Impact of IKZF1 Deletions in the Prognosis of Childhood Acute Lymphoblastic Leukemia in Argentina

SIMPLE SUMMARY: An association of deletions in the IKZF1 gene (IKZF1del) with poor prognosis in acute lymphoblastic leukemia (ALL) has been demonstrated. However, the co-occurrence of IKZF1del with deletions in other genes (IKZF1plus) seems to better define prognosis. Our aim was to analyze the influence of IKZF1del and/or IKZF1plus profiles on the survival of children with ALL. We analyzed 1023 eligible cases who were classified into three subsets: IKZF1not-del: IKZF1-not-deleted (n = 835), IKZF1del: IKZF1deleted (n = 94) and IKZF1plus: IKZF1del plus deletion of other genes (n = 94). Leukemia-free-survival probability (standard deviation) (LFSp(SE)) was 75 (2)% for IKZF1not-del, 51 (6)% for IKZF1del and 48 (6)% for IKZF1plus (p-value < 0.00001). The LFSp(SE) according to ALL-IC risk-group stratification showed a statistically significant difference within Intermediate-Risk patients, LFSp (SE) being 77 (2)% for IKZF1not-del, 61 (10)% for IKZF1del and 54 (7)% for IKZF1plus (p-value = 0.0005). The LFSp(SE) of the high-risk group was: 61 (4)% IKZF1not-del, 38 (8)% IKZF1del and 35 (9)% IKZF1plus (p-value = 0.0102). Thus, the IKZF1 status was shown to define a population of patients with a poor outcome, mainly in those with intermediate risk. However, not-significant differences were observed between the LFSp of IKZF1del versus IKZF1plus groups. The study of the IKZF1 status should be incorporated into the risk-group stratification of pediatric ALL. ABSTRACT: An association of deletions in the IKZF1 gene (IKZF1del) with poor prognosis in acute lymphoblastic leukemia (ALL) has been demonstrated. Additional deletions in other genes (IKZF1plus) define different IKZF1del subsets. We analyzed the influence of IKZF1del and/or IKZF1plus in the survival of children with ALL. From October 2009 to July 2021, 1055 bone marrow samples from patients with ALL were processed by Multiplex ligation-dependent probe amplification (MLPA). Of them, 28 patients died during induction and 4 were lost-in-follow-up, resulting in an eligible 1023 cases. All patients were treated according to ALLIC-BFM-2009-protocol. Patients were classified into three subsets: IKZF1not-deleted (IKZFF1not-del), IKZF1deleted (IKZF1del) and IKZF1del plus deletion of PAX5, CDKN2A, CDKN2B and/or alterations in CRLF2 with ERG-not-deleted (IKZF1plus). The LFSp and SE were calculated with the Kaplan–Meier calculation and compared with a log-rank test. From the 1023 eligible patients, 835 (81.6%) were defined as IKZF1not-del, 94 (9.2%) as IKZF1del and 94 (9.2%) as IKZF1plus. Of them, 100 (9.8%) corresponded to Standard-Risk (SRG), 629 (61.5%) to Intermediate-Risk (IRG) and 294 (28.7%) to High-Risk (HRG) groups. LFSp(SE) was 7 5(2)% for IKZF1not-del, 51 (6)% for IKZF1del and 48 (6)% for IKZF1plus (p-value < 0.00001). LFSp(SE) according to the risk groups was: in SRG, 91 (4)% for IKZF1not-del, 50 (35)% IKZF1del and 100% IKZF1plus (p-value = ns); in IRG, 77 (2)% IKZF1not-del, 61 (10)% IKZF1del and 54 (7)% IKZF1plus (p-value = 0.0005) and in HRG, 61 (4)% IKZF1not-del, 38 (8)% IKZF1del and 35 (9)% IKZF1plus (p-value = 0.0102). The IKZF1 status defines a population of patients with a poor outcome, mainly in IRG. No differences were observed between IKZF1del versus IKZF1plus. MLPA studies should be incorporated into the risk-group stratification of pediatric ALL.