Prognostic significance of <i>IKZF1</i> deletions and IKZF1 <sup>plus</sup> profile in children with B‐cell precursor acute lymphoblastic leukemia treated according to the ALL‐IC BFM 2009 protocol
Marcin Braun, Agata Pastorczak, Łukasz Sędek, Joanna Taha, Joanna Madzio, Izabela Jatczak‐Pawlik, Kamila Wypyszczak, Michał Matysiak, Katarzyna Derwich, Monika Lejman, Bernarda Kazanowska, Tomasz Szczepański, Jerzy Kowalczyk, Wojciech Młynarski, the Polish Pediatric Leukemia/Lymphoma Study Group
Abstract
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.