IKZF1 Deletions and Risk Stratification in Paediatric B-Cell Precursor Acute Lymphoblastic Leukemia

Abstract

IKZF1 deletion is among the most reproducible adverse genetic markers in childhood leukaemia and is routinely described as an independent prognostic factor. The refined version of the marker turns out to carry almost no independent weight at all: its effect is conditional on measurable residual disease, and in good responders it disappears. Objectives: To review the published evidence on IKZF1 deletions in paediatric B-cell precursor acute lymphoblastic leukaemia: how often they occur, what they predict, how the refined IKZF1plus profile behaves across residual disease strata, and what role the marker should play in risk stratification. Material and Methods: Narrative review of cooperative group trial analyses, population-based cohorts, international collaborative studies and mechanistic work indexed in PubMed and the major haematology journals. Studies were eligible if they reported the frequency, prognostic effect or biological consequences of IKZF1 alteration in a defined paediatric B-cell precursor acute lymphoblastic leukaemia population. No new patient data were generated and no patients were recruited; every estimate quoted is one published by the original investigators. Results: IKZF1 deletion occurs in approximately 15 per cent of cases. In a population-based cohort of 334 children, deletion was associated with ten-year event-free survival of 60 against 83 per cent (p < 0.001) and overall survival of 73 against 89 per cent (p = 0.001), and remained the strongest independent factor for relapse and death after adjustment for white cell count and residual disease. Screening 694 samples from a separate trial gave five-year event-free survival of 0.69 against 0.85 (p < 0.0001) with cumulative relapse of 0.21 against 0.10 (p = 0.001). The refined IKZF1plus profile behaved very differently across residual
disease strata: five-year event-free survival was 94 per cent in residual disease standard-risk patients, 40 per cent in intermediate-risk and 30 per cent in high-risk (p ≤ 0.001), with corresponding relapse incidences of 6, 60 and 60 per cent. Conclusion: The unrefined deletion carries independent prognostic weight; the refined profile does not, behaving instead as a modifier that identifies very poor
prognosis only among patients already flagged by residual disease. A child with the adverse genotype and a clean day-33 marrow has a 94 per cent event-free survival. Abbreviations: ALL – Acute Lymphoblastic Leukaemia, BCP-ALL – B-Cell Precursor ALL, IKZF1 – IKAROS Family Zinc Finger 1, ∆IKZF1 – IKZF1 Deletion, MRD – Minimal Residual Disease, EFS – Event-Free Survival, OS – Overall Survival, RFS – Relapse-Free Survival, MLPA – Multiplex Ligation-Dependent Probe Amplification, SNP – Single Nucleotide Polymorphism, WBC – White Blood Cell Count, HR – Hazard Ratio.