miR-155 expression and correlation with clinical outcome in pediatric AML: A report from Children's Oncology Group

Abstract Molecular alterations of the WT1 gene have been associated with clinical outcome in adult AML. We evaluated the prevalence and prognostic significance of WT1 mutations in a cohort of 842 pediatric patients treated on pediatric AML trials CCG-2941, CCG-2961, or COG-AAML03P1. Exons 6–10 of the WT1 gene were evaluated by microcapillary electrophoresis and direct sequencing. Of the 842 samples diagnostic specimens analyzed, 68 (8%) contained mutations in exon 7 (n=62), exon 8 (n= 5), or exon 9 (n=1). Correlation analyses were done to determine whether the presence of WT1 mutations is associated with laboratory and disease characteristics and clinical outcome. There were no differences in sex, race, median diagnostic blast %, or median diagnostic WBC count between samples from patients carrying WT1 mutations and those from patients who did not; however, such mutations were less common in the younger patients (age, 0–2 years; p<0.001) and in those with FAB M5 AML (p=0.009). Our evaluation of clinical outcome showed that the rate of complete remission after the first round of induction chemotherapy for those with and without WT1 mutations 74% and 80%, respectively (P=0.3) Actuarial overall survival (OS) from the time of study entry for patients with WT1 mutations was 35% vs. 52% for those without WT1 mutations; p=0.014. Corresponding event-free survival (EFS) was also significantly worse for those with WT1 mutations (27% vs. 41%; p=0.013). We also evaluated associations between WT1 mutations and cytogenetic and molecular alterations. In the patients with WT1 mutations, 31% had inv(16) or t(8;21). There was also substantial overlap between WT1 mutation and FLT3/ITD, i.e., 29% of those carrying a WT1 mutation were FLT3/ITD- positive, whereas only 7% of patients without WT1 were FLT3/ITD-positive (p<0.001). In addition, 11q23 alterations were rare in patients with WT1 mutations (4% vs. 24%; p=0.002). Prognostic significance of WT1 mutations in FLT3/ITD-negative patients was determined. In a comparison of samples from FLT3/ITD-negative patients with WT1 mutations and those from patients who did not carry the 2 mutations, the OS (51% vs. 54%, respectively; p=0.5) and the corresponding EFS (34% and 43%, respectively; p=0.22) were not significantly different. The prognostic significance of the WT1 mutation was also determined in patients with a normal karyotype who were FLT3/ITD-negative. No significant differences were found in the OS (40% and 55%, respectively; p=0.23) or in the corresponding EFS values (31% and 45%, respectively; p=0.335). We conclude that about 8% of children with AML carry WT1 mutations, including novel mutations identified in exon 8. These mutations are associated with other cytogenetic and molecular alterations, and despite their overall association with poor outcome, the prognostic significance of WT1 mutations is less pronounced once the data are corrected for FLT3/ITD and cytogenetic abnormalities.

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High Expression of the Very Late Antigen (VLA)-4 (CD49d) Integrin Predicts for Reduced Risk of Relapse and Better Outcome in Pediatric Acute Myeloid Leukemia (AML): A Report From the Children's Oncology Group.

Blood ◽

10.1182/blood.v114.22.1592.1592 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1592-1592

Author(s):

Walter B. Walter ◽

Todd A. Alonzo ◽

Robert B. Gerbing ◽

Franklin O. Smith ◽

Susana C. Raimondi ◽

...

Keyword(s):

High Risk ◽

Clinical Outcome ◽

Risk Classification ◽

Low Risk ◽

Significant Heterogeneity ◽

Oncology Group ◽

Monosomy 7 ◽

Entire Cohort ◽

The Impact ◽

Standard Risk

Abstract Abstract 1592 Poster Board I-618 Background Previous studies highlighted the importance of the cell adhesion molecule, VLA-4, for chemoresistance and minimal residual disease (MRD) in AML, suggesting promise as therapeutic target. By comparison, the prognostic role of VLA-4 in AML remains controversial with retrospective studies implying either adverse or favorable prognosis. Therefore, we prospectively evaluated VLA-4 expression in participants of a recent Children's Oncology Group (COG) AML pilot protocol. Methods COG-AAML03P1 enrolled 340 newly diagnosed children (aged 1 month - 21 years) with de novo non-acute promyelocytic AML, excluding those with Down syndrome, and tested the feasibility of combining gemtuzumab ozogamicin (GO) with intensive induction chemotherapy followed by GO-containing intensification therapy or matched related donor stem cell transplantation; 216 patients submitted diagnostic marrow specimens for flow cytometric determination of VLA-4 expression that was then correlated with patient demographics, laboratory characteristics, and clinical outcome. Cytogenetics and molecular prognostic markers were used for risk classification as follows: low risk (mutation in core-binding factor, NPM1, or CEBPa; n=73), high risk (-5/5q-, monosomy 7, or FLT3/ITD with high allelic ratio; n=25), or standard risk (all other patients with cytogenetic/molecular data; n=101); 17 patients had insufficient data for risk classification. Results Among the 216 diagnostic specimens, the mean fluorescence intensity (MFI) of VLA-4 expression varied over 35-fold from a baseline of 30 to 1110 (median, 219.5). Patients with high VLA-expression (>median MFI) were younger (p<0.001), had a lower prevalence of FLT3/ITD (p=0.002). Presence of extramedullary disease (EMD, chloroma or CNS involvement) was significantly higher in patients with high VLA-4 expression (16% vs. 5%, p=0.013), where 17/22 (77%) of patients with EMD had high VLA-4 expression. We initially inquired whether VLA-4 expression as a continuous variable correlated with disease outcome. We demonstrated that over the range of VLA-4 expression levels, every 10-unit increase in VLA-4 MFI corresponded to a 2% decrease in relapse risk (RR; p=0.023) and 2% increase in disease-free survival (DFS) from end of induction I (p=0.015). We subsequently divided the study patients into two cohorts based on median MFI and determined the clinical outcome per median VLA-4 MFI for the entire cohort as well as in specific risk groups (i.e., high risk, low risk, and standard risk). In the evaluation of the entire cohort, patients with high VLA-4 expression had a significantly superior DFS (67% vs 48%, p=0.023) and lower RR (24% vs 44%, p=0.011) compared to those with lower VLA-4 expression. In subgroup analyses, high VLA-4 expression was associated with significantly superior DFS (69% vs 34%, p=0.011) and lower RR (26% vs 61%, p=0.009) in patients with standard-risk AML but not in patients with high or low risk disease. In multivariate Cox regression analyses that included age, cytogenetics, and molecular prognostic factors, low VLA-4 expression remained significantly associated with elevated RR (hazard ratio for low VLA-4: 2.25, p=0.011). Finally, we determined the impact of MRD in the context of VLA-4 expression. The prevalence of MRD was similar for patients with low or high VLA-4 expression (29% vs. 25%, p=0.70). In patients with low VLA-4 expression, those with MRD had a RR of 75% compared to that of 35% for the MRD negative cohort (p=0.005). Corresponding DFS was 19% and 54% for those with and without MRD (p=0.018), a difference mainly attributable to increased RR. In patients with high VLA-4 expression, those with MRD had a RR of 31% vs. 23% for the MRD-negative patients (p=0.28) with a corresponding DFS of 46% and 75% for the MRD positive and negative patients (p=0.014), a difference mainly explained by higher treatment-related mortality in MRD positive patients. Conclusion This study demonstrates significant heterogeneity of VLA-4 expression in pediatric AML and its association with EMD and clinical outcome. This study further demonstrates that VLA-4 expression is an independent prognostic factor for clinical outcome and can identify the risk status in patients with no identifiable cytogenetic or molecular risk factors. Disclosures No relevant conflicts of interest to declare.

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Elevated BAALC Gene Expression Lacks Clinical Significance in Pediatric AML- A Report From the Children's Oncology Group.

Blood ◽

10.1182/blood.v120.21.2553.2553 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2553-2553

Author(s):

Jessica A. Pollard ◽

Todd A. Alonzo ◽

Robert B. Gerbing ◽

Phoenix A. Ho ◽

Susana C. Raimondi ◽

...

Keyword(s):

Platelet Count ◽

High Risk ◽

Clinical Outcome ◽

Clinical Significance ◽

Disease Risk ◽

High Expression ◽

Study Entry ◽

Pediatric Aml ◽

Normal Cytogenetics ◽

Median Expression

Abstract Abstract 2553 Background: High expression of the brain and acute leukemia, cytoplasmic (BAALC) gene is associated with inferior outcomes in adult AML patients with normal cytogenetics. Studies regarding the significance of BAALC expression in pediatric AML are limited. We studied BAALC expression in a cohort of children with de novo AML to evaluate its clinical significance in pediatric AML, particularly in patients with standard-risk (SR) disease. Methods: BAALC mRNA expression was measured via qRT-PCR in diagnostic specimens obtained from 206 patients enrolled on COG AAML03P1. Expression levels were normalized against pooled normal blood controls (PNB). To evaluate the impact of BAALC expression values on clinical outcome, samples were dichotomized at the median expression level (14.9) into a BAALClow (N= 103, median expression 2.9; range 0.0089–14.897) and BAALChigh (N=103; median expression 65; range 15.064–369.53) subset. Baseline clinical features were compared for BAALClow vs. BAALChigh patients and categorical variables compared using the chi-square test and Fisher exact test when data were sparse. The Kaplan-Meier method was used to estimate OS, EFS and DFS for the 2 groups. Estimates of RR were obtained using methods that accounted for competing events. Similar methods were used for sub-analysis of n=99 SR patients. Results: Compared to expression in PNB, BAALC expression varied over 5 log fold (range 0.0089–369.53); the median BAALC expression was 14.98. There were no differences between BAALClow and BAALChigh patients with respect to disease presentation (WBC, BM blast%, Hb, platelet count) though patients with BAALChigh expression were older (median age 12.2 vs. 7.8; years; p=0.001). NPM1 mutations were more frequent in the BAALClow subset (12% vs 0%, p=0.002) however CEBPA and FLT3/ITD mutations were not associated with BAALC expression. Favorable cytogenetics were associated with BAALChigh expression [t(8;21): 1% vs. 23%, p=<0.001; inv (16) 5% vs. 26%;p=<0.001] whereas normal cytogenetics and 11q23abnormalities were more frequent in the BAALClow cohort [normal cytogenetics 32% vs 13%; p=0.002; 11q23: 33% vs. 6%; p=<0.001]. High-risk cytogenetic features were not associated with BAALC expression in limited analysis (n=6 patients). BAALC expression was also correlated with disease-risk, a classification derived from prognostic cytogenetic and molecular features. BAALChigh was more common in patients with low-risk disease (19% vs. 54%, p=<0.001) whereas BAALClow was more frequently seen in SR patients (69% vs 32% p=<0.001). There was no association between high-risk patients and BAALC expression in a limited number of samples analyzed (n=26). Induction response was independent of BAALC expression (77% vs. 82%, p=0.442) although minimal residual disease (MRD) at end of induction was marginally associated with high expression (20% vs. 35%, p=0.058). There were no differences in OS and EFS from study entry for BAALClow vs. BAALChigh patients (5 year OS: 64% vs. 63%, p=0.832; EFS 49% vs. 48%, p=0.868) Corresponding DFS and RR from CR were also comparable (DFS: 58% vs. 56%, p=0.608; RR 34% vs. 31%, p=0.735). We further evaluated the association of BAALC expression with outcome in patients with SR disease. SR BAALClow and SR BAALChigh patients had similar disease presentation (WBC, BM blast %, platelet count, Hb) and were similar in age. Abnormalities of 11q23 were associated with SR BAALClow expression (51% vs. 24%; p=0.006) but other SR cytogenetic abnormalities including normal cytogenetics were not. Rates of induction CR were similar for SR BAALClow versus SR BAALChigh patients (77% vs. 66%, p=0.225) as were rates of end induction MRD (21% vs. 37%, p=0.178). Importantly, there were no differences in OS and EFS from study entry for SR BAALClow vs. SR BAALChigh patients (5 year OS: 56% vs. 59%, p=0.464; EFS 42% vs. 37%, p=0.899). Corresponding DFS and RR from CR were also comparable (DFS: 56% vs. 47%, p=0.756; RR 36% vs. 41%, p=0.990). Conclusions: In this study, elevated BAALC expression was not associated with clinical outcome, within our total study cohort and in those patients with SR disease. This suggests that BAALC expression may lack independent prognostic significance within pediatric AML, despite its association with specific disease characteristics. Validation of our findings in a larger pediatric cohort, and in all disease-risk groups, is ongoing within COG protocol AAML0531. Disclosures: Franklin: Amgen: Employment.

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Comprehensive Genomic and Transcript Profiling of CBL Gene in Childhood AML: A Report from Children's Oncology Group Studies AAML03P1, AAML0531 and COG/NCI Target AML Initiative

Blood ◽

10.1182/blood.v126.23.170.170 ◽

2015 ◽

Vol 126 (23) ◽

pp. 170-170

Author(s):

Diana Chin ◽

Matthew A. Kutny ◽

Jonathan Grim ◽

Robert B. Gerbing ◽

Kristen Miller ◽

...

Keyword(s):

Clinical Characteristics ◽

Somatic Mutations ◽

De Novo ◽

Transcript Variant ◽

Oncology Group ◽

Core Binding Factor ◽

Transcript Variants ◽

Binding Factor ◽

De Novo Aml ◽

Pediatric Aml

Abstract The Casitas B-Lineage Lymphoma (CBL) gene encodes for an E3 ubiquitin ligase that targets activated receptor tyrosine kinases for degradation. Mutations of the CBL gene have been described in juvenile myelomonocytic leukemia (JMML) but less is known about mutations and variants of CBL in de novo AML. We previously reported that somatic mutations of CBL are rare in pediatric AML. In this report we present a comprehensive evaluation of genomic and transcript variants of CBL including novel deletion events as well as transcript variants which, in combination with somatic mutations, account for over 6% of pediatric AML with extreme association with inv(16) and favorable outcome. Initial assessment of CBL transcript in a cohort of 100 patients identified previously reported deletion of exon 8 (CBL ΔE8, N=2) associated with CBL splice mutations as well as a novel whole exon 8 and 9 deletion variant (CBL ΔE8+9, N=3) without identifiable underlying somatic alterations. Long distance PCR, as well as custom Nanostring CNV array evaluation revealed a genomic deletion underlying this transcript variant. Subsequent whole genome sequencing as part of COG/NCI TARGET AML initiative, identified discrete genomic deletions of 1998, 3588 and 6189 bp across exon 8 and 9, leading to the generation of this novel variant. We evaluated the functional consequence of the novel CBL ΔE8+9 deletion variant by expressing it in IL3-dependent Ba/F3 cell line. Compared to control cells, Ba/F3 cells expressing CBL ΔE8+9 demonstrated cytokine independent growth. A comprehensive profiling of CBL variants was conducted in 796 pediatric de novo AML patients by transcript profiling (transcript variants) or by exome capture sequencing (somatic mutations including point mutations and smaller indels). All patients were treated on Children's Oncology Group studies AAML03P1 (N=167) and AAML0531 (N=629) and presence of CBL variants was correlated with disease characteristics and clinical outcome. Of the 796 patient specimens tested, 50 patients (6.3%) had one of 3 distinct CBL variants; transcript variant (N=28), somatic mutation (N=14), or dual transcript variant and somatic mutation (N=8). All cases of CBL ΔE8+9 were associated with a corresponding genomic deletion. Out of 14 cases of CBL ΔE8 and 1 case of CBL ΔE9, only 4 cases (27%) had a splice site mutation identified as the underlying mechanism of splice variant. Presence of CBL variants was correlated with clinical characteristics and outcome. Those with CBL variants had a significantly higher prevalence of inv(16) compared with CBL wild type (WT) (37% vs. 13%, p<0.001). This association differed by CBL variant type; 44% transcript variants and 50% dual variants had inv(16) compared to 14% somatic mutations and 13% CBL WT (p<0.001). NPMc+ was more prevalent in those with CBL somatic mutations (29%) than transcript variant (4%), dual variant (0%) or CBL WT (8%) (p=0.035). Similarly, genetic risk groups differed between CBL variants vs. WT (Low risk 70% vs 39%, p=<0.001; Standard risk 22% vs. 46%, p=0.001; High risk 8% vs. 15%, p=0.196). Clinical characteristics including gender, age, race and ethnicity were not significantly different. FAB morphologic assessment revealed an enrichment for the M4 subtype in CBL variant vs. WT (53% vs. 23%, P<.001) which is likely accounted for by the association of inv(16) with this morphologic group. Patients with CBL variants had a 100% clinical remission rate by end of induction II compared to 89% for CBL WT patients (p=0.014). Survival from study entry was similar between CBL mutant vs. WT patients (5 year OS 72% vs. 66%, p=0.24; 5 year EFS 61% vs. 50%, p=0.11). Due to the strong association of CBL mutation with core binding factor leukemia, we assessed whether CBL variant was prognostic of outcome within this favorable risk group, but there was no significant difference in outcomes. Variants of the CBL gene in pediatric AML include genetic mutations with and without whole exon deletions. These CBL variants are highly associated with low risk AML but do not provide independent risk prognosis. The cooperating events of CBL variants in core binding factor leukemia deserve greater study. Our initial analysis of the transcript variants in a cell line model suggest that these large exon 8+9 deletions represent important oncogenic events. The authors would like to gratefully acknowledge the important contributions of the late Dr. Robert Arceci to the AML TARGET initiative. Disclosures No relevant conflicts of interest to declare.

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The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study

Cancer ◽

10.1002/cncr.29961 ◽

2016 ◽

Vol 122 (9) ◽

pp. 1408-1416 ◽

Cited By ~ 59

Author(s):

Tomoki Nakamura ◽

Akihiko Matsumine ◽

Akira Kawai ◽

Nobuhito Araki ◽

Takahiro Goto ◽

...

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Clinical Outcome ◽

Japanese Patients ◽

Oncology Group ◽

Musculoskeletal Oncology

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Association of immune parameters with clinical outcome in stage III colon cancer: results of Southwest Oncology Group Protocol 9009

Cancer Immunology Immunotherapy ◽

10.1007/s002620050602 ◽

1999 ◽

Vol 48 (9) ◽

pp. 533-539 ◽

Cited By ~ 12

Author(s):

Randall F. Holcombe ◽

Joth Jacobson ◽

Shaker R. Dakhil ◽

Ruby M. Stewart ◽

Kenneth S. Betzing ◽

...

Keyword(s):

Colon Cancer ◽

Clinical Outcome ◽

Stage Iii ◽

Oncology Group ◽

Southwest Oncology Group ◽

Stage Iii Colon Cancer ◽

Immune Parameters

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Effectiveness of supportive care measures to reduce infections in pediatric AML: a report from the Children’s Oncology Group

Blood ◽

10.1182/blood-2013-01-476614 ◽

2013 ◽

Vol 121 (18) ◽

pp. 3573-3577 ◽

Cited By ~ 72

Author(s):

Lillian Sung ◽

Richard Aplenc ◽

Todd A. Alonzo ◽

Robert B. Gerbing ◽

Thomas Lehrnbecher ◽

...

Keyword(s):

Supportive Care ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Oncology Group ◽

Infection Rates ◽

Key Points ◽

Pediatric Aml ◽

Stimulating Factor ◽

Related Mortality ◽

Systemic Antibacterial

Key Points Systemic antibacterial and granulocyte colony-stimulating factor prophylaxis appear to reduce bacterial infection rates. Mandatory hospitalization during profound neutropenia did not reduce infection or significantly reduce nonrelapse-related mortality.

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