Concurrent deIetions of IKZF1 and PAX5, CDKN2A, CDKN2B or PAR1 (IKZF1plus) confer a very poor prognosis in pediatric acute lymphoblastic leukemia

Recently, we described GATA3 (rs3824662) as a new susceptibility locus for pediatric acute lymphoblastic leukemia (ALL; Blood;122:3298 – 3307). The variant GATA3 allele was specifically associated with so-called B-other ALL and conferred a dismal outcome. Here, we analyzed in 500 patients treated on trial AIEOP-BFM 2000 which somatic genetic aberrations describe the group of B-other ALLs associated with rs3824662 to identify the leukemia genetics underlying the prognostic effect of GATA3 germline genetic variation. GATA3 rs3824662 genotype was negatively associated with hyperdiploidy and positively associated with prednisone poor-response, higher loads of minimal residual disease (MRD), and deletions of IKZF1, PAX5, CDKN2A and CDKN2B. In single marker analyses, IKZF1 deletion was the strongest determinator of outcome in the discovery and in an independent validation cohort (n = 599). When IKZF1 deletions were analyzed in combination with PAX5, CDKN2A, CDKN2B or previously described prognostic PAR1 deletions, additional deletions to that of IKZF1 conferred the worst outcome (Blood 2010;115:5293 – 5397). Consequently, we defined a group by presence of IKZF1 deletion and at least an additional deletion in PAX5, CDKN2A, CDKN2B or PAR1. This IKZF1 ^plus-termed group had a very poor outcome: 5-year event-free survival 55%± 0.07 compared to 85%± 0.01 in IKZF1 ^plus-negatives (p < 0.0001); 5-year-cumulative incidence of relapse 42%± 0.07 compared to 11%± 0.01 (p < 0.0001). In multivariate analyses including MRD, slow early response, prednisone response, ETV6/RUNX1 status, and WBC (≥100.000/µl), IKZF1 ^plus displayed the highest hazard ratio for relapse (3.29; 95% CI 2.01 – 5.38; p < 0.001). The definition of IKZF1plus will aid in the clinical implementation of newly detected markers for risk stratification in pediatric ALL.