Dutch ALL11 Study: Improved Outcome for Acute Lymphoblastic Leukemia By Prolonging Therapy for IKZF1 Deletion and Decreasing Therapy for ETV6::RUNX1, Down Syndrome and Prednisone Poor Responders

Introduction The former ALL10 protocol of the Dutch Childhood Oncology Group improved outcome for children with ALL by stratifying therapy according to minimal residual disease (MRD) levels into standard risk (SR), medium risk (MR) and high risk (HR) and subsequently reducing therapy for SR and intensifying therapy for MR and HR patients. However, there was still a poor outcome for IKZF1 deleted ALL, which is a poor prognostic feature in contemporary treatment protocols worldwide, in particular in the large MR group and not in the smaller MRD based SR and HR groups. As patients with ALL and IKZF1 deletions have a ~3-fold increased risk of relapse and are therefore responsible for a high number of all relapses nowadays, it is important to develop more effective therapy for them. In addition, ALL10 showed a high toxic death rate in Down syndrome and an excellent outcome in ETV6::RUNX1 ALL. Poor prednisone responders (PPR) were treated in ALL10 according to the HR arm which is questionable in the era of MRD stratification.

For these reasons, we intensified therapy for IKZF1 deleted ALL by prolonging therapy from 2 to 3 years with an extra year of maintenance therapy with intermittent 6-mercaptopurine and methotrexate. Furthermore, we reduced therapy for children with Down syndrome by omitting anthracyclines completely, for ETV6::RUNX1 ALL by deleting anthracyclines in intensification, and for PPR by shifting them from HR to MR.

Methods 819 consecutive patients aged 1-18 years with ALL were enrolled on ALL11 and stratified by MRD as in ALL10. Results were compared to the historical control ALL10.

Results Five year percentages of 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), 2.3 (0.6) respectively versus 91.8 (1.0), 87.1 (1.2), 8.4 (1.0) and 2.9 (0.6) on ALL10. Five year percentages of OS for SR (23.6% of all patients), MR (70.4%) and HR (6.0%) patients were 97.5 (SE 1.3%), 96.4 (0.8) and 71.1 (7.0) respectively.

Prolonged maintenance for IKZF1 deleted MR patients significantly reduced the 5-year CIR by 2.2-fold from 23.4% to 10.8% (p = 0.028) and improved EFS from 72.3% to 87.1% (p = 0.019). Using a landmark analysis at 2 years to correct for events occurring before the 3^rd year showed a significant 2.9-fold reduction of the 5-year CIR from 25.6% to 8.8% (p < 0.01) and improved EFS from 74.4% to 91.2% (p < 0.01).

Omitting anthracyclines from intensification did not abrogate the outcome of ETV6::RUNX1 (5-yr EFS 98.3%; OS 99.4%). Fully omitting anthracyclines from therapy for Down syndrome children was successful with 5-yr OS, EFS and CIR of 87.0, 87.0 and 0.0% respectively. Therapy reduction for PPR patients was also successful as illustrated by the 5-year EFS (81.1% on ALL11MR vs 73.8% on ALL10HR) and OS (94.9% vs 81.0% respectively).

Conclusion Most importantly, children with IKZF1 deleted ALL benefit from a third year of maintenance therapy, which suggests to change therapy accordingly for this class of patients. Chemotherapy was successfully reduced for ETV6::RUNX1, Down syndrome and PPR patients.

van der Velden:Cytognos: Other: laboratory services agreement ; BD biosciences: Other: laboratory services agreement ; Agilent: Other: laboratory services agreement ; Euroflow: Patents & Royalties.