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

Ruth W Wang’ondu; Emily Ashcraft; Ti-Cheng Chang; Kathryn G Roberts; Samuel W Brady; Yiping Fan; William Evans; Mary V Relling; Kristine R Crews; Jun Yang; Wenjian Yang; Stanley Pounds; Gang Wu; Meenakshi Devidas; Kelly Maloney; Leonard Mattano; Reuven J Schore; Anne Angiolillo; Eric Larsen; Wanda Salzer; Michael J Burke; Mignon L Loh; Sima Jeha; Ching-Hon Pui; Hiroto Inaba; Cheng Cheng; Charles G Mullighan

doi:10.1038/s41375-025-02633-3

. Author manuscript; available in PMC: 2026 Jan 4.

Published in final edited form as: Leukemia. 2025 May 13;39(7):1595–1606. doi: 10.1038/s41375-025-02633-3

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

Ruth W Wang’ondu ¹, Emily Ashcraft ², Ti-Cheng Chang ³, Kathryn G Roberts ^1,⁴, Samuel W Brady ⁵, Yiping Fan ³, William Evans ⁵, Mary V Relling ⁵, Kristine R Crews ⁵, Jun Yang ⁵, Wenjian Yang ⁵, Stanley Pounds ², Gang Wu ³, Meenakshi Devidas ⁶, Kelly Maloney ⁷, Leonard Mattano ⁸, Reuven J Schore ⁹, Anne Angiolillo ¹⁰, Eric Larsen ¹¹, Wanda Salzer ¹², Michael J Burke ¹³, Mignon L Loh ¹⁴, Sima Jeha ⁶, Ching-Hon Pui ^6,¹⁵, Hiroto Inaba ¹⁵, Cheng Cheng ², Charles G Mullighan ^1,⁴

¹Department of Pathology, St. Jude Children’s Research Hospital, Memphis TN, USA

²Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis TN, USA

³Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis TN, USA

⁴Center of Excellence for Leukemia Studies, St. Jude Children’s Research Hospital, Memphis TN, USA

⁵Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis TN, USA

⁶Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis TN, USA

⁷Department of Pediatrics and Children’s Hospital Colorado, University of Colorado, Aurora CO, USA

⁸HARP Pharma Consulting, Mystic CT, USA

⁹Division of Oncology, Center for Cancer and Blood Disorders, Children’s National Hospital, Washington DC, USA and Department of Pediatrics and Clinical and Translational Oncology Program, George Washington University School of Medicine and Health Sciences, Washington DC, USA

¹⁰Servier Pharmaceuticals, Boston, MA, USA

¹¹Department of Pediatrics, Maine Children’s Cancer Program, Scarborough ME, USA

¹²Uniformed Services University, School of Medicine, Bethesda, MD, USA

¹³Division of Pediatric Hematology-Oncology, Medical College of Wisconsin, Milwaukee WI, USA

¹⁴Ben Towne Center for Childhood Cancer Research and the Department of Pediatrics, Seattle Children’s Hospital, University of Washington, and the Fred Hutchinson Cancer Center, Seattle, WA

¹⁵Department of Oncology, St. Jude Children’s Research Hospital, Memphis TN, USA

^✉

Corresponding author Charles G. Mullighan, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 342, Memphis, TN 38105, charles.mullighan@stjude.org

AUTHOR CONTRIBUTIONS

RWW, HI and CGM designed the study. EA, TC and CC performed statistical analysis. RWW, KGR, TC, SWB, YF and WY, interpreted genomic data and TC, SWB, YF, WY and GW processed and analyzed high-throughput sequencing data. WE, MVR, KRC, JY, SP, SJ, CP, MD, KM, LM, RJS, AA, EL, WS, MJB and MLL provided data. CGM supervised the project. All authors revised and approved the final version of the manuscript.

PMCID: PMC12759290 NIHMSID: NIHMS2125429 PMID: 40360879

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.

INTRODUCTION

Five-year survival rates for pediatric patients with acute lymphoblastic leukemia (ALL) exceed 90%, however relapses affect 10-20% of patients and remain a leading cause of death (1-5). Alterations in the IKZF1 tumor suppressor gene, encoding the lymphoid transcription factor IKAROS, are associated with increased risk for relapse even in the context of risk-directed therapy (6-11).

Somatic IKZF1 alterations are present in up to 15% of B-ALL cases and are heterogeneous, including broad and intragenic deletions and sequence mutations (6, 7, 9, 12-16). Deletions of exons 4-7 (Δ4-7) are the most common focal IKZF1 deletion, and result in the expression of the dominant negative IK6 isoform, which lacks the N-terminal DNA binding domains but retains the C-terminal dimerization domains (6, 12, 14). To refine the predictive power of IKZF1 alterations in B-ALL, the IKZF1^plus composite genotype has been described (7). It utilizes targeted DNA copy number profiling by multiplex-ligation dependent probe amplification (MLPA) assays to identify IKZF1 deletions co-occurring with deletions of either PAX5, CDKN2A, CDKN2B (homozygous deletion) or the pseudoautosomal region 1 (PAR1) at Xp22.33/Yp11.31 (as a surrogate for P2RY8::CRLF2), which are enriched in high-risk leukemia subtypes such as BCR::ABL1-like ALL; but excludes cases with deletion of ERG, which is common in favorable risk DUX4-rearranged (DUX4r) ALL (7, 8, 10, 17-19).

Although IKZF1 alterations are associated with poor outcome overall in ALL (6, 9, 11, 20-28), and several reports suggest that the IKZF1^plus genotype identifies a higher risk group of patients than those with IKZF1 alterations alone (7, 17, 18), the relationship between IKZF1 alterations and outcomes remains incompletely understood for several reasons. Many studies have been limited to specific subtypes of leukemia or risk groups or have relied solely on the MLPA assay to define IKZF1^plus, which does not detect all CRLF2 (CRLF2r) or DUX4 (DUX4r) rearrangements, and may overcall IKZF1 alterations by including those cases with aneuploidy of chromosome 7 (7). Moreover, most studies have not considered the full molecular landscape of B-ALL defined by recent genomic studies (29, 30). Thus, the full nature of interaction between the type of IKZF1 alteration, concomitant genetic alterations, and genomic subtype in the context of contemporary risk-adapted therapy is not understood.

Here, using genomic analyses to characterize a wide spectrum of alterations and genetic subtypes of B-ALL, we studied the impact of IKZF1 alterations on the outcome of pediatric patients enrolled in the St. Jude Total Therapy XV and 16 studies. Associations between IKZF1 alterations, subtypes and outcomes were also examined in a cohort of children with NCI standard risk (SR) B-ALL or high-risk (HR) B-ALL, with favorable cytogenetic features, from the Molecular Profiling to Predict Responses to Therapy (MP2PRT) study (31). We identified the combination of IKZF1 Δ4-7 and unfavorable genomic subtype and genomics-based definition of IKZF1^plus with focal IKZF1 deletions as optimal predictors of relapse in children with B-ALL.

DESIGN AND METHODS

Patients, risk stratification, and diagnosis

Patients enrolled on Total Therapy XV (Total XV) (2), (NCT00137111 (n=498) from June 2000 to October 2007) and on Total Therapy 16 (Total 16) (32), NCT00549848 (n=598) from October 2007 to March 2017. Eligibility for this study was assessed for 916 children with B-ALL (Fig. S1) with 688 patients, for whom sufficient genomic data were available, selected for study (Table S1). Study protocols were approved by the institutional review boards of St. Jude Children’s Research Hospital and Cook Children’s Hospital. Studies were conducted in accordance with the Declaration of Helsinki. Written consent was obtained from the parents or guardians and assent from the patients, as appropriate.

Low-risk presenting features were age between 1 and 10 years at diagnosis with white blood cell count (WBC) of < 50 × 10³/μL, DNA index ≥ 1.16 as a surrogate for high hyperdiploidy, or the presence of ETV6::RUNX1, without the following: TCF3::PBX1, hypodiploidy (< 44 chromosomes), testicular leukemia, CNS-3 status ( ≥ 5 leukocytes/μL present in the cerebrospinal fluid with blasts or cranial palsy) at diagnosis, minimal/measurable residual disease (MRD) ≥ 1% on day 19 (Total XV) or day 15 (Total 16) of induction or MRD ≥ 0.01% at end of induction (EOI). Patients with BCR::ABL1, patients with EOI MRD ≥ 1% or persistent MRD during the consolidation phase were classified as having high-risk ALL. In Total Therapy 16, infants with KMT2A rearrangement (KMT2Ar) were considered high-risk. All other patients were considered to have standard-risk (SR) ALL. MRD was monitored by flow cytometry.

The MP2PRT study group comprised 1496 pediatric patients with predominantly SR B-ALL, 1360 patients from AALL0331 (33, 34) and AALL0932 (35, 36) with favorable and neutral cytogenetics) or HR B-ALL, 115 patients from AALL0232 (3, 4) and AALL1131 (37) with favorable cytogenetics (31) (Table S2 and Supplemental methods).

Ethics approval and consent to participate

All methods were performed in accordance with the relevant guidelines and regulations. Approval for the study was obtained from the Institutional Review Board of St. Jude Children’s Research Hospital (IRB #00000029, FWA00004775). Informed consent and/or assent was obtained from research subjects and/or their legal guardians.

Definitions of IKZF1^plus and IKZF1 deletions

Genetic and genomic analyses are described in supplementary methods. Different studies have used different types of IKZF1 alterations including deletions varying in size, dominant negative mutants or sequence mutations, and the composite IKZF1^plus genotype, which are not mutually exclusive and cannot be directly compared in a single analysis. Consequently, we have used the following approach to compare different types of variants and co-alterations. Three definitions of IKZF1^plus were used, varying based on the size of the IKZF1 deletion (ΔIKZF1) and the comprehensiveness of detection of CRLF2 and DUX4 rearrangement: 1) “genomic IKZF1^plus (focal ΔIKZF1)” includes focal [≤20 Mb] IKZF1 deletions and all CRLF2 rearrangements (CRLF2r), PAX5 deletions or CDKN2A or CDKN2B (homozygous) deletions, and excludes all cases with DUX4r; 2) “genomic IKZF1^plus (any ΔIKZF1)” which considers any IKZF1 deletion (including −7/del(7p) and focal deletions), and includes all CRLF2 rearrangements (CRLF2r), PAX5 deletions or CDKN2A or CDKN2B (homozygous) deletions, and excludes all cases with DUX4r; 3) “IKZF1^plus”, according to the original MLPA-based criteria (7), with any IKZF1 deletion (including −7/del(7p) and focal deletions) and PAR1 deletion, as a surrogate for CRLF2r, or deletions of PAX5 or CDKN2A or CDKN2B (homozygous), and excludes cases with ERG deletion, as a surrogate for DUX4r. The IKZF1 Δ4-7 focal deletion represented deletion of genomic exons 4-7, which encodes the dominant negative IK6 allele (Table 1). Definitions of genomic subtypes for B-ALL (Table 2) have been previously described (29, 38-40).

Table 1. Definitions of IKZF1 alterations.

Alteration type	Definition
Genomic IKZF1^plus (focal ΔIKZF1)	Focal (≤20 Mb) IKZF1 deletions only and any CRLF2 rearrangement (including IGH::CRLF2 and P2RY8::CRLF2), or PAX5 deletion, any CDKN2A deletion or homozygous CDKN2B deletion, and absence of DUX4 rearrangement
Genomic IKZF1^plus (any ΔIKZF1)	Any IKZF1 deletion (including −7/del(7p) and focal deletions) and any CRLF2 rearrangement (including IGH::CRLF2 and P2RY8::CRLF2), or PAX5 deletion, any CDKN2A deletion or homozygous CDKN2B deletion, and absence of DUX4 rearrangement
IKZF1 ^plus	Any IKZF1 deletion (including −7/del(7p) and focal deletions) and PAR1 deletion, as a surrogate for CRLF2r, or deletions of PAX5 or CDKN2A or CDKN2B (homozygous), and excludes cases with ERG deletion, as a surrogate for DUX4r – according to the original MLPA-based criteria (7)
Focal IKZF1 deletions only	Focal deletion, of up to 20 Mb, in chromosome 7 involving IKZF1, without whole chromosome or 7p deletion
Any ΔIKZF1 only	Any IKZF1 deletion (including −7/del(7p) and focal deletions)
IKZF1 mutations	Missense, non-sense, and frameshift mutations
IKZF1 Δ4-7 deletions	Focal IKZF1 deletions with deletion of genomic exons 4, 5, 6, and 7
Other focal IKZF1 deletions	Focal IKZF1 deletions which are not IKZF1 Δ4-7 deletions

Open in a new tab

Table 2. Criteria for B-ALL genomic subtypes.

Subtype	Criteria
B-Other	No criteria for other genomic B-ALL subtypes met
*BCL2::MYC*	BCL2, MYC or BCL6-rearrangement by RNA-seq. ^*
*BCR::ABL1*	BCR::ABL1 fusion by FISH or RNA-seq.^*
BCR::ABL1-like with CRLF2r	BCR::ABL1 GEP by PAM (coefficient ≥0.75) and/or grouping with BCR::ABL1 tSNE cluster, but lacking BCR::ABL1 fusion and with CRLF2 rearrangements
BCR::ABL1-like without CRLF2r	BCR::ABL1 GEP by PAM (coefficient ≥0.75) and/or grouping with BCR::ABL1 tSNE cluster, but lacking BCR::ABL1 fusion and without CRLF2 rearrangements
*CDX2/UBTF*	UBTF::ATXN7L3 fusion by RNAseq, high CDX2 expression by RNAseq, and grouping with CDX2/UBTF tSNE cluster
DUX4r	DUX4 rearrangement (most commonly IGH::DUX4) or high DUX4 expression by RNA-seq. ^*
*ETV6::RUNX1*	ETV6::RUNX1 fusion by FISH or RNA-seq.^*
ETV6::RUNX1-like	ETV6::RUNX1 GEP by PAM (coefficient ≥0.95) and grouping with ETV6::RUNX1 tSNE cluster, but lacking ETV6::RUNX1 fusion.
Hyperdiploidy	Greater than 50 chromosomes determined by cytogenetics or RNA-seq CNV ^*
iAMP21	intrachromosomal amplification of chromosome 21 detected by FISH or DNA CNA.
IKZF1 N159Y	IKZF1 N159Y mutation by RNA-seq or DNA-seq. ^**
KMT2Ar	KMT2A-rearrangement by FISH or RNA-seq.^*
Low hypodiploid	Chromosome number determined by cytogenetics or RNA-seq CNV.
MEF2Dr	MEF2D-rearrangement by RNA-seq.^*
NUTM1r	NUTM1-rearrangement by RNA-seq. ^**
Near haploid	Chromosome number determined by cytogenetics or RNA-seq CNV. GEP by PAM similar to hyperdiploid.
PAX5 P80R	PAX5 P80R mutation by RNA-seq or DNA-seq. ^*
PAX5alt	PAX5alt GEP by PAM (coefficient ≥0.75) and/or grouping with PAX5alt tSNE cluster.
*TCF3::HLF*	HLF-rearrangement by RNA-seq. ^**
*TCF3::PBX1*	TCF3::PBX1 fusion by FISH or RNA-seq.^*
*ZEB2/CEBP*	ZEB2 H1038R mutation and/or IGH::CEBPE or IGH::CEBPA rearrangement by RNA-seq.^**
ZNF384r	ZNF384-rearrangement by RNA-seq.^*

Open in a new tab

Distinct gene expression profile (GEP) with Prediction Analysis of Microarrays (PAM) and t-distributed stochastic neighbor embedding (tSNE) cluster.

^**

Distinct tSNE cluster.

CNV: copy number variant

Of the 916 patients with B-ALL in the Total XV/16 cohorts, 228 patients did not have sufficient genomic data, resulting in 688 evaluable patients. The analysis cohort had a lower frequency of self-identified white patients (79.4% vs 83.3%), a higher frequency of self-identified black patients (15.4% vs 8.3%; P = 0.009), and a greater proportion of patients with presenting peripheral blood white cell count of ≥ 10,000, including those with WBC ≥ 100,000; 8.7% vs 4.4%; P < 0.0001 compared to patients with insufficient genomic data; All other clinical features were comparable between the two groups (Table S3). Differences in the distribution of genomic subtypes were inclusion of all patients with BCR::ABL1 B-ALL in the studied cohort and a higher percentage of undefined genomic subtypes (B other) in the unstudied group (Table S4; P = 0.0004).

Statistical Analysis for the Total XV/16 study groups

Associations between IKZF1 alterations and other variables were assessed by Chi squared or Fisher's exact tests. Event-free survival (EFS) was defined as the time from diagnosis to the date of last follow-up in complete remission (censored time) or first adverse event. Adverse events included relapse (hematologic, isolated CNS, CNS and ocular relapse, testicular, or any combination), secondary malignancy, lineage switch, or death of any cause. Early death during remission induction and non-response to induction therapy were considered as events at time zero. Mean EFS probabilities were estimated using the Kaplan-Meier method, with standard errors (SE) and compared using the log rank test. The cumulative incidence of any relapse was calculated with the method of Kalbfleisch and Prentice (accounting for competing risk), with SE, and was compared between groups using Gray’s test. Cox regression models were used to estimate hazard ratios, with 95% confidence interval (CI), and assess independent effects of prognostic factors. All statistical tests were two-sided with a significance level set at P ≤ 0.05. All cox regression models included a time interaction term to account for time-dependent covariate effects. Statistical analyses were performed using SAS 9.4 and RStudio version 4.1.2.

RESULTS

Frequency of IKZF1 alterations among B-ALL subtypes

In the Total XV/16 selected study group, alterations in IKZF1 were detected in 16.7% of patients (115 out of 688), 13.2% with IKZF1 deletions (both focal and −7/del(7p)), 2.9% with IKZF1 mutations and 0.6% with a combination of deletions and mutations (Fig. S2, A). Genomic IKZF1^plus (any ΔIKZF1) was detected in 44 (6.4%) patients (Fig. S2, B). IKZF1 p.R162P was present in matched non-tumor material obtained at remission, suggesting it was germline, whereas all other mutations were somatic (Fig. S2, C). Among 56 patients with focal ΔIKZF1, Δ4-7 deletions were most frequent (32.1%). Other types of focal deletions such as deletion of the entire IKZF1 locus, and other focal deletions, were each present in less than 15% of patients with focal deletions. IKZF1 Δ4-7, non-IKZF1 Δ4-7 focal deletions, and −7/del(7p) were present in 2.6%, 5.5%, and 5.1% of all 688 studied patients, respectively (Fig. S2).

Patients in the Total Therapy XV/16 selected study group were classified into outcome-based subtype groups. Subtypes with 5-year EFS ≥ 94% were DUX4r, ETV6::RUNX1, hyperdiploid, and intrachromosomal amplification of chromosome 21 (iAMP21) and were grouped as favorable. Notably, patients with the iAMP21 subtype in the studied cohort had 5-year EFS of 100% without any relapse. BCR::ABL1-like without CRLF2r, ETV6::RUNX1-like, near haploid, PAX5alt, and TCF3::PBX1 subtypes, each associated with 5-year EFS ranging between 80% and 93%, were grouped as intermediate. CRLF2-rearranged BCR::ABL1-like, BCR::ABL1, low hypodiploid, and KMT2Ar B-ALL had 5-year EFS of 50-79% and were classified as unfavorable. With these criteria, outcomes for patients with defined subtypes in our cohort were divided into favorable (5-year EFS 95.8 ± 1% and CIR 3.5 ± 0.9%), intermediate (5-year EFS 87.3 ± 3% and CIR 8.7 ± 2.5%), and unfavorable subgroup (5-year EFS 67.7 ± 5.4% and CIR 21.6 ± 4.8%, P < 0.0001) (Fig. S3).

Prior studies examining IKZF1 alterations and outcomes in ALL, including IKZF1^plus have considered −7/del(7p) as IKZF1 deletions. The IKZF1^plus definition underestimates the frequency of CRLF2r and DUX4r as it cannot detect rearrangements directly but uses PAR1/ERG deletions as surrogates for these rearrangements, but these deletions are not present as in all cases with the corresponding rearrangement (7). To precisely define the frequency of IKZF1 alterations among B-ALL subtypes, we examined the frequencies of IKZF1 alterations in different subtypes (Fig. 1) for each classification of IKZF1 alterations (Table 1). We identified the frequencies of genomic IKZF1^plus (any ΔIKZF1) versus other alterations (Fig. 1A), IKZF1^plus versus other alterations (Fig. 1B), genomic IKZF1^plus (focal ΔIKZF1) versus other alterations (Fig. 1C), and IKZF1 Δ4-7 versus other alterations (Fig. 1D) in different subtypes.

Figure 1. — A, Genomic *IKZF1*^plus (focal Δ*IKZF1*) and other alterations B, Genomic *IKZF1*^plus (any Δ*IKZF1*) 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 *DUX4*r (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 Δ*IKZF1* 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.

Favorable subtypes had the lowest frequencies of IKZF1 alterations and IKZF1 deletions were enriched in BCR::ABL1 and BCR::ABL1-like (both CRLF2r and non-CRLF2r) ALL (Fig. 1). Compared to genomic IKZF1^plus (any ΔIKZF1) (Fig. 1A), IKZF1^plus misclassified 7% of DUX4r without ERG deletion as IKZF1^plus and 10% of IKZF1^plus with CRLF2r as IKZF1 deletions only (Fig. 1B). Genomic IKZF1^plus (focal ΔIKZF1) was identified most frequently in patients with BCR::ABL1-like ALL, and was present in 60% of BCR::ABL1-like ALL with CRLF2r, 30% of BCR::ABL1 ALL , and 25% of BCR::ABL1-like ALL without CRLF2r (Fig. 1C). Focal IKZF1 deletions were not observed in low hypodiploid and near haploid subtypes (Fig. 1C and D.

Association of IKZF1 alterations with clinical features and response to therapy

Significantly higher frequencies of genomic IKZF1^plus (any ΔIKZF1) and IKZF1^plus, compared to no IKZF1 alterations, were observed among patients older than 10 years of age (P = 0.002 and 0.003, respectively) and those classified as NCI high risk (P = 0.0002 and 0.0001, respectively) (Table S5). There were no statistically significant differences in sex, race or CNS status in patients with any type of IKZF1 alterations compared to patients without alterations (Table S5). In patients with genomic IKZF1^plus (any ΔIKZF1) 38.6% of patients had an EOI MRD ≥ 0.01% compared to 25.5% of patients with any ΔIKZF1 only, 20% of patients with IKZF1 mutations, and 12% of patients without IKZF1 alterations, P < 0.0001(Table S5).

IKZF1 alterations and clinical outcome in Total Therapy XV/16 and MP2PRT studies

Clinical outcomes were worse for patients with any type of IKZF1 alteration than for patients without IKZF1 alterations. In Total XV/16 studies, 5-year EFS of 78.2 ± 3.9% and 5-year CIR of 14.8 ± 3.3% observed in patients with any type of IKZF1 alteration were significantly worse than EFS and CIR of 93.4% ± 1% and 5.0 ± 0.9% in patients without IKZF1 alterations (P < 0.0001) (Fig. 2). Any IKZF1 alteration, compared to no IKZF1 deletion or mutation, conferred significantly worse 5-year EFS among both NCI SR (79.2 ± 5.9% vs 96.3 ± 1.0%; P < 0.0001) and NCI high-risk patients (77.6 ± 5.1 vs 88.36 ± 2.2%; P = 0.008) (Table 3). Five-year CIR of 19.4 ± 4.9% for patients with IKZF1 alterations in the NCI high-risk group was significantly worse than 5-year CIR of 7.3 ± 1.8% for patients without IKZF1 alterations, P = 0.001 (Table 3).

Figure 2. — 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.

Table 3: EFS and CIR in IKZF1 alteration groups stratified by NCI Risk in Total XV/16 studies.

Event Free Survival (EFS)
	NCI Standard Risk			NCI High Risk
Factor	N	Events	5-year EFS (SE)	P value	N	Events	5-year EFS (SE)	P value
Any IKZF1 deletion or mutation	48	11	79.2±5.9	<0.0001	67	18	77.6±5.1	0.008
No IKZF1 deletion or mutation	365	16	96.3±1.0	<0.0001	208	28	88.3±2.2	0.008
Cumulative Incidence of Relapse (CIR)
	NCI Standard Risk			NCI High Risk
	N	Events	5-year CIR (SE)	P value	N	Events	5-year CIR (SE)	P value
Any IKZF1 deletion or mutation	48	5	8.3±4.0	0.06	67	15	19.4±4.9	0.001
No IKZF1 deletion or mutation	365	16	3.7±1.0	0.06	208	17	7.3±1.8	0.001

Open in a new tab

P values are for differences in outcome for the duration of follow up.

All definitions of IKZF1^plus conferred worse EFS and CIR relative to patients without any IKZF1 alterations (Fig. 3 and Table 4). Patients with genomic IKZF1^plus (focal ΔIKZF1) had significantly inferior 5-year EFS of 64.5 ± 8.6% compared to patients without focal ΔIKZF1 or IKZF1 mutations (92.6 ± 1.1%, P < 0.0001) (Table 4). IKZF1 Δ4-7 was associated with inferior outcomes compared to with 5-year EFS of 66.7 ± 11.1% (P < 0.0001) and 5-year CIR of 27.8 ± 10.9% (P = 0.007, Table 4).

Figure 3. — 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 (Δ*IKZF1*) are defined as focal *IKZF1* deletions or −7/del(7p). Mutations: missense, nonsense or frameshift mutations.

Table 4: Outcomes for patients with IKZF1 alteration types from univariable and multivariable analysis in Total XV/16 studies.

	UNIVARIABLE ANALYSES							MULTIVARIABLE ANALYSES
		EFS			CIR			EFS		CIR
Genomic IKZF1^plus (any ΔIKZF1) and other alterations	N	Events	5-y EFS (SE)	P value	Events	5-y CIR (SE)	P value	Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value
Genomic IKZF1^plus (any ΔIKZF1)	44	16	65.8±7.2	<0.0001	10	20.5±6.2	<0.0001	5.10 (1.87-13.92)	0.002	4.65 (1.54-14.06)	0.0007
Any ΔIKZF1 only	47	10	85.7±6.6		8	12.8±4.9		2.94 (1.09-7.91)	0.03	4.27 (1.43-12.77)	0.009
IKZF1 mutations	20	3	86.1±7.4		2	10.0±6.9		2.66 (0.61-11.59)	0.19	1.9 (0.23-15.45)	0.55
No ΔIKZF1or IKZF1 mutation	573	44	92.6±1.1		33	5.0±0.9		-		-
IKZF1^plus and other alterations
IKZF1 ^plus	44	15	68.1±7.0	<0.0001	10	20.5±6.2	<0.0001	4.72 (1.72-12.99)	0.0027	4.73 (1.59 −14.02)	0.005
Any ΔIKZF1 only	47	11	83.0±5.5		8	12.8±4.9		3.32 (1.26 - 8.75)	0.015	4.19 (1.41 - 12.51)	0.01
IKZF1 mutations	20	3	84.7±8.1		2	10.0±6.9		2.66 (0.61-11.57)	0.19	1.90 (0.23-15.45)	0.55
No ΔIKZF1or IKZF1 mutation	573	44	93.4±1.0		33	5.0±0.9		-		-
*Genomic IKZF1^plus (focal ΔIKZF1)* and other alterations**
Genomic IKZF1^plus (focal ΔIKZF1)	31	11	64.5±8.6	<0.0001	6	19.4±7.2	0.06	6.88 (2.29-20.67)	0.0006	7.40 (2.32-23.53)	0.0007
Focal IKZF1 deletions only	28	5	85.7±6.6		3	10.7±6.0		3.39 (0.94-12.28)	0.06	4.88 (0.96-24.68)	0.05
IKZF1 mutations	22	3	86.1±7.4		2	9.1±6.3		2.65 (0.59-11.82)	0.2	2.33 (0.25-21.84)	0.46
No focal ΔIKZF1 or IKZF1 mutation	606	54	92.6±1.1		42	5.7±1.0		-		-
IKZF1 Δ4-7 and other alterations
IKZF1 Δ4-7 deletions	18	6	66.7±11.1	<0.0001	5	27.8±10.9	0.007	6.81 (1.81-25.67)	0.005	11.54 (3.24-41.09)	0.0002
Non-IKZF1 Δ4-7 deletions	40	10	77.5±6.6		4	10.0±4.8		6.30 (2.20-18.02)	0.0006	5.02 (1.07-23.59)	0.04
IKZF1 mutations	22	3	86.1±7.4		2	9.1±6.3		3.1 (0.68 - 14.18)	0.14	2.67 (0.27 - 26.36)	0.4
No focal ΔIKZF1 or IKZF1 mutation	606	54	92.6±1.1		42	5.7±1.0		-		-

Open in a new tab

For univariate analyses, P values are for the entire duration of follow up. For multivariable analyses (MVA), estimated hazard ratios for EFS and CIR are shown. Models were adjusted for WBC, age, subtype group and end of induction minimal residual disease. Complete MVA results are shown on Supplemental Table 10.

We studied the effect of IKZF1 alterations on clinical outcome and prognosis in the independent MP2PRT study of children with standard risk B-ALL or high risk B-ALL with normal cytogenetics enrolled in COG studies, in a 2:1 relapse:continuous remission case control design (31) (Supplemental Methods and Table S2). The frequency and types of IKZF1 alterations in the MP2PRT study were comparable to those in the Total Therapy XV/16 studies (Tables S6 and S7). There were no patients with BCR::ABL1, near haploid, and low hypodiploid B-ALL in the MP2PRT study group (Table S8). BCR::ABL1-like subtypes, PAX5alt, and ETV6::RUNX1-like subtypes harbored the highest frequency of genomic IKZF1^plus (any ΔIKZF1), IKZF1^plus, and genomic IKZF1^plus (focal ΔIKZF1) alterations (Fig. S4). Unlike the genomic IKZF1^plus definitions that excluded all DUX4r cases, IKZF1^plus misclassified 4% of DUX4r patients (Fig. S4, C and D). A higher percentage of patients with genomic IKZF1^plus (any ΔIKZF1) or genomic IKZF1^plus (focal ΔIKZF1) or IKZF1 Δ4-7, in the MP2PRT study group, harbored WBC ≥10,000 at diagnosis and positive EOI MRD, compared to patients without IKZF1 alterations (Table S9). As observed in the Total Therapy XV/16 studies, clinical outcomes were worse for patients with IKZF1 alterations in the MP2PRT study group compared to patients without IKZF1 alterations (Fig. S5-S7). Genomic IKZF1^plus (any ΔIKZF1) was associated with 5-year EFS of 80.0 ± 5.3% compared to 94.5 ± 0.4% in patients without genomic IKZF1^plus, IKZF1 deletions or mutations (Fig. S5; P<0.0001). IKZF1 sequence mutations conferred significantly worse outcomes for patients in the MP2PRT study group with 5-year EFS of 87.3 ± 4.2% (Fig. S5; P = 0.02).

Independently prognostic IKZF1 alterations

In models considering each definition of IKZF1^plus separately, all definitions of genomic IKZF1^plus (any ΔIKZF1), IKZF1^plus, genomic IKZF1^plus (focal ΔIKZF1), IKZF1 Δ4-7 and other focal deletions were independent adverse prognostic factors associated with increased hazard ratios (HR) for EFS and CIR (Table 4 and Table S10). As a group, IKZF1 missense mutations were not independent prognostic factors. Among IKZF1^plus definitions, genomic IKZF1^plus (focal ΔIKZF1) was associated with the highest risk of relapse with HR = 7.4 (95% CI: 2.32 – 23.53). Hazard ratios for CIR for genomic IKZF1^plus (any ΔIKZF1) and IKZF1^plus were 4.65 (95% CI: 1.54 −14.06) and 4.73 (1.59 – 14.02), respectively. Among all independently prognostic IKZF1 alterations, IKZF1 Δ4-7 focal deletions were associated with the highest HR for CIR of 11.54 (95% CI 3.24 – 41.09, P = 0.0002) compared to patients without IKZF1 focal deletions or mutations (Table 4 and Table S10). Patients with genomic IKZF1^plus (focal ΔIKZF1) with the IKZF1 Δ4-7 focal deletion had a significantly increased risk of poor outcomes with HR of 11.28 for CIR (95% CI 3.32-38.35, P = 0.0001 (Table S11).

The impact of B-ALL genomic subtypes and IKZF1 alterations on outcome

We examined the association of IKZF1 alteration groups on survival outcomes among genomic subtypes. Poor outcomes were observed in patients with BCR::ABL1 subtype, with 5-year EFS of 60.0 ± 21.9% for patients without any IKZF1 alteration (Table S12). Among patients without BCR::ABL1, IKZF1 alterations conferred significantly worse EFS than patients without IKZF1 alterations and genomic IKZF1^plus (any ΔIKZF1) was associated with worse 5-year CIR, 17.1 ± 6.5% compared to 4.9 ± 0.9% for patients without IKZF1 alterations, P = 0.003 (Table S13).

Patients with IKZF1 Δ4-7 and unfavorable subtype group had the highest 5-year CIR (40 ± 16.5%) compared to patients without IKZF1 Δ4-7 or unfavorable subtype group (P < 0.0001) (Fig. 4 and Table S14). Although limited by a small sample size, the combination of IKZF1 Δ4-7 and unfavorable subtype group (specifically BCR::ABL1 and BCR::ABL1-like with CRLF2r) was associated with increased HR of 58.3 (95% CI 11.91-285.37, P < 0.0001) for CIR (Table S15). For EFS, among patients with unfavorable subtype group, the higher HR (52.4) for patients with non-IKZF1 Δ4-7 focal deletions vs those with IKZF1 Δ4-7 focal deletions (40.01) was due to non-relapse events (Table S15).

Figure 4. — 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.

Effect of IKZF1 alterations among patients with negative MRD

IKZF1 alterations conferred poor outcomes in patients despite undetectable EOI MRD. Patients with genomic IKZF1^plus (any ΔIKZF1) and undetectable EOI MRD had 5-year CIR of 15.0±7.1 (P = 0.004) compared to patients without IKZF1 deletions or mutations (Table S16). The 5-year CIR of 40.0 ± 25.0%; P < 0.0001) for patients with IKZF1 Δ4-7 and unfavorable subtype group and negative EOI MRD was significantly worse compared to patients without IKZF1 Δ4-7 or unfavorable subtype (Table S16).

DISCUSSION

In this study, we show the effect of IKZF1 alterations, including different definitions of IKZF1^plus, on outcomes in a cohort of patients comprising both BCR::ABL1 positive and negative B-ALL in the context of risk-directed therapy. All definitions of IKZF1^plus were associated with inferior outcomes compared to patients without IKZF1 alterations and were adversely prognostic independent of other variables including subtype group, and EOI MRD. Genomic IKZF1^plus (any ΔIKZF1) and the original MLPA-based definition of IKZF1^plus were comparable in identifying patients at high risk of relapse. IKZF1 Δ4-7 focal deletions conferred a higher risk of relapse compared to other focal deletions. Relative to other definitions of IKZF1^plus, genomic IKZF1^plus (focal ΔIKZF1) identified patients at the highest risk of relapse. IKZF1 missense mutations did not exert an independently prognostic effect on EFS or CIR upon adjusting for genomic subtype in the Total XV/16 studies.

Consistent with previous studies (8, 10, 26) we show that both IKZF1^plus and IKZF1 deletions only are independent prognostic factors. This contrasts with the original study defining IKZF1^plus which showed that IKZF1^plus was an independently adverse prognostic factor but IKZF1 deletions only were not independently prognostic (7). Our genomic IKZF1^plus (focal ΔIKZF1) definition is superior to focal IKZF1 deletions only as a predictor of relapse. Thus, genomic IKZF1^plus (focal ΔIKZF1) is a clinically informative tool for distinguishing the effects of co-occurring lesions from effects of IKZF1 deletions alone. We identified an independent adverse prognostic effect of IKZF1 Δ4-7 on relapse and worse outcomes for patients with both IKZF1 Δ4-7 and BCR::ABL1 and BCR::ABL1-like with CRLF2r unfavorable subtypes, despite negative EOI MRD. We speculate that the association between types of focal IKZF1 deletions and outcomes may be related to distinct molecular mechanisms associated with different IKZF1 variants (41, 42). Although the small sample size of patients with IKZF1 alterations and unfavorable subtype groups is a limiting factor, our results underscore the potential utility of identifying patients with IKZF1 Δ4-7 for intensified therapy or employing more sensitive MRD detection methods in BCR::ABL1 and BCR::ABL1-like subtypes. Notably, TKI therapy was not administered to patients with BCR::ABL1-like subtypes in our study.

The frequencies of IKZF1 alterations among different B-ALL subtypes may elucidate observed differences between types of IKZF1 alterations and clinical features or outcomes. The higher frequency of patients older than 10 years within the genomic IKZF1^plus (any ΔIKZF1) category may, in part, stem from the inclusion of some patients with low hypodiploid B-ALL, a subtype associated with older age (43, 44). Limitations of our study include the retrospective design and small sample sizes for some genetic subtypes which preclude accurate assessment of the impact of IKZF1 alterations within each subtype.

Although comprehensive genomic profiling is not available in many centers, detection of key abnormalities can improve the identification of IKZF1^plus cases to approximate our genomic definition. For example, to maximize detection of CRLF2 and DUX4 rearrangements, flow cytometry assays for CRLF2 overexpression and DUX4 RNA quantification can be included. ERG deletion should not be used as the only indication of DUX4r given limitations of detection methods and absence of clonal ERG deletions in 30-50% of DUX4r cases (19, 30, 45). Furthermore, widely used MLPA assays can be improved with probes differentiating focal IKZF1 deletions from 7p or whole chromosome 7 losses.

In summary, our study underscores the importance of leukemia subtype classification, characterization of IKZF1 alterations, and genomics-based analysis of cooperating lesions, in the prognosis of pediatric patients with B-ALL undergoing MRD-directed therapy. Although all definitions of IKZF1^plus are independently adversely prognostic, genomic IKZF1^plus (focal ΔIKZF1) identifies patients at greater risk of relapse compared to IKZF1 deletions only. IKZF1 Δ4-7 is independently adversely prognostic, by itself or in combination with IKZF1^plus, and is associated with the highest risk of relapse. We advocate for the inclusion of IKZF1 Δ4-7 and genomic IKZF1^plus (focal ΔIKZF1) into risk stratification protocols to inform treatment decisions.

Supplementary Material

Supplementary Figures, Table list, Figures

NIHMS2125429-supplement-Supplementary_Figures__Table_list__Figures.docx^{(1.6MB, docx)}

Supplementary Tables 1-16

NIHMS2125429-supplement-Supplementary_Tables_1-16.xlsx^{(298.3KB, xlsx)}

ACKNOWLEDGEMENTS

American Society of Hematology Minority Hematology Fellow award (R.W.W.). National Cancer Institute Cancer Center Support Grant P30 CA021765 (C.G.M.), CA015704 (M.L.L.). R35 CA197695 (C.G.M.), the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. National Cancer Institute (NCI), National Institutes of Health under the Cancer Moonshot Initiative, under Contract No. HHSN261201500003I. The COG clinical trials were supported by NIH grants U10 CA98543 and U10 CA180886 (COG Chair's grants), U10 CA98413 and U10 CA180899 (COG Statistics and Data Center grants), U24 CA114766 and U24 CA196173 (COG Specimen Banking) and the St. Baldrick’s Foundation. M.L.L. is the Aldarra Foundation, June and Bill Boeing, Founders, Endowed Professor of Pediatric Cancer Research at Seattle Children’s Hospital.

Footnotes

COMPETING FINANCIAL INTERESTS

C.G.M. has received consulting fees from Illumina, speaking fees/honoraria from Amgen, and research funding from Pfizer. H.I. has received consulting fees from Jazz Pharmaceuticals and Servia, and research funding from Servier, Amgen, and Incyte.

DATA SHARING STATEMENT

Genomic data generated and analyzed in this study are available in the European Genome-phenome Archive (EGA) under accession numbers EGAS00001000447, EGAS00001000654, EGAS00001002217, EGAS00001003266, EGAS00001003975, EGAS00001004998, EGAS00001005250, EGAS00001001923, EGAS00001004739, EGAS50000000106 and EGAS00001005084. The TARGET genomic data used in this study are available through the TARGET website (https://ocg.cancer.gov/programs/target/data-matrix) and through the database of Genotypes and Phenotypes under accession number phs000218 (TARGET). For the MP2PRT study group, genomic analyses data are available from the genomic data commons portal using the phs002005.v1.p1 accession number and the MP2PRT-ALL project ID.

REFERENCES

1.Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol. 2012;30(14):1663–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Eng J Med. 2009;360(26):2730–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: A report from children's oncology group study AALL0232. J Clin Oncol. 2016;34(20):2380–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Burke MJ, Devidas M, Chen Z, Salzer WL, Raetz EA, Rabin KR, et al. Outcomes in adolescent and young adult patients (16 to 30 years) compared to younger patients treated for high-risk B-lymphoblastic leukemia: report from Children's Oncology Group Study AALL0232. Leukemia. 2022;36(3):648–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Pieters R, Mullighan CG, Hunger SP. Advancing Diagnostics and Therapy to Reach Universal Cure in Childhood ALL. J Clin Oncol. 2023;41(36):5579–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Mullighan CG, Su X, Zhang J, Radtke I, Phillips LAA, Miller CB, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Stanulla M, Dagdan E, Zaliova M, Möricke A, Palmi C, Cazzaniga G, et al. IKZF1 plus defines a new minimal residual disease-dependent very-poor prognostic profile in pediatric b-cell precursor acute lymphoblastic leukemia. J Clin Oncol. 2018;36(12):1240–9. [DOI] [PubMed] [Google Scholar]
8.Braun M, Pastorczak A, Sedek L, Taha J, Madzio J, Jatczak-Pawlik I, et al. Prognostic significance of IKZF1 deletions and IKZF1plus profile in children with B-cell precursor acute lymphoblastic leukemia treated according to the ALL-IC BFM 2009 protocol. Hematological Oncology. 2022;40(3):430–41. [DOI] [PubMed] [Google Scholar]
9.Clappier E, Grardel N, Bakkus M, Rapion J, De Moerloose B, Kastner P, et al. IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951. Leukemia. 2015;29(11):2154–61. [DOI] [PubMed] [Google Scholar]
10.Kicinski M, Arfeuille C, Grardel N, Bakkus M, Caye-Eude A, Plat G, et al. The prognostic value of IKZF1(plus) in B-cell progenitor acute lymphoblastic leukemia: Results from the EORTC 58951 trial. Pediatr Blood Cancer. 2023;70(6):e30313. [DOI] [PubMed] [Google Scholar]
11.Van Der Veer A, Zaliova M, Mottadelli F, De Lorenzo P, Te Kronnie G, Harrison CJ, et al. IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL. Blood. 2014;123(11):1691–8. [DOI] [PubMed] [Google Scholar]
12.Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110–4. [DOI] [PubMed] [Google Scholar]
13.Moorman AV, Schwab C, Ensor HM, Russell LJ, Morrison H, Jones L, et al. IGH@ translocations, CRLF2 deregulation, and microdeletions in adolescents and adults with acute lymphoblastic leukemia. J Clin Oncol. 2012;30(25):3100–8. [DOI] [PubMed] [Google Scholar]
14.Clappier E, Auclerc MF, Rapion J, Bakkus M, Caye A, Khemiri A, et al. An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. Leukemia. 2014;28(1):70–7. [DOI] [PubMed] [Google Scholar]
15.Li JF, Dai YT, Lilljebjörn H, Shen SH, Cui BW, Bai L, et al. Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. Proc Natl Acad Sci U S A. 2018;115(50):E11711–E20. [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446(7137):758–64. [DOI] [PubMed] [Google Scholar]
17.Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo M-C, et al. Dasatinib–Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020;383(17):1613–23. [DOI] [PubMed] [Google Scholar]
18.Sasaki Y, Kantarjian HM, Short NJ, Wang F, Furudate K, Uryu H, et al. Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib. Leukemia. 2022;36(5):1253–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Zhang J, McCastlain K, Yoshihara H, Xu B, Chang Y, Churchman ML, et al. Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nat Genet. 2016;48(12):1481–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Buitenkamp TD, Pieters R, Gallimore NE, van der Veer A, Meijerink JPP, Beverloo HB, et al. Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia. 2012;26(10):2204–11. [DOI] [PubMed] [Google Scholar]
21.DeBoer R, Koval G, Mulkey F, Wetzler M, Devine S, Marcucci G, et al. Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL): molecular analysis of CALGB (Alliance) 10001 and 9665. Leuk Lymphoma. 2016;57(10):2298–306. [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Hinze L, Möricke A, Zimmermann M, Junk S, Cario G, Dagdan E, et al. Prognostic impact of IKZF1 deletions in association with vincristine–dexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial ALL-BFM 95. Leukemia. 2017;31(8):1840–2. [DOI] [PubMed] [Google Scholar]
23.Mangum DS, Meyer JA, Mason CC, Shams S, Maese LD, Gardiner JD, et al. Association of Combined Focal 22q11.22 Deletion and IKZF1 Alterations With Outcomes in Childhood Acute Lymphoblastic Leukemia. JAMA Oncol. 2021;7(10):1521–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Martinelli G, Iacobucci I, Storlazzi CT, Vignetti M, Paoloni F, Cilloni D, et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: A GIMEMA AL WP report. J Clin Oncol. 2009;27(31):5202–7. [DOI] [PubMed] [Google Scholar]
25.Olsson L, Ivanov Öfverholm I, Norén-Nyström U, Zachariadis V, Nordlund J, Sjögren H, et al. The clinical impact of IKZF1 deletions in paediatric B-cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in Nordic Society for Paediatric Haematology and Oncology treatment protocols used between 1992 and 2013. Br J Haematol. 2015;170(6):847–58. [DOI] [PubMed] [Google Scholar]
26.Pieters R, de Groot-Kruseman H, Fiocco M, Verwer F, Van Overveld M, Sonneveld E, et al. Improved Outcome for ALL by Prolonging Therapy for IKZF1 Deletion and Decreasing Therapy for Other Risk Groups. J Clin Oncol. 2023;41(25):4130–42. [DOI] [PubMed] [Google Scholar]
27.Petra D, Barbara M, Martin Z, Anja M, André S, Jean-Pierre B, et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica. 2013;98(3):428–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Dorge P, Meissner B, Zimmermann M, Moricke A, Schrauder A, Bouquin JP, et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica. 2013;98(3):428–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Jeha S, Choi J, Roberts KG, Pei D, Coustan-Smith E, Inaba H, et al. Clinical Significance of Novel Subtypes of Acute Lymphoblastic Leukemia in the Context of Minimal Residual Disease–Directed Therapy. Blood Cancer Discov. 2021;2(4):326. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Brady SW, Roberts KG, Gu Z, Shi L, Pounds S, Pei D, et al. The genomic landscape of pediatric acute lymphoblastic leukemia. Nat Genet. 2022;54(9):1376–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Chang TC, Chen W, Qu C, Cheng Z, Hedges D, Elsayed A, et al. Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia. J Clin Oncol. 2024;42(29):3491–503. [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Jeha S, Pei D, Choi J, Cheng C, Sandlund JT, Coustan-Smith E, et al. Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16. J Clin Oncol. 2019;37(35):3377–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Maloney KW, Taub JW, Ravindranath Y, Roberts I, Vyas P. Down syndrome preleukemia and leukemia. Pediatr Clin North Am. 2015;62(1):121–37. [DOI] [PubMed] [Google Scholar]
34.Mattano LA Jr., Devidas M, Maloney KW, Wang C, Friedmann AM, Buckley P, et al. Favorable Trisomies and ETV6-RUNX1 Predict Cure in Low-Risk B-Cell Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Trial AALL0331. J Clin Oncol. 2021;39(14):1540–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Schore RJ, Angiolillo AL, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, et al. Outstanding outcomes with two low intensity regimens in children with low-risk B-ALL: a report from COG AALL0932. Leukemia. 2023;37(6):1375–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, et al. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021;39(13):1437–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Salzer WL, Burke MJ, Devidas M, Dai Y, Hardy KK, Kairalla JA, et al. Impact of Intrathecal Triple Therapy Versus Intrathecal Methotrexate on Disease-Free Survival for High-Risk B-Lymphoblastic Leukemia: Children's Oncology Group Study AALL1131. J Clin Oncol. 2020;38(23):2628–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J, et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nature Genetics. 2019;51(2):296–307. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Kimura S, Montefiori L, Iacobucci I, Zhao Y, Gao Q, Paietta EM, et al. Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia. Blood. 2022;139(24):3519–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Gao Q, Ryan SL, Iacobucci I, Ghate PS, Cranston RE, Schwab C, et al. The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21. Blood. 2023;142(8):711–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Churchman ML, Low J, Qu C, Paietta EM, Kasper LH, Chang Y, et al. Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia. Cancer Cell. 2015;28(3):343–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Churchman ML, Qian M, te Kronnie G, Zhang R, Yang W, Zhang H, et al. Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell. 2018;33(5):937–48.e8. [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Mullighan CG, Jeha S, Pei D, Payne-Turner D, Coustan-Smith E, Roberts KG, et al. Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels. Blood. 2015;126(26):2896–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
44.Pui CH, Rebora P, Schrappe M, Attarbaschi A, Baruchel A, Basso G, et al. Outcome of children with hypodiploid acute lymphoblastic leukemia: A retrospective multinational study. J Clin Oncol. 2019;37(10):770–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Marketa Z, Eliska P, Lenka H, Alena M, Lucie W, Karel F, et al. ERG deletions in childhood acute lymphoblastic leukemia with DUX4 rearrangements are mostly polyclonal, prognostically relevant and their detection rate strongly depends on screening method sensitivity. Haematologica. 2019;104(7):1407–16. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Figures, Table list, Figures

NIHMS2125429-supplement-Supplementary_Figures__Table_list__Figures.docx^{(1.6MB, docx)}

Supplementary Tables 1-16

NIHMS2125429-supplement-Supplementary_Tables_1-16.xlsx^{(298.3KB, xlsx)}

Data Availability Statement

[R1] 1.Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol. 2012;30(14):1663–9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R2] 2.Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Eng J Med. 2009;360(26):2730–41. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] 3.Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: A report from children's oncology group study AALL0232. J Clin Oncol. 2016;34(20):2380–8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R4] 4.Burke MJ, Devidas M, Chen Z, Salzer WL, Raetz EA, Rabin KR, et al. Outcomes in adolescent and young adult patients (16 to 30 years) compared to younger patients treated for high-risk B-lymphoblastic leukemia: report from Children's Oncology Group Study AALL0232. Leukemia. 2022;36(3):648–55. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] 5.Pieters R, Mullighan CG, Hunger SP. Advancing Diagnostics and Therapy to Reach Universal Cure in Childhood ALL. J Clin Oncol. 2023;41(36):5579–91. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R6] 6.Mullighan CG, Su X, Zhang J, Radtke I, Phillips LAA, Miller CB, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–80. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] 7.Stanulla M, Dagdan E, Zaliova M, Möricke A, Palmi C, Cazzaniga G, et al. IKZF1 plus defines a new minimal residual disease-dependent very-poor prognostic profile in pediatric b-cell precursor acute lymphoblastic leukemia. J Clin Oncol. 2018;36(12):1240–9. [DOI] [PubMed] [Google Scholar]

[R8] 8.Braun M, Pastorczak A, Sedek L, Taha J, Madzio J, Jatczak-Pawlik I, et al. Prognostic significance of IKZF1 deletions and IKZF1plus profile in children with B-cell precursor acute lymphoblastic leukemia treated according to the ALL-IC BFM 2009 protocol. Hematological Oncology. 2022;40(3):430–41. [DOI] [PubMed] [Google Scholar]

[R9] 9.Clappier E, Grardel N, Bakkus M, Rapion J, De Moerloose B, Kastner P, et al. IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951. Leukemia. 2015;29(11):2154–61. [DOI] [PubMed] [Google Scholar]

[R10] 10.Kicinski M, Arfeuille C, Grardel N, Bakkus M, Caye-Eude A, Plat G, et al. The prognostic value of IKZF1(plus) in B-cell progenitor acute lymphoblastic leukemia: Results from the EORTC 58951 trial. Pediatr Blood Cancer. 2023;70(6):e30313. [DOI] [PubMed] [Google Scholar]

[R11] 11.Van Der Veer A, Zaliova M, Mottadelli F, De Lorenzo P, Te Kronnie G, Harrison CJ, et al. IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL. Blood. 2014;123(11):1691–8. [DOI] [PubMed] [Google Scholar]

[R12] 12.Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110–4. [DOI] [PubMed] [Google Scholar]

[R13] 13.Moorman AV, Schwab C, Ensor HM, Russell LJ, Morrison H, Jones L, et al. IGH@ translocations, CRLF2 deregulation, and microdeletions in adolescents and adults with acute lymphoblastic leukemia. J Clin Oncol. 2012;30(25):3100–8. [DOI] [PubMed] [Google Scholar]

[R14] 14.Clappier E, Auclerc MF, Rapion J, Bakkus M, Caye A, Khemiri A, et al. An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. Leukemia. 2014;28(1):70–7. [DOI] [PubMed] [Google Scholar]

[R15] 15.Li JF, Dai YT, Lilljebjörn H, Shen SH, Cui BW, Bai L, et al. Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. Proc Natl Acad Sci U S A. 2018;115(50):E11711–E20. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R16] 16.Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446(7137):758–64. [DOI] [PubMed] [Google Scholar]

[R17] 17.Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo M-C, et al. Dasatinib–Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020;383(17):1613–23. [DOI] [PubMed] [Google Scholar]

[R18] 18.Sasaki Y, Kantarjian HM, Short NJ, Wang F, Furudate K, Uryu H, et al. Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib. Leukemia. 2022;36(5):1253–60. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R19] 19.Zhang J, McCastlain K, Yoshihara H, Xu B, Chang Y, Churchman ML, et al. Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nat Genet. 2016;48(12):1481–9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R20] 20.Buitenkamp TD, Pieters R, Gallimore NE, van der Veer A, Meijerink JPP, Beverloo HB, et al. Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia. 2012;26(10):2204–11. [DOI] [PubMed] [Google Scholar]

[R21] 21.DeBoer R, Koval G, Mulkey F, Wetzler M, Devine S, Marcucci G, et al. Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL): molecular analysis of CALGB (Alliance) 10001 and 9665. Leuk Lymphoma. 2016;57(10):2298–306. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R22] 22.Hinze L, Möricke A, Zimmermann M, Junk S, Cario G, Dagdan E, et al. Prognostic impact of IKZF1 deletions in association with vincristine–dexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial ALL-BFM 95. Leukemia. 2017;31(8):1840–2. [DOI] [PubMed] [Google Scholar]

[R23] 23.Mangum DS, Meyer JA, Mason CC, Shams S, Maese LD, Gardiner JD, et al. Association of Combined Focal 22q11.22 Deletion and IKZF1 Alterations With Outcomes in Childhood Acute Lymphoblastic Leukemia. JAMA Oncol. 2021;7(10):1521–8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R24] 24.Martinelli G, Iacobucci I, Storlazzi CT, Vignetti M, Paoloni F, Cilloni D, et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: A GIMEMA AL WP report. J Clin Oncol. 2009;27(31):5202–7. [DOI] [PubMed] [Google Scholar]

[R25] 25.Olsson L, Ivanov Öfverholm I, Norén-Nyström U, Zachariadis V, Nordlund J, Sjögren H, et al. The clinical impact of IKZF1 deletions in paediatric B-cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in Nordic Society for Paediatric Haematology and Oncology treatment protocols used between 1992 and 2013. Br J Haematol. 2015;170(6):847–58. [DOI] [PubMed] [Google Scholar]

[R26] 26.Pieters R, de Groot-Kruseman H, Fiocco M, Verwer F, Van Overveld M, Sonneveld E, et al. Improved Outcome for ALL by Prolonging Therapy for IKZF1 Deletion and Decreasing Therapy for Other Risk Groups. J Clin Oncol. 2023;41(25):4130–42. [DOI] [PubMed] [Google Scholar]

[R27] 27.Petra D, Barbara M, Martin Z, Anja M, André S, Jean-Pierre B, et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica. 2013;98(3):428–32. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R28] 28.Dorge P, Meissner B, Zimmermann M, Moricke A, Schrauder A, Bouquin JP, et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica. 2013;98(3):428–32. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R29] 29.Jeha S, Choi J, Roberts KG, Pei D, Coustan-Smith E, Inaba H, et al. Clinical Significance of Novel Subtypes of Acute Lymphoblastic Leukemia in the Context of Minimal Residual Disease–Directed Therapy. Blood Cancer Discov. 2021;2(4):326. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R30] 30.Brady SW, Roberts KG, Gu Z, Shi L, Pounds S, Pei D, et al. The genomic landscape of pediatric acute lymphoblastic leukemia. Nat Genet. 2022;54(9):1376–89. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R31] 31.Chang TC, Chen W, Qu C, Cheng Z, Hedges D, Elsayed A, et al. Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia. J Clin Oncol. 2024;42(29):3491–503. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R32] 32.Jeha S, Pei D, Choi J, Cheng C, Sandlund JT, Coustan-Smith E, et al. Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16. J Clin Oncol. 2019;37(35):3377–91. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R33] 33.Maloney KW, Taub JW, Ravindranath Y, Roberts I, Vyas P. Down syndrome preleukemia and leukemia. Pediatr Clin North Am. 2015;62(1):121–37. [DOI] [PubMed] [Google Scholar]

[R34] 34.Mattano LA Jr., Devidas M, Maloney KW, Wang C, Friedmann AM, Buckley P, et al. Favorable Trisomies and ETV6-RUNX1 Predict Cure in Low-Risk B-Cell Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Trial AALL0331. J Clin Oncol. 2021;39(14):1540–52. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R35] 35.Schore RJ, Angiolillo AL, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, et al. Outstanding outcomes with two low intensity regimens in children with low-risk B-ALL: a report from COG AALL0932. Leukemia. 2023;37(6):1375–8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R36] 36.Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, et al. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021;39(13):1437–47. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R37] 37.Salzer WL, Burke MJ, Devidas M, Dai Y, Hardy KK, Kairalla JA, et al. Impact of Intrathecal Triple Therapy Versus Intrathecal Methotrexate on Disease-Free Survival for High-Risk B-Lymphoblastic Leukemia: Children's Oncology Group Study AALL1131. J Clin Oncol. 2020;38(23):2628–38. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R38] 38.Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J, et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nature Genetics. 2019;51(2):296–307. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R39] 39.Kimura S, Montefiori L, Iacobucci I, Zhao Y, Gao Q, Paietta EM, et al. Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia. Blood. 2022;139(24):3519–31. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R40] 40.Gao Q, Ryan SL, Iacobucci I, Ghate PS, Cranston RE, Schwab C, et al. The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21. Blood. 2023;142(8):711–23. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R41] 41.Churchman ML, Low J, Qu C, Paietta EM, Kasper LH, Chang Y, et al. Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia. Cancer Cell. 2015;28(3):343–56. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R42] 42.Churchman ML, Qian M, te Kronnie G, Zhang R, Yang W, Zhang H, et al. Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell. 2018;33(5):937–48.e8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R43] 43.Mullighan CG, Jeha S, Pei D, Payne-Turner D, Coustan-Smith E, Roberts KG, et al. Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels. Blood. 2015;126(26):2896–9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R44] 44.Pui CH, Rebora P, Schrappe M, Attarbaschi A, Baruchel A, Basso G, et al. Outcome of children with hypodiploid acute lymphoblastic leukemia: A retrospective multinational study. J Clin Oncol. 2019;37(10):770–9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R45] 45.Marketa Z, Eliska P, Lenka H, Alena M, Lucie W, Karel F, et al. ERG deletions in childhood acute lymphoblastic leukemia with DUX4 rearrangements are mostly polyclonal, prognostically relevant and their detection rate strongly depends on screening method sensitivity. Haematologica. 2019;104(7):1407–16. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

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

Ruth W Wang’ondu, M.D. Ph. D.

Emily Ashcraft, M.P.H.

Ti-Cheng Chang, Ph. D.

Kathryn G Roberts, Ph. D.

Samuel W Brady, Ph. D.

Yiping Fan, Ph. D.

William Evans, Pharm. D.

Mary V Relling, Pharm. D.

Kristine R Crews, Pharm. D.

Jun Yang, Ph. D.

Wenjian Yang, Ph. D.

Stanley Pounds, Ph. D.

Gang Wu, Ph. D.

Meenakshi Devidas, Ph. D.

Kelly Maloney, M.D.

Leonard Mattano, M.D.

Reuven J Schore, M.D.

Anne Angiolillo, M.D.

Eric Larsen, M.D.

Wanda Salzer, M.D.

Michael J Burke, M.D.

Mignon L Loh, M.D.

Sima Jeha, M.D.

Ching-Hon Pui, M.D.

Hiroto Inaba, M.D. Ph. D.

Cheng Cheng, Ph. D.

Charles G Mullighan, M.B.B.S, M.D.

Abstract

INTRODUCTION

DESIGN AND METHODS

Patients, risk stratification, and diagnosis

Ethics approval and consent to participate

Definitions of IKZF1plus and IKZF1 deletions

Table 1. Definitions of IKZF1 alterations.

Table 2. Criteria for B-ALL genomic subtypes.

Statistical Analysis for the Total XV/16 study groups

RESULTS

Frequency of IKZF1 alterations among B-ALL subtypes

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.

Association of IKZF1 alterations with clinical features and response to therapy

IKZF1 alterations and clinical outcome in Total Therapy XV/16 and MP2PRT studies

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

Table 3: EFS and CIR in IKZF1 alteration groups stratified by NCI Risk in Total XV/16 studies.

Figure 3. Outcomes based on type of IKZF1 alterations, including IKZF1plus (genomic, any ΔIKZF1) and sequence mutations in the Total XV/16 study group.

Table 4: Outcomes for patients with IKZF1 alteration types from univariable and multivariable analysis in Total XV/16 studies.

Independently prognostic IKZF1 alterations

The impact of B-ALL genomic subtypes and IKZF1 alterations on outcome

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

Effect of IKZF1 alterations among patients with negative MRD

DISCUSSION

Supplementary Material

ACKNOWLEDGEMENTS

Footnotes

DATA SHARING STATEMENT

REFERENCES

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Definitions of IKZF1^plus and IKZF1 deletions

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.