Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia

Abstract

Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-progenitor acute lymphoblastic leukemia (B-ALL). The relationship between the type of IKZF1 alteration, B-ALL genomic subtype and outcome are incompletely understood. B-ALL subtype and genomic alterations were determined using transcriptome and genomic sequencing, and SNP microarray analysis in 688 pediatric patients with B-ALL in the St. Jude Total Therapy XV and 16 studies. IKZF1 alterations were identified in 115 (16.7%) patients, most commonly in BCR::ABL1 (78%) and CRLF2-rearranged, BCR::ABL1-like B-ALL (70%). These alterations were associated with 5-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration (P < 0.0001). In separate multivariable analyses adjusting for genetic subtype groups and other factors, IKZF1 deletions of exons 4-7 (P = 0.0002), genomic IKZF1^plus with any IKZF1 deletion (P = 0.006) or with focal IKZF1 deletion (P = 0.0007), and unfavorable genomic subtypes (P < 0.005) were independently adverse prognostic factors. Associations of genomic IKZF1^plus and exon 4-7 deletions with adverse outcomes were confirmed in an independent cohort. The type of IKZF1 alteration, together with the subtype, are informative for risk stratification and to predict response in patients with B-ALL.

Figure 1.. Frequency of IKZF1 alterations within B-ALL genetic subtypes, in eligible patients with B- ALL in the Total XV/16 study group (n=688), by classifications and definitions of Ikaros alterations.

A, Genomic IKZF1^plus (focal ΔIKZF1) and other alterations B, Genomic IKZF1^plus (any ΔIKZF1) and other alterations; C, IKZF1^plus (according to the original MLPA-based criteria) and other alterations IKZF1^plus definition is consistent with the published definition with PAR1 deletion serves as surrogate for P2RY8::CRLF2 fusions and ERG deletions are a surrogate of DUX4r (7). D, IKZF1 Δ4-7 and other alterations. Color-coded, stacked, horizontal bar graphs represent the proportion of patients with IKZF1 alterations (X axis) within respective subtypes (Y axis). The classification legend for parts A-D is located below each graph and describes the color and number associated with each IKZF1 alteration. Definitions of alterations are shown on Table 1. Any ΔIKZF1 includes −7/del(7p) and focal deletions. B-Other (n = 34) and rare subtypes (BCL2/MYC, CDX/UBTF, IKZF1 N159Y, TCF3::HLF, and ZEB2/CEBP; n = 6) detected in 2 or fewer patients are not included. Mutation: missense, nonsense, or frameshift mutations.

Figure 2.. Outcomes of patients with or without any IKZF1 alterations in the Total XV/16 study group.

A, Event-free survival (EFS) and B, Cumulative Incidence of Relapse (CIR) for patients based on presence or absence of IKZF1 deletion or mutations in studied patients. IKZF1 deletion includes focal IKZF1 deletions, −7/del(7p). mut: missense, nonsense or frameshift mutations.

Figure 3.. Outcomes based on type of IKZF1 alterations, including IKZF1^plus (genomic, any ΔIKZF1) and sequence mutations in the Total XV/16 study group.

A, Event-free survival (EFS) and B, Cumulative Incidence of Relapse (CIR). P values for pairwise comparisons for 5-year EFS compared to the no IKZF1 alteration group are < 0.0001 for IKZF1^plus group, 0.0006 for IKZF1 deletions only, and 0.19 for IKZF1 mutations. Alteration groups are mutually exclusive; data are shown for patients with only one type of alteration. IKZF1 deletions (ΔIKZF1) are defined as focal IKZF1 deletions or −7/del(7p). Mutations: missense, nonsense or frameshift mutations.

Figure 4.. Outcomes based on type of IKZF1 alteration (IKZF1 Δ4-7 or not) and subtype group in the Total XV/16 study group.

A, Event-free survival (EFS) and B, Cumulative Incidence of Relapse (CIR) for patients based on type of focal IKZF1 deletions (IKZF1 Δ4-7 or not) or other IKZF1 alterations (missense or frameshift mutations or −7/del(7p)), and presence or absence of unfavorable subtype group, among eligible patients with B-ALL. Five-year EFS and CIR are shown on Table 4. Alteration groups are mutually exclusive; data are shown for patients with only one type of alteration.