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  • 1
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    Development and Validation Of a Highly Sensitive and Specific Gene Expression Classifier To Prospectively Screen and Identify B-Precursor Acute Lymphoblastic Leukemia (ALL) Patients With a Philadelphia Chromosome-Like (“Ph-like” or “BCR-ABL1-Like”) Signature For Therapeutic Targeting and Clinical Intervention
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 826-826
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 826-826
    Abstract: Using gene expression profiling, we and others identified a novel subgroup of B-precursor acute lymphoblastic leukemia (B-ALL) with a gene expression signature similar to Philadelphia (Ph) chromosome (BCR-ABL1)-positive ALL. Termed “Ph-like” or “BCR-ABL1-like” ALL, this subgroup constitutes 10-15% of pediatric and 25% of adolescent/young adult ALL cases and is associated with a very poor clinical outcome. Using next generation sequencing, we have shown that Ph-like ALL is characterized by a highly heterogeneous spectrum of activating mutations or gene fusions targeting genes regulating cytokine receptor and tyrosine kinase signaling (JAK1/2, ABL1/2, PDGFRB, EPOR, CSF1R, AKT2, STAT5B, CRLF2, IL7R, SH2B3). As Ph-like ALLs may be sensitive to tyrosine kinase inhibitors (TKIs) in vivo, incorporating TKIs into therapy may significantly improve clinical outcomes. Here we report the development and validation of a robust gene expression classifier that can prospectively identify Ph-like ALL patients for therapeutic intervention. Methods Supervised learning methods were applied to gene expression profiles (Affymetrix U133_Plus_2.0; RMA normalized) generated from pre-treatment leukemic samples from 811 B-ALL patients accrued to COG High-Risk ALL Trials P9906 and AALL0232. Patients were partitioned into a training (P9906: n=207; AALL0232: n=278) and an independent test set (AALL0232: n=325). Next generation sequencing was used to identify Ph-like ALL-associated genomic lesions in these cohorts. The 54,675 Affymetrix probe sets were evaluated using Prediction Analysis of Microarrays (PAM), applying the method of nearest shrunken centroids to identify those probe sets best distinguishing Ph-like ALL. These probe sets were then distilled by 100 iterations of 10-fold cross-validation using three optimization criteria (overall error, average error, and ROC accuracy), leading to the identification of the 64 most predictive probe sets (derived from 38 unique genes). Quantitative RT-PCR assays were developed for each of the 38 genes by selecting optimized primer/probe sets and assays were run on 384-well Low Density Microarray (LDA) cards; 780/811 cases had residual material for LDA testing. LDA data were remodeled in the training set using double loop cross validation, resulting in a best and final predictive model and statistical algorithm containing 15 of the 38 genes (IGJ, SPATS2L, MUC4, CRLF2, CA6, NRXN3, BMPR1B, GPR110, CHN2, SEMA6A, PON2, SLC2A5, S100Z, TP53INP1, IFITM1). The sensitivity and specificity of the predictor was then evaluated in the independent test set. Results The 15 gene LDA classifier was able to predict Ph or Ph-like ALL in the test set with a high degree of sensitivity (93.0%) and specificity (89.7%) and identified the heterogeneous genomic lesions associated with Ph-like ALL with very high frequency (Table 1). When compared to non-Ph-like ALL, Ph-like cases had a significantly poorer event-free survival (HR 3.58; p 〈 .0001) (Fig. 1, left). A second predictive classifier modeled on the same training/test sets but with true BCR-ABL1 cases excluded yielded a virtually identical performance (97.2% sensitivity, 87.1% sensitivity; HR: 2.9; p 〈 .0001). Strikingly, Ph-like ALL cases with IKZF1 deletions had a significantly worse outcome when compared to ALL cases with IKZF1 deletions alone, emphasizing the clinical importance of the Ph-like signature (Fig. 1, right). Concordance between the LDA predictor and our previously reported PAM method (NEJM 360:470, 2009) was 87.2%, with the largest difference being additional CRLF2 lesions identified by LDA. Conclusions We have developed and validated a highly robust gene expression classifier for the prospective identification of Ph-like ALL. Rapidly screened patients will then undergo targeted sequencing to confirm the presence of specific genomic lesions. This approach will facilitate the therapeutic targeting of Ph-like ALL patients to novel clinical trials, hopefully leading to improved outcomes. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.826.826
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 2
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    Integrated Genomic and Mutational Profiling Of Adolescent and Young Adult ALL Identifies a High Frequency Of BCR-ABL1-Like ALL with Very Poor Outcome
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 825-825
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 825-825
    Abstract: The genetic basis underlying inferior outcome of adolescent and young adult acute lymphoblastic leukemia (AYA ALL) as compared to childhood cases is largely unknown. To comprehensively characterize the genetic landscape of AYA ALL we studied 423 adolescent (16-21 yrs; median 17.7±1.3 yrs) and 250 young adult (21-39 yrs; median 28.3±7.0 yrs) samples from the Children's Oncology Group high-risk trial AALL0232, St Jude Children's Research Hospital Total XV and XVI, Eastern Cooperative Oncology Group E2993, MD Anderson Cancer Center and the Alliance - CALGB trials. Single nucleotide polymorphism (SNP) microarray analysis and gene expression profiling were performed to identify copy number alterations and distinct genetic subgroups. Samples were also sub classified using hierarchical clustering, ROSE outlier and PAM analysis of gene expression profiling data. Sequence mutation analysis was performed on candidate genes known to be mutated in pediatric ALL (including IKZF1, PAX5, JAK1/2, NRAS, KRAS, FLT3, IL7R, SH2B3, TP53 and CREBBP), and mRNA-seq was performed on selected BCR-ABL1-like cases (n=41). The genetic subgroups were divided into ETV6-RUNX1, TCF3-PBX1, hyperdiploid ( 〉 50 chromosomes), MLL rearrangements, BCR-ABL1, BCR-ABL1-like, ERG and other (cases with no known lesions). As expected, ETV6-RUNX1 and hyperdiploid ALL were less frequent in adolescents (4% and 11%, respectively) and adults (2% for both) than in childhood ALL ( 〈 16 years; 25% for both). In contrast, the frequency of BCR-ABL1-like ALL, a recently described subgroup in 10-15% of pediatric ALL associated with kinase-activating lesions and a poor outcome, was very frequent and increased with age (21% in adolescent, 25% in young adults), similar to cases with the classic BCR-ABL1 translocation (6% in adolescent, 22% in young adults). Notably, BCR-ABL1 and BCR-ABL1-like ALL patients presented with higher white blood counts at diagnosis compared to non BCR-ABL1-like ALL patients in both adolescents (117.6 and 76.8 vs 21.9 x109/L, p 〈 0001), and young adults (72.6 and 94.1 vs 17.6 x109/L, p 〈 0001). BCR-ABL1-like ALL patients were also more likely to be male compared to non BCR-ABL1-like ALL patients, with 74% vs 62% in adolescents (p 〈 0.05; Fisher's exact test), and 81% vs 63% in young adults (p=0.07; Fisher's exact test). The outcome of BCR-ABL1 and BCR-ABL1-like ALL was markedly inferior to other ALL subtypes, with 5-year event free survival (EFS) rates of 53.7+18.3 and 40.0+7.1 vs 85.0±3.3 (p 〈 0.0001) in adolescent cases, and 23.2±9.1 and 16.1±8.5 vs 57.9±8.0 (p=0.006) for young adults (Figure 1). IKZF1 alterations, a marker of poor outcome in pediatric ALL, were enriched in BCR-ABL1 and BCR-ABL1-like ALL cases (70% and 77%, respectively) compared to non BCR-ABL1-like patients (26%). Regardless of genetic subtype, the presence of an IKZF1 alteration correlated with inferior 5 year EFS in adolescent (60.3±6.0 vs 77.4±4.1; p=0.0015) and young adults (25.7±7.0 vs 52.7±6.4; p=0.0011). We then sought to characterize the alterations activating kinase signaling in AYA BCR-ABL1-like ALL cases. As observed in pediatric ALL, approximately 55% of these cases harbored CRLF2 rearrangements. Using mRNA-seq we identified a variety of additional rearrangements involving the tyrosine kinase or cytokine receptor genes ABL1, ABL2, CSF1R, JAK2, EPOR or PDGFRB, with a marked enrichment of fusions involving JAK2 (6 different fusions in 9/20 cases sequenced), thus providing a rationale for the investigation of targeted therapies directed against these alterations. Collectively, the kinase-activating BCR-ABL1 and BCR-ABL1-like subtypes are associated with poor outcome and make up ∼25% of adolescent and ∼50% of young adult ALL patients. The identification of these patients at diagnosis will provide an opportunity to incorporate tyrosine kinase inhibitor treatment to current chemotherapeutic regimens, and significantly improve the treatment outcome for AYA ALL. Disclosures: Hunger: Bristol Myers Squibb: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.825.825
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 3
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    Genomic Characterization and Experimental Modeling Of BCR-ABL1-Like Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 232-232
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 232-232
    Abstract: BCR-ABL1-like B-progenitor acute lymphoblastic leukemia (B-ALL) accounts for 10-15% of childhood B-ALL and is characterized by alteration of IKZFI, a gene expression profile similar to BCR-ABL1 ALL and poor outcome. Using next-generation sequencing, we have shown that BCR-ABL1-like ALL patients harbor genetic alterations activating kinase pathways that are sensitive to tyrosine kinase inhibitors (TKIs), and have shown that refractory BCR-ABL1-like ALL is responsive to TKIs in vivo (Weston et al., J. Clin. Oncol 2013). Furthermore, the outcome of ALL in adolescent and young adult (AYA) patients is inferior to children, yet the genetic basis underlying treatment failure is poorly understood. To define the frequency and genomic landscape of BCR-ABL1-like ALL in children, adolescents, and young adults we have extended our studies to include 665 high-risk childhood ( 〈 16 years, 14% BCR-ABL1-like), 370 adolescent (16-21 years, 21% BCR-ABL1-like) and 161 young adult (21-39 years; 26% BCR-ABL1-like) B-ALL cases from the Children's Oncology Group, St Jude Children's Research Hospital, Eastern Cooperative Oncology Group, MD Anderson Cancer Center and the Alliance - CALGB trials. Event-free survival (EFS) for BCR-ABL1-like cases was inferior to non BCR-ABL1-like cases with 5-year EFS rates of 40.0±7.1 vs 85.0±3.3 (p 〈 0.0001) for adolescent cases and 16.1±8.5 vs 57.9±8.0 (p=0.006) for young adult cases. In each age group, 50-60% of BCR-ABL1-like cases harbored rearrangements of CRLF2 (IGH@-CRLF2 or P2RY8-CRLF2) (Fig. 1). To characterize the full spectrum of kinase lesions in the remaining BCR-ABL1-like ALL cases we performed mRNA-seq on pediatric (n=39), adolescent (n=21) and young adult (n=22) cases, and whole genome (WGS; n=18) or exome sequencing (n=10) on cases with matched tumor and normal material. Fusion transcripts were identified using deFuse and CICERO, a novel assembly-based structural variation detection method specifically designed for mRNA-seq analysis. We identified 23 different kinase rearrangements involving 7 tyrosine kinase or cytokine receptor genes. These consist of 5 ABL1, 2 PDGFRB, 8 JAK2 fusions and 2 EPOR translocations to IGH@ and IGK@ loci, along with new fusions involving the tyrosine kinases ABL2 (n=3), CSF1R (n=1), AKT2 (n=1) and STAT5B (n=1). We performed frequency testing for 15 of these fusions on 555 cases from the COG AALL0232 trial of high-risk B-ALL. Several alterations were recurrent in BCR-ABL1-like ALL, including NUP214-ABL1, RCSD1-ABL2, SSBP2-CSF1R, PAX5-JAK2 and EPOR translocations. Notably, we did not identify any of these fusions in non BCR-ABL1-like cases. The frequency of ABL1/ABL2 and EPOR translocations was consistent across all age groups (∼16% and 7% of BCR-ABL1-like cases, respectively), while JAK2 rearrangements were more common in young adult than in pediatric and adolescent ALL (12%). Importantly, ∼10% of BCR-ABL1-like ALL cases lacked a kinase-activating alteration on analysis of mRNA-seq data. Notably, we identified two additional cases with IL7R or SH2B3 sequence mutations, indicating the requirement for complementary approaches such as WGS to fully define the genomic landscape of BCR-ABL1-like ALL. Current functional studies include the development of experimental models using the Ba/F3 hematopoietic progenitor cell line, primary mouse pre-B cultures and the generation of xenografts to determine the role of these alterations in leukemogenesis, and to enable testing of targeted therapies. For example, we show that RCSD1-ABL1 and SSBP2-CSF1R confer factor-independent growth and constitutive activation of JAK/STAT pathways in Ba/F3 cells. Furthermore, RCSD1-ABL1 and SSBP2-CSF1R are both sensitive to the TKIs, imatinib (IC50 378nM and 327nM, respectively) and dasatinib (IC50 2.1nM and 2.5nM, respectively). Together, these complementary approaches will further define the genetic landscape of both pediatric and AYA ALL, and facilitate the development of diagnostic and therapeutic strategies to improve the treatment outcome for high-risk BCR-ABL1-like ALL patients. Disclosures: Hunger: Bristol Myers Squibb: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.232.232
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
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    A BCR-ABL1-Like Gene Expression Profile Confers a Poor Prognosis In Patients with High-Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report From Children's Oncology Group (COG) AALL0232
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 743-743
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 743-743
    Abstract: Abstract 743 We have previously identified a subset of National Cancer Institute (NCI)-HR B-cell precursor (BCP) ALL patients with a gene expression profile similar to that of BCR-ABL1 ALL (BCR-ABL1-like ALL (Mullighan, N Engl J Med 2009; den Boer, Lancet Oncology 2009; Harvey, Blood, 2010, and unpublished data) and poor outcome on the COG P9906 trial, which was limited to a selected subset of HR BCP ALL patients. These cases are BCR-ABL1-negative but commonly have deletion or mutation of IKZF1. Up to half of these cases harbor rearrangements, deletions and/or mutations activating cytokine receptors and tyrosine kinase signaling (e.g. CRLF2 and activating JAK1/2 mutations), although the kinase-activating mutations in many cases remain unknown. In this analysis, we have assessed the prognostic significance of this BCR-ABL1-like signature in an unselected cohort of BCR-ABL1 negative BCP ALL patients consecutively enrolled on COG AALL0232. This phase 3 trial utilized a 2×2 factorial design comparing dexamethasone (DEX) versus prednisone (PRED) during induction, and high dose methotrexate (HD-MTX) versus Capizzi methotrexate (C-MTX) during interim maintenance 1 (IM-1). We recently reported improved event free survival (EFS) for patients receiving HD-MTX versus C-MTX (Larsen, J Clin Oncol 29: 6s, 2011) and for DEX versus PRED among patients 〈 10 years old randomized to HD MTX (Winick, J Clin Oncol 29: 586s, 2011). We used two algorithms, Recognition of Outliers by Sampling Ends (ROSE) and Predictive Analysis of Microarrays (PAM), to define 66 of 565 (ROSE) and 81 of 572 (PAM) patients as BCR-ABL1-like. Event-free survival (EFS) for BCR-ABL1-like cases was inferior to that of non-BCR-ABL1-like cases, irrespective of the clustering algorithm used to identify them, with 5-yr EFS rates of 63.1±7.2% vs. 84.9±2.0% (p 〈 0.0001) for ROSE clustering and 62.6±6.9% vs. 85.8±2.0% (p 〈 0.0001) for PAM. These differences were maintained regardless of randomized treatment arm. We next examined variables that contributed to outcome in patients who displayed the BCR-ABL1-like signature, identified either by ROSE or PAM. Older (≥ 10 years) BCR-ABL1-like patients were significantly more likely to have an initial white blood count greater than 100,000/ul (ROSE: p 〈 0.001, PAM: p 〈 0.001). Interestingly, older females with the BCR-ABL1-like signature had superior EFS compared to males (4-yr EFS for ROSE: 73. ±9.8% vs. 43.0 ±10.3%, p=0.02; 4-yr EFS for PAM: 69. ±10.2% vs. 43. ±9.4%, p=0.04). In a multivariate COX regression analysis of the entire cohort that included identification of BCR/ABL1-like by PAM (HR 1.88, p=0.011), the other significant predictors of poor outcome were the presence of minimal residual disease (MRD) ≥ 0.01% in the bone marrow as measured by flow cytometric methods on day 29 (HR 3.09, p 〈 0.0001) and the presence of hypodiploidy (HR 3.14, p=0.027). In a COX model including identification of BCR/ABL1-like by ROSE (HR 1.65, p=0.053), other significant factors were day 29 MRD positivity (HR 3.26, p 〈 0.0001), age ≥ 10 years (HR 1.61, p=0.047), presenting white blood cell count 〉 100,000/ul at diagnosis (HR 1.62, p=0.047), and hypodiploidy (HR 3.0, p=0.034). In summary, the BCR-ABL1-like gene expression profile identified a subset of unselected BCP ALL patients using two different clustering algorithms that was strongly associated with a high rate of treatment failure, even with the best available therapy recently identified in COG AALL0232. The prognostic significance of these gene signatures was also independent of other known risk factors. Ongoing work to determine the genetic and biochemical landscape that contribute to this phenotype will hopefully yield new approaches to treatment for these BCR-ABL1-like patients in order to improve outcome. Disclosures: Borowitz: BD Biosciences: Research Funding. Wood:BD Biosciences: Research Funding. Hunger:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speaker's children own stock in BMS.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.743.743
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    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 5
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    Identification of CRLF2 Genomic Lesions in Patients with Pediatric B-Precursor Acute Lymphoblastic Leukemia (BCP ALL) by Flow Cytometry or Quantitative RT-PCR: A Children's Oncology Group (COG) Stud.
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 2529-2529
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2529-2529
    Abstract: Abstract 2529 Genomic alterations involving the CRLF2 gene lead to over-expression of intact CRLF2 and have significant prognostic value in pediatric BCP-ALL. Not only do patients with these lesions have inferior outcomes, they also have a very high frequency of JAK1 and JAK2 mutations and may be candidates for targeted therapies. The two major CRLF2 lesions include cryptic translocations that produce IgH@-CRLF2 and interstitial deletions of the pseudoautosomal region of X/Y causing P2RY8-CRLF2 fusion. Both lesions can be detected by fluorescence in situ hybridization (FISH), and genomic PCR or RT-PCR can identify P2RY8-CRLF2. To develop rapid and inexpensive assays for detection/screening of these events, we developed a flow cytometry based method to measure CRLF2 expression and compared this assay to quantitative RT-PCR (qPCR) measurement of CRLF2 expression by evaluating their performance in an unselected cohort of 279 newly diagnosed pediatric BCP-ALL patients consecutively enrolled on the COG AALL03B1 biology/classification study between 10/30/09-5/1/10. Flow cytometry was performed first in real time on diagnostic specimens shipped to a central COG reference laboratory and then residual diagnostic material was shipped to a separate laboratory for RNA isolation and qPCR analysis. Of the 279 cases analyzed by flow, 257 (92%) yielded sufficient RNA quality and quantity for qPCR analysis. In our previous studies with qPCR and CRLF2 it was shown that CRLF2 lesions occurred only among those cases with the highest expression (ΔCt 〈 8). In order to assure that we identified all cases with CRLF2 lesions, we performed FISH and P2RY8-CRLF2 PCR on all cases with qPCR expression ΔCt 〈 10 (n = 109) and an additional 14 cases with a flow blast/lymph CRLF2 mean fluorescence intensity (MFI) ratio 〉 1.15. Of these 123 cases, 11 were determined by FISH to have the IGH@-CRLF2 translocation and 15 were shown to have P2RY8-CRLF2 fusions by PCR. Figure 1 shows the locations of these genomic lesion-positive cases among the qPCR (panel A) and flow cytometry (panel B) CRLF2 expression data. The overall frequency of CRLF2 lesions among these patients is 10.1% (assuming all lesions were identified among the highest expressing cases) and, surprisingly, the frequencies of IgH@-CRLF2 and P2RY8-CRLF2 were very similar (4.3% and 5.8%, respectively). With both methods, the 11 IgH@-CRLF2 cases were found to be the highest expressing (among the top 12 cases by qPCR and 16 cases by flow). Receiver operating curve analysis of each method identified cutoffs with excellent performance: qPCR cutoff CRLF2 ΔCt = 5.47 with 96.9% specificity and 88.5% sensitivity; flow cutoff MFI CRLF2 ratio of 2.04 with 95.9% specificity and 92.3% sensitivity. The broader dynamic range of the qPCR assay may be necessary for the identification of poor risk cases with high CRLF2 expression that lack genomic lesions, however both methods are rapid, highly effective and very comparable for finding ALL cases that harbor CRLF2 genomic lesions, and suitable for incorporation in large scale clinical trials. Figure 1. qPCR and Flow Cytometry Results for CRLF2 Expression. Panel A (qPCR ΔCt values) and Panel B (log2 blast/lymphocyte ratios) plot the expression values for the 123 patients with the highest CRLF2 expression. Panel B plots the log2 blast/lymphocyte ratio for CRLF2 expression determined by flow cytometry. Small dots show the expression for each patient while the large diamonds highlight cases proven to have CRLF2 lesions either by FISH (IGH@-CRLF2) or PCR (P2RY8-CRLF2). Each unit of expression represents a two-fold difference in intensity. Figure 1. qPCR and Flow Cytometry Results for CRLF2 Expression. Panel A (qPCR ΔCt values) and Panel B (log2 blast/lymphocyte ratios) plot the expression values for the 123 patients with the highest CRLF2 expression. Panel B plots the log2 blast/lymphocyte ratio for CRLF2 expression determined by flow cytometry. Small dots show the expression for each patient while the large diamonds highlight cases proven to have CRLF2 lesions either by FISH (IGH@-CRLF2) or PCR (P2RY8-CRLF2). Each unit of expression represents a two-fold difference in intensity. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.2529.2529
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 6
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    Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia
    Massachusetts Medical Society ; 2014
    In:  New England Journal of Medicine Vol. 371, No. 11 ( 2014-09-11), p. 1005-1015
    Details
    In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 371, No. 11 ( 2014-09-11), p. 1005-1015
    Type of Medium: Online Resource
    ISSN: 0028-4793 , 1533-4406
    URL: Article
    DOI: 10.1056/NEJMoa1403088
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    Language: English
    Publisher: Massachusetts Medical Society
    Publication Date: 2014
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  • 7
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    Flow-cytometric vs. -morphologic assessment of remission in childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group (COG)
    Springer Science and Business Media LLC ; 2018
    In:  Leukemia Vol. 32, No. 6 ( 2018-6), p. 1370-1379
    Details
    In: Leukemia, Springer Science and Business Media LLC, Vol. 32, No. 6 ( 2018-6), p. 1370-1379
    Type of Medium: Online Resource
    ISSN: 0887-6924 , 1476-5551
    URL: Article
    DOI: 10.1038/s41375-018-0039-7
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
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  • 8
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    Improved Post-Induction Chemotherapy Does Not Abrogate Prognostic Significance of Minimal Residual Disease (MRD) for Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (ALL). A Report From Children's Oncology Group (COG) Study AALL0232
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1440-1440
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1440-1440
    Abstract: Abstract 1440 Improved Post-Induction Chemotherapy Does Not Abrogate Prognostic Significance of Minimal Residual Disease (MRD) for Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (ALL). A Report from Children's Oncology Group (COG) Study AALL0232. Minimal residual disease is one of the strongest prognostic factors in pediatric ALL. COG AALL0232 was a phase 3 randomized trial for patients 1–30 years old with newly diagnosed NCI HR B precursor ALL that used a 2×2 factorial study design comparing dexamethasone (DEX) versus(vs.) prednisone(PRED) during induction, and high dose methotrexate (HD-MTX) vs. Capizzi methotrexate (C-MTX) during interim maintenance 1(IM-1). We previously reported improved event-free survival (EFS) for patients receiving HD-MTX vs. C-MTX (J Clin Oncol 29: 6s, 2011) and for DEX vs. PRED among patients 〈 10 years old randomized to HD-MTX(J Clin Oncol 29: 586s,2011). MRD was measured by 6 color flow cytometry in two central labs (MJB and BLW) to a level of sensitivity of 0.01% at end induction. Patients with 〉 =0.1% MRD at end induction, as well as patients with morphologic slow early response or specific adverse genetic features received intensified therapy including IM-2 and a second delayed intensification, and then had MRD determined at end consolidation, (about 13 weeks post diagnosis). End induction MRD 〉 =0.01% was highly predictive of inferior outcome, though patients with 0.1–1% MRD who received intensive therapy had very low rates of early relapse and a much higher rate of late relapse. 5 year EFS for end-induction MRD positive ( 〉 =0.01%) patients was 63±5% vs. 86±2% for MRD negative patients. However, patients who were MRD positive at end induction who became negative by end consolidation had improved 5y EFS of 79±9%(n=136) compared to 52±14% for those who remained MRD positive(n=52) (p=.0012). Both end induction MRD positive and negative patients benefitted from HD-MTX vs. C-MTX, though the effect was small and did not reach statistical significance for MRD positive patients. By contrast, end-induction MRD was highly predictive of outcome for patients receiving either HD-MTX or C-MTX. 5 y EFS as a function of MRD status and IM regimen.End induction MRDCapizziHDMTXP value 〈 .01%84 ± 3%88 ± 2%.04 〉 .01%59 ± 6%67 ± 7%.12P value 〈 .0001 〈 .0001 End induction MRD negative patients 〈 10y receiving DEX had better outcome than those getting PRED (5 y EFS 92±3% vs. 87±4% P=.027) while MRD positive patients or those 〉 10y showed no difference. However, DEX patients 〈 10y if anything had a slightly higher rate of end induction MRD positivity than those given PRED (22% vs. 17%, p=.073). In multivariate analysis, end consolidation MRD was the most powerful prognostic factor for the small subset of patients in whom this was assessed. Excluding this, end induction MRD was the most significant variable; age, white blood cell count, day 15 marrow morphology and HD-MTX vs. C-MTX were also significant. We conclude that MRD remains the most powerful prognostic factor even in the context of improved therapy. Additionally, for those patients who were MRD positive at end induction, achieving MRD negative status by end consolidation improved outcome significantly. The higher frequency of MRD in younger patients receiving DEX calls into question the validity of using end induction MRD as a surrogate for outcome when testing novel interventions during induction therapy. Disclosures: Borowitz: BD Biosciences: Research Funding. Wood:BD Biosciences: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1440.1440
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 9
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    iAMP21 Is Associated with Inferior Outcomes in Children with Acute Lymphoblastic Leukemia (ALL) on Contemporary Children's Oncology Group (COG) Studies
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 739-739
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 739-739
    Abstract: Abstract 739 Intrachromosomal amplification of a region of chromosome 21 (iAMP21) occurs in a 1–3% of children with ALL and can be identified by RUNX1 fluorescence in situ hybridization (FISH). We monitored the outcome of patients with iAMP21 in recent COG trials for newly diagnosed standard risk (SR; AALL0331) and high risk (HR; AALL0232) B-precursor ALL based on reports of inferior outcomes associated with this cytogenetic alteration. (Moorman et al Blood 2007) We examined the incidence, clinical characteristics and outcome for 7799 children, adolescents and young adults 1–30 years old enrolled on COG AALL0331 and AALL0232 between 2003 and 2011. All patients had testing for prognostically relevant cytogenetic alterations including ETV6-RUNX1 performed in COG central laboratories (2003-2006) or approved local cytogenetics laboratories with central review (2007-2011). Ascertainment of iAMP21 may have been incomplete prior to 2007 as ETV6-RUNX1 was primarily assessed centrally by RT-PCR. Classification as iAMP21 required 〉 4 RUNX1 signals on a single chromosome ( 〉 5 total RUNX1 signals). If metaphase FISH was not possible, iAMP21 was identified as multiple copies of RUNX1 clumped in at least some of the nuclei. ALL cases defined as very high risk with t(9;22), hypodiploidy with 〈 44 chromosomes or MLL rearrangements and slow early response to treatment were excluded from this analysis. Treatment on AALL0331 and AALL0232 consisted of a 3- (AALL0331) or 4-drug (AALL0232) induction, with post-induction therapy based on early response and established prognostic cytogenetic features. Therapy was not altered for patients with iAMP21. iAMP21 was identified in 158/7799 (2%) cases; 75/5060 (1.5%) SR cases and 83/2739 (3.0%) HR cases. Patients with iAMP21 were more likely to be ≥10 years old (49% vs. 33%, p 〈 0.0001), have white blood cell counts (WBC) 〈 50,000/μL (96% vs. 85%, p 〈 0.0001), be female (54% vs. 34%, p=0.036) and to have ≥0.01% end Induction bone marrow minimal residual disease (MRD) (41% vs. 21%, p 〈 0.0001) than those without iAMP21. While earlier analyses suggested that iAMP21 was not associated with inferior outcomes in COG AALL0232 and AALL0331 (Heerema et al, ASH 2009 abstract; 114: 2598), new analyses with larger patient numbers and longer follow-up show that the outcome for patients with iAMP21 is worse than for patients without iAMP21 (Table 1). These differences were statistically significant in SR, but not HR patients. Outcome comparisons were also made examining iAMP21 status and end induction MRD ( 〈 0.01% vs. ≥0.01%). Pooled SR and HR patients with iAMP21 who were MRD positive (≥0.01%) had significantly inferior outcomes with 4-year event-free survival (EFS) of 55.8±12.4% vs. 76.5±2% among non-iAMP21 MRD positive patients, p=0.037. For MRD negative patients, 4-year EFS for those with iAMP21 was significantly worse (81.4±7.8%) than for those without this feature (92.2±0.6%; p=0.016). In multivariate Cox regression analysis of AALL0331 patients, iAMP21 (hazard ratio (HR) 2.246; p=0.0021), day 29 MRD ≥0.01% (HR 2.430; p 〈 0.0001) and favorable genetics (ETV6-RUNX1 or trisomies of chromosomes 4 and 10 (HR 0.361; p 〈 0.0001) all had high prognostic significance, while iAMP21 was not significant in a multivariate Cox model in AALL0232 patients. In conclusion, patients with iAMP21 have inferior outcomes with contemporary chemotherapy in COG ALL trials and may benefit from more intensive or novel treatment approaches. In particular, lower intensity therapy given to SR ALL patients in COG AALL0331 led to significantly inferior outcomes for those with iAMP21.Table 1.Outcomes in iAMP21 SR and HR ALLiAMP21Othersp-valueAALL0232+AALL0331N15876414-year EFS70.2 ± 7%88.1 ± 0.7% 〈 0.00014-year OS84.7 ± 5.6%93.9 ± 0.5%0.0132AALL0331N7549854-year EFS70.4 ± 9.3%91.8 ± 0.7% 〈 0.00014-year OS87 ± 6.9%96.5 ± 0.5%0.004AALL0232N8326564-year EFS70 ± 10.6%81 ± 1.3%0.464-year OS82.7 ± 9.2%88.9 ± 1.1%0.65 Disclosures: Borowitz: BD Biosciences: Research Funding. Mattano:Pfizer, Inc.: Employment. Wood:BD Biosciences: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.739.739
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 10
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    Intrachromosomal Amplification of Chromosome 21 Is Associated With Inferior Outcomes in Children With Acute Lymphoblastic Leukemia Treated in Contemporary Standard-Risk Children's Oncology Group Studies: A Report From the Children's Oncology Group
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 27 ( 2013-09-20), p. 3397-3402
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 27 ( 2013-09-20), p. 3397-3402
    Abstract: Five-year overall survival (OS) for children with B-cell precursor acute lymphoblastic leukemia (B-ALL) exceeds 90% with risk-adapted therapy. Age, initial WBC count, genetic aberrations, and minimal residual disease (MRD) are used for risk stratification. Intrachromosomal amplification of a region of chromosome 21 (iAMP21; three or more extra copies of RUNX1 on an abnormal chromosome 21) is a recently identified recurrent genomic lesion associated with inferior outcome in some studies. We investigated the impact of iAMP21 in a large cohort treated in contemporary Children's Oncology Group (COG) ALL trials. Patients and Methods Fluorescent in situ hybridization for specific genetic aberrations was required at diagnosis. MRD was measured by flow cytometry at end induction. Outcome was measured as event-free survival (EFS) and OS. Results iAMP21 was found in 158 (2%) of 7,793 patients with B-ALL age ≥ 1 year; 74 (1.5%) of 5,057 standard-risk (SR) patients, and 84 (3.1%) of 2,736 high-risk (HR) patients. iAMP21 was associated with age ≥ 10 years, WBC less than 50,000/μL, female sex, and detectable MRD at day 29. Four-year EFS and OS were significantly worse for patients with iAMP21 and SR B-ALL, but iAMP21 was not a statistically significant prognostic factor in HR patients. There was no interaction between MRD and iAMP21. Among SR patients, day 29 MRD ≥ 0.01% and iAMP21 were associated with the poorest EFS and OS; absence of both was associated with the best outcome. Conclusion iAMP21 is associated with inferior outcome in pediatric B-ALL, particularly SR patients who require more intensive therapy and are now treated on HR COG ALL protocols.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2013.49.1308
    RVK:
    XA 52760
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    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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