IKZF1 deletions predict a poor prognosis in children with B-cell progenitor acute lymphoblastic leukemia: a multicenter analysis in Taiwan

Abstract

Despite current risk-directed therapy, approximately 15-20% of pediatric patients with acute lymphoblastic leukemia (ALL) have relapses. Recent genome-wide analyses have identified that an alteration of IKZF1 is associated with very poor outcomes in B-cell progenitor ALL. In this study, we determined the prognostic significance of IKZF1 deletions in patients with childhood ALL. This study analyzed 242 pediatric B-cell progenitor ALL patients in Taiwan. We developed a simple yet sensitive multiplex quantitative PCR coupled with capillary electrophoresis to accurately determine the allele dose of IKZF1, and high resolution melting was used for mutation screening for all coding exons of IKZF1. Twenty-six (10.7%) pediatric B-cell progenitor ALL patients were found to harbor these deletions. Most of the deletions were broader deletions that encompassed exon 3 to exon 6, consistent with previous reports. Genomic sequencing of IKZF1 was carried out in all cases and no point mutations were identified. Patients with IKZF1 deletions had inferior event-free survival (P < 0.001), and overall survival (P = 0.0016). The association between IKZF1 deletions and event-free survival was independent of age, leukocyte count at presentation, and cytogenetic subtype by multivariate Cox analysis (P = 0.003, hazard ratio = 2.45). This study indicates that detection of IKZF1 deletions upon diagnosis of B-cell progenitor ALL may help to identify patients at risk of treatment failure. IKZF1 deletions could be incorporated as a new high-risk prognostic factor in future treatment protocols. To the best of our knowledge, this is the first study to examine the poor prognosis of IKZF1 deletions in an Asian population.

Figure 1

Separation of amplified DNA fragments by capillary electrophoresis on the high‐performance DNA analysis (HDA) system. (A) Multiplex PCR I with FGFR2, exons 1, 3, and 5 of IKZF1 gene. (B) multiplex PCR II with FGFR2, exons 2, 4, and 6 of IKZF1 gene. Arrows indicate the deletion of the target exon.

Figure 2

Survival curves of childhood acute lymphoblastic leukemia patients with and without IKZF1 deletions. (A,B) All patients with acute lymphoblastic leukemia who participated in this study (n = 242). (C,D) Patients from this study who were grouped as high‐risk and very high‐risk. Non, wild‐type IKZF1; Del, deletions of IKZF1.

Figure 3

Survival curves of childhood acute lymphoblastic leukemia patients in this study. (A,B) Comparison of 5‐year event‐free survival (EFS) and overall survival (OS) for patients treated with TPOG‐ALL‐2002 or TPOG‐ALL‐93 + TPOG‐97‐VHR protocols. (C,D) Comparison of EFS and OS for patients with or without IKZF1 deletions treated with TPOG‐ALL‐93 and TPOG‐97‐VHR. (E,F) Comparison of EFS and OS for patients with or without IKZF1 deletions treated with TPOG‐ALL‐2002.