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  • American Society of Hematology  (5)
  • Kim, Heeje  (5)
  • 1
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    RUNX1 Mutation in Cytogenetically Normal Acute Myeloid Leukemia : Clinical Implications, Co-Mutation Analysis
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 5253-5253
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5253-5253
    Abstract: Background and Objectives Acute Myeloid Leukemia (AML) is a cytogenetically and molecularly heterogeneous disease. In the recent decades, many genetic mutations and their clinical significances in AML have been identified with the development of new genomics technology. Based on these advances, new 2 entities were added to the WHO 2008 classification : AML with mutated NPM1 and AML with mutated CEBPA. Likewise, AML with RUNX1 mutation are now considered as a new provisional entity in the next update of WHO classification. In this work, we characterized patients with cytogenetically normal AML according to RUNX1 mutational status and analyzed several co-mutations by next generation sequencing. Patients and Methods A total of 419 patients were included in the present study who met the following eligibility criteria: 1) age ≥ 15 years; 2) a diagnosis of AML with normal karyotype confirmed by conventional cytogenetic analysis. Analysis of genetic mutations were performed using targeted resequencing by Illumina Hiseq 2000 (Sureselect custom probe set targeting 94 myeloid gene panel including RUNX1 mutation). Samples for the confirmation of first complete response were also analyzed in 163 patients. The majority of patients (97%) received '3+7' standard induction chemotherapy. Median age was 53(range 15-84). Results Overall, most common mutations for this cohort were NPM1(33.9%), DNMT3A(30.3%), NRAS(20.2%), IDH2(15.0%), FLT3(12.2%), CEBPA(11.1%). RUNX1 mutations were found in 22 of 419 (5.4%) patients. 7 of 13 available samples in complete remission still had RUNX1 mutation. The patients with RUNX1 mutations were older than those with wild-type RUNX1. (p=0.006) and RUNX1 mutation had a trend of male preponderance. The WBC count and blast percentage of peripheral blood and bone marrow were not different according to RUNX1 mutational status. The complete response rate was significantly lower in RUNX1 mutated group compared with wild-type group. (57% vs. 84%, p=0.005) In univariable survival analysis, RUNX1 mutations were significantly associated with inferior event-free survival (EFS) (p 〈 0.001), relapse-free survival (RFS) (p=0.009) and overall survival (OS) (p=0.002). However, in multivariable analysis, RUNX1 mutation was not an independent prognostic factor for inferior EFS (hazard ratio(HR) 1.48, p=0.286), RFS (HR 2.15, p=0.057) OS (HR 1.14, p=0.716). Co-mutation analysis revealed that ASXL1 (26%,p=0.001), KRAS (26%, p=0.009), BCOR (16%, p=0.032) were correlated with RUNX1 mutation. None of the patients with RUNX1 mutation had NPM1 mutation and only one patient had CEBPA mutation. Conclusion In cytogenetically normal AML, RUNX1 mutation is observed in 5.4% and is mutually exclusive of the NPM1 and CEBPA mutation. Older age and lower complete response rate is correlated with RUNX1 mutation. In univariable survival analysis, RUNX1 mutation is associated with poor clinical 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.V128.22.5253.5253
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Prognostic Predictability of 2022 European Leukemianet (ELN) Risk Stratification in the Real World
    American Society of Hematology ; 2022
    In:  Blood Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1018-1019
    Details
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1018-1019
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2022-166182
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Replication of New Genomic Classification System in Acute Myeloid Leukemia with Normal Karyotype
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 2876-2876
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2876-2876
    Abstract: Introduction Acute myeloid leukemia (AML) is a genetically heterogeneous disease. A recent study (NEJM, 2016) classified 1540 patients into 14 subgroups using mutation information from targeted next generation sequencing data as well as cytogenetic information [1]. The classification criteria of 7 of these subgroups rely solely on mutation information. NK-AML is characterized by its lack of cytogenetic abnormalities. In this study, we attempted to replicate the prognostic stratification in an independent set of NK-AML patients using the NEJM study's genomic classification criteria. Patients and Methods This study included a total of 393 patients who met the following eligibility criteria: 1) age ≥ 15 years; 2) a diagnosis of NK-AML confirmed by conventional cytogenetic analysis; 3) treatment with induction chemotherapy using a standard protocol (a 3-day course of anthracycline with a 7-day course of cytosine arabinoside). The median follow-up duration was 55.1 months (range, 0.7-182.9). Analysis of genetic mutations were performed using targeted sequencing by Illumina Hiseq 2000 (Agilent custom probe set targeting entire exon regions of a myeloid panel consisting of 94 genes). Results We identified driver mutations across 28 genes or genomic regions, with 2 or more driver mutations identified in 15/393 patients (3.8%). Based on the genomic classification criteria, the patients were classified as follows: 136 patients (34.6%) with NPM1 mutations, 42 patients (10.7%) with mutated chromatin modifiers and/or RNA-splicing genes, 6 patients (1.5%) with TP53 mutations, 40 patients (10.2%) with biallelic CEBPA mutations, 8 patients (2.0%) with IDH2-R172 mutations and no other class-defining lesions, 108 patients (27.5%) with driver mutations but no detected class-defining lesions, 38 patients (9.7%) with no detected driver mutations, and 15 patients (3.8%) who met the criteria of more than one genomic subgroup. Of the 393 patients, 325 patients (82.7%) achieved complete remission (CR). CR rates vary depending on the genomic subgroup (75.9%-97.4%). The CR rate for each subgroup was as follows: 86.8% (118/136) of patients with NPM1 mutations61.9% (26/42) of patients with mutated chromatin and/or RNA-splicing genes83.3% (5/6) of patients with TP53 mutations97.5% (38/40) of patients with biallelic CEBPA mutations87.5% (7/8) of patients with IDH2-R172 mutations and no other class-defining lesions75.9% (82/108) of patients with driver mutations but no detected class-defining lesions97.3% (37/38) of patients with no detected driver mutations80.0% (12/15) of patients meeting criteria of more than one subgroup 5-year OS and 5-year relapse incidence (RI) for each subgroup was as follows: 49.3% (95% CI, 40.1-58.5) and 39.8% (95% CI, 30.1-49.2) of patients with NPM1 mutations11.6% (95% CI, 1.4-21.8) and 71.4% (95% CI, 45.7-86.5) of patients with mutated chromatin and/or RNA-splicing genes50.0% (95% CI, 10.0-90.0) and 20.0% (95% CI, 0.4-61.2) of patients with TP53 mutations68.3% (95% CI, 53.4-83.2) and 19.7% (95% CI, 8.5-34.4) of patients with biallelic CEBPA mutations56.3% (95% CI, 17.3-95.3) and 21.4% (95% CI, 0.3-67.3) of patients with IDH2-R172 mutations and no other class-defining lesions26.6% (95% CI, 17.4-35.8) and 53.2% (95% CI, 40.7-64.3) of patients with driver mutations but no detected class-defining lesions29.1% (95% CI, 14.2-44.0) and 43.8% (95% CI, 27.1-59.3) of patients with no detected driver mutations40.0% (95% CI, 15.3-64.7) and 33.3% (95% CI, 9.2-60.3) of patients that meet the criteria of more than one subgroup. The CR rates of the subgroup with mutated chromatin and/or RNA-splicing genes was significantly lower than the rest of the cohort (61.9% vs. 85.2%, p=0.00016). The 5-year OS and 5-year RI of the subgroup were also poorer than the others [61.9% vs. 85.2% in OS (p=0.00016), 71.4% vs. 40.1% in RI (p 〈 0.0001)]. Conclusion Our NK-AML cohort showed similar survival patterns to the cohort in Papaemmanuil et al (NEJM 2016). The subgroup in AML with mutated chromatin and/or RNA-Splicing genes had the poorest prognosis with respect to CR rate and overall survival. This analysis replicates the result of recently published genomic classification and supports its use for categorizing NK-AML patients. Reference [1] Genomic Classification and Prognosis in Acute Myeloid Leukemia. Papaemmanuil E et al. N Engl J Med, 2016 vol. 374 (23) pp. 2209-2221. Figure Figure. Disclosures Jang: Kyowa Hakko Kirin Co., Ltd.: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.2876.2876
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
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  • 4
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    Longitudinal Tracking of MDS Patients Using Next Generation Sequencing Provides a Predictive Measure for Azacitidine Response and AML Progression
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 52-52
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 52-52
    Abstract: Introduction: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by dysplastic changes in one or more cellular lineages causing impaired bone marrow function. One third of patients diagnosed with MDS progress to secondary acute myeloid leukemia (sAML). These patients have significantly worse prognoses than de novo AML patients. Azacitidine (AZA), a hypomethylating agent is commonly used to treat MDS patients as a frontline therapy. Although its survival benefits over supportive care in a randomized trial has been demonstrated, the underlying genetics and clonal dynamics upon AZA response/AML progression have not been well examined. Using next generation sequencing (NGS) technology, we attempted to assess the clinical relevance of somatic mutations and their dynamics as they relate to AZA treatment in MDS patients using longitudinal samples. Patients and Methods: Ninety-five MDS patients (56 lower risk and 39 higher risk MDS based on the revised IPSS scoring system) were enrolled in this study. The median age of the 95 patients is 67 years (range of 31 Ð 84) and median follow-up duration was 747 days (range of 137-3328 days). We performed targeted deep sequencing (entire exon region of a panel of 84 myeloid genes, Agilent custom probe set) on 285 bone-marrow samples including the longitudinal samples taken at diagnosis (n=95) and post-AZA treatment, (median 4 cycles) as well as T-cell fraction (CD3+). We multiplexed and sequenced the samples using an Illumina Hiseq 2000. After read mapping and variant calling, hierarchical clustering, pathway and survival analyses were performed in R. Results: Targeted sequencing on the myeloid gene panel revealed 176 mutations in 68 patients (68/95, 71.6%) with a median of 2 mutations per patient (ranges 2-6). The average on-target coverage for 285 sequenced samples was 1205x. Twenty-five of 44 mutated genes were recurrently mutated. ASXL1 was the most frequently mutated in the cohort (21%), followed by TET2 (15%), DNMT3A (11%), and SRSF2 (11%). Mutated genes were then grouped into 8 biological pathways, defined in The Cancer Genome Atlas (TCGA) AML study. The most frequent biological pathway with mutated genes at diagnosis was DNA methylation (28.4%), followed by spliceosome (25.2%), chromatin modifiers (22.1%), myeloid transcription factors (TFs) (11.6%), activated signaling (11.6%), tumor suppressors (12.6%), and cohesin complex (6.3%). When assessing the differences in patterns of variant allele frequency (VAF), we found significant VAF reduction in responders compared to non-responders (p = 0.007, repeated measures using general linear model, Figure A). Multivariate analyses revealed that mutation burden in different genes and biological pathways have distinct impact on AZA response, AML transformation, and overall survival. Higher bone marrow blast percentage (5%) was associated with all three measures (Figure B). Most significantly, mutations in activated signaling pathway genes are associated with AML progression (p=0.002). In addition, we could not detect decreased VAFs in activated signalling pathway genes even in responders (Figure C-D). Patients with SRSF2 mutations tend to respond to AZA (OR 14.084, p=0.003). Mutations in tumor suppressors (HR 4.825, p 〈 0.001) and myeloid TFs (HR 3.070, p=0.020) were adverse prognostic factors in overall survival. Of interest, mutations in DNA methylation pathway were not independent prognostic factor for AZA response, AML transformation, or overall survival. Conclusion: These data and analyses show that reduction in mutation burden is correlated with AZA response. Mutations in different genes and biological pathways are associated with distinct clinical measures that tumor suppressors and myeloid TFs were identified as poor prognostic factors in terms of OS. Persistent mutation burden in activated signaling pathways is a strong predictor for AML transformation. In summary, longitudinal tracking of MDS patients using NGS may improve criteria for AZA response and early detection of AML progression. Figure 1. Figure 1. Disclosures Jang: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.52.52
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
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    5-Hydroxymethylcytosine Is Correlated with TET2 or IDH1/2 Mutations However, May Not be a Prognostic Value to Predict the Survivals in Normal Karyotype AML
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 3832-3832
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3832-3832
    Abstract: Background: Stem cells display remarkably high levels of 5-hydroxymethylcytosine (5hmC) and, both TET2 or IDH1/2 mutations can impair 5hmC generation. However, the implications of 5hmC have not been evaluated comprehensively in patients with normal karyotype (NK)-AML, especially in aspect of prognostic value in survivals. Methods: A total of 407 patients were included in the present study, and all met the following eligibility criteria: 1) age ≥ 15 years; 2) a diagnosis of NK-AML confirmed by conventional cytogenetic analysis; and, 3) treatment with induction chemotherapy using a standard protocol (a 3-day course of anthracycline with a 7-day course of cytosine arabinoside). NK-AML patients were diagnosed from October 1998 to September 2012 in seven participating institutes. Among 407 patients with NK-AML who received induction therapy, we selected the 376 patients available the analysis of 5-hmC, retrospectively. For quantitation of 5hmC, Quest 5-hmC DNA ELISA kits (Zymo Research) were used following the manufacturer's protocol. TET2 or IDH1/2 mutation analysis were performed using direct sequencing. We analyzed for 5hmC levels in patients with TET2 or IDH1/2 mutations and, to know the correlation of 5hmC levels with mutant alleles. Results: The prevalence rates for the mutations were 13.0% in TET2mut, 7.2% in IDH1 and,14.1% in IDH2mut. Mutation rates of TET2 or IDH1/2 was 34.6% (130/376). We examined whether the range of 5hmC values correlated with each mutations. TET2, IDH1/2 mutated patients had significant lower levels of 5hmC compared with patients without any TET2 or IDH1/2 mutations (all, p 〈 0.001). The median value of 5hmC level were: TET2mut (median: 0.051%, range: 0.002%-0.120%), IDH1mut (median: 0.044%, range: 0.004%-0.641%), IDH2mut (median: 0.050%, range: 0.001%-0.457%), any mutation of TET2 or IDH1/2 (median: 0.048% , range: 0.001%-0.641%) and, TET2 wild-type and IDH1/2 wild type (median: 0.084%, range: 0.0003%-0.999%). In control group (TET2 wild-type and IDH1/2 wild type), 5hmC levels distributed with broad range but, 5hmC levels were tightly clustered in patients with TET2, IDH1 or IDH2 mutations. With a median follow-up duration of 55.5 months (range, 0.7-179.8 months), there was no significant difference in overall survival (OS), event free survival (EFS) and relapse risk according to TET2mut or IDH1/2mut (all, p 〉 0.05). To identify the role of 5hmC levels in clinical significances, we sub-classified this group with tertile category for 5hmC values. However, we could not find the clinical significant in OS, EFS and relapse risk according to the 5hmC levels (all, p 〉 0.05). Conclusion: TET2 or IDH1/2 mutated patients had lower levels of 5hmC. 5hmC levels distributed with wide range in patients with TET2 and IDH1/2 wild type and tightly clustered in patients with TET2, IDH1 or IDH2 mutations. Apart from affecting the methylation status of the DNA, other processes may be influenced by 5hmC levels in patients with NK-AML with TET2 wild-type and IDH1/2 wild type. In addition, 5hmC may not be a prognostic value to predict the survivals of relapse risk in NK-AML. Disclosures Jang: Alexion Pharmaceuticals: Research Funding. Kim:Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.3832.3832
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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