Refining risk stratification in paediatric B‐acute lymphoblastic leukaemia: Combining IKZF1plus and Day 15 MRD positivity

Summary This study investigates the potential utility of IKZF1 deletion as an additional high‐risk marker for paediatric acute lymphoblastic leukaemia (ALL). The prognostic impact of IKZF1 status, in conjunction with minimal/measurable residual disease (MRD), was evaluated within the MRD‐guided TPOG‐ALL‐2013 protocol using 412 newly diagnosed B‐ALL patients aged 1–18. IKZF1 status was determined using multiplex ligation‐dependent probe amplification. IKZF1 deletions, when co‐occurring with CDKN2A , CDKN2B , PAX5 or PAR1 region deletions in the absence of ERG deletions, were termed IKZF1 plus . Both IKZF1 deletion (14.6%) and IKZF1 plus (7.8%) independently predicted poorer outcomes in B‐ALL. IKZF1 plus was observed in 4.1% of Philadelphia‐negative ALL, with a significantly lower 5‐year event‐free survival (53.9%) compared to IKZF1 deletion alone (83.8%) and wild‐type IKZF1 (91.3%) ( p < 0.0001). Among patients with Day 15 MRD ≥0.01%, provisional high‐risk patients with IKZF1 plus exhibited the worst outcomes in event‐free survival (42.0%), relapse‐free survival (48.0%) and overall survival (72.7%) compared to other groups ( p < 0.0001). Integration of IKZF1 plus and positive Day 15 MRD identified a subgroup of Philadelphia‐negative B‐ALL with a 50% risk of relapse. This study highlights the importance of assessing IKZF1 plus alongside Day 15 MRD positivity to identify patients at increased risk of adverse outcomes, potentially minimizing overtreatment.