Improved Outcome for ALL by Prolonging Therapy for <i>IKZF1</i> Deletion and Decreasing Therapy for Other Risk Groups.

Abstract

The ALL10 protocol improved outcomes for children with ALL by stratifying and adapting therapy into three minimal residual disease-defined risk groups: standard risk, medium risk (MR), and high risk. <i>IKZF1</i>-deleted (<i>IKZF1</i>del) ALL in the largest MR group still showed poor outcome, in line with protocols worldwide, accounting for a high number of overall relapses. ALL10 showed high toxicity in Down syndrome (DS) and excellent outcome in <i>ETV6::RUNX1</i> ALL. Poor prednisone responders (PPRs) were treated as high risk in ALL10. In ALL11, we prolonged therapy for <i>IKZF1</i>del from 2 to 3 years. We reduced therapy for DS by omitting anthracyclines completely, for <i>ETV6::RUNX1</i> in intensification, and for PPR by treatment as MR. Eight hundred nineteen patients with ALL (age, 1-18 years) were enrolled on ALL11 and stratified as in ALL10. Results were compared with those in ALL10. The five-year overall survival (OS), event-free survival (EFS), cumulative risk of relapse (CIR), and death in complete remission on ALL11 were 94.2% (SE, 0.9%), 89.0% (1.2), 8.2% (1.1), and 2.3% (0.6), respectively. Prolonged maintenance for <i>IKZF1</i>del MR improved 5-year CIR by 2.2-fold (10.8% <i>v</i> 23.4%; <i>P</i> = .035) and EFS (87.1% <i>v</i> 72.3%; <i>P</i> = .019). Landmark analysis at 2 years from diagnosis showed a 2.9-fold reduction of CIR (25.6%-8.8%; <i>P</i> = .008) and EFS improvement (74.4%-91.2%; <i>P</i> = .007). Reduced therapy did not abrogate 5-year outcome for <i>ETV6::RUNX1</i> (EFS, 98.3%; OS, 99.4%), DS (EFS, 87.0%; OS, 87.0%), and PPR (EFS, 81.1%; OS, 94.9%). Children with <i>IKZF1</i>del ALL seem to benefit from prolonged maintenance therapy. Chemotherapy was successfully reduced for patients with <i>ETV6::RUNX1</i>, DS, and PPR ALL. It has to be noted that these results were obtained in a nonrandomized study using a historical control group.