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Children with IKZF1-deleted (IKZF1del) acute lymphoblastic leukemia (ALL) benefit from an additional year of maintenance therapy, and chemotherapy can be safely reduced for patients in several other ALL risk groups, according to findings from the Dutch Childhood Oncology Group (DCOG) ALL11 study, conducted in the Netherlands (ClinicalTrialRegister.nl Identifier: EudraCT 2012-000067-25; NL3227).
“IKZF1-deleted ALL pays a benefit from a third year of therapy, with a threefold-reduced relapse rate,” Rob Pieters, MD, reported at SIOP 2023, the 55th Congress of the International Society of Paediatric Oncology in Ottawa, Canada. Dr Pieters is chief medical officer at the Princess Máxima Center for Pediatric Oncology, and professor of Pediatric Oncology at the University of Utrecht, in Utrecht, the Netherlands.
“Chemotherapy can be successfully reduced for ETV6::RUNX1 and Down Syndrome children, especially [by] taking out anthracyclines, and for poor prednisone responders,” he said.
The IKZF1 gene is a member of the IKAROS family of transcription factor genes, involved in B- and T-cell development. Previous research (the ALL10 study) showed that medium-risk patients with IKZF1del ALL experience higher relapse rates than other patients, and that children with Down Syndrome experience high rates of treatment toxicity, which can be fatal.
In this study, using the ALL11 protocol, the study team sought to improve patient outcomes with prolonged therapy for children with IKZF1del ALL; and reduced therapy for children with Down Syndrome-associated ALL by removing anthracyclines from their treatment. They also omitted anthracyclines from intensification therapy for children with ETV6::RUNX1 ALL, and reduced therapy for patients with poor prednisone response by treating them with a regimen for medium risk rather than high risk patients.
A total of 819 children aged 1 to 18 years at diagnosis with ALL were enrolled and stratified into adapted-therapy groups defined by minimal residual disease (MRD) as standard risk (SR), medium risk (MR), or high risk (HR). Baseline patient demographic, hematologic, and cancer phenotype characteristics were very similar for the ALL10 and ALL11 patient populations, Dr Pieters noted. Most (70%) patients were assigned to the MR group, and those with IKZF1del ALL received intensified treatment with an additional, third year of maintenance therapy (methotrexate once every 3 weeks and intermittent 6-mercaptopurine).
Therapy was reduced for children with Down Syndrome who did not have IKZF1del by completely omitting anthracyclines from therapy. Similarly, for children with ETV6::RUNX1 ALL, anthracyclines were omitted from intensification therapy.
Compared with ALL10 protocol outcomes, intensified maintenance therapy for children with IKZF1del ALL was associated with a 2.2-fold improvement in 5-year cumulative risk of relapse (CIR; 10.8% vs 23.4%; P =.035) and improved event-free survival (EFS; 87.1% vs 72.3%; P =.019), Dr Pieters reported. A landmark analysis at 2 years, comparing patients who survived without events for at least 2 years after diagnosis of IKZF1del ALL, showed a 2.9-fold reduction in CIR (25.6% to 8.8%; P =.008) and improved EFS (74.4% to 91.2%; P =.007).
Compared with patients with Down syndrome in the ALL10 protocol, who received anthracyclines, patients with Down syndrome in the ALL11 protocol saw reduced risk of death, Dr Pieters noted.
Reduced therapy did not degrade the 5-year outcomes for patients with ETV6::RUNX1 (EFS, 98.3%; overall survival [OS], 99.4%), Down Syndrome (EFS 87.0%; OS 87.0%), or poor prednisone response ALL (EFS, 81.1%; OS, 94.9%), he reported.
Targeted risk stratified ALL treatment can improve outcomes for children with IKZF1del ALL and reduce drug exposure for other patients, reducing long-term morbidity without impairing efficacy, Dr Pieters concluded.
“Children with IKZF1del ALL benefit from prolonged maintenance therapy, [and] chemotherapy was successfully reduced for ETV6::RUNX1, DS, and poor prednisone response ALL,” he said. “This is very remarkable, with the drugs that we already have, that we still improved outcomes further, which is kind of [a] miracle.”
Disclosures: Dr Pieters did not announce any financial disclosures.
Reference
Pieters R. Improved outcome for children with acute lymphoblastic leukemia by prolonging therapy for IKZF1 deletion and decreasing therapy for ETV6/RUNX1, Down Syndrome or prednisone poor response. Presented at SIOP 2023. October 11-14, 2023. Ottowa, Canada. Abstract O182.
