High CD45 (PTPRC) Expression Is Associated with An Overall Poor Outcome in Childhood Acute Lymphoblastic Leukemia Treated on the ALL-BFM 2000 Protocol and Exerts An Especially Pronounced Effect in Intermediate Risk Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 742-742
Author(s):  
Gunnar Cario ◽  
Rita Mitlohner ◽  
Martin Zimmermann ◽  
Renja Romey ◽  
Peter Rhein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Protein Expression ◽  
Lymphoblastic Leukemia ◽  
Treatment Resistance ◽  
Intermediate Risk ◽  
Prognostic Relevance ◽  
Risk Patients ◽  
Low Expression

Abstract Abstract 742 Further improvement of outcome in childhood acute lymphoblastic leukemia (ALL) could be achieved by identifying additional high-risk (HR) patients who then may benefit from an intensified treatment. In trial ALL-BFM 2000, the HR group was defined by inadequate initial response to induction treatment [poor prednisone response on treatment day eight (PPR), non remission on treatment day 33, and/or a high load of minimal residual disease (MRD, ≥10E-3) after 12 weeks of treatment (TP2)] and/or by positive cytogenetics for a t(4;11) or t(9;22). No MRD already on treatment day 33 defined standard risk (SR) patients, a measurable MRD at a low level characterized the intermediate risk (IR) group. Of importance, the majority of relapses occurred within this heterogeneous group of patients. In order to identify potential new stratification markers we earlier compared gene expression profiles of MRD resistance (HR) and sensitive (SR) ALL in a case-control setting (Cario et al, Blood 2005). Subsequently, we aimed at confirming the potential prognostic relevance of genes identified and their respective proteins in representative study populations. CD45 (also PTPRC, protein-tyrosine phosphatase, receptor-type, C) was one of these candidate genes. In order to assess its prognostic relevance, CD45 gene expression was first analyzed by quantifiable RT-PCR in a set of 555 precursor B-ALL (pB-ALL); its protein expression subsequently in 422 pB-ALL patients by flow cytometry. About one third of patients were included in both study sets. Normalization of protein expression was done by assessing the density of surface expression relative to its density on normal lymphocytes. The 90th percentile was used as a cut-off to distinguish a CD45-high from a CD45-low expression group in both analyses. In gene expression analysis we observed a significant association of a high CD45 expression with a high white blood cell count at diagnosis (WBC) (P = 0.0004), NCI-HR (P = 0.03) as well as presence of the MLL-AF4 rearrangement (P < 0.0001). Moreover, a high CD45 expression was associated with in-vivo treatment resistance as defined by MRD (P = 0.0025). Analyzing CD45 protein expression confirmed the association of a high expression with a high WBC (P < 0.0001), NCI-HR (P = 0.0002) as well as presence of the MLL-AF4 rearrangement (P < 0.0001). Moreover, although the association to treatment resistance was lower (P = 0.055), patients with a high CD45 expression had a significantly worse 5-years EFS probability of 62±8% compared to 82±2% for those in the low-expression group (P=0.002). Focussing on the IR group, patients with a high CD45 expression had a very poor outcome (EFS 45±15%) as compared to those with a low expression (EFS 86±3%, P < 0.0001). This effect was mainly related to a higher cumulative relapse incidence (55±16% vs. 13±3%, P < 0.0001). Of interest, no significant differences in EFS were seen in HR patients. Based on our results, consideration of CD45 protein expression may serve as additional stratification tool in BFM-based protocols to further refine true non-high-risk patients with a low risk of relapse by identifying additional patients at high relapse risk. Of importance, in view of the fact that CD45 expression was not prognostic in the high-risk group, patients with a high CD45 expression currently treated on non high risk arms, may potentially benefit from an intensified treatment in the HR arm. Disclosures: No relevant conflicts of interest to declare.

Minimal Residual Disease–Guided Treatment Deintensification for Children With Acute Lymphoblastic Leukemia: Results From the Malaysia-Singapore Acute Lymphoblastic Leukemia 2003 Study

2012 ◽  
Vol 30 (19) ◽  
pp. 2384-2392 ◽  
Author(s):  
Allen Eng Juh Yeoh ◽  
Hany Ariffin ◽  
Elaine Li Leng Chai ◽  
Cecilia Sze Nga Kwok ◽  
Yiong Huak Chan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Intermediate Risk ◽  
Risk Patients ◽  
Standard Risk ◽  
Minimal Residual

Purpose To improve treatment outcome for childhood acute lymphoblastic leukemia (ALL), we designed the Malaysia-Singapore ALL 2003 study with treatment stratification based on presenting clinical and genetic features and minimal residual disease (MRD) levels measured by polymerase chain reaction targeting a single antigen-receptor gene rearrangement. Patients and Methods Five hundred fifty-six patients received risk-adapted therapy with a modified Berlin-Frankfurt-Münster–ALL treatment. High-risk ALL was defined by MRD ≥ 1 × 10−3 at week 12 and/or poor prednisolone response, BCR-ABL1, MLL gene rearrangements, hypodiploid less than 45 chromosomes, or induction failure; standard-risk ALL was defined by MRD ≤ 1 × 10−4 at weeks 5 and 12 and no extramedullary involvement or high-risk features. Intermediate-risk ALL included all remaining patients. Results Patients who lacked high-risk presenting features (85.7%) received remission induction therapy with dexamethasone, vincristine, and asparaginase, without anthracyclines. Six-year event-free survival (EFS) was 80.6% ± 3.5%; overall survival was 88.4% ± 3.1%. Standard-risk patients (n = 172; 31%) received significantly deintensified subsequent therapy without compromising EFS (93.2% ± 4.1%). High-risk patients (n = 101; 18%) had the worst EFS (51.8% ± 10%); EFS was 83.6% ± 4.9% in intermediate-risk patients (n = 283; 51%). Conclusion Our results demonstrate significant progress over previous trials in the region. Three-drug remission-induction therapy combined with MRD-based risk stratification to identify poor responders is an effective strategy for childhood ALL.

CRLF2/JAK Signaling in Adult and Pediatric Acute Lymphoblastic Leukemia Is Highly Similar to BCR/ABL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3461-3461
Author(s):  
Kartik Mani ◽  
Akinori Yoda ◽  
Sabina Chiaretti ◽  
Robin Foa ◽  
David M Weinstock
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Janus Kinase ◽  
Gene Set Enrichment Analysis ◽  
Type I ◽  
Over Expression ◽  
High Risk Patients ◽  
Risk Patients

Abstract Abstract 3461 Poster Board III-349 Introduction We and others recently identified the type I-like cytokine receptor CRLF2 as an oncoprotein in precursor B-cell acute lymphoblastic leukemia (B-ALL). Overexpression of CRLF2, which can occur through translocation to the IGH locus or interstitial deletion, is confined to B-ALL that lack rearrangements involving MLL, E2A, TEL, and BCR/ABL. Importantly, adults with B-ALL that overexpress CRLF2 have reduced disease-free survival compared to patients with similar karyotypes that do not overexpress CRLF2. In this study, we used high-throughput gene expression microarrays and publicly available data in the Gene Expression Omnibus (GEO) to characterize the epidemiology, transcriptional signatures and dysregulated pathways associated with CRLF2 overexpression. Methods We searched the GEO for pediatric B-ALL cases profiled on the Affymetrix U133 platforms (which contain the CRLF2 probe set 208303_s_at) and identified 9 applicable datasets (3 exclusively high-risk), totaling 1,253 samples. These datasets were individually normalized using robust multi-array average. Based on the assumption that CRLF2 over-expression would manifest as a bimodal distribution (one peak for the background levels and a smaller peak for the overexpressed levels), points falling 5 standard deviations outside a computed background mean were selected as CRLF2 positive. An equal number of underexpressed cases were selected and a student t-test was applied to identify differentially expressed genes associated with CRLF2. The resultant ranked list was compared with several other expression signatures using Gene Set Enrichment Analysis (GSEA). Sequencing data from patients was integrated where available to obtain genetic-genomic associations. Results Among the 3 pediatric datasets that included only high-risk patients, 52 (14.8%) of 351 B-ALL that lacked characteristic rearrangements had CRLF2 overexpression, compared with 23 (4.1%) of 559 cases in the six datasets that included both standard-risk and high-risk patients (p<0.0001). Two pediatric datasets (GSE11877 and GSE12995) were selected for supervised analysis based on the presence of a clear subset of CRLF2 overexpressing cases (n=29 and n=8 respectively). Genes associated with CRLF2 overexpression in these datasets showed significant enrichment of a signature associated with CRLF2 overexpression in adult B-ALL (p<0.001 in both up-regulated and down-regulated sets). Furthermore, both pediatric signatures showed similarly striking enrichment of genes associated with BCR/ABL-expressing B-ALL, obtained from the Oncomine® database (p<0.001 in both up- and down-regulated sets). Lastly, when previously published data on Janus kinase (JAK) mutations in the GSE11877 cohort were integrated, 18 (90%) out of 20 patients harboring JAK mutations had CRLF2 over-expression; 16 (100%) of 16 harboring JAK2 mutations (p=0, below machine precision). This result was further supported by strong enrichment of the JAK-STAT signaling pathway (KEGG) in both expression signatures (p<0.001 in up-regulated sets). Conclusions The expression signature associated with CRLF2 overexpression is highly similar between children and adults, and consistent with the high-risk nature of disease in both age groups. The same signature is strongly associated with BCR/ABL-expressing B-ALL, suggesting that overlapping pathways are activated by tyrosine kinase signaling from BCR/ABL and mutated CRLF2/JAK. Disclosures No relevant conflicts of interest to declare.

scholarly journals Personalized therapy in pediatric high-risk B-cell acute lymphoblastic leukemia

2020 ◽  
Vol 11 ◽  
pp. 204062072092757 ◽  
Author(s):  
Seth E. Karol ◽  
Ching-Hon Pui
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Risk Patients ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Disease Stratification ◽  
Cure Rates ◽  
Minimal Residual

Although cure rates for pediatric acute lymphoblastic leukemia (ALL) have now risen to more than 90%, subsets of patients with high-risk features continue to experience high rates of treatment failure and relapse. Recent work in minimal residual disease stratification and leukemia genomics have increased the ability to identify and classify these high-risk patients. In this review, we discuss this work to identify and classify patients with high-risk ALL. Novel therapeutics, which may have the potential to improve outcomes for these patients, are also discussed.

Minimal Residual Disease At 3 Months, Combined to the Presence of IKZF1 Deletion in B-Lineage or Absence of NOTCH1 pathway Mutation in T-Lineage, Recapitulates the Disease Risk Assessment in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia - A GRAALL Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 572-572 ◽  
Author(s):  
Kheira Beldjord ◽  
Elizabeth Macintyre ◽  
Véronique Lhéritier ◽  
Marie-Laure Boulland ◽  
Thibaut Leguay ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Disease Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cns Involvement ◽  
Risk Patients ◽  
Minimal Residual

Abstract Abstract 572 Aim. In recent series of adults with acute lymphoblastic leukemia (ALL), the GRAALL (ASH 2009, abstract 577) and other cooperative groups have confirmed the strong prognostic value of Ig/TCR minimal residual disease (MRD) on patient outcome. Despite this, age, WBC, CNS involvement, recurrent chromosomal translocations, and early response to steroids and chemotherapy remain frequently used to tailor post-remission therapy and envision allogeneic stem cell transplantation (SCT) in most adult ALL trials. We updated our MRD study, now with 262 patients who all achieved complete remission (CR) after the first induction and were assessed for MRD after induction (MRD1, at 6 weeks) and consolidation (MRD2, at 12 weeks). One hundred and fifty-eight patients had Philadelphia chromosome (Ph)-negative B-cell precursor ALL (BCP-ALL), while 104 had T-cell ALL (T-ALL). Since 107 of the BCP-ALL (68%) were studied for IKZF1 deletion and 90 of the T-ALL patients (87%) for NOTCH1/FBXW7 mutations, we were able to reassess the MRD significance according to these newly described oncogenic markers. These two covariates (i.e. MRD and IKZF1/NOTCH1/FBXW7 genetics) allowed us to redefine a much simpler yet more powerful stratification of disease risk in both BCP- ALL and T-ALL subsets. Methods. All 262 patients studied (median age, 31.5 years) were treated in the GRAALL-2003 and GRAALL-2005 trials. Although they were younger and had more frequently circulating blasts, other characteristics and outcome did not differ from patients treated in the same trials but not assessed for MRD. Ig/TCR MRD levels were determined according to Euro-MRD guidelines (Leukemia 2007;21:604). IKZF1 deletions were assessed by multiplex multi-fluorescent PCR. NOTCH1/FBXW7 mutations were assessed as previously described (Blood 2009;113:3918). Multivariate backward stepwise selection Cox models were used for the cumulative incidence of relapse (CIR), disease-free (DFS) and overall survival (OS) endpoints, after censoring transplanted patients at SCT. Models were always adjusted on age (35-year cutoff), WBC (30 and 100 G/L cutoff for BCP- and T-ALL, respectively), CNS involvement, and trial. Additional BCP-specific covariates included CD20 expression, t(4;11) and t(1;19) translocations, and IKZF1 deletion. Additional T-specific covariates included cortical immunophenotype according to the EGIL classification, TLX1 overexpression, and NOTCH1/FBXW7 mutation. Finally, allogeneic SCT was re-evaluated in the newly defined risk subsets, as a time-dependent covariate. Results. An initial multivariate analysis revealed that among blood response after 1 week of steroid, bone marrow response after 2 weeks of therapy, and molecular response at both MRD1 and MRD2 time-points, the MRD2 level was the main and sole independent predictor of relapse (P=0.003). In BCP-ALL patients, persistent MRD2 and IKZF1 deletion were the only two independent factors identified, the presence of at least one factor defining 51% high-risk patients with 52% versus 15% CIR (HR, 3.8; P= 0.008), 41% versus 81% DFS (HR, 3.6; P= 0.005), and 54% versus 80% OS (HR, 3.9; P= 0.015) at 4 years. Allogeneic SCT in first CR significantly decreased relapse incidence and prolonged DFS in these new high-risk BCP-ALL patients (HR, 0.23 and 0.40; P= 0.016 and 0.05, respectively). In T-ALL patients, persistent MRD2 and lack of NOTCH1/FBXW7 mutation were the only two independent factors identified, the presence of at least one factor defining 49% high-risk patients with 64% versus 12% CIR (HR, 6.4; P= 0.002), 36% versus 88% DFS (HR, 6.4; P= 0.002), and 41% versus 95% OS (HR, 7.3; P= 0.015) at 4 years. SCT had no significant effect on relapse incidence and DFS in these new high-risk T-ALL patients. Conclusion. In adult patients with Ph-negative ALL treated with the pediatric-inspired GRAALL regimen, IKZF1 deletion in BCP-ALL, NOTCH1/FBXW7 mutation in T-ALL, and MRD at 3 months in both subsets replace all classical risk factors, leading to a new simplified prognostic scoring system based only on IKZF1 and NOTCH1/FBXW7 genetics and MRD clearance. This new risk score identifies approximately half of the patients as good-risk, with a relapse incidence as low as 10–15%. It will be validated and used prospectively in the next generation of GRAALL trials, to stratify both new drug evaluation and SCT in first CR. Disclosures: No relevant conflicts of interest to declare.

Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 821-826 ◽  
Author(s):  
Gunnar Cario ◽  
Martin Stanulla ◽  
Bernard M. Fine ◽  
Oliver Teuffel ◽  
Nils v. Neuhoff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Treatment Response ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Treatment Resistance ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Resistance To Chemotherapy ◽  
Intrinsic Feature

AbstractTreatment resistance, as indicated by the presence of high levels of minimal residual disease (MRD) after induction therapy and induction consolidation, is associated with a poor prognosis in childhood acute lymphoblastic leukemia (ALL). We hypothesized that treatment resistance is an intrinsic feature of ALL cells reflected in the gene expression pattern and that resistance to chemotherapy can be predicted before treatment. To test these hypotheses, gene expression signatures of ALL samples with high MRD load were compared with those of samples without measurable MRD during treatment. We identified 54 genes that clearly distinguished resistant from sensitive ALL samples. Genes with low expression in resistant samples were predominantly associated with cell-cycle progression and apoptosis, suggesting that impaired cell proliferation and apoptosis are involved in treatment resistance. Prediction analysis using randomly selected samples as a training set and the remaining samples as a test set revealed an accuracy of 84%. We conclude that resistance to chemotherapy seems at least in part to be an intrinsic feature of ALL cells. Because treatment response could be predicted with high accuracy, gene expression profiling could become a clinically relevant tool for treatment stratification in the early course of childhood ALL.

scholarly journals Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3080-3087 ◽  
Author(s):  
Jinghui Zhang ◽  
Charles G. Mullighan ◽  
Richard C. Harvey ◽  
Gang Wu ◽  
Xiang Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
High Frequency ◽  
Lymphoblastic Leukemia ◽  
Cell Development ◽  
B Cell Development ◽  
Ras Signaling ◽  
Somatic Alterations

Abstract We sequenced 120 candidate genes in 187 high-risk childhood B-precursor acute lymphoblastic leukemias, the largest pediatric cancer genome sequencing effort reported to date. Integrated analysis of 179 validated somatic sequence mutations with genome-wide copy number alterations and gene expression profiles revealed a high frequency of recurrent somatic alterations in key signaling pathways, including B-cell development/differentiation (68% of cases), the TP53/RB tumor suppressor pathway (54%), Ras signaling (50%), and Janus kinases (11%). Recurrent mutations were also found in ETV6 (6 cases), TBL1XR1 (3), CREBBP (3), MUC4 (2), ASMTL (2), and ADARB2 (2). The frequency of mutations within the 4 major pathways varied markedly across genetic subtypes. Among 23 leukemias expressing a BCR-ABL1-like gene expression profile, 96% had somatic alterations in B-cell development/differentiation, 57% in JAK, and 52% in both pathways, whereas only 9% had Ras pathway mutations. In contrast, 21 cases defined by a distinct gene expression profile coupled with focal ERG deletion rarely had B-cell development/differentiation or JAK kinase alterations but had a high frequency (62%) of Ras signaling pathway mutations. These data extend the range of genes that are recurrently mutated in high-risk childhood B-precursor acute lymphoblastic leukemia and highlight important new therapeutic targets for selected patient subsets.

scholarly journals Biology of t(6;11) Fusion Proteins and Their Role in MLL-Rearranged Acute Leukemia Lineage Determination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5033-5033
Author(s):  
Arpita Kundu ◽  
Eric Kowarz ◽  
Jennifer Reis ◽  
Rolf Marschalek
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Acute Leukemia ◽  
Fusion Proteins ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Fusion Genes ◽  
Disease Phenotype ◽  
Acute Leukemias

Chromosomal translocations are genetic rearrangements where a chromosomal segment is transferred to a non-homologous chromosome which give rise to novel chimeras. Chromosomal rearrangements play a significant role in the development of acute leukemias (acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML)). Chromosomal translocation events occurring at 11q23 involving the KMT2A or Mixed-Lineage Leukemia (MLL) gene (n=102) can be diagnosed in about 5-10% of all acute leukemia patients (Marschalek Ann Lab Med 2016), especially prevalent in infant acute leukemias (up to 70% of cases). Different chromosomal translocation partner genes (such as AF4, AF6, AF9orENL and ELL) account for the majority of leukemia cases and have their genomic breakpoints within a major breakpoint cluster region (BCR intron 9-11; Meyer et. al. Leukemia 2018). Some rearrangements are specifically associated with particular disease phenotype e.g. the majority of ALL patients (~ 90%) are mainly caused by the following gene fusions, MLL-AF4, MLL-AF9, MLL-ENL. We are interested in a rare but yet drastic chromosomal translocation t(6;11)(q27;q23) which fuses KMT2A/MLL to Afadin (AFDN/AF6) gene. This chromosomal rearrangement has a very poor prognosis (survival-rate is ~10%) and is predominantly diagnosed in patients with high-risk AML. In this project, we investigate the molecular consequences of two different MLL-AF6 fusions and their corresponding reciprocal AF6-MLL fusions. MLL-AF6 fusions are mainly occurring within MLL intron 9 to 11 and are associated with an AML disease phenotype, while the same fusion occurring within the minor breakpoints region in MLL intron 21 until exon (ex) 24 are mainly diagnosed with T-ALL (T-cell acute lymphoblastic leukemia) disease phenotype. The molecular mechanism that determines the resulting disease phenotype is yet unknown. Therefore, we cloned all of these t(6;11) fusion proteins in order to investigate the functional consequences of the two different breakpoints (MLLex1-9::AF6ex2-30, AF6ex1::MLLex10-37; MLLex1-21::AF6ex2-30, AF6ex1::MLLex22-37). All 4 fusion genes were introduced into our inducible Sleeping Beauty system (Ivics et. al. Mobile DNA 2010; Kowarz et. al. Biotechnol J. 2015) and stably transfected reporter cell lines. Basically, these 4 fusion proteins differ only in the presence or absence of their Plant homeodomain 1-3/Bromodomain (PHD1-3/BD) domain (see Figure 1). The PHD domain regulates the epigenetic and transcriptional regulatory functions of wildtype MLL. Subsequently, we analyzed gene expression differences by the MACE-Seq (Massive Analyses of cDNA Ends). MACE data revealed fundamental differences in gene expression profiles when analyzing the two different sets of t(6;11) fusion genes. The resulting profiles have similarities to either AML or T-ALL and might give a rational explanation for the different lineages in these t(6;11) patients. Altogether, these results notably indicate that our study will provide a novel insight into this type of high-risk leukemia and subsequently will be useful for developing of novel and appropriate therapeutic strategies against acute leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of IKZF1 Deletions and IKZF1 Plus in Pediatric Acute Lymphoblastic Leukemia Outcome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4091-4091
Author(s):  
Maria Sara Felice ◽  
Patricia Laura Rubio ◽  
Myriam Ruth Guitter ◽  
Jorge Gabriel Rossi ◽  
Jorge Alberto Digiorge ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Relapse Rate ◽  
Copy Number ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Rank Test ◽  
Copy Number Alterations ◽  
Risk Patients ◽  
Pediatric All

Abstract Introduction: Survival of children with acute lymphoblastic leukemia (ALL) has improved in the last decades, achieving approximately 80% in Argentina. However, relapses remain the most frequent adverse event and the identification of patients with higher risk need to be refined. Deletions in IKZF1(IKZF1del) in addition with deletion of CDKN2A, CDKN2B,PAX5 or PAR1 region define a new subgroup of patients (IKZF1plus) with higher relapse rate and poor survival. Objectives: To analyze the characteristics of patients with IKZF1del and IKZF1plus, assessing the impact of the copy number alterations in several genes on survival of pediatric ALL treated with ALLIC strategy. Methods: This is a retrospective analysis performed in the population of patients admitted from October 2009 to May 2018. Samples of 432 patients with diagnosis of ALL were collected and analyzed by MLPA P-335 (MRC-Holland) for copy number alterations of IKZF1, EBF1, JAK2, CDKN2A, CDKN2B, PAX5, ETV6, BTG1, RB1 genes and PAR1 region. IKZF1plus cases were defined as those with IKZF1del with at least one additional deletion in: PAX5, CDKN2A, CDKN2B, PAR1 region. Patients were treated with 2 consecutive ALLIC protocols, according to studies stratification. Patient characteristics were compared with chi-square and Wilcoxon-sum-rank-test. Survival probability was analyzed with Kaplan-Meier calculation and survival results compared with Log-rank-test. Results: IKZF1 was not deleted in 345 cases, IKZF1del was detected in 87 cases and 47 of them were defined as IKZF1plus. Statistically significant higher WBC, MRD+ positivity on day 15, day 33 and week 12, more BCR-ABL+ and high-risk group cases, null response and higher relapse rate were observed in the IKZF1del group (total) when comparing with IKZF1 not del, and also when comparing IKZF1plus vs IKZF1 not del + IKZF1del only. EFS (SE) and DFS (SE) probabilities were: 73 (4)% and 75 (3)% for IKZF1 not del, 66 (9)% and 70 (9)% for IKZF1del, and 20 (10)% and 21 (10)% for IKZF1plus, respectively (p<0.00001).DFS of the standard-risk group was not influenced by the presence of only 1 case of IKZF1del detected in this risk-group of patients. However, DFS of intermediate-risk patients was 41 (11)% for IKZF1plus while 70 (7)% and 73 (4)% were achieved for IKZF1del and IKZF1 not del respectively (p=0,0083). Therefore, high-risk patients with IKZF1plus achieved DFS of 12 (19)% vs 65 (7)% and 50 (21)% for IKZF not del and IKZF1del respectively (p=0.0085). DFS of patients with IKZF1del + CDKN2Adel was 30 (10)% and CDKN2A not deleted 67 (9)% (p=0.0433). DFS of patients with IKZF1del + CDKN2Bdel was 42 (12)% and 66 (9)% for CDKN2B not del. DFS of cases with IKZF1del in addition to deletion of ETV6, BTG1, EBF1 orJAK2 did not show statistically significant differences when comparing with IKZF1del + normal copy number of these genes. In addition, DFS of cases with RB1del was 36 (13)% while cases without RB1del showed 70 (3)% (p=0.0071). Conclusions: 1- Patients with IKZF1del and IKZF1plus disclosed biological features related to poor outcome. 2- IKZF1plus was associated with a poor outcome in intermediate and high-risk groups according to ALLIC stratification. 3- The addition of CDKN2Adel to IKZF1del influence the outcome. However, CDKN2Bdel did not show the same effect. 4- Copy number alterations of ETV6, BTG1, EBF1 or JAK2 did not demonstrate prognostic impact. 5- RB1 showed negative influence in survival. 6- Identification of patients with IKZF1plus at diagnosis could be very useful for improving risk-group stratification of pediatric ALL patients. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document