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Effect of Concurrent Focal 22q11.22 Deletions and IKZF1 Alterations on Outcomes in Pediatric Patients With B-Cell ALL


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In a study reported in JAMA Oncology, Mangum et al found that focal deletions in chromosome 22q11.22 were associated with poor outcomes in pediatric patients with B-cell acute lymphoblastic leukemia (ALL) with IKZF1 alterations.

As stated by the investigators, “Alterations in the IKZF1 gene drive B-cell ALL but are not routinely used to stratify patients by risk because of inconsistent associations with outcomes. We describe a novel deletion in 22q11.22 that was consistently associated with very poor outcomes in patients with B-cell ALL with IKZF1 alterations.”

Study Details

The study included 1,310 primarily high-risk pediatric patients from six independent cohorts. The hypothesis that 22q11.22 deletions may stratify the prognostic effect of IKZF1 alterations arose during investigation of nearby deletions in VRPEB1 in two initial cohorts (n = 270). Investigation of the potential impact of 22q11.22 deletions on risk stratification in the setting of IKZF1 was then expanded to four additional cohorts (n = 1,040).

This cohort study suggests that 22q11.22 deletions identify patients with [B-cell] ALL and IKZF1 alterations who have very poor outcomes and may offer a new genetic biomarker to further refine [B-cell] ALL risk stratification and treatment strategies.
— Mangum et al

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Key Findings

Among the 1,310 patients with B-cell ALL, focal 22q11.22 deletions were found in 518 (39.5%); 299 (22.8%) had IKZF1 alterations. Among the 299 patients with IKZF1 alterations, 159 (53.2%; 13.1% of total population) shared concomitant focal 22q11.22 deletions.

In the combined cohorts, patients with IKZF1 alterations and wild-type 22q11.22 had poorer 5-year event-free survival (68.5% vs 81.2%, hazard ratio [HR] = 1.84, 95% confidence interval [CI] = 1.34–2.51, P < .001) and 5-year overall survival (83.9% vs 87.3%, HR = 1.73, 95% CI = 1.15–2.60, P = .01) vs those with wild-type IKZF1.

Patients with combined IKZF1 alterations and 22q11.22 deletions had worse outcomes compared with those with IKZF1 alterations and wild-type 22q11.22 alleles in each of the six cohorts. For the combined cohorts, 5-year event-free survival was 43.3% vs 68.5% (HR = 2.18, 95% CI = 1.54–3.07, P < .001) and 5-year overall survival was 66.9% vs 83.9% (HR = 2.05, 95% CI = 1.32–3.21, P = .001). No significant difference in outcomes was observed for 22q11.22 deletions vs wild-type 22q11.22 among patients with wild-type IKZF1.

Concurrent 22q11.22 deletions in patients with IKZF1 alterations stratified outcomes across additional risk groups, including patients who met the IKZF1plus criteria. In this latter group, those with IKZF1plus and 22q11.22 deletion had significantly poorer outcomes vs those with IKZF1plus and wild-type 22q11.22, with 5-year event-free survival of 32.5% vs 68.8% (HR = 3.02, 95% CI = 1.65–5.55, P < .001), and 5-year overall survival of 56.4% vs 80.4% (HR = 2.61, 95% CI = 1.26–5.42, P = .01).

On multivariate analysis, 22q11.22 deletion in patients with an IKZF1 alteration was an independent predictor of event-free survival (HR = 2.05, 95% CI = 1.27–3.29, P = .003) and overall survival (HR = 1.83, 95% CI = 1.01–3.34, P = .05).

The investigators concluded, “This cohort study suggests that 22q11.22 deletions identify patients with [B-cell] ALL and IKZF1 alterations who have very poor outcomes and may offer a new genetic biomarker to further refine [B-cell] ALL risk stratification and treatment strategies.”

Joshua D. Schiffman, MD, of Huntsman Cancer Institute, University of Utah, Salt Lake City, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by the Intermountain Healthcare and Primary Children’s Hospital Foundations, Leukemia Lymphoma Society Translational Research Program, National Institutes of Health, American Lebanese Syrian Associated Charities, and others. For full disclosures of the study authors, visit jamanetwork.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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