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Improved Outcome for ALL by Prolonging Therapy for IKZF1 Deletion and Decreasing Therapy for Other Risk Groups
Rob Pieters1,2, Hester de Groot-Kruseman1,2, Marta Fiocco1,2,3,4
1Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Insights
The ALL11 protocol improved outcomes for children with acute lymphoblastic leukemia (ALL) by adjusting therapy based on minimal residual disease. Prolonged treatment for IKZF1-deleted ALL reduced relapse rates, while reduced therapy for other groups maintained excellent survival.
Area of Science:
- Pediatric Oncology
- Hematology
- Clinical Trial Analysis
Background:
- The ALL10 protocol stratified acute lymphoblastic leukemia (ALL) treatment by minimal residual disease (MRD) risk groups.
- While effective, ALL10 showed high toxicity in Down syndrome (DS) and poor outcomes for IKZF1-deleted (IKZF1del) ALL, necessitating protocol adjustments.
Purpose of the Study:
- To evaluate the efficacy of the modified ALL11 protocol in improving outcomes for pediatric ALL patients.
- To reduce treatment intensity for specific ALL subtypes including IKZF1del, DS, ETV6::RUNX1, and poor prednisone responders (PPRs) while maintaining or improving survival.
Main Methods:
- The ALL11 protocol enrolled 819 pediatric ALL patients (age 1-18 years), stratified similarly to ALL10.
- Treatment modifications included prolonged maintenance for IKZF1del ALL and reduced chemotherapy for DS, ETV6::RUNX1, and PPR ALL.
- Results were compared to the historical ALL10 cohort.
Main Results:
- The ALL11 protocol achieved a 5-year overall survival of 94.2% and event-free survival of 89.0%.
- Prolonged maintenance therapy for IKZF1del ALL significantly reduced the cumulative incidence of relapse (CIR) by 2.2-fold and improved EFS.
- Reduced chemotherapy for DS, ETV6::RUNX1, and PPR ALL did not compromise 5-year survival outcomes.
Conclusions:
- Prolonged maintenance therapy is beneficial for children with IKZF1del ALL, significantly decreasing relapse rates.
- Chemotherapy reduction in ALL11 for specific ALL subtypes (ETV6::RUNX1, DS, PPR) was successful without negatively impacting patient outcomes.
- These findings, from a nonrandomized study with historical controls, suggest a refined risk-adapted approach to pediatric ALL treatment.
Purpose:
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. IKZF1-deleted (IKZF1del) 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 ETV6::RUNX1 ALL. Poor prednisone responders (PPRs) were treated as high risk in ALL10. In ALL11, we prolonged therapy for IKZF1del from 2 to 3 years. We reduced therapy for DS by omitting anthracyclines completely, for ETV6::RUNX1 in intensification, and for PPR by treatment as MR.
Methods:
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.
Results:
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 IKZF1del MR improved 5-year CIR by 2.2-fold (10.8% v 23.4%; P = .035) and EFS (87.1% v 72.3%; P = .019). Landmark analysis at 2 years from diagnosis showed a 2.9-fold reduction of CIR (25.6%-8.8%; P = .008) and EFS improvement (74.4%-91.2%; P = .007). Reduced therapy did not abrogate 5-year outcome for ETV6::RUNX1 (EFS, 98.3%; OS, 99.4%), DS (EFS, 87.0%; OS, 87.0%), and PPR (EFS, 81.1%; OS, 94.9%).
Conclusion:
Children with IKZF1del ALL seem to benefit from prolonged maintenance therapy. Chemotherapy was successfully reduced for patients with ETV6::RUNX1, DS, and PPR ALL. It has to be noted that these results were obtained in a nonrandomized study using a historical control group.
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