%, 7-9y 7.8%, p<0.0001), and risk group (SRL 2.6%, SRA 2.9%, SRH 5.7%, p=0.0009). Before 6/08, ON CI was higher for SRA pts given intensive vs standard consolidation (5.8% vs 1.9%, p=0.002), and trended higher for SRL pts given additional PEG-ASNase (4.0 vs 2.3%, p=0.09). Use of AWD significantly reduced ON CI at 3y among SRH pts (7.4% vs 1.5%, p=0.003) and further reduced ON events in SRL/SRA pts. Conclusions: Young children receiving intensified therapy for SR-ALL therapy are at risk for ON. Extended exposure to PEG-ASNase is a likely contributing factor, possibly by potentiating DEX exposure during DI. ON risk can be significantly reduced by using AWD during DI, which is now COG standard of care. Clinical trial information: NCT00103285.