Prognostic significance of <i>IKZF1</i> deletions and IKZF1 ^plus profile in children with B‐cell precursor acute lymphoblastic leukemia treated according to the ALL‐IC BFM 2009 protocol

Abstract

The strongest predictors of outcome in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are minimal residual disease (MRD) and specific molecular abnormalities. One unfavorable prognostic factor is the presence of IKZF1 gene aberrations, particularly when co-occurring with high MRD level at the end of induction treatment. The present study determines the predictive value of a recently-defined IKZF1-plus (IKZF1^plus ) microdeletion profile in 373 children with BCP-ALL treated according to the ALL-intercontinental Berlin-Frankfurt-Munster protocol 2009 protocol. IKZF1-wild type (IKZF1^wt ) patients demonstrated lower leukemic burden parameters than those carrying IKZF1 deletion (IKZF1^del [n = 26, 7.0%]) or IKZF1^plus pattern (n = 34, 9.1%): (i) median blast percentage at diagnosis (78.0% vs. 86.9% vs. 86.0%; p = 0.021); (ii) median MRD level at day 15 of induction protocol (0.3% vs. 2.1% vs. 0.8%; p = 0.011); (iii) poor steroid response (7.6% vs. 26.5% vs. 12.5%; p = 0.010). Minimal residual disease level at day 33 (MRD33) exceeding 10^-4 was more frequently observed in both the IKZF1^del and IKZF1^plus subgroups than in IKZF1^wt patients (n = 9 [36.0%] vs. n = 13 [41.9%] vs. n = 70 [24.0%], p = 0.051). IKZF1^plus individuals showed a tendency for a lower MRD reduction between day 15 and 33 compared to IKZF1^del patients (p = 0.124). IKZF1^del and IKZF1^plus patients showed decreased relapse-free survival (HR [95%CI] for IKZF1^wt as reference = 2.72 [1.21-6.11] and 2.00 [0.87-4.49], respectively, p = 0.023). Both genetic markers including IKZF1^del and IKZF1^plus microdeletion profile provide additional predictive value of treatment outcome in childhood BCP-ALL and may contribute to more efficient patient stratification; the same is true in MRD guided protocols, which are based on flow cytometric measurements on day 15 of induction protocol.