Originally published by 2 Minute Medicine^® (view original article). Reused on AccessMedicine with permission.

1. 22q11.22 deletion alone was not associated with poor outcomes, but in combination with IKZF1 alteration predicted poor outcomes in pediatric B-cell acute lymphoblastic leukemia.

2.Patients with IKZF1 alteration without 22q11.22 deletion had relatively better outcomes than IKZF1 alteration with 22q11.22 deletion patients.

Evidence Rating Level: 2 (Good)

Study Rundown:

IKZF1 alterations on chromosome 7 that occur in 15% of pediatric B-cell acute lymphoblastic leukemia (B-ALL) are associated with poor 5-year event-free survival (EFS), with events including leukemia relapse, induction failure, secondary malignancy, or death. Some patients with IKZF1 alterations have excellent outcomes, suggesting the prognostic value of IKZF1 alterations is dependent on context. This study investigated whether a context that determines the prognostic value of IKZF1 alterations is 22q11.22 status. Specifically, it assessed whether double deletion (IKZF1 alteration and 22q11.22 focal deletion), compared to IKZF1 alteration alone decreased EFS and overall survival (OS). An IKZF1 alteration was defined as a loss of coding exons or an inactivating point variation, or somatic variation. EFS and OS were aggregated from eligible studies of B-ALL patients with IKZF1 alterations, 22q11.22 deletions, or double deletions. Patients with IKZF1 alterations had decreased 5-year EFS compared to those without. By contrast, patients with 22q11.22 deletion had comparable 5-year EFS and OS to those with wild-type (WT) 22q11.22. Patients with an IKZF1 alteration and 22q11.22 deletion had worse 5-year EFS and OS than patients with only 22q11.22 deletions or only IKZF1 alterations; those with double deletions had even worse outcomes. 22q11.22 was useful to predict the prognosis of some patient populations, like MRD or National Cancer Institute (NCI) high-risk patients, but not Ph-positive patients. On multivariate analysis, IKZF1 alteration patients with a 22q11.22 deletion were more at risk for lower EFS and OS than those with WT 22q11.22. One limitation of this meta-analysis is that gene expression data only was available for one included study, the P9906 cohort, so conclusions about the association of the 22q11.22 to nearby genes cannot occur. Additionally, many of the studies that were included in this meta-analysis, while high quality, occurred at a time before the understanding of the importance of Ph-like phenotype in ALL was known, and so Ph-like patients were not routinely identified, leading to a more conservative estimate of the effect of 22q11.22 deletion status in this subgroup analysis.

Click to read the study in JAMA Oncology

Relevant Reading:IKZF1 alterations in acute lymphoblastic leukemia: The good, the bad and the ugly

In-Depth [retrospective cohort]:

Data on the leukemia and germline copy number profile of pediatric patients with newly diagnosed B-ALL was aggregated from studies done in Utah, the Children’s Oncology Group (COG) P9906, COG AALL0232, St Jude Hospital, and Children’s Hospital of Philadelphia. B-ALL patients had frequent 22q11.22 deletions in the λ light chain that varied in size (mode = 12 kb; maximum = 142 kb). 53.2% of the 299 patients with IKZF1 alterations had a 22q11.22 deletion. 12.1% of the 1310 patients in the meta-analysis had a double deletion. Patients with only an IKZF1 alteration had decreased 5-year EFS (68.5% vs 81.2%, hazard ratio [HR] = 1.84; 95% CI = 1.34-2.51, P < 0.001) and OS (83.9% vs 87.3%; HR = 1.73, 95% CI = 1.15-2.60, P = 0.01) compared to those with WT IKZF1. Patients with only a 22q11.22 deletion had comparable outcomes to those without the deletion. Patients with both IKZF1 alterations and 22q11.22 deletions had worse outcomes than patients with only IKZF1 alterations (5-year EFS: 26.4% vs 59%, HR = 2.62, 95% CI = 1.33-5.16, P = 0.004; OS: 64.2%vs 92.4%, HR = 2.62, 95% CI = 1.11-6.2, P = 0.02). The outcomes were even worse for 22q11.22 and IKZF1 double deletion patients compared to those with only IKZF1 alterations for 5-year EFS (43.3% vs 68.5%, HR = 2.18; 95% CI = 1.54-3.07, P < 0.001) and OS (66.9% vs 83.9%; HR = 2.05, 95% CI = 1.32-3.21, P = 0.001). 72.7% of Down syndrome patients with IKZF1 alteration also had a 22q11.22 deletion. 22q11.22 deletions occurred more with certain genetic abnormalities, including BCR-ABL1 translocations (52.9%) or ETV6-RUNX1 alterations (67.0%). Double deletions of 22q11.22 and IKZF1 were common in the in Ph-like ALL patients (54.1%), MRD positive (≥0.01%) patients (28.7% vs 7.6%, P < 0.001), and National Cancer Institute (NCI) high-risk patients (14.4% vs 5.7%, P < 0.001). Ph-positive patients had worse prognosis if they had an IKZF1 alteration, regardless of 22q11.22 status. But 22q11.22 status was useful to predict the prognostic effect of IKZF1 alteration in MRD positive and NCI high-risk patients. IKZF1^plus deletion (co-deletion of IKZF1 and PAX5 or homozygous CDKN2A/B without ERG deletion), correlated with 22q11.22 deletion (Pearson correlation = 0.21, P < 0.001). IKZF1^plus deletion patients with 22q11.22 deletion had worse the outcomes than those with only IKZF^plus deletion (5-year EFS: 32.5% vs 68.8%, HR = 3.02, 95% CI = 1.65-5.55, P < 0.001; OS: 56.4% vs 80.4%, HR = 2.61, 95% CI = 1.26-5.42, P = 0.01). Multivariate analysis demonstrated that 22q11.22 status interacted with BCR-ABL1 status to influence EFS and OS. Given the importance of BCR-ABL1 to treatment status, it was used as a variable in subgroup analysis. In IKZF1 alteration patients, 22q11.22 deletion was a risk factor for decreased EFS (HR = 2.05, 95% CI = 1.27-3.29, P = 0.003) and OS (HR = 1.83, 95% CI = 1.01-3.34, P = 0.05).

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