Co-occurring 22q11.22 Deletions and IKZF1 Alterations Linked With Poor Outcomes in Pediatric B-ALL

Co-occurring focal 22q11.22 deletions and IKZF1 alterations were associated with inferior outcomes vs IKZF1 alterations alone in pediatric patients with B-cell acute lymphoblastic leukemia.

Co-occurring focal 22q11.22 deletions and IKZF1 alterations were associated with inferior outcomes vs IKZF1 alterations alone in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL), according to findings from a cohort study published in JAMA Oncology.1

The results showed that the 5-year event-free survival (EFS) rate was 43.3% in patients with IKZF1 alterations and 22q11.22 deletions vs 68.5% in patients with IKZF1 alterations alone (HR, 2.18; 95% CI, 1.54-3.07; P < .001). The 5-year overall survival (OS) rate was 66.9% vs 83.9%, respectively (HR, 2.05; 95% CI, 1.32-3.21; P = .001).

“The study results suggest that 22q11.22 deletions are associated with very poor clinical outcomes in patients with B-ALL with IKZF1 alterations,” wrote lead study author David Spencer Mangum, MD, of Nemours Children’s Health, and coauthors in the study publication. “Recognizing the substantially worse outcomes of patients with B-ALL with this concomitant deletion may help to stratify patients with IKZF1 alterations into higher and lower risk categories and suggests that 22q11.22 deletions are another marker for informing risk-adapted therapy in B-ALL.”

IKZF1 alterations drive B-ALL but are not generally used for risk stratification because of conflicting reports of associations with outcomes. However, IKZF1 alterations in the presence of a novel deletion in 22q11.22 has been repeatedly shown to be associated with poor outcomes in patients with B-ALL.

To determine whether co-occurring IKZF1 alterations and focal deletions in the λ variable chain region in chromosome 22q11.22 worsened prognosis in B-ALL, investigators conducted a cohort study, which included 1310 primarily high-risk pediatric patients with B-ALL.

Patient data were taken from 6 independent clinical cohorts, consisting of 3 multicenter cohorts––AALL0232, P9906, and patients with Down syndrome who were pooled from national and international studies––and 3 single-institution cohorts from the University of Utah, Children’s Hospital of Philadelphia, and St. Jude Children’s Hospital.

Data analysis began in 2011 and ended in 2021.

The cohort included 717 male (56.1%) and 562 female patients (43.9%). Focal 22q11.22 deletions were common (n = 518/1310; 39.5%) in B-ALL and uncommon with physiologic V(D)J recombination.

Just under 300 patients (n = 299/1310) with B-ALL had IKZF1 alterations. Among patients with IKZF1 alterations, over half had a co-occurring focal 22q11.22 deletion (n = 159/299; 53.2%); this population comprised 12.1% of the overall cohort.

Additional results showed that patients with IKZF1 alterations and wild-type 22q11.22 had decreased survival vs patients with wild-type IKZF1. The 5-year EFS rate was 68.5% vs 81.2%, respectively (HR, 1.84; 95% CI, 1.34-2.51; P < .001). The 5-year OS rate was 83.9% vs 87.3%, respectively (HR, 1.73; 95% CI, 1.15-2.60; P = .01).

Patients with 22q11.22 deletions and wild-type IKZF1 did not have any worse prognosis than patients with wild-type 22q11.22.

Although 22q11.22 deletions were not prognostic in patients with wild-type IKZF1, co-occurring 22q11.22 deletions and IKZF1 alterations demonstrated tiered outcomes across other risk groups, including patients who met the IKZF1plus criteria, and maintained independent significance in multivariate analysis for EFS (HR, 2.05; 95% CI, 1.27-3.29; P = .003) and OS (HR, 1.83; 95% CI, 1.01-3.34; P = .05).

IKZF1plus was defined by codeletion of IKZF1 with PAX5 or homozygous CDKN2A/B deletion in the absence of ERG deletions.

Notably, co-occurring 22q11.22 deletions and IKZF1 alterations were enriched in patients who had minimal residual disease (MRD) positivity (≥ 0.01%) at the end of induction (n = 70/244; 28.7%) vs MRD negativity (n = 43/567; 7.6%; P < .001) and in National Cancer Institute (NCI) high-risk vs standard-risk patients, respectively (n = 138/957; 14.4% vs n = 19/332; 5.7%; P < .001). Though, 22q11.22 deletions maintained prognostic significance among patients with IKZF1 alterations, regardless of MRD status or NCI risk group.

“The ability of 22q11.22 plus IKZF1 double deletions to robustly predict very poor prognosis could be used to identify pediatric patients with B-ALL who might benefit from novel therapies, such as immunotherapy, retinoids, or focal adhesion kinase inhibition. Moreover, risk stratification using these double deletions could lessen overtreatment of lower-risk patients with IKZF1 alterations with aggressive therapy, which is particularly important in patients with Down syndrome given their increased risk for toxic effects,” concluded the study authors.


  1. 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. Published online August 19, 2021. Accessed August 24, 2021. doi:10.1001/jamaoncol.2021.2723