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Original Investigation
August 19, 2021

Association of Combined Focal 22q11.22 Deletion and IKZF1 Alterations With Outcomes in Childhood Acute Lymphoblastic Leukemia

Author Affiliations
  • 1Nemours/Alfred I. DuPont Hospital for Children, Division of Pediatric Hematology/Oncology, Wilmington, Delaware
  • 2Division of Pediatric Hematology & Oncology, Department of Pediatrics, University of Utah, Salt Lake City
  • 3Division of Pediatric Hematology and Oncology, University of California, San Francisco
  • 4BioDiscovery, El Segundo, California
  • 5Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City
  • 6Department of Medicine, Massachusetts General Hospital, Boston
  • 7Department of Biostatistics, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 8Department of Pathology & Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 9Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 10Division of Oncology and the Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 11Institute of Cancer Research, London, England
  • 12JUNO Therapeutics, Seattle, Washington
  • 13Department of Pediatrics, NYU Langone Health, New York, New York
  • 14Jimmy Everest Section of Pediatric Hematology-Oncology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City
  • 15Department of Pathology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 16Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Virginia, Charlottesville
  • 17Department of Pathology, University of Utah Health Sciences Center, Salt Lake City
  • 18Department of Pediatrics, Baylor College of Medicine, Houston, Texas
  • 19PEEL Therapeutics, Inc, Salt Lake City, Utah
JAMA Oncol. 2021;7(10):1521-1528. doi:10.1001/jamaoncol.2021.2723
Key Points

Question  Do focal 22q11.22 deletions identify patients with IKZF1 alterations who will have worse outcomes in childhood B-cell acute lymphoblastic leukemia (B-ALL)?

Findings  In this cohort study of 1310 patients with B-ALL in 6 independent cohorts, focal 22q11.22 deletions were common (39.5%) in B-ALL and, when co-occurring with IKZF1 alterations, were associated with poor outcomes compared with patients with IKZF1 alterations alone (5-year event-free survival rates, 43.3% vs 68.5%; 5-year overall survival rates, 66.9% vs 83.9%).

Meaning  The study results suggest that 22q11.22 deletions are associated with very poor clinical outcomes in patients with B-ALL with IKZF1 alterations.

Abstract

Importance  Alterations in the IKZF1 gene drive B-cell acute lymphoblastic leukemia (B-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-ALL with IKZF1 alterations.

Objective  To determine whether focal deletions within the λ variable chain region in chromosome 22q11.22 were associated with patients with B-ALL with IKZF1 alterations with the highest risk of relapse and/or death.

Design, Setting, and Participants  This cohort study included 1310 primarily high-risk pediatric patients with B-ALL who were taken from 6 independent clinical cohorts, consisting of 3 multicenter cohorts (AALL0232 [2004-2011], P9906 [2000-2003], and patients with Down syndrome who were pooled from national and international studies) and 3 single-institution cohorts (University of Utah [Salt Lake City], Children’s Hospital of Philadelphia [Philadelphia, Pennsylvania], and St. Jude Children’s Hospital [Memphis, Tennessee]). Data analysis began in 2011 using patients from the older studies first, and data analysis concluded in 2021.

Exposures  Focal 22q11.22 deletions.

Main Outcomes and Measures  Event-free and overall survival was investigated. The hypothesis that 22q11.22 deletions stratified the prognostic effect of IKZF1 alterations was formulated while investigating nearby deletions in VPREB1 in 2 initial cohorts (n = 270). Four additional cohorts were then obtained to further study this association (n = 1040).

Results  This study of 1310 patients with B-ALL (717 male [56.1%] and 562 female patients [43.9%]) found that focal 22q11.22 deletions are frequent (518 of 1310 [39.5%]) in B-ALL and inconsistent with physiologic V(D)J recombination. A total of 299 of 1310 patients with B-ALL had IKZF1 alterations. Among patients with IKZF1 alterations, more than half shared concomitant focal 22q11.22 deletions (159 of 299 [53.0%]). Patients with combined IKZF1 alterations and 22q11.22 deletions had worse outcomes compared with patients with IKZF1 alterations and wild-type 22q11.22 alleles in every cohort examined (combined cohorts: 5-year event-free survival rates, 43.3% vs 68.5%; hazard ratio [HR], 2.18; 95% CI, 1.54-3.07; P < .001; 5-year overall survival rates, 66.9% vs 83.9%; HR, 2.05; 95% CI, 1.32-3.21; P = .001). While 22q11.22 deletions were not prognostic in patients with wild-type IKZF1 , concomitant 22q11.22 deletions in patients with IKZF1 alterations stratified outcomes across additional risk groups, including patients who met the IKZF1plus criteria, and maintained independent significance in multivariate analysis for 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).

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

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