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A recent study provides evidence showing that focal 22q11.22 deletions may be correlated with poor outcomes in patients with pediatric B-cell acute lymphoblastic leukemia with alterations in IKZF1.
Investigators believe that 22q11.22 deletions may be able to predict poor clinical outcomes in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) and IKZF1 alterations, offering the potential for a new genetic biomarker, according to results from a cohort study published in JAMA Oncology.
Although patients with wild-type IKZF1 alleles and focal 22q11.22 deletion had similarly poor outcomes to the remaining P9906 cohort, patients who had combined 22q11.22 and IKZF1 double deletion had significantly worse 5-year event-free survival (EFS) outcomes (26.4%) and overall survival (OS; 64.2%) compared with patients with IKZF1 alterations with wild type 22q11.22 (59% and 92.4%; hazard ratio [HR], 2.62; 95% CI, 1.33-5.16; P = .004; HR, 2.62; 95% CI, 1.11-6.2; P = .02).
“A functional basis for the association between 22q11.22 deletions and adverse outcomes in ALL remains unknown and beyond the scope of this article,” the investigators wrote. “Some have suggested that genomic instability and increased copy number alterations contribute to poor outcomes in patients with IKZF1 alterations, and the 22q11.22 region is known for genomic instability because of low copy repeats, which facilitate nonallelic homologous recombination.”
Patient data were collected from independent cohorts of pediatric patients from several institutions, including Utah, Children’s Oncology Group (COG) P9906, COG AALL0232, St Jude Hospital, Children’s Hospital of Philadelphia, and a group of patients with Down syndrome who were pooled from prior cohorts with the addition of cohorts from UKALL, AIEOP, Texas Children’s Hospital, and COG.
A total of 299 of 1310 primarily high-risk pediatric patients with B-ALL had IKZF1 alterations, more than half of whom also sharing concomitant focal 22q11.22 deletions (159 of 299 patients). Patients who enrolled on the trial were required to have known IKZF1, 22q11.22, and evaluable EFS status in order to be eligible to be included in the statistical analysis.
Investigators initially examined focal 22q11.22 deletions in the Utah (n = 56) and P9906 (n = 214) cohorts and were found to be associated with significantly worse outcomes. However, since IKZF1 alterations have been associated with very poor outcomes, investigators also examined the association between IKZF1 alterations and focal 22q11.22 deletions.
After combining study cohorts, investigators reported that 53.2% of the patients with IKZF1 alterations had a 22q11.22 deletion and double deletions were observed in 12.1% of patients. Of this population, patients with IKZF1 alterations and wild-type 22q11.22 had both a decreased 5-year EFS (68.5%) and OS (83.9%) compared with the 5-year EFS (81.2%) and OS 87.3%) for patients with wild-type IKZF1 (EFS: HR, 1.84; 95% CI, 1.34-2.51; P <.001; OS: HR, 1.73; 95% CI, 1.15-2.60; P = .01).
Additionally, patients with 22q11.22 and IKZF1 double deletions had an even worse 5-year EFS (43.3% vs 68.5%; HR, 2.18; 95% CI, 1.54-3.07; P <.001) and OS (66.9% vs 83.9%; HR, 2.05; 95% CI, 1.32-3.21; P = .001) outcomes when compared with patients who had IKZF1 alterations and wild-type 22q11.22.
“Further studies are needed to better understand the functional consequences of 22q11.22 and IKZF1 double deletions and how to best assess and incorporate this predictive marker into clinical studies to improve patient outcomes. These data add to the increasing evidence that genetic interactions in individual cancer cells may determine their therapeutic sensitivity,” the investigators concluded.
Mangum DS, Meyer JA, Mason CC, et al. Association of combined focal 22q11.22 deletion and IKZF1 alterations with outcomes in childhood acute lymphoblastic leukemia. JAMA Oncol. 2021. doi:10.1001/jamaoncol.2021.2723.