bluuebunny/crossref_metadata_2025_split huggingface dataset:
PF258 REAL‐WORLD DATA ON DOSE‐RELATED EFFECT OF ARSENIC TRIOXIDE IN THE RELAPSE OF ACUTE PROMYELOCYTIC LEUKEMIA
Authors: Wang H. , Gong S. , Zhang H. , Zhang X. 
Published: June 2019

Background:Acute promyelocytic leukemia (APL) has evolved from a highly fatal to a highly curable disease because of all‐trans retinoic acid (ATRA) based regimens. Although the cure rate has been improved with the addition of arsenic trioxide (ATO), the relapse rate is still 1–10%. It is not known whether ATO dosage is related to the relapse rate in real‐world.Aims:This study was designed to elucidate the relationship between the dosage of ATO in post‐remission therapy and relapse rate in APL, and to explore the optimum dosage of ATO.Methods:According to 2019 NCCN guideline, the recommended ATO dosage in post‐remission therapy is 12 mg/kg in low‐risk and 7.95–12 mg/kg in high‐risk APL. 112 patients with newly diagnosed APL, receiving the combination of ATRA and anthracycline‐based chemotherapy and different dose of ATO for variable cycles, were divided into the high‐dose group (ATO dosage ≥12 mg/kg) and low‐dose group (ATO dosage <12 mg/kg). The 4‐year cumulative relapse‐free survival(RFS) was compared. Receiver operating characteristic (ROC) curve was used to determine the cutoff value.Results:Based on the total ATO dosage in post‐remission therapy, 72 (64.3%) patients were in the low‐dose group, whereas 40 (35.7%) patients were in the high‐dose group. There was no significant difference in the baseline characteristics between the two groups. After a median follow‐up time of 53 months, the 4‐year cumulative relapse‐free survival was 83% in the low‐dose group and 100% in the high‐dose group respectively (p = 0.008). ROC analysis indicated if the dose of ATO in post‐remission reached 5.49 mg/kg, the relapse rate had no significant difference with the dose of ATO more than 12 mg/kg (p < 0.001). In the binary logistic regression analysis, an increased ATO dosage has an independent protective factor in terms of probability of relapse (odds ratio = 0.67, 95%CI, 0.51–0.88, p = 0.004). Age, WBC count, and the occurrence of differentiation syndrome had no relationship with relapse rate (p > 0.05).Summary/Conclusion:The results indicate that the relapse rate of APL is significantly associated with the dosage of ATO in post‐remission therapy. Regardless of low or high‐risk APL, the ATO dosage should be 12 mg/kg or at least more than 5.49 mg/kg.image
PF262 COMPREHENSIVE DIAGNOSTICS OF ACUTE MYELOID LEUKEMIA BY WHOLE TRANSCRIPTOME RNA SEQUENCING
Authors: Griffioen M. , Arindrarto W. , Borràs D.M. , Locher I.J. , van Diessen S.A. , van der Holst R. , van der Meijden E.D. , Honders M.W. , de Leeuw R.H. , Jedema I. , Kroes W.G. , Knijnenburg J. , Vermaat J.S. , Valk P.J. , Janssen B. , de Knijff P. , van Bergen C.A. , van den Akker E.B. , ’t Hoen P.A. , Kiełbasa S.M. , Laros J.F. , Veelken H. 
Published: June 2019

Background:Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of malignant myeloid precursor cells in the bone marrow. Genetic aberrations play an important role in pathogenesis as well as in classification of AML, which is relevant for accurate diagnosis, risk assessment and personalized treatment of AML. Genetic aberrations in AML are structurally diverse and currently measured by different diagnostic tests.Aims:The aim of the study is to establish whole transcriptome messenger RNA sequencing (RNAseq) as single and flexible diagnostic platform for AML classification, prognostication, and choice of targeted agents.Methods:Whole transcriptome RNA sequencing was performed on 100 AML cases and the bioinformatics pipeline HAMLET (Human AML Expedited Transcriptomics) was developed for simultaneous detection of fusion genes, small variants, long tandem duplications and gene expression. HAMLET results were validated by reference assays and targeted resequencing.Results:HAMLET accurately detected all fusion genes and overexpression of EVI1 irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and internal tandem duplications in FLT3 (FLT3‐ITD) and partial tandem duplications in KMT2A (KMT2A‐PTD) were detected by a novel algorithm based on soft clipped reads with 100% sensitivity and 97.1% specificity.Summary/Conclusion:HAMLET accurately provides comprehensive diagnostic information relevant for AML classification, risk assessment and personalized therapy on a single technology platform. Instead of current AML diagnostics based on various assays that target selected aberrations, RNAseq‐HAMLET represents a new diagnostic paradigm according to a “measure all – analyse relevant” approach, which can be adapted to advances in sequencing technology and novel insights in AML pathogenesis, and allows individual retrospective reassessment.
PF275 NAT10 UPREGULATION INDICATES A POOR PROGNOSIS IN ACUTE MYELOID LEUKEMIA
Authors: Liang P. , Hu R. , Liu Z. , Miao M. , Jiang H. , Li C. 
Published: June 2019

Background:Acute myeloid leukemia (AML) is a series of hematologic malignancies with high morbidity and mortality. It is characterized by impaired differentiation, excessive proliferation, and apoptosis escape. N‐acetyltransferase 10 (NAT10) is a transcriptional activator of telomerase reverse transcriptase (hTERT)[1]. It has acyltransferase domain and participates in microtubule acetylation, rRNA modification, DNA damage response, and cytokinesis[2–5]. NAT10 was upregulated in various kinds of tumors such as hepatocellular carcinoma, colorectal cancer, ovarian cancer and melanoma[6–9]. NAT10 upregulation is associated with poor prognosis. This study investigated NAT10 expression in AML patients and its correlation with clinical characteristics, chemotherapy response and prognosis.Aims:N‐acetyltransferase 10 (NAT10) is considered as an oncogene in many tumors. This study investigated the NAT10 expression in Chinese acute myeloid leukemia patients and evaluated the predictive significance of NAT10 with a single‐center retrospective study.Methods:We collected bone marrow samples of 48 newly diagnosed acute myeloid leukemia patients and 20 benign controls in our center. NAT10 mRNA expression levels were detected by Real‐time qPCR. Clinical data was obtained from inpatient medical records.Results:AML patients had higher NAT10 expression level than the normal controls (P < 0.01). NPM1‐mutant patients had higher NAT10 expression level than NPM1‐wt patients. NAT10 expression level was higher in non‐remission group than that of overall remission group (P < 0.05). High NAT10 expression indicated a poor progress free survival and overall survival.Summary/Conclusion:The results support NAT10 as a potential prognostic and therapeutic biomarker for acute myeloid leukemia.image
PF282 THE EFFECT OF MODERN THERAPEUTICS IN ADULT ACUTE MYELOID LEUKEMIA (AML): POPULATION‐BASED ANALYSIS OF LONG‐TERM OUTCOMES FROM THE MANITOBA CANCER REGISTRY
Authors: Tapley L. , Bucher O. , Galloway K. , Paulson K. , Seftel M. 
Published: June 2019

Background:While the prognosis for adults with acute myeloid leukemia (AML) is historically poor, advances in supportive care and new therapeutics such as blood and marrow transplant (BMT) and hypomethylating agents may have improved overall outcomes. In the Canadian province of Manitoba, all patients with AML are managed at a single cancer centre with support from a community cancer program. Clinical and demographic data are collected in a provincial cancer registry. This registry captures all cases of AML, increasing the reliability of population‐based data as case ascertainment and follow‐up follow a uniform approach.Aims:We sought to describe the clinical characteristics, incidende and relative survival for patients with AML in the province of Manitoba, with attention to temporal trends and outcomes in rural patients, where access to care may be challenging.Methods:We collected data on consecutively diagnosed adult cases of AML that were reported to the Manitoba Cancer Registry (MCR) from 1990 ‐ 2014. Life tables from Statistics Canada were used as a reference for expected survival in the general population. Patient demographics were stratified by age, time period and residence at diagnosis. Two‐year age‐standardized relative survival estimates of patients in Manitoba with AML were estimated using the cohort method within various subcategories, including time period of diagnosis (in 5 year increments), sex and urban (Winnipeg) versus non‐Winnipeg location.Results:A total of 910 patients from the ages of 15 to 99 were diagnosed from 1990 ‐ 2014 with available survival data to 2016. Of the 910 patients, 517 were men and 393 were women and 511 (56%) were residents of Winnipeg at diagnosis. Two‐year crude relative survival estimates by time period and age group demonstrated improving relative survival for each age quintile category within each 5‐year time period, with the most notable increase over time in patients aged 15–44 and 45–54. Total two‐year age‐standardized relative survival for all patients was 20.37% (CI 95% 17.81–23.05%). Two‐year age‐standardized relative survival in males was 19.22% (CI 95% 15.95–22.73%) and 21.93% (CI 95% 17.88–26.25%) in females. Two‐year age‐standardized relative survival by residence at diagnosis was 20.32% (CI 95%. 16.92–23.94%) for urban (Winnipeg) residents, and 20.54% (CI 95% 16.74–24.62%) for those outside of Winnipeg.Summary/Conclusion:We demonstrate improved relative survival in adult AML over time, most notably in adults aged 15–54, where BMT has played an increasingly important therapeutic role. Advanced supportive care and hypomethylating agents may also have contributed to improved outcomes, especially in older patients. Similar relative survival for urban and rural patients supports the benefits of a centralized and coordinated leukemia centre with its closely linked community cancer program.
PF313 NEW TREATMENT FOR DOUBLE/TRIPLE HIT LYMPHOMA WITH DOSE INTENSE PROTOCOL: RITUXIMAB,DOXORUBICIN,ETOPOSIDE,PREDNISOLONE/GEMCITABINE+OXALIPLATIN SHAWING BETTER SURVIVAL RATE
Authors: Salamoon M. , balti M. , kenj M. 
Published: June 2019

Background:unclassifiable B‐cell lymphoma with features between diffuse large B‐cell and Burkitt, Burkitt‐like with a complex karyotype involving MYC and BCL‐2 genes (double hit) and BCL‐6 gene (triple hit). This kind of lymphoma shows high mitotic rates and an aggressive course for which no definitive treatment have been established so far.Aims:the study is aiming at evaluating a new dose intense chemotherapy in patients with double/triple hit lymphoma with end points including progression free and overall survival at 5 years.Methods:this is a multicenter study with Al Bairouni university cancer center in Damascus, Syria as the main investigator performed between 2014 and 2018 where we recruited 66 patients with ages between 18 and 65 years having double/triple hit lymphoma confirmed by immuno‐histochemistry as well as FISH technique. Patients received a dose intense protocol as follows: (Rituximab 375 mg/m2 with Doxorubicin 75 mg/m2, Cyclophosphamide 1200 mg/m2, Etopdside 300 mg/m2 and Prednisolone 1 mg/kg for 5 days) repeated every 21 days for 6 cycles with 5 days G‐csf support. Then partial and complete responders were given (Gemcitabine 1gr/m2+ Oxaliplatin 85 mg/m2) for 6 cycles repeated every 14 days. End‐points were progression free survival and overall survival at 5 years.Results:overall response rate (ORR) was documented in 58 patients (87.8%) (42 complete responders and 16 partial responders). 12 patients progressed at different stages of follow up with a progression free survival (PFS) of 82% (95% CI 77–88). However, 51 patients were found to still alive at 5 years with an overall survival (OS) rate of 77.2(95% CI 71–82). Survival was shorter in those presented with synchronous central nervous system and abdominal localizations (P value 0.02). The most frequent toxicities were, neutropenia and thromcytopenia of different grades, tumorlysis syndrome in few patients and different degrees of mucositis and peripheral neuropathy, however, no documented death was attributed to toxicity profile.Summary/Conclusion:double/triple hit lymphoma is a new subtype of lymphoma involving a 2–3 genes abnormalities which increase the aggressiveness course of disease with most patients resisting the old standards. Recently, patients were responding to the classical R‐CHOP as well as to R‐EPOCH in both young and elderly patients, however, survival rates were not exceeding 65% at 5 years. That is why we have developed this protocol with high dose chemotherapy in order to overcome resistance and consolidate the primary response. Compared with studies published in the literature, our protocol confers better progression free and overall survival rates, however, bigger trials should be performed to validate our results
PF317 ELEVATION OF SERUM IL‐10 IS ASSOCIATED WITH ADVERSE CLINICAL OUTCOMES IN PATIENTS WITH DIFFUSE LARGE B‐CELL LYMPHOMA WHO WERE TREATED WITH R‐CHOP
Authors: Yi J.H. , Yoon S.E. , Ko Y.H. , Kim W.S. , Kim S.J. 
Published: June 2019

Background:Cytokines are one of the major non‐cellular component of tumor microenvironment, and they act as messengers between malignant cells and the cellular component of tumor microenvironment to promote cancer cell proliferation and to evade immune surveillance. While the role of cytokine had been widely investigated in patients with DLBLC, their impacts on secondary CNS involvement had rarely been reported.Aims:To address prognostic roles of serum cytokines regarding the OS and CNS events in DLBCL patients.Methods:Patients out of our prospective cohort study (NCT#00822731) who met the following criteria were included in the present study. 1) Patients with newly diagnosed, histologically confirmed DLBCL, other than primary CNS lymphoma; 2) Patients who were treated with R‐CHOP as the first‐line treatment; 3) Patients whose serum samples were collected. The clinical data of patients were collected. Serum levels of IL‐2, IL‐6, IL‐10, IL‐21, CXCL10, CCL3, CCL5, PAI‐1, survivin, and TNFα were measured. The primary end‐point of the current study was estimated 3‐year overall survival (OS) rate, and the secondary end‐point was time to secondary CNS involvementResults:A total of 313 patients were eligible for the analysis. The median age was 56 years (range, 16 to 86 years) and 177 patients (57%) were male. The 3‐year OS rate was 73.6% ( ±  2.5%), and all the factors in IPI significantly discriminated the OS. Six cytokines were correlated with the 3‐year OS rate (FIGURE). Time to CNS involvement was assess in 294 patients, and 16 events (5.4%) of secondary CNS involvement were detected. Only one cytokine could predict it, as patients with elevated IL‐10 was associated with significantly short time to CNS involvement compared to patients without IL‐10 elevation (p = 0.012). While only 1 out of 99 patients (1.0%) without IL‐10 elevation developed secondary CNS involvement, 15 out of 195 patients (7.7%) with IL‐10 elevation developed secondary CNS involvement (p = 0.017). Of note, among 19 patients who initially had CNS involvement, 14 patients (74%) had elevated serum IL‐10.Summary/Conclusion:We have found that elevation of CCL3, CCL5, CXCL10, IL‐6, IL‐10, and survivin were associated with inferior 3‐year OS rate, and elevation of IL‐10 was associated with short time to secondary CNS involvement. Considering their biologic roles in lymphomagenesis, further studies are required to incorporate these results to conventional prognostic factors to better predict outcomes of patients with DLBCLimage
PF326 VITAMIN D INSUFFICIENCY AND PROGNOSIS IN LYMPHOMA
Authors: Sanchez‐Gonzalez B. , Platero J. , Ortuño A. , Garcia‐Pallarols F. , Perez S. , Torres E. , Bento L. , Parraga I. , Gimeno E. , Gutierrez A. , Salar A. 
Published: June 2019

Background:Vitamin D deficiency has been recently associated, as an independent risk factor, with lower rates of progression‐free survival (PFS) and overall survival (OS) in patients with Hodgkin (HL) and non‐Hodgkin's lymphoma (NHL).Aims:To investigated the impact of vitamin D status on the outcome of lymphoma patients in two Institutions.Methods:From 2015 to 2018, we tested circulating 25‐hydroxyvitamin D3 (25[OH]D3) levels in a prospective cohort of 135 newly diagnosed patients with NHL and HL in two Institutions in Spain. 25[OH]D3 levels were measured by chemoluminescent immunoassay. Determinations were based on guidelines from the Food and Nutrition Board of the Institute of Medicine. According to current guidelines, we considered the following thresholds: vitamin D deficient (<10 ng/ml), vitamin D insufficiency (10 to 30 ng/ml) and normal vitamin D level (>30 ng/ml). Patients with <20 ng/ml from one Institution had vitamin D substitution. OS and PFS were calculated using Kaplan‐Meier estimators, comparison between categories performed by log‐rank test and Cox PH regression, and the effect of covariates reported with 95% confidence interval (95 CI).Results:135 newly diagnosed patients with NHL and HL were included. Median age at diagnosis was 67 years (range, 20 to 91 years). NHL subtypes: 47% diffuse large b cell lymphoma (DBCL), 30% Indolent lymphoma, 5% mantle cell lymphoma, 6% Tcell lymphoma, 10% Hodgkin lymphoma and 3% others NHL 34% had advanced stage and and 39% of NHL patient had ≥ 3score of International Pronostic Index (IPI).55% of the patients were diagnosed in spring or summer. Median 25(OH)D levels at diagnosis were 18 ng/ml. 11% of patients had normal 25(OH)D levels, 77% had insufficient 25(OH)D levels and 12% were deficient at lymphoma diagnosis. Median follow‐up was 12 months and 22 deaths were observed. The three groups of vitamin D levels were associated with OS, but this difference was not statistically significant (Figure 1).In the DLBCL subset, we inspected in a Cox Model the effect of Vitamin D levels for OS/PFS, adjusting for IPI Score and vitamin D substitution. Vitamin D levels did not achieve statistical significance for PFS (hazard ratio [HR], 1.02; 95% CI, 0.99 to 1.04) and OS (HR: 0.99; 95% CI, 0.94 to 1.06). Remarkably, there was a tendency towards a better statistically significant outcome in patients supplemented (HR for PFS: 0.36; 95% CI, 0.10 to 1.29; p = 0.10).Summary/Conclusion:Most of our patients present with low levels of vitamin D[JPD1]. In our limited series, with the current follow‐up time, baseline vitamin D values did not significantly impact PFS and OS. Further studies are needed to confirm our data.image
PF341 LUSUTROMBOPAG FOR TREATMENT OF THROMBOCYTOPENIA IN PATIENTS WITH CHRONIC LIVER DISEASE WHO ARE UNDERGOING PLANNED INVASIVE PROCEDURES: POOLED SAFETY ANALYSIS OF BLEEDING‐RELATED ADVERSE EVENTS
Authors: Giannini E.G. , Kano T. , Ochiai T. , Bentley R. , Shrestha P. 
Published: June 2019

Background:Thrombocytopenia is a common complication in patients with chronic liver disease. Furthermore, a low platelet count in chronic liver disease patients who require an invasive procedure is a serious condition that may be associated with an increased risk of bleeding during or after the procedure. Lusutrombopag is a thrombopoietin receptor agonist approved in Japan and US for improvement of thrombocytopenia, and in EU for severe thrombocytopenia, associated with chronic liver disease in patients undergoing planned invasive procedures.Aims:A pooled safety analysis was performed to assess differences in bleeding events following treatment with lusutrombopag without platelet transfusion or placebo with platelet transfusion.Methods:Safety data were pooled from 3 double‐blind, placebo‐controlled studies, in patients with thrombocytopenia associated with chronic liver disease undergoing a planned invasive procedure (Phase 2b: M0626 [Japan; JapicCTI‐121944]; Phase 3: L‐PLUS 1 [Japan; JapicCTI‐132323], L‐PLUS 2 [global; NCT02389621]). Patients enrolled in these studies were randomized to lusutrombopag 3 mg or placebo for up to 7 days prior to procedure. Platelet transfusion was administered if platelet count was <50x109/L no more than 2 days prior to procedure. Patients were classified into 1 of 4 subgroups: lusutrombopag with or without platelet transfusion or placebo with or without platelet transfusion. This analysis focused on patients in the lusutrombopag without platelet transfusion and placebo with platelet transfusion subgroups. Bleeding events were summarized pre‐, during, and post‐procedure.Results:Lower bleeding event rates, regardless of severity and timing of onset, were observed for lusutrombopag alone vs placebo+platelet transfusion (Table). Percent of patients with bleeding events was numerically higher with placebo+platelet transfusion vs lusutrombopag alone, both during (4.8% vs 3.2%) and post‐procedure (7.1% vs 4.0%). Percent of patients with bleeding events in liver‐related procedures was greater in the placebo+platelet transfusion arm (16.1%) vs lusutrombopag alone (11.1%), and a larger difference was seen with gastrointestinal‐related procedures in placebo+platelet transfusion (8.9%) vs lusutrombopag alone (2.0%).Summary/Conclusion:In this pooled analysis, a trend toward lower bleeding event rates was observed with lusutrombopag alone vs placebo+platelet transfusion, regardless of type of invasive procedure.image
PF346 ZEBRAFISH AS A NOVEL MODEL TO STUDY GATA2 HAPLOINSUFFICIENCY SYNDROMES
Authors: Gioacchino E. , Koyunlar C. , de looper H. , Peulen J. , Bosch D. , hoogenboezem R. , van strien P. , Bindels E. , Touw I. , de Pater E. 
Published: June 2019

Background:Patients with GATA2 mutations have up to 80% chance to develop a myeloid malignancy. MonoMAC and Emberger syndromes are GATA2 deficiency syndromes and are characterized by monocytopenia, B, NK cell lymphopenia and a predisposition to acute myeloid leukemia (AML). Although the disease initiating mutation is known, it is unclear how these patients develop hematological malignancies.Aims:In our research we use both mouse and zebrafish models of Gata2 haploinsufficiency to describe their phenotypes and study the mechanisms of malignant transformation.Methods:In mice we analyzed the transcriptome and functionality of LSK SLAM in Gata2 mutants. In zebrafish, two orthologues of Gata2 exist: gata2a and gata2b of which gata2b was shown to be predominantly expressed in hematopoietic cells. We used CRISPR‐Cas9 to generate zebrafish gata2b mutants and evaluate their phenotype using flow cytometry, RNAseq, histology and in situ hybridization. Using single‐cell RNA sequencing we aim to identify early onset markers of dysplasia and unveil the mechanism of malignant transformation.Results:Gata2 heterozygous mutant mice survive into adulthood without developing signs of alterations in the myeloid lineage. Phenotypic HSCs of these mutant adult mice have unchanged Gata2 expression but are lower in frequency, more proliferative and transcriptionally more committed to differentiation compared to WT. Additionally, they display increased DNA damage indicating these HSCs experience proliferative stress. gata2b

+/− zebrafish show reduced myeloid differentiation and the kidney marrow smears of this aged fish show dysplastic myeloid cells.Summary/Conclusion:Our mouse model doesn’t incur a malignancy even though it acquires an HSCs phenotype. Our zebrafish model develops a dysplastic kidney marrow and recapitulates characteristics of the GATA2 deficiency syndromes. Both models can give new insights into the physiopathology of these diseases.