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  • American Society of Hematology  (25)
  • 1
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2207-2207
    Abstract: Neutrophil trafficking during the inflammatory response is effectively regulated by the enhanced IL-6 expression which orchestrates chemokine production and leukocyte apoptosis. Inappropriate regulation of leukocyte trafficking can lead to impaired neutrophil clearance and increased tissue damage from the accumulation of neutrophil-secreted proteases and reactive oxygen species at the site of inflammation. In collagen-induced arthritis (CIA) mouse model, arthritic symptoms were recapitulated with an increase of IL-6 level in the synovium, which was recuperated by the treatment of EC-18 to the level comparable with commercial therapeutics (such as Remicade or Methotrexate). When the tissues were stained with neutrophil-specific antibodies, EC-18 significantly reduced the infiltration of neutrophils into the synovium. EC-18, a monoacetyl-diglyceride (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol), has been isolated from the antlers of Sika deer (Cervus nippon Temminck), which were known to have immunosuppressive and anti-arthritic activities. In this study, we have discovered that EC-18 regulates the activity of signal transducer and activator of transcription 3 (STAT3), which is a master regulator of IL-6 expression. EC-18 caused the decrease of IL-6 production in a macrophage cell line, RAW264.7, and RA-fibroblast-like synoviocyte (RA-FLS) via the regulation of STAT3 signaling without affecting NF-κB signaling, which is also a well-known regulator of IL-6 expression. The expression of RANKL, a key factor for osteoclast differentiation and activation, was also regulated by STAT3, and decreased by EC-18 treatment. In fact, EC-18 inhibited osteoclastogenesis of hematopoietic stem cells. Therefore, blocking STAT3 activity by EC-18 treatment was able to inhibit the inflammatory cytokine loop triggering RANKL expression, thereby inhibiting joint destruction. Cardinal features of rheumatoid arthritis (RA) are chronic synovial inflammation and joint damage caused by the activity of cytokines and proteins expressed from cells in synovial fluid. Interleukin (IL)-6, a multifunctional pro-inflammatory cytokine, plays a critical role in the pathogenesis of joint and systemic inflammation in RA. Therefore, EC-18 could be utilized as a potential therapeutic agent for the treatment of sustained inflammation and joint destruction. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 2
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4035-4035
    Abstract: Introduction T-cell lymphoma is a group of heterogeneous diseases with various clinical behaviors and treatment outcomes, representing 10-15% of non-Hodgkin lymphomas. Owing to its rarity and heterogeneity, the standard treatment approach for T-cell lymphoma is still not established. Accordingly, conventional chemotherapy regimens adapted from B-cell lymphoma treatment has been used for T-cell lymphoma. However, their outcome is still not satisfactory, and there are limited data representing the real-world situation in terms of clinical features and treatment outcomes. Given the incidence of T-cell lymphoma is relatively higher in Asian than Western countries; a comprehensive registry study focusing on Asian patients with T-cell lymphoma could be helpful for better understanding of T-cell lymphoma as well as the development of more effective treatment strategy. Methods We performed a multi-national, multi-center, prospective registry study for patients with T-cell lymphoma and enrolled patients between 01-March-2016 and 31-January-2019. All patients received chemotherapy with curative intent after diagnosis, and were pathologically diagnosed with T-cell lymphoma according to the 2008 World Health Organization classification of lymphoid neoplasms. Patients belonged to any one of following clinical situations could be enrolled: (1) newly diagnosed, treatment-naïve patients; (2) patients who started treatment or completed treatment; (3) relapsed or refractory patients. After we enrolled the planned number of patients (n = 500), we analyzed clinical features and treatment outcomes. Results Out of 500 patients enrolled from nine Asian countries (Korea, China, Taiwan, Singapore, Indonesia, Bangladeshi, Vietnam, Malaysia, and Philippines), 490 patients were analyzed because 10 patients with insufficient information were excluded. The median age was 59 years (range, 20-85), male patients (59%) were predominant compared to female patients (41%). Extranodal NK/T-cell lymphoma (ENKTL) was the most common (28%) and angioimmunoblastic T-cell lymphoma (AITL) was the second common (24%). Peripheral T-cell lymphoma, not-otherwise specified (PTCL-NOS, 20%) and ALK+/- anaplastic large cell lymphoma (ALCL, 16%) were also major subtypes of T-cell lymphoma. The proportion of stage IV was 40%, however, the distribution of stage was different between ENKTL and nodal T-cell lymphomas such as PTCL-NOS. The CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens accounted for the mainstay of primary treatment for nodal T-cell lymphoma whereas non-anthracycline-based chemotherapy regimens such as SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) and GemOx-L (gemcitabine, oxaliplatin, and L-asparagainase) were mainly used for ENKTL. The overall survival of ENKTL was not significantly different from that of PTCL-NOS, AITL and ALK+/- ALCL. Conclusions Our study showed the distribution of T-cell lymphoma subtypes and tumor burdens at the time of diagnosis in Asian countries. Although clinical features of ENKTL are different from that of nodal T-cell lymphomas consisting of PTCL-NOS, AITL and ALK+/- ALCL, and the different types of treatment were used, survival outcome of patients were not significantly different. This finding might be associated with improved treatment outcomes of ENKTL compared to the past. However, considering a substantial number of patients experienced treatment failure in patients with PTCL-NOS as well as ENKTL, more effective treatment strategy should be warranted. Figure Disclosures Kim: F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 3
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2210-2210
    Abstract: Chemotherapy-induced neutropenia (CIN) is a common dose-limiting side-effect that often compromises chemotherapy resulting in dose reduction and/or delayed treatment. Chemotherapy-induced myeloid suppression is a prevalent mechanism to describe CIN. However, diapedesis of neutrophils from the blood is also a possible mechanism of CIN. Cytokines, chemokines, and damage- (or danger-) associated molecular pattern molecules (DAMPs) are produced from the damaged tissues by chemotherapy, which accelerates neutrophil transmigration. EC-18 is a synthetic monoacetyldiglyceride (MW=635) currently under development as an oral agent to treat and potentially prevent CIN. Here, we showed that neutrophil transmigration is induced in CIN model, and the efficacy and potential mechanism of EC-18 have been evaluated in mice and various cell models. Gemcitabine (50mg/Kg), cyclophosphamide (100mg/Kg) or tamoxifen (50mg/Kg) was administered daily for 3 days in mice (C57BL/6), followed by oral administrations of EC-18 (50mg/Kg) for 21 days. Blood neutrophils were analyzed by complete blood count (CBC) and fluorescence-activated cell sorting (FACS). All three chemotherapeutic agents significantly reduced absolute neutrophil count (ANC) in the blood; 40.4% decrease in gemcitabine, 19.8% in cyclophosphamide, and 21.8% in tamoxifen, which were recovered by the co-administration of EC-18. Microarray analysis of the lymph nodes from gemcitabine-treated mice revealed that the expression of DAMP molecules, S100A8 and S100A9, was induced by gemcitabine and decreased by the co-treatment of EC-18. Using immune cell lines, the expression of neutrophil transmigratory molecules, such as C3 anaphylatoxin, IL-6 and IL-8, was increased by gemcitabine treatment, and EC-18 blocked the expression of those cytokines in dose-dependent manners. Western blot analysis showed that EC-18 regulated STAT3 and STAT6 signaling pathways to modulate the expression of DAMPs, C3, IL-6, and IL-8. The decrease of C3 and IL-6 levels by EC-18 treatment was also verified in PBMCs from normal adults. In a pilot clinical study (WJON 2015 accepted, ASCO e20697), orally administrated EC-18 (1,000mg/day) alleviated neutropenic phenotypes in patients with pancreatic cancer who had been treated with gemcitabine (1,000mg/m2) and erlotinib (100mg daily). As a supportive oncology agent, EC-18 can maximize the antitumor efficacy of myelo-suppressive chemotherapeutic agents by enabling the treatment to continue or even higher doses to be administered. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
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  • 4
    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
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 5
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2593-2593
    Abstract: Abstract 2593 Background: NK-AML represents genetically heterogeneous group of disease. However genetic lesions affecting treatment outcome in patients with NK-AML are relatively unknown. Methods: The discovery cohort consists of 67 NK-AML patients in complete remission (median age: 49.2, ranges: 19–70) without FLT-3 mutations. Genomic DNA was extracted from enriched AML cells at diagnosis or control specimens obtained after complete remission. Whole exomes were captured using Agilent SureSelect and sequencing were performed by HiSeq2000 with 41∼89× coverage. Bioinformatics analysis and identification of somatic mutation has been done by series of software such as BWA, Picard, GATK, VarScan 2, and custom-made scripts. All the data has been re-checked by manual inspection. Validation has been done independent set of cohort (358 NK-AML patients, median age: 51, ranges: 15–85) with Sanger sequencing on highly mutated target sites. Results: Filtering against dbSNP and COSMIC database generated 485 genes with somatic and structural variations. Among them, 41 genes were detected in more than two patients. In addition to well-known 28 mutations, 13 novel mutations with different frequencies were identified including genes responsible for structural maintenance of chromosome (SMC1A, 6.0%) and tumor suppressor function (FAT1, 6.0%). Most common type of mutation was missense mutation (70.8%), and substantial fraction of mutation was splicing site mutations (3.8%). The hematological system development and hematologic function were most highly enriched by the Ingenuity Pathway Analysis (IPA) as expected. CIRCOS plot analysis showed similar co-occurring pattern of recurrent mutations with previous reports. Hierarchical clustering analysis divided into four different groups according to the number of harboring mutations. In network analysis four distinct subgroups were observed ranging 21 to 3 gene network. Conclusion: Using whole exome sequencing approach, a catalog of recurrent mutations was successfully defined in the patients with NK-AML without FLT3/ITD mutation. This candidate list of novel mutations should be tested further for therapeutic target and prognostic marker in the patients with NK-AML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 6
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2275-2275
    Abstract: Abstract 2275 Background: Dasatinib is known to induce large granular lymphocyte (LGL) expansion, which correlates with better clinical efficacy. The current retrospective study attempted to investigate the incidence of lymphocytosis following second-line dasatinib therapy in chronic myeloid leukemia (CML) and to analyze the clinical factors predictive of the development of lymphocytosis, as well as association with treatment outcomes. Method: Fifty CML patients who failed imatinib treatment and received dasatinib for 3 months or more, were enrolled from 9 centers in the Republic of Korea. The cumulative incidence of lymphocytosis was assessed, and cytogenetic and molecular response, treatment failure, loss of response, progression to advanced disease, and survival were evaluated and analyzed according to the development of lymphocytosis. Results: After a median of 17 months of dasatinib therapy, complete cytogenetic (CCR) and major molecular response (MMR) was noted in 23 and 16 patients, respectively. Twenty three patients (46%) developed lymphocytosis following dasatinib therapy (median onset 4 months). No clinical predictive factor for the development of lymphocytosis was found. The cytogenetic response was significantly better in the group that developed lymphocytosis (LC+), as compared to the group without lymphocytosis (LC-); the LC+ group showed a higher complete cytogenetic response (CCyR; 78.3% vs. 29.6%, p=0.001) and major molecular response (MMR; 52.2% vs. 14.8%, p=0.005), in comparison to the LC- group. The development of lymphocytosis after dasatinib was identified as a favorable independent marker for predicting a CCyR (p=0.002) or MMR following dasatinib therapy (p=0.003). Conclusion: The present study suggested that 1) lymphocytosis following dasatinib therapy is not rare phenomenon with incidence of 46%; 2) it might be associated with higher response following dasatinib therapy. Further study is necessary to identify which subset of lymphocytes was expanded and to reveal the exact mechanism by which dasatinib induces lymphocyte expansion. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 7
    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
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 8
    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
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 9
    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
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 10
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4421-4421
    Abstract: Introduction Although several previous studies addressed the role of radiation in treating localized diffuse large B-cell lymphoma (DLBCL), chemotherapy alone has shown promising efficacy with the emergence of Rituximab. Thus, we evaluated the clinical efficacy outcomes and failure patterns of patients with localized DLBCL according to two different treatment strategies, either 6 or more cycles of R-CHOP chemotherapy alone or 3 or 4 cycles of R-CHOP followed by involved field radiotherapy (IFRT). Methods A prospectively collected database from 21 tertiary centers participating the Consortium for Improving Survival of Lymphoma (CISL), built up for PROCESS study (NCT01202448) for secondary central nervous system involvement in DLBCL, was recruited for current study in addition to the Asan Medical Center (AMC) Lymphoma Registry. CISL database and AMC lymphoma registry consisted of data from patients with newly diagnosed DLBCL between August 2010 and August 2012, and between February 2004 and February 2012, respectively. Inclusion criteria were localized (stage I or II), non-bulky ( 〈 10cm in longest diameter) DLBCL treated with R-CHOP as 1st line chemotherapy, and patients either who received 6 or more cycles of R-CHOP chemotherapy only (R-CHOP alone group) or received 3 or 4 cycles of R-CHOP chemotherapy followed by IFRT (R-CHOP plus RT group). Comparisons of clinicopathologic parameters, clinical outcomes and the patterns of relapse were performed between two groups. The types of relapse were classified as either locoregional or distant, according to whether it involves any separate region from primary sites. Efficacy outcomes included complete response (CR) rate, 2-year overall survival (OS) rate, and 2-year event-free survival (EFS) rate. Results A total of 357 patients (CISL prospective cohort: 161 patients, AMC registry: 196 patients) were eligible for the analyses. Two hundred ninety nine patients (83.5%) received 6 or more cycles of R-CHOP chemotherapy alone, and 58 patients (16.2%) underwent 3 or 4 cycles of R-CHOP followed by IFRT. Median age was 54 years (range, 16-87). During the median follow-up of 24 months (range, 4-116 months), 35 patients (9.8%) experienced relapse, and 22 patients (6.1%) died. Two-year OS and EFS rate was 94.7% and 89.9%, respectively, and 345 out of 357 patients (96.6%) achieved CR. Comparing R-CHOP alone to R-CHOP plus RT group, there was no significant difference in clinicopathologic parameters. R-CHOP alone could achieve significantly higher CR rate of 97.7 % than 91.4% of R-CHOP plus RT group (p = 0.030). Two-year OS and EFS were significantly longer in R-CHOP alone group than R-CHOP plus RT group (96.1 vs 89.9 %, p = 0.029 and 91.7% vs 81.8%, p= 0.028) (Figure 1). Relapse rate was significantly lower in R-CHOP alone group compared with R-CHOP plus RT group than group (7.4% vs 22.4%, p=0.001), and distant relapses were also significantly lower (15.5% vs 2.7%, p 〈 0.001). In addition, even only in relapsed patients, R-CHOP alone group showed lower incidence of distant relapses with marginal statistical significance (36.4% vs 69.2 %, p=0.062) (Table 1). Conclusion In our cohort, R-CHOP alone for six to eight cycles without IFRT could achieve significantly higher 2-year OS and EFS rate as well as CR compared with R-CHOP plus RT group. In addition, the rate of relapse and systemic failure were significantly lower in R-CHOP alone group, which altogether warrant further validation in prospective trial. Table 1. Explorative comparison of overall clinical outcomes and patterns of relapse between two subgroups: patients who underwent six or more cycles of R-CHOP chemotherapy alone and who underwent 3 or 4 cycles of R-CHOP followed by IFRT Total (%) R-CHOP alone group (%) R-CHOP plus RT group (%) P -value Number of patients 357 (100) 299 (83.5) 58 (16.2) Treatment response Complete response 345 (96.6) 292 (97.7) 53 (91.4) 0.030 Overall response 351 (98.3) 294 (98.3) 57 (98.3) 1.000 Rate of relapse 35 (9.8%) 14 (7.4) 11 (22.4) 〈 0.001 Median time to relapse (95% CI) 11 (7-15) 11 (8-14) 10 (5-14) 0.346 Pattern of relapse 〈 0.001 (0.062) Locoregional 14 (4.7) (63.6) 4 (6.9) (30.8) Distant 8 (2.7) (36.4) 9 (15.5) (69.2) Figure 1. Comparison of overall survival and event-free survival in two subgroups: patients who underwent six or more cycles of R-CHOP chemotherapy alone and who underwent 3 or 4 cycles of R-CHOP followed by IFRT Figure 1. Comparison of overall survival and event-free survival in two subgroups: patients who underwent six or more cycles of R-CHOP chemotherapy alone and who underwent 3 or 4 cycles of R-CHOP followed by IFRT Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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