bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNMT3A Mutations In AML: Incidence, Prognostic Influence and Association With Other Molecular Markers
Authors: Wolfgang Blau Igor , Berenstein Rimma , Baldus Claudia D. , Schlabitz Sophie , Kar Asiye , Cay Ruhiye , Sindram Annette , Seide Claudia , Pezzutto Antonio , Dörken Bernd , Blau Olga 
Published: October 2019

Abstract
Abnormal epigenetic regulation has been implicated in oncogenesis. Mutations in the DNA methyltransferase 3A (DNMT3A) gene were recently demonstrated in acute myeloid leukemia (AML) as a candidate for the initiating of lesions in AML with adverse clinical outcome.
Using direct sequencing, identification of the DNMT3A mutations was done in 320 AML patients. Additionally, we analyzed NPM1, FLT3-ITD, FLT3-D835, IDH1 and IDH2 mutations by PCR and DNA sequencing. The retrospective analysis of diagnostic bone marrow samples was performed in AML patients treated in our institution. In all AML patients double induction therapy containing of “7+3” therapy followed by 4 cycles of high dose AraC consolidation was implicated in accordance with therapeutic standards of our institution. We identified DNMT3A mutations in 22% of AML patients. The most common of mutations affect amino acid R822 in exon 23. The DNMT3A mutation was highly enriched in the group of patients with intermediate-risk profile (35%, P<0.01). Unlikely FLT3, DNMT3A mutations were absent in all AML patients with favorable-risk group (P<0.001). AML patients with DNMT3A mutations were older (P=0.05), had higher WBC and platelet counts (P=0.02 for both comparison) and higher relapse rate (P=0.01). The median overall survival among AML patients with DNMT3A mutations was significantly shorter than among patients without such mutation (13.3 months versus 31.3 months, P<0.01). Occurrence of DNMT3A mutations was associated with presence of other common mutations, such as NPM1, FLT3-ITD, FLT3-D835, IDH1 and IDH2. Correlations of the DNMT3A mutations with NPM1 and FLT3-ITD mutations were significant (P<0.001).
Our results indicate that DNMT3A mutations are highly recurrent in AML patients with intermediate-risk profile. DNMT3A mutations are highly correlated with NPM1/FLT3-ITD mutations and are associated with an unfavorable prognosis. The discovery of recurrent mutations in DNMT3A gene may provide a new prognostic marker for the risk stratification for AML patients.

Disclosures:
No relevant conflicts of interest to declare.
Immune Monitoring In Patients With Early Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Treated With Frontline Nilotinib
Authors: Sopper Sieghart , Mustjoki Satu , Loskog Angelica , Gjertsen Bjorn T , Greil Richard , Lang Alois , Linkesch Werner , Thaler Josef , Gedde-Dahl Tobias , Hjorth-Jansen Henrik , Majeed Waleed , Lofti Kourosh , Richter Johan , Lehman Sören , Stenke Leif , Olsson-Strömberg Ulla , Stentoft Jesper , Posthuma Ward , Smit Willem , Vellenga Edo , Verhoef Gregor , Ferrant Augustin , Van Droogenbroeck Jan , Mark Ute , Haenig Jens , Jurjonas Nidas , Gastl Gunther , Giles Frank , Hochhaus Andreas , Ossenkoppele Gert J. , Porkka Kimmo , Wolf Dominik 
Published: October 2019

Background
Imatinib and dasatinib modulate immune responses in vitro and in vivo. Immunological surveillance in the MRD-situation might be of particular relevance for long-term control or even elimination of CML-repopulating stem cells. Little is known about potential immune-modulatory effects of nilotinib in vivo. The ENEST1st study (NCT01061177) is focused on examining the role of firstline nilotinib therapy in CML-CP - this ENEST1st substudy involves a comprehensive immunological monitoring program.
Efficacy and Toxicity Of Decitabine Versus CHG Priming Regimen In Patients With Higher Risk Myelodysplastic Syndrome
Authors: Wu Lingyun , Li Xiao , Xu Feng , Chang Chunkang , He Qi , Zhang Zheng , Song Luxi , Zhang Xi , Su Jiying , Zhou Liyu 
Published: October 2019

Abstract

Objectives
Decitabine has been approved for the treatment of myelodysplastic syndrome (MDS). CHG regimen (low-dose cytarabine and homoharringtonine in combination with granulocyte colony-stimulating factor (G-CSF)) has been reported to be effective in higher risk MDS patients. The comparative efficacy of these 2 forms of treatment in MDS is unknown. The objective of the current study was to compare the efficacy and toxicity of decitabine and CHG regimen in higher risk MDS.

Methods
We compared lower intensity decitabine with CHG regimen in higher risk MDS (International Prognostic Scoring System (IPSS) intermediate- or high-risk or chronic myelomonocytic leukemia (CMML)). Decitabine was given 20 mg/m2 intravenously over 1 hour daily for 5 days. CHG chemotherapy consisted of an intravenous continuous infusion of low-dose cytarabine (25 mg/d) (days 1–14) and homoharringtonine (1 mg/d) (days 1–14) in combination with G-CSF (300 μg/d) by subcutaneous injection from day 0 until peripheral neutrophil count recovery to 2.0× 109/L. The complete remission (CR), overall response (OR), overall survival and toxicity was compared between the two groups.

Results
A total of 132 patients with higher risk MDS were enrolled in this study, 70 cases in decitabine group and 62 cases in CHG group. The CR rate was 25.7% with decitabine, compared to 32.3% with CHG regimen (p=0.538). The overall response rate (including CR, partial remission (PR), marrow CR and hematological improvement (HI)) between the two groups was also not significantly different (68.6% with decitabine and 58.1% with CHG regimen) (p = 0.209). Overall survival was not significantly different between the two groups (median survival: 18.2 months in decitabine group vs 15.3 months in CHG group; p=0.176). Grade 4 neutropenia occurred more frequently with decitabine (58.3 %) than with CHG regimen (32.3 %) (p = 0.004). Grade 4 thrombocytopenia was also more frequently with decitabine (61.4 %) than with CHG regimen (38.7 %) (p = 0.009).

Conclusions
Both decitabine and CHG regimens were effective in treating patients with higher risk MDS. The two regimens did not differ in terms of clinical responses. However, decitabine showed severer hematological toxicities than CHG regimen. This trial was registered at www.clinicaltrials.gov as ChiCTR-ONC-11001501.

Disclosures:
No relevant conflicts of interest to declare.
Optimizing Notification Of Hospital Admission: A Fellow-Led Quality Initiative
Authors: Kasi Loknath Kumar Anup Kumar , Satyan Megha Teeka , Pal Aroop , Sarah Taylor 
Published: October 2019

Abstract

Background
There is increasing attention nationally to improve the continuum of care for patients. The advent of hospitalists has created significant challenges in effective communication of patient care. The quality and reliability of hospital admission notification of patients to primary hematologists/oncologists, including fellows, anecdotally was a concern.

Objective
To determine the current level of satisfaction for University of Kansas Cancer Center practice (faculty and fellows) with notification of admission to University of Kansas Hospital and determine desired means of notification by Cancer Center practice. Based on a survey, an intervention would be developed to improve quality and satisfaction.

Methods
A pre-intervention survey was administered to determine the desired means and satisfaction of KU Cancer Center faculty and fellows. Based on the results of the survey, an intervention was devised with the use of the Electronic Medical Records (EMR) to generate an inbasket message with desired details. A post-intervention survey will be administered to evaluate the intervention.

Results
Pre-intervention survey was completed by 23 of 51 (45%) invited participants. 16 of 23 (70%) who completed the survey were not notified of admissions. The remaining 7 (30%) participants were notified of admissions but there were no standard means of notification [Fig 1]. Only 4 (17%) of the participants were satisfied and 12 (52%) of the participants were dissatisfied and very dissatisfied with admission notification [Fig 2]. Only 3 (13%) were satisfied and 14 (60%) were dissatisfied and very dissatisfied with the timeliness of admission notification [Fig 3]. The top 3 preferred means of admission notification desired by participants included in-basket message in EMR (n=18), email (n=18), text page (n=14) [table 1]. The top 2 preferred content of the notification desired by participants included Admission Date (n=20) and Diagnosis (n=20) [table 2]. Post-intervention survey is yet to be completed but preliminary results are promising, and will be reported at the time of poster presentation.

Conclusion
A key component of the continuity of care for patients is good, timely communication, including the notification of the admission of patients. A fellow-led intervention highlights opportunities for fellows to participate and execute quality initiatives that meet both educational and professional needs. Utilization of the EMR and technology can improve communication, as demonstrated by this initiative. We achieved great improvement in the provider satisfaction with the quality and timeliness of notification, which should facilitate better care for patients.

Disclosures:
No relevant conflicts of interest to declare.
Prognostic Implication Of Circulating Vascular Endothelial Growth Factor In Patients With Diffuse Large B-Cell Lymphoma
Authors: Lee Hyewon , Eom Hyeon-Seok , Kim Min Kyeong , Kim Hyun-Ju , Park Weon Seo , Kong Sun-Young 
Published: October 2019

Abstract

Background
Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and progression of cancer, and blood level of VEGF has been known to predict of outcome in several types of cancer. However, the impact of blood VEGF levels on prognosis of diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. Here we investigated the prognostic implication of circulating VEGF levels in patients with DLBCL.

Patients and Methods
The study involved 127 DLBCL patients treated by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at National Cancer Center, Korea. Both serum and plasma of the patients were obtained at diagnosis. VEGF were measured using ELISA kit (R&D systems) according to manufacturer’s guidance. We investigated the correlation between clinical parameters and blood VEGF levels. Survival rates and hazard ratios (HRs) in terms of risk for overall survival were determined using Kaplan-Meier method and Cox proportional hazard regression analysis.

Results
The median patient age was 56 years, and 75 (59%) patients were men. Clinical characteristics and international prognostic index (IPI), including age, performance, lactate dehydrogenase (LDH), Ann Arbor stage and extranodal involvement were evaluated. The mean (±SD) value of serum and plasma VEGFs were 713 (±599.8) and 107 (±164.4) pg/mL, and they were correlated as r=0.61 (p<0.001). Both serum and plasma VEGF showed the significant (p<0.01) correlation with serum LDH level, Ann Arbor stage and multiple extranodal involvement, but not with age, gender nor performance. IPI showed strong prediction for prognosis in our data set (HR 3.80, 95%CI 1.64-8.81, p=0.02), and the VEGF levels of high/high-intermediate IPI group were significantly higher than those of low/low-intermediate group [serum VEGF 1088(±838.0) and 557(±377.2), p<0.001 and plasma VEGF 79(±131.6) and 176(±212.2), p=0.002]. With the median follow-up of 44 months, high serum VEGF levels (higher than the median) were significantly associated with short survival (HR 2.74, 95%CI 1.13-6.60, p=0.025), though the plasma VEGF levels did not show the association similar to the serum samples (HR 1.40, 95%CI 0.63-3.12, p=0.414). The patients with higher serum VEGF than the median value showed significantly lower survival rate compared to the low group (3-year survival rates, 68.6% vs. 85.6%, p=0.019).

Conclusion
These findings suggest that high serum VEGF levels can predict poor clinical outcome in patients with DLBCL. This study also represents the different type of specimen for VEGF measurement affected the results. We might have to select adequate specimen type for VEGF measurement, although further validation in large cohort and mechanism studies for this data are warranted.

Disclosures:
No relevant conflicts of interest to declare.
The Prognostic Significance Of DUSP3 In DLBCL
Authors: Fang Rachel R. , Xu Yulian , Qi Chen-feng , Morse Herbert , Zhou Jeff Xiwu 
Published: October 2019

Abstract
DUSP3 (also called VHR) is a member of the dual-specificity protein phosphatase family which can dephosphorylate target proteins at phosphoserine/threonine and phosphotyrosine residuals. There are evidences that DUSP3 is highly expressed in cervical and prostate cancers, and may exert its function in inhibiting apoptosis. By analyzing publicly available data on diffuse large B-cell lymphoma (DLBCL), we found that the expression levels of DUSP3 mRNA were inversely associated with overall survival (OS) in DLBCL. Patients with low levels of DUSP3 mRNA had significant longer OS than did those with high levels of DUSP3 (P=0.0002) (Figure 1). The association between the levels of DUSP3 mRNA and clinical outcome was confirmed using an independent DLBCL cohort. To decipher the role of DUSP3 in DLBCL, we used lentiviral system to stably express shRNA against DUSP3 in the DLBCL cell line, OCI-Ly01. Reduced expression of DUSP3 was associated with significantly decreased proliferation of cells as compared to the control group (P<0.001) (Figure 2). Because the standard chemotherapy for DLBCL depends largely on induction of DNA damage, we were interested in examining possible effects of DUSP3 on the DNA damage response. We found that the levels of phosphorylated H2A.X, a marker for DNA damage response, were significantly increased in cells with reduced levels of DUSP3 (P<0.01) (Figure 3). This may suggest that low levels of DUSP3 in tumor tissues render cells more vulnerable to therapy-induced DNA damage, leading to increasing efficacy of chemotherapy. More molecular and animal studies are underway to determine if DUSP3 can serve as a prognostic biomarker for DLBCL and to identify the underlying molecular mechanisms.

Disclosures:
No relevant conflicts of interest to declare.
Improved Risk Stratification With Addition Of Male Sex (S) To The Elderly International Prognostic Index (S-EIPI) For DLBCL Patients > 60 Years Treated With R-CHOP: An International Collaboration Of The US Intergroup, German High-Grade Non-Hodgkin Lymphoma Study Group and Groupe d’Etude De Lymphome d’Adultes
Authors: Advani Ranjana H. , Hong Fangxin , Habermann Thomas M. , Li Hailun , Kahl Brad S. , Morrison Vicki A. , Weller Edie A. , Varma Gaurav , Fisher Richard I , Peterson Bruce A. , Cheson Bruce D. , Gascoyne Randy D. , Horning Sandra J. , Bousetta Sami , Coiffier Bertrand , Ziepert Marita , Pfreundschuh Michael 
Published: October 2019

Abstract

Background
We have previously reported and validated that the E-IPI, provided better discrimination of overall survival (OS) than the IPI for DLBCL patients > 60 years of age treated with R-CHOP (Advani et al., BJH 2010 and 12-ICML 2013 Abstract 222). Recent reports suggest that males > 60 years treated with R-CHOP have worse outcomes likely related to differences in rituximab clearance (Muller et al., Blood 2012). In this study, we explored if the addition of male sex to the E-IPI further improved risk stratification.

Methods
DLBCL patients > 60 years treated with R-CHOP on the E4494, RICOVER-60 and GELA 98-5 trials were included. A multivariate analysis was performed to assess whether male sex is an independent prognostic factor for OS in addition to the five E-IPI risk factors, E-IPI score, and E-IPI risk group. Male sex (S) was added as an additional risk factor to the E-IPI (S-EIPI, 0-6) and patients regrouped according to the number of risk factors: low (L)=0-1, low intermediate (LI)=2, high intermediate (HI)=3 and high (H)=4-6 based on the observed OS using Kaplan-Meier curves. C-statistic was used to compare the discrimination ability. The 5 year OS was estimated using the Kaplan-Meier method.

Results
1079 patients (E4494, n=267; RICOVER-60, n=610; GELA 98-5, n=202) with a median follow-up of 8.9 years were included. In multivariate analyses, male sex was a significant independent predictor for OS adjusting for all five E-IPI factors, (HR 1.5, p < 0.0001), E-IPI score (HR 1.42, p < 0.001), and E-IPI risk group (HR 1.42, p < 0.001) (Table 1). C-statistic was 0.66 for S-EIPI and 0.64 for EIPI. Incorporation of sex into the E-IPI shifted 35% patients to higher risk groups, including 110 patients into the highest risk group (Table 2). The estimated 5 year OS for the S-EIPI L, LI, HI, and H risk groups was 87%, 70%, 58%, and 40%, respectively (Table 3). Compared to E-IPI, the 95% C.I. did not overlap among S-EIPI risk groups.

Conclusion
For DLBCL patients >60 years treated with R-CHOP, our results suggest the addition of male sex to the E-IPI may improve categorization of patients into well-defined clinically relevant risk groups. Patients with low risk S-EIPI have an excellent outcome (5 year OS 87%). Patients with high risk S-EIPI have a 5 year OS of only 40% and therapies beyond standard R-CHOP need to be explored.

Disclosures:
Horning: Genentech: Employment; Roche: Equity Ownership.
Significant Activity Of The mTOR Inhibitor Sirolimus and HDAC Inhibitor Vorinostat In Heavily Pretreated Refractory Hodgkin Lymphoma Patients
Authors: Janku Filip , Garrido-Laguna Ignacio , Velez-Bravo Vivianne , Falchook Gerald S. , Subbiah Vivek , Hong David S. , Oki Yasuhiro , Westin Jason R. , Nunez Cesar A. , Fayad Luis E , Kwak Larry W. , Shpall Elizabeth J , Wheler Jennifer J. , Liang Winnie , Salhia Bodour , Meric-Bernstam Funda , Kurzrock Razelle , Fanale Michelle 
Published: October 2019

Abstract

Background
Preclinical models have suggested that HDAC and mTOR inhibitors have synergistic antineoplastic activity in Hodgkin lymphoma and other cancers by reducing the activity of AKT, mTOR and HDAC.

Methods
We designed a phase I study to determine the safety of the mTOR inhibitor sirolimus (1mg-5mg PO daily q 28 days) and HDAC inhibitor vorinostat (100mg-400mg PO daily q 28 days) in advanced cancers with an expansion cohort at the recommended phase 2 dose (RP2D) of sirolimus 4mg and vorinostat 300mg for patients with refractory classical Hodgkin lymphoma. The expansion cohort included optional pre- and post-treatment tumor biopsies, peripheral blood mononuclear cells (PBMCs), plasma/serum collections for pharmacodynamic (PD) and pharmacokinetic (PK) endpoints.

Results
A total of 16 patients (men, n=8; women, n=8), median age 33 years, median of 6.5 prior therapies (including autologous SCT [n=15], autologous and allogeneic SCT [n=4]) were enrolled in dose escalation (n=1) or RP2D (n=15) cohorts. At the median follow-up of 3.2 months, 15 (94%) patients demonstrated decreased FDG uptake including 2 CRs (13%) and 5 PRs (31%) using CHESON criteria, with a total CR+PR rate of 44%. The median reduction of tumor was -27% (-100% to +20%, Figure). The estimated median time-to-treatment failure has not been reached and 63% of the patients continued on therapy with further improvement in their level of disease response. Major grade 3-4 treatment-related toxicities included grade 3 thrombocytopenia (4 patients, 25%), grade 4 thrombocytopenia (6, 38%), grade 3 anemia (1, 6%), febrile neutropenia (1, 6%) and led to treatment interruptions and/or dose modifications in 10 (63%) patients. Five (31%) patients had archival tissue available for targeted next-generation sequencing and one patient had a loss of TSC2, an abnormality that putatively activates mTOR. This patient has had a continuing response to therapy (-56%) for 8.4+ months. PD studies in pre- and post-treatment tumor biopsies, PBMCs and plasma as well as PK analysis continue.

Conclusion
The combination of sirolimus and vorinostat is well tolerated with encouraging activity in very heavily pretreated patients with Hodgkin lymphoma refractory to standard therapies. Enrollment continues.

Disclosures:
Off Label Use: sirolimus - mTOR inhibitor vorinostat - HDAC inhibitor.
Pomalidomide Augments Fetal Hemoglobin Production In Primary Erythroid Cells By a Novel Mechanism Modulating BCL11A But Not KLF-1
Authors: Appiah-Kubi Abena O. , Blanc Lionel , Singh Sharon A. , Didier Sebastien , Dsilva Sehba , Chan Kyle W.H. , Lipton Jeffrey Michael , Liu Johnson M. 
Published: October 2019

Abstract

Fetal hemoglobin (HbF) is a known modifier of sickle cell disease (SCD) severity. KLF-1 is a regulator of the globin switch. It does so by increasing beta-globin production and up-regulating BCL11A, a repressor of HbF synthesis. Pomalidomide, a second generation immunomodulatory drug (IMiD), regulates HbF and F-cell production during erythropoiesis in human CD34+ cells. The mechanism by which pomalidomide enhances F-cell production is not well understood. In this study, CD34+ cells were obtained after purification of peripheral blood and positive selection and cultured using a three-phase in vitro liquid culture system which recapitulates erythropoiesis, including terminal differentiation and enucleation, in the presence of no drug, pomalidomide, hydroxyurea, or dimethyl sulfoxide (DMSO; vehicle control). Erythroid differentiation was assessed morphologically and by flow cytometry using the transferrin receptor and glycophorin A as markers of erythroid maturation. Flow cytometry was used to quantify F-cells. RT-qPCR was used to quantify mRNA expression of BCL11A, KLF-1, and gamma-globin. Western blot was used to measure the total expression levels of BCL11A. In this culture system pomalidomide increased F-cells more than hydroxyurea in both SCD and normal control erythroid cultures. There was a significant decrease in BCL11A expression levels, a repressor of HbF synthesis, with pomalidomide but not with hydroxyurea. This decrease was seen in both SCD and normal samples. KLF-1 was not affected by pomalidomide. These findings suggest a very different mechanism of action for pomalidomide versus hydroxyurea in increasing F-cell production. Pomalidomide appears to target the erythroid specific BCL11A but not the more pleiotropic transcription regulator KLF-1. Since the F-cell production was augmented in the presence of pomalidomide in controls as well as SCD erythroid cultures this study suggests a role for pomalidomide in the pharmacologic augmentation of fetal hemoglobin levels, perhaps in addition to hydroxyurea, not only in SCD but in any beta-hemoglobinopathy.

Disclosures:
Chan: BioTheryX Inc: Employment.