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  • 1
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    A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults
    American Society of Hematology ; 2015
    In:  Blood Vol. 125, No. 4 ( 2015-01-22), p. 680-686
    Details
    In: Blood, American Society of Hematology, Vol. 125, No. 4 ( 2015-01-22), p. 680-686
    Abstract: In this first ALL GWAS in AYAs, we determined that inherited GATA3 variants strongly influence ALL susceptibility in this age group. These findings revealed similarities and differences in the genetic basis of ALL susceptibility between young children and AYAs.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2014-09-595744
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 2
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    A Genome-Wide Association Study of Susceptibility to Acute Lymphoblastic Leukemia in Adolescents and Young Adults
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 132-132
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 132-132
    Abstract: Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared to pediatric ALL. Age, as a continuous variable, is negatively correlated with prognosis, in spite of risk-adapted combination chemotherapy. To better understand the etiology of ALL in this age group, we performed the first genome-wide association study (GWAS) to comprehensively examine germline single nucleotide polymorphisms (SNPs) for their association with susceptibility to B-ALL in AYAs. In the discovery GWAS, we compared genotype frequency at 635,297 SNPs between 308 AYA ALL cases (age 16-39 years, treated on the Children’s Oncology Group [COG], the Alliance-Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, MD Anderson Cancer Center, and St. Jude Children’s Research Hospital trials) vs. 6,661 non-ALL controls. The association between genotypes at each SNP and ALL susceptibility was tested by using a logistic regression model after adjusting for genetic ancestries to control for population stratification. SNPs that reached P≤ 5×10-8 in the discovery GWAS were tested in an independent cohort of 82 AYA ALL cases from the COG protocols and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus on 10p14 signified by two SNPs within the GATA3 gene: rs3824662, P=2.8x10-10, odds ratio (OR)=1.77; rs3781093, P=3.2x10-9, OR=1.73, both of which were validated in the replication cohort (P=1.9x10-8 and P=4.3x10-5, respectively). We also examined the association signals in AYAs for susceptibility loci previously identified in pediatric ALL: ARID5B, IKZF1 and PIP4K2A variants were nominally significant in AYAs in the discovery GWAS and/or in the replication analysis, whereas CEBPE or CDKN2A/CDKN2B were not significant. These results imply both similarities and differences in genetic predisposition to ALL between children and AYAs. At the GATA3 locus, rs3824662 risk variant was over-represented in Philadelphia chromosome (Ph)-like ALL in AYAs (P=0.02), confirming our previous report of Ph-like ALL susceptibility variants in GATA3 (Nat Genet 45:1494). Importantly, even after excluding Ph-like cases, rs3824662 remained associated with the risk of developing ALL in AYAs, suggesting that the influence of the GATA3risk variant on ALL susceptibility in AYAs extends beyond the predisposition to Ph-like subtype. We next examined the relationship between GATA3 risk allele frequency and age at diagnosis in a cohort of unselected childhood and adolescent ALL cases enrolled in the COG P9900 protocols (N=1,827). Dividing patients into four consecutives age groups ( 〈 5, 5-10, 10-15 and 〉 15 years), we observed a clear progressive increase in the risk allele frequency at rs3824662 (P=6.29×10-11) with increasing allelic odds ratio (i.e. relative risk of ALL conferred by each copy of the risk allele). This correlation between genotype and age was evident regardless of genetic ancestry, although the risk variant was more common among individuals with higher Native American ancestry. In contrast, the frequency of ALL susceptibility variant in ARID5B decreased progressively with increasing age at diagnosis (P=0.006), whereas PIP4K2A, CDKN2A/CDKN2B, IKZF1 and CEBPE variants were not related to age. Finally, we compared rs3824662 risk variant frequency by age in the COG P9900 protocols after stratifying the ALL cases into TCF3-PBX1, ETV6-RUNX1, hyperdiploid, MLL-rearranged and B-other. There was a trend that the risk allele was more frequent in cases older than 16 years compared to those below 16 in the five subtypes examined. In conclusion, we have identified inherited GATA3 genetic variants that strongly influence ALL susceptibility in adolescent and young adults, indicating potential age-related differences in ALL biology. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.132.132
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 3
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    Genome-Wide DNA Methylation Analysis Reveals Biological and Clinical Insights In Relapsed Childhood Acute Lymphoblastic Leukemia: A Report From The COG ALL Target Project
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3736-3736
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3736-3736
    Abstract: Although survival of children with B-cell acute lymphoblastic leukemia (B-ALL) has improved substantially over time, 15% to 20% of patients will relapse, and most of those who experience a bone marrow relapse will die. A better understanding of genetic and epigenetic aberrations in relapsed ALL will facilitate new strategies for risk stratification and targeted therapy. In this collaborative study with the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project, we performed high resolution genome-wide DNA methylation profiling using the HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) array on a total of 178 (110 diagnosis, 68 relapse) leukemia samples from 111 patients with childhood B-ALL enrolled on the Children’s Oncology Group (COG) clinical trials who experienced relapsed, and 12 normal preB samples isolated from the bone marrows of 12 healthy individuals. The HELP array covers 117,521 CpG sites, annotated to ∼22,000 gene promoters. For eight diagnosis/relapse pairs, base-pair resolution DNA methylation using the eRRBS (enhanced Reduced Representation Bisulfite Sequencing) method was also performed on Illumina HiSeq2000. The median relapse time for the 111 patients was 21.8 months (range 2.1 to 56.2). Unsupervised clustering analysis using the HELP data revealed seven clusters: one cluster contained only the 12 normal preB samples; four clusters were enriched with MLLr, ETV6/RUNX1, Trisomy 4+10, and TCF3/PBX1 samples, respectively. The sixth cluster was not enriched for specific cytogenetic cases, but interestingly, all cases in this cluster were NCI High Risk (age 〉 10 years or WBC 〉 =50,000; p 〈 0.0001, Fisher’s Exact test) while the seventh cluster has a mixture of other cases. Supervised analysis of HELP profiles between paired relapse/diagnosis samples (n=67) revealed a markedly aberrant DNA methylation signature (1011 probesets, 888 genes, FDR 〈 0.01 and methylation difference dx 〉 25%, paired t-test), with 70% of the genes hyper- and 30% hypo-methylated in relapse samples. Using a Bayesian predictor and leave-one-out cross validation, this methylation signature could predict a sample as diagnosis or relapse with 95.3% accuracy. When comparing early ( 〈 36 months; n=50) versus late relapses ( 〉 =36 months; n=18), we detected a profound hypermethylation signature in early relapse (96.6% of the 610 probesets, 544 genes, FDR 〈 0.01, dx 〉 25%). Finally, we identified 1800 probesets (1658 genes) as differentially methylated within all cytogenetic subtypes described above compared to the normal preB samples (Dunnett’s test with normal preB as reference, FDR 〈 0.01, dx 〉 25%). Again the majority (70%) of those genes were hypermethylated in relapse as compared to diagnostic and normal preB. The base-pair resolution and more comprehensive eRRBS methylation analysis for the eight pairs of samples identified 39,679 CpG sites as differentially methylated (dx 〉 25%, FDR 〈 0.01), with 78.2% CpG sites hyper- and 21.2% hypo-methylated in relapse samples. Remarkably, the hypermethylated CpGs are primarily in promoter regions (50%, defined as +/-1kb to TSS), followed by intergenic (26%), then intragenic (14%), and exonic (10%) regions. In contrast, the hypomethylated CpGs are mainly in intragenic (48%), followed by intergenic (31%), exonic (14%) and promoter (7%) regions. The hypermethylated CpGs were mainly in CpG islands (86%) or CpG shores (10%), while hypomethylated CpGs were not (CpG islands: 8%, CpG shores: 27%). We further identified 3040 differentially methylated regions (DMRs) with a median size 426 bp. 78.4% of those DMRs were hyper- (1362 gene promoters) and 21.6% hypo-methylated (98 promoters) in relapse compared to diagnostic samples. Gene set enrichment and Ingenuity pathway analysis showed epigenetically disrupted pathways that are highly involved in cell signaling, and embryonic and organismal development. Taken together, our genome-wide high resolution DNA methylation analysis on a large cohort of relapsed childhood B-ALL from the COG trial identified unique methylation signatures that correlated with relapse and with specific genetic subsets. Those methylation signatures featured prevailing promoter hypermethylation and to a lesser extent, intrageneic hypomethylation. Epigenetically dysregulated gene networks in those relapse samples involved cell signaling, and embryonic and organismal development. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.3736.3736
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
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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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  • 5
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    Outcomes of Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia Based on Blast Genotype at Diagnosis: A Report from the Children's Oncology Group
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 451-451
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 451-451
    Abstract: Survival for childhood acute lymphoblastic leukemia (ALL) now approaches 90% with risk adapted therapy based on National Cancer Institute risk group (NCI RG) at diagnosis, somatic lymphoblast genetics, and early response to therapy as measured by minimal residual disease (MRD). The Children's Oncology Group AALL03B1 ALL Classification trial enrolled 11,145 children, adolescents, and young adults less than 31 years of age with newly diagnosed B- or T-lineage ALL between December 2003 and September 2011. Companion therapeutic trials for B-lineage ALL included AALL0331 (n= 5226) for NCI standard risk (SR-ALL)(age 1-10 years and white blood cell count (WBC) 〈 50,000/uL) and AALL0232 (n=2907] for NCI high risk (HR) ALL (age 〉 10 years or presenting WBC 〉 50,000/uL). Assessing outcome by lymphoblast genetics revealed statistically significant distributions of genotype and NCI RG, as well as differences in event-free and overall-survival (EFS, OS) (Table 1). Not surprisingly, favorable genetic groups of Trisomy 4/10/17 (TT) and ETV6/RUNX1 were significantly more common in NCI SR patients (p 〈 0.0001 for each) while those with unfavorable characteristics (MLL rearranged [MLLr], intrachromosomal amplification of chromosome 21 [iAMP21] , BCR/ABL1 and hypodiploidy [n 〈 44]) occurred more frequently in NCI HR patients (p 〈 0.0001 for each). Event-free and OS were correspondingly poorer in NCI HR patients with the exception of iAMP21, where EFS in those treated on AALL0232 was better than that in NCI SR (Table 1). Surprisingly, NCI SR BCR/ABL1 positive patients (N= 64, 1.2%) had a 5-year EFS of 85±5.0%, although these patients came off study at end induction and likely received imatinib with chemotherapy on a companion ALL trial for Ph+ ALL. Notably, hypodiploidy was associated with the worst EFS and OS regardless of NCI RG, with 5-year EFS and OS of 51.3±5.0% and 58.2±5.0%, respectively, suggesting that these patients continue to fare poorly with salvage therapies. Multivariable analysis demonstrated age, WBC, and day 29 MRD as significant independent risk factors for sustained CR, and the individual genetic groups of TT, ETV6/RUNX1, iAMP21, BCR/ABL1 and hypodiploidy, but notably, not MLLr, all retained independent prognostic significance when added to the model individually. A subset of consecutively enrolled (N=605) AALL0232 NCI HR patients underwent additional genomic interrogation, including assessment of Ph-like status, ABL1 class fusions, CRLF2r, JAK mutations (JAKm), and IKZF1 alterations. Based on sample availability, patients studied were younger (p 〈 0.0001) and had a higher WBC (p 〈 0.0001) compared to the remainder of AALL0232. There were 85/605 (14.0%) Ph-like patients defined using PAM clustering algorithms and Ph-like status was significantly associated with an IKZF1 alteration (75%) (p 〈 0.0001) and day 29 MRD 〉 .01% (p 〈 0.0001). Five-year EFS for Ph-like versus non Ph-like was 62.3±5.8% vs. 83.9±1.7% (p 〈 0.0001). Outcomes of Ph-like ALL with or without CRLF2r were similar (60.6±8.3% versus 65.4±8.0%, p =0.86). Similarly, 5-year EFS of Ph-like ALL was no different with or without IKZF1 alterations (61.5±7.0% vs. 64.6 ±11.1%). There were 155 (27.1%) IKZF1 alterations, 60 of which occurred in Ph-like ALL with a trend towards concomitant CRLF2r/JAKm (p=0.055). Five-year EFS for patients with IKZF1 alterations was 66.8±4.0% (p 〈 0.0001) versus 86.4±1.8% for those without IKZF1 lesions. Multivariable analysis demonstrated age, WBC and day 29 MRD as independent risk factors for sustained CR while only Ph-like status, IKZF1 alteration, BCR/ABL1 and ETV6/RUNX1retained independent prognostic significance when added to the model individually. In summary, somatic sentinel cytogenetic alterations are independently prognostic in childhood ALL and are strongly associated with NCI RG and outcome, supporting continued incorporation into risk stratification algorithms. Notably, 〉 44% of all patients have favorable blast cytogenetics with 5-year overall survival rates approaching 100%. In contrast, NCI HR patients with Ph-like ALL have poor outcomes with currently available therapy and this subtype is associated with CRLF2 r and IKZF1 alterations, which do not confer an inferior EFS within the Ph-like subgroup. Novel therapies for genomicallydefined Ph-like ALL may improve outcomes. Disclosures Loh: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Borowitz:HTG Molecular: Consultancy; Bristol-Myers Squibb: Research Funding; MedImmune: Research Funding; BD Biosciences: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.451.451
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 6
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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
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 7
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    Assessment of end induction minimal residual disease (MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day 14 marrow examination: A Children’s Oncology Group study.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 10001-10001
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 10001-10001
    Abstract: 10001 Background: Response to initial therapy is a powerful prognostic factor in pediatric ALL. Traditionally, slow early response (SER) has been defined by marrow morphology 8 or 15 days after start of induction therapy. More recently, MRD has been identified as the most important predictor of adverse outcome. The value of morphologic assessment of response in the setting of MRD has not been established. Methods: In COG studies AALL0331 (for NCI Standard Risk (SR) B ALL patients (pts)) and AALL0232 (High Risk (HR) B ALL pts), SER was defined by morphology as either ≥5% blasts in a day 15 marrow, or by flow cytometry as ≥0.1% MRD in a d29 marrow (SER MRD). Assignment to treatment arms also depended upon cytogenetic findings and extramedullary disease; each protocol had randomized treatment questions. SER pts were non-randomly assigned to receive augmented BFM therapy (ABFM) with 2 interim maintenance and delayed intensification phases (and CNS radiation for HR SER pts only). All pt treatment groups were combined for these analyses. Rapid early responders (RER) had a better outcome than SER pts (Table). However, pts who were SER only by morphology had a 5y DFS that was not significantly different from that of RER pts, and superior to that of pts who were SER MRD, or SER by both morphology and MRD. In multivariate analysis, SER by morphology was not an adverse prognostic factor after adjusting for risk group and MRD, or separately in SR or HR pts after adjusting for MRD. However, pts with .01-.1% MRD who were SER by morphology had a better 5y DFS than the.01-.1% MRD pts who were RER (90±6%, n=91 vs 77±3%, n=592). Only the former group received ABFM, suggesting intensification based on response rescues some poor risk pts. We conclude that a day 15 marrow is not needed to assess response if MRD is measured at end induction, provided that SER MRD is defined using a .01% cutoff, the threshold for intensifying therapy in current COG ALL trials. Clinical trial information: NCT00103285, NCT00075725. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.10001
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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  • 8
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    Abstract 3083: The genetic landscape of Ph-like acute lymphoblastic leukemia
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3083-3083
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3083-3083
    Abstract: BCR-ABL1-like, or “Ph-like” B-progenitor acute lymphoblastic leukemia (B-ALL) constitutes up to 15% of childhood and 30% of adult ALL, and is characterized by a gene expression profile similar to BCR-ABL1 ALL, alteration of IKZF1, and poor outcome. A pilot next-generation sequencing study identified kinase activating alterations in 15 Ph-like ALL cases. The goals of this study were to define the genomic landscape of Ph-like ALL in children and young adults, and to examine the utility of tyrosine kinase inhibitors (TKIs) in patients harboring genetic alterations activating kinase signaling. We studied 1665 B-ALL cases, including 309 childhood standard risk (10.8% Ph-like), 826 childhood high risk (14% Ph-like), 370 adolescent (16-21 years, 21% Ph-like) and 160 young adult (21-39 years; 26% Ph-like) cases. Approximately 50% of Ph-like cases harbored a CRLF2 rearrangement (IGH-CRLF2 or P2RY8-CRLF2). Next-generation sequencing was performed for 160 non-CRLF2 expressing Ph-like cases, including mRNA-seq (141 cases), whole genome sequencing (30 cases) and/or exome sequencing (12 cases). Fusion transcripts were identified using CICERO, a novel mRNA-seq assembly-based structural variation detection method. Over 100 chimeric in-frame fusions were identified, including 29 involving 12 tyrosine kinase or cytokine receptor genes, 15 of which were recurrent: JAK2 (10 partners), ABL1 (6), ABL2 (3), PDGFRB (3), CSF1R, TYK2, NTRK3, PTK2B, IL2RB (1 partner each), and rearrangements of EPOR into the IGH and IGK loci. Together, these rearrangements were present in ∼30% of Ph-like ALL cases. Additional sequence and structural alterations activating kinase signaling were identified in ∼10% of cases (e.g IL7R, FLT3, SH2B3). Despite the diversity of kinase alterations, the majority are predicted to respond to a limited number of TKIs, but many are novel or have not been tested in suitable preclinical models of ALL. We show that expression of RCSD1-ABL1, RANBP2-ABL1, ZMIZ1-ABL1, RCSD1-ABL2, SSBP2-CFS1R and PAX5-JAK2 in Ba/F3 and primary mouse pre-B cultures induces cytokine-independent proliferation and constitutive activation of JAK/STAT signaling. Furthermore, the ABL1, ABL2 and CSF1R fusions were sensitive to dasatinib (IC50 range 1-2nM), whilst PAX5-JAK2 only responded to the JAK2 inhibitor, ruxolitinib. Notably, we show efficacy of dasatinib (20mg/kg/day p.o) in a xenograft model of ETV6-ABL1, with reduction of circulating human CD45+ cells (17.4 vs 88.2%; p & lt;0.0001) and spleen weight (117 vs 321mg; p & lt;0.0001) in dasatinib treated mice (n=5) compared to vehicle treated mice (n=5). These data define the genomic landscape of Ph-like ALL and show that the majority of cases harbor genetic alterations that activate a limited number of kinase signaling pathways. These results provide the basis for prospective precision medicine clinical trials that identify and direct patients with Ph-like ALL to logical TKI therapy. Citation Format: Kathryn G. Roberts, Yongjin Li, Debbie Payne-Turner, Jinghui Zhang, Richard C. Harvey, Yung-Li Yang, Guangchun Song, Jing Ma, Shann-Ching Chen, Jinjun Cheng, Natalia Santiago-Morales, Ilaria Iacobucci, Meenakshi Devidas, I-Ming Chen, Shalini Reshmi, Michael Rusch, Pankaj Gupta, Naomi J. Winick, William L. Carroll, Nyla A. Heerema, Andrew J. Carroll, Elizabeth A. Raetz, Guido Marcucci, Clara D. Bloomfield, Wendy Stock, Steven M. Kornblau, Elisabeth Paietta, Ching-Hon Pui, Sima Jeha, James Downing, Daniela S. Gerhard, Julie M. Gastier-Foster, Mignon L. Loh, Cheryl Willman, Stephen P. Hunger, Charles G. Mullighan. The genetic landscape of Ph-like acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3083. doi:10.1158/1538-7445.AM2014-3083
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-3083
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 9
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    Excellent Event Free (EFS) and Overall Survival (OS) For Children With Standard Risk Acute Lymphoblastic Leukemia (SR ALL) Despite The Absence Of a Significant Impact On Outcome With The Addition Of An Intensified Consolidation: Results Of Children’s Oncology Group (COG) AALL0331
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 837-837
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 837-837
    Abstract: The EFS/OS for SR (age 1-9.99 yrs and initial white blood cell count 〈 50,000/microliter) B-cell precursor (B-ALL) patients (pts) has steadily improved over time. The COG AALL0331 SR ALL trial utilized a 3 drug induction without anthracylines, with post-induction assignment into refined risk groups (SR-Low, SR-Average (Av), SR-High) based on leukemia genetics and early response. COG studies have shown that intensified post-induction therapy improved EFS/OS in NCI high risk ALL patients 〈 10 yrs of age; however, the relative value of individual components is uncertain. AALL0331 included a 2 X 2 randomization at end-induction to standard (SC) vs. intensified consolidation (IC) and standard interim maintenance (IM) / delayed intensification (DI) vs. intensified IM/DI for SR-Av (not Low or High) pts, defined as those whose leukemic blasts did not show triple trisomies (TT) of chromosomes 4+10+17, ETV6-RUNX1, or very high risk features and had an excellent early response based on day 8 (or 15) M1 ( 〈 5% blasts) bone marrow (BM) and end-induction minimal residual disease (MRD) 〈 0.1%. The IM/DI randomization was closed in 2008 due to superior results of escalating IV methotrexate (MTX) during IM for SR ALL pts treated on CCG 1991; all pts subsequently received escalating IV MTX during IM. AALL0331 enrolled 5311 SR B-ALL pts from 4/2005-5/2010. All patients received a 3 drug induction (dexamethasone, vincristine (VCR), PEG-asparaginase (PEG), intrathecal (IT) MTX). SR-Av pts were randomized at end-induction between SC (mercaptopurine (MP) 75 mg/m2 d 1-28, VCR 1.5 mg/m2 d 1, IT MTX d 1, 8, 15) vs. IC (cyclophosphamide 1000 mg/m2 d 1,29, cytarabine 75 mg/m2 d 1-4, 8-11, 29-32, 36-39, MP 60 mg/m2 d 1-14, 29-42, VCR 1.5 mg/m2 d 15, 22, 43, 50, PEG 2500 units/m2 d 15, 43, IT MTX d 1, 8, 15, 22). Therapy following consolidation was the same for all SR-Av pts after 2008. The 5-yr EFS/OS for all evaluable SR B-ALL pts was 89% and 96% (see Table 1). IC did not significantly improve outcome for SR Av pts, with 5-yr continuous complete remission (CCR) rates for SC vs. IC of 88% (1.6%) vs. 89.3% (1.5%) (p=0.13) and 5-yr OS rates for SC vs. IC of 95.8% (1.0%) vs. IC 95.7% (1.0%) (p=0.93). Because COG has now shown that end-induction MRD of 0.01% is a better discriminator of poor outcome than the 0.1% level used in AALL0331, we examined overall outcome and the results of the randomized intervention in two different MRD defined subsets of SR-Av pts (Table 1). The 5-yr CCR rates for pts with MRD 0.01%- 〈 0.1% were 77% (6%) and 76% (6%) for SC and IC (p=0.31) and 89% (1.6%) vs 91.5% (1.5%) for IC (p=0.08) for MRD 〈 0.01%.Table 1Risk Group (# pts)5 year EFS (SE)5 year CCR (SE)5 year OS (SE)All pts  (5192)89% (0.6%)96% (0.4%)SR-High (636)85% (2%)94% (1%)SR-Low (1857)95% (0.7%)99% (0.3%)SR-Av (1500)89% (1.1%)96% (0.7%)MRD 〈 0.01% (1310)91% (1.2%)96% (0.6%)MRD 〉 0.01- 〈 0.1% (172)77% (4.5%)92% (3%) The outcome for the 1857 SR-Low pts (TT or ETV6-RUNX1 plus d 8 (or 15) M1 BM and d 29 MRD 〈 0.1%) was outstanding, with 5-yr EFS/OS of 95% and 99%. SR-High pts (d 15 BM ≥5% blasts and/or d 29 MRD ≥0.1%) who were non-randomly assigned to IC and 2 intensified IM/DI phases did very well with 5-yr EFS/OS 85% and 94%. The 5-yr EFS for this group (85%) was much better than that of SR Av pts (77%) with MRD 0.01- 〈 0.1% who received less intensive therapy, emphasizing the benefit of intensifying treatment for pts with MRD 〉 0.01% that is now part of all COG protocols. COG AALL0331 is the largest trial of SR B-ALL pts ever conducted and establishes the value of risk directed treatment intensification. Disclosures: Matloub: Novartis: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.837.837
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 10
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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
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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