Prognostic significance of IKZF1 deletions and IKZF1plus profile in children with B-cell precursor acute lymphoblastic leukemia treated according to the ALL-IC BFM 2009 protocol

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.

Automated summary

The presence of minimal residual disease (MRD) and specific molecular abnormalities, such as IKZF1 gene aberrations, are strong predictors of outcome in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). A recently-defined IKZF1-plus microdeletion profile can provide additional predictive value for treatment outcome in childhood BCP-ALL and contribute to more efficient patient stratification.