bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association Analysis Between Oncogenic Genes and the Efficacy of Demethylation Drug
Authors: Wang Bianhong 
Published: October 2019

Abstract
Objectives:
In the present study, we investigated the relation between genetic mutations and complete remission (CR) in 78 leukemia patients treated with demethylation drug.
Methods:
One hundred and eleven leukemia-related genes were sequenced by ultra-deep targeted sequencing. Among these, 52 genes were found to be mutated, such as DNMT3A, TET2, IDH1, IDH2, etc., hotspot genes of demethylation drug treatment.
Results:
No DNMT3A nor TET2 mutations were found in 17 patients without significant remission after demethylation drug treatment, while 18% (11/61) patients with complete remission after demethylation drug treatment harbored DNMT3A mutations, and 10% (6/61) patients achieving complete remission after demethylation drug treatment harbored TET2mutations. The difference was statistically significant when compared with non-mutant group (P<0.05).
Conclusions:
Our study indicated a significant association between mutations of DNMT3A and TET2 and efficacyof demethylation drug-treated leukemia patients. Complete remission after demethylation drug treatment was achieved more frequently in the cohort harboring mutated DNMT3A or TET2, which is consistent with previous studies. Our findings suggest ultra-deep targeted sequencing is helpful for investigating the relation between mutated genes and the efficacy of drug. Moreover, it could be a way for screening more suitable patients for demethylation drug treatment in consideration of its extremely high expense.

Disclosures
No relevant conflicts of interest to declare.
Prognostic Genomic Biomarkers for Acute Myeloid Leukemia (AML) Based on French-American-British (FAB) Subtypes
Authors: Ping Zheng , McIntosh Eleanor R , Tao Guo , Shen Dejun , Reddy Vishnu 
Published: October 2019

Abstract
Background: The FAB classification system divides AML into eight subtypes, M0-M7, based on the blast cell morphology and its degree of myeloid maturation. It's an older system to classify AML, but is still used in some treatment protocols. Some prognostic factors related to patient and tumor characteristics have been previously described for AML, including age, Karnofsky score, and karyotype etc. However, the prognostic genomic biomarkers for detailed FAB subtypes of AML are not well defined.
Design: Whole genome sequencing data were analyzed in 197 cases of AML. Twenty-four mutation genes and 38 copy number altered genes were selected based on change rate >=2% as a cutoff. Kaplan Meier Survival analysis for these genes was performed in five FAB subtypes (M0-M5). M6 and M7 are excluded from this study because of small sample size (M6, n=3; M7, n=3). All sequencing data and corresponding pathology information were from The Cancer Genome Atlas (Acute Myeloid Leukemia, TCGA provisional) and were analyzed via cBioPortal bioinformatics tool.
Result: Total of seven mutation genes and two copy number altered genes show prognostic values. TP53 gene mutation is associated with worse overall survival in M0 (n=18). DNMT3A gene mutation is associated with worse overall survival in M1 (n=44). Gene mutations of NPM1, FLT3, IDH1 and gene amplification of KMT2A are associated with worse overall survival in M2 (n=44). BRINP3 gene mutation is associated with worse overall survival in M3 (n=21). TP53 gene mutation and gene amplification of KMT2A and ERG are associated with worse overall survival in M4 (n=39). KRAS mutation is associated with worse overall survival in M5 (n=22). (Log-rank test, p<0.05 for all tests)
Conclusion: These data suggest that different FAB subtypes of AML could have unique prognostic genomic biomarkers. Compared with whole exome sequencing, targeted gene sequencing for these biomarkers may save time and money for patients. Further studies are necessary to understand the biological effects of these gene mutations/amplifications and confirm the above associations.

Disclosures
No relevant conflicts of interest to declare.
Doublet Versus Triplet PET: Is END of Therapy PET Needed IF Interim PET Is Negative in Hodgkin'S or Diffuse Large B CELL Lymphoma?
Authors: Tailor Imran K , Btoosh Bilal , Hamdy Shaimaa , Raja Shanker , Alharbi Mohammed O , Motabi Ibraheem H , Alshehry Nawal Faiez , Qureshi Mohammed S , AlGhamdi Mubarak S. , Zaidi Syed Ziauddin A. 
Published: October 2019

Abstract
Introduction:
Baseline (PETb) and end of therapy (PETe) FDG PET is standard of care in the management of hodgkin's lymphoma (HL) and diffuse large B cell lymphoma (DLBCL). The role of interim PET (PETi) in HL is well established while its role in DLBCL is not well defined. We evaluated the utility of triPET (PETb, PETi and PETe ) in management of these two lymphomas.
Methods:
Retrospective review of PET archives revealed a total of 37 pts (HL=22, DLBCL=15). TriPET were acquired per accepted protocol. SUVmax and Deauville scores (DSc) were obtained from five target lesions, the average i.e. composite SUVmax & DSc were computed for each pt. Statistical analyses were performed with the composite maxSUV (cSUV) and Deauville scores (cDSc) (using EXCEL). Following statistics were performed (separately and combined in HL and DLBCL); mean+SD, PPV and NPV for complete response (CR) Vs. progressive disease (PD) on PETi using the following variables 1. cSUV and 2. cDSc and 3. delta change (DELT). Median progression free survival (PFS) was the clinical endpoint for response.
Results:
The mean PFS in our group was 17 and 15 months in HL and DLBCL respectively. Using cut off thresholds for intP to predict CR at cSUV<=2.0, , cDSC<=2.0 and DELT >=80%,. In HL: for cSUV- PPV 67%, NPV 95%; for DELT of cSUV PPV 100%, NPV 95%; for cDSC-PPV 30%, NPV 100%. In DLBCL: for cSUV- PPV 25%, NPV 100%; for DELT of cSUV PPV 33%, NPV 100%; for cDSC- PPV 50%, NPV 100%.
Conclusion:
The results from our series suggest that PETi has a role not only in HL but in DLBCL as well. Our modest cohort suggests that a negative PETi in DLBCL had a NPV of 100% across cSUV, cDSc and DELT, with regards to CR. Our data also suggests that PETe is not needed if PETi is -ve. While in HL subset, our results concur with results from other groups, this needs to be validated in a larger series.

Disclosures
No relevant conflicts of interest to declare.
Novel Bruton's Tyrosine Kinase Inhibitor Bgb-3111 Demonstrates Potent Activity in Mantle Cell Lymphoma
Authors: Li Carrie J , Liu Yang , Bell Taylor , Wang Jack , Guo Hui , Ahmed Makhdum , Zhang Hui , Lam Laura T , Nomie Krystle , Wang Lai , Zhang Liang , Wang Michael 
Published: October 2019

Abstract
Background:
Aberrant B-cell receptor signaling is an important contributor to lymphomagenesis in mantle cell lymphoma (MCL). Bruton's Tyrosine Kinase (BTK), a component of the BCR signaling axis, has been validated as a clinically relevant target, and BTK inhibitor ibrutinib received FDA approval for treatment of MCL in 2013. Growing concerns that single agent ibrutinib exerts off-target effects that interfere with other treatments such as rituximab-induced antibody-dependent cell cytotoxicity limit its utility in combination treatments. In this study, we assessed the in vitro and in vivo effects of BGB-3111in MCL models.
Methods:
We performed cell viability assays with BGB-3111 treated MCL cell lines to determine inhibition of cellular proliferation. The same assays were conducted on primary human MCL cells and patient-derived xenograft (PDX) tumor samples. Dose-dependent inhibition of BTK auto-phosphorylation and inhibition of downstream targets such as PLC-γ were determined by phospho-protein immunoblotting and immunoprecipitation. A reverse-phase protein assay (RPPA) was conducted on BGB-3111-treated Mino cells to evaluate changes in MCL oncogenic signaling. Induction of apoptosis in MCL cells treated with increasing doses of BGB-3111 was quantified using flow cytometry. For in vivo experiments, an ibrutinib-sensitive MCL PDX mouse model was treated with 50 mg/kg/day BGB-3111 and monitored for mean tumor burden and survival.
Results:
BGB-3111 potently inhibited cell viability in a panel of MCL cell lines, with an activity range of 1-10 uM, and induced apoptosis in a dose-dependent manner in several MCL cell lines.BGB-3111 treatment of MCL cells demonstrated a dose-dependent decrease in p-BTK (Y223) and inhibition of downstream effectors without impacting total protein levels, while RPPA revealed upregulation of the PI3K-Akt signaling axes. In addition, BGB-3111 treatment did not impact phosphorylation of off-target kinases affected by ibrutinib treatment. In vivo, BGB-3111 suppressed tumor growth and prolonged tumor survival in BGB-3111 treated mice.
Conclusion:
The second generation BTK inhibitor BGB-3111 demonstrates selectivity for BTK in vitro and BTK inhibition in vivo. BGB-3111-treated PDX mouse models examining survival, tumor growth, and other factors point to BGB-3111 as an effective single agent BGB-3111 is being investigated in Phase I clinical trials.

Disclosures
Wang: Beigene: Employment. Wang:Asana BioSciences: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Acerta: Consultancy, Research Funding; Kite Pharma: Research Funding; BeiGene: Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Juno Therapeutics: Research Funding.
NCCN-IPI in Patients with Diffuse Large B CELL Lymphoma Treated with DA-R-EPOCH. Retrospective Analysis
Authors: Bergua Burgues Juan Miguel , Lopez-Gomez Luis , Ibañez Fatima , Suarez-Varela Sara , Prieto-Fernandez Julio , Carnicero Fernando , Casas Ignacio , Martín-Mateos Maria Luisa , Cabrera Carmen , Arcos-Carmona María José , Bañas M Helena , Bermejo Nuria , Sanz Miguel A. , Bobillo-Varela Sara , Lopez Andres 
Published: October 2019

Abstract
We analyzed the value of new NCCN-IPI index in patients affected of Large B cell lymphoma (LBCL) treated with DA-EPOCH-R in order to assess the validity of this index in patients treated homogenously with dose adjusted R-EPOCH.
Patients and protocol: We analyzed the use of NCCN-IPI (Zhou et al, 2014) index in a retrospective cohort of 98 DLBCL patients treated with -EPOCH. These patients were included in DA-EPOCH using IPI(Shipp M.A., 1993) as criteria of inclusion, including only patients (95 patients, 96%)with suspected bad prognosis based in IPI (2-5) and 3 patients with primary mediastinal large B cell lymphoma (PMLBCL). R-EPOCH was administered as reported previously(Wilson et al, 2013). Only 10 patients (10%) were Ann Arbor stage I or II.
Results: The median age of the cohort was 57,13(15-82), 47 woman, 75 patients alived. The median follow-up of the patients alive is 6,7 years (1,3-11). Ann Arbor stage was IVB in 44 patients, and IVA in 21. Responses during treatment: Complete response (CR): 81 (82%), refractory during treatment: 7 (7%), death during treatment: 7 (7%). The number of patients who relapsed after treatment was 19 (20%). The median overall (OS) survival of all patients was not reached, (at 5 years, 0.669, CI: 0.562-0.798). The progression free survival (PFS) at 5 years is 0.62, CI: 0.483-0.795. We classify by the new NCCN-IPI the patients in Low-Intermediate risk (L-I)(3 patients, 3%), High-Intermediate risk (H-I)(38, 44%) and High risk (HR) (45, 52%). The OS at 5 years in H-I is 0.839 (CI: 0.73-0.96) and HR was 0.56 (CI: 0.421-0.754), p=0.025. The PFS at 5 years in H-I is 0.65 (CI: 0.518-0.826) and HR is 0.57 (CI: 0.43-0.755), p=0.4.
Conclusions: NCCN-IPI discriminates well prognosis between HR/H-I patients with DLBCNHL treated with DA-EPOCH-R. The results of this retrospective analysis of high and intermediate high-risk patients compares better than the published in patients treated with R-CHOP. PFS were similar in H-I and HR; differences in OS could be explain by differences in outcome after salvage treatment with autologous stem cell

Disclosures
No relevant conflicts of interest to declare.
Ponatinib Facilitates Treatment-Free Remission By Inducing Deep Molecular Responses
Authors: Wisniowski Brendan , Mapp Sally , Knop Louise , Morton James , Eliadis Paul , Mills Anthony K. 
Published: October 2019

Abstract
Multiple trials now demonstrate the potential for treatment-free remission (TFR) in patients with sustained deep molecular response to tyrosine kinase inhibitors (TKIs). We describe two patients who remain in treatment-free remission after achieving undetectable BCR-ABL with ponatinib on the phase II PACE trial, despite being multiply resistant/intolerant to other agents or carrying the T315I mutation.
Patient 1 previously had a suboptimal response to imatinib (BCRABL >10% at 15mo) and then was intolerant of nilotinib and dasatinib due to grade 3 liver enzyme abnormalities. He achieved undetectable BCR-ABL (Molecular MD laboratories) by six months on ponatinib. His ponatinib dose was gradually reduced from 45mg/d to 15mg/d due to vascular events (myocardial infarction requiring stenting, carotid stenosis requiring endarterectomy, recurrent ischaemic colitis). At the time of his last episode of colitis, his BCR-ABL had been undetectable for 47 months and hence a decision to attempt TFR was made. He remains in TFR 11 months post-cessation.
Patient 2 progressed on imatinib and was found to carry the T315I mutation. He achieved undetectable BCR-ABL by nine months on ponatinib. His ponatinib dose was also gradually reduced from 45mg/d to 15mg/d due to vascular events (popliteal stenosis requiring stenting, embolic stroke, coronary artery disease requiring stenting). At the time of his last event, his BCR-ABL had been undetectable for 30 months and hence a decision to attempt TFR was made. He remains in TFR 17 months post-cessation.
This series adds to the one prior case report of ponatinib facilitating treatment-free remission (Engel NW et al. J Oncol Pract 2016. 12(6);592-4) and these remissions are notable because they occur in patients not considered for other TFR studies because of refractoriness to other agents or known T315I mutations. This is an alternative avenue to dose reduction to reduce the risk of vascular events in ponatinib-treated patients.

Disclosures
Mills: Ariad: Other: This clinical study funded by Ariad.
Incidence of Elevated Expression of wt1 in Primary Myelofibrosis (pmf) and Postpv-, Postet Myelofibrosis and Its Dynamics during Ruxolitinib Treatmeny
Authors: Siordiya Nadiya , Lisina Ekaterina , Butylin Pavel , Matuhina Natalia , Bogdanov Konstantin , Silutina Anna , Lomaia Elza , Zaritskiy Andrey , Konopleva Marina 
Published: October 2019

Abstract
Background. Wt1 expression is thoroughly studied in acute myeloblastic leukemia and widely used for disease response monitoring.Its role in MPN is less known.
Aim. The aim of the study was to reveal the incidence of elevated Wt1 expression in PMF and secondary MF, as well as to find out clinical significance during ruxolitinib therapy.
Patients and methods. 38 pts were included ( Primary Mf-31, post PV- and post ET Mf- 8, males - 12, females- 26). Wt1 expression in peripheral blood was studied by qPCR at diagnosis and during ruxolitinib treatment using Quiagen kit. Dynamics of Wt1 expression was studied in 20 pts treated by ruxolininib. Spleen size was measured in cm below costal margin.
Results.
Wt1 increased expression was found in 35/38 pts. Correlation of Wt1 expression and DIPSS was not found. The relation between blast cell and Wt1 expression was studied by dividing pts in 3 subgroups according to the number of blast cells in peripheral blood- 0, 1-2, >2. Wt1 expression was lowest in the 1st group, and the highest in the 3rd group((p<.05). Ruxolitinib treatment resulted in the decrease of spleen size and parallel decrease of Wt1 level( p<.05 -Fig1).Pts with transformation to acute leukemia(5) had higher level of Wt1 than before transformation.
Conclusion.
Wt1 expression is elevated in the majority of pts with PMF as well as in secondary MF. Correlation was found with blast level and spleen size. Wt1 could be used for monitoring efficacy of ruxolitinib therapy

Disclosures
Konopleva: Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.
Ribosomal Protein L23 Negatively Regulates Cell Apoptosis Via Its Suppression of Miz1 and Activation c-Myc in Higher-Risk Myelodysplastic Syndromes
Authors: Qi Yuekun , Wu Lingyun , Chang Chunkang , Xu Feng , He Qi , Li Xiao 
Published: October 2019

Abstract
Ribosomal protein (RP) L23 has been suggested to be a negative regulator of cell apoptosis. Previously, we reported that RPL23 is over-expressed in higher -risk myelodysplastic syndromes (MDS), which is negatively correlated with apoptosis of bone marrow CD34+ cells and predicts poor prognosis. However, the mechanism of the negative regulation of cell apoptosis by RPL23 in higher- risk MDS remains unclear. In the present study, lentiviral transfection of a RPL23-RNAi vector led to generate RPL23-knockdown (KD) in MDS cell line (SKM-1). Gene microarray was performed in RPL23-KD and control (NC) cells. We employed Gene Set Enrichment Analysis (GSEA) to identify functional gene sets and pathways differentially expressed between the two groups. The results showed that RPL23 knockdown induced remarkable proliferation inhibition, distinct pro-apoptosis and cell cycle arrest when compared with NC. Global gene expression profile showed, by comparison to NC samples, 306 genes upregulated while 448 genes downregulated. Among genes varying wildly, increased expression of Miz-1 (FC = 3.79, p=1.19E-20) and lowered expression of c-Myc (FC= -2.613, p=1.49E-05) were identified in RPL23-KD cell, which were verified both by qRT-PCR and western-blot. mRNA and protein levels of p15and p21significantly increased in RPL23-KD cells. In bone marrow sample from 46 patients with higher risk MDS, the mRNA level of Miz1 was remarkably lower than normal controls, which was negatively correlated to RPL23 expression level (r= -0.252, p = 0.048). The mRNA expression level of c-Myc in higher-risk MDS was significantly higher than normal control, which is positively correlated to the RPL23 expression level (r = 0.70, p = 0.004). IHC showed equidirectionally increased c-Myc and RPL23 and lowered expression of Miz1 in patients with higher-risk MDS compared to normal control. In conclusion, the negative regulation of cell apoptosis by RPL23 in higher-risk MDS might be through its suppression of Miz1 and activation of c-Myc.

Disclosures
No relevant conflicts of interest to declare.
Efficacy of First-Line CLL Treatments in Comparison to Chlorambucil: A Network Meta-Analysis
Authors: Firwana Belal , Sonbol Mohamad Bassam , Atrash Shebli , Ravilla Rahul , Raval Mihir , Hao Lin , Jethava Yogesh , Veeraputhiran Muthu , Makhoul Issam , Sasapu Appalanaidu 
Published: October 2019

Abstract
Background: In the past several years, biology of CLL is being unleashed which had led to discovery of novel treatments, including ofatumumab and obinutuzumab, CD20 monoclonal antibodies (mAb), and ibrutinib, a Bruton tyrosine kinase inhibitor, which exhibited a paradigm shift in CLL. Available clinical trials provided direct comparison with chlorambucil, with no head-to-head trials to compare them. We conducted a network meta-analysis (NMA) to summarize the evidence on first-line treatments of CLL.
Methods: We included randomized controlled trials (RCTs) that evaluated the efficacy of ofatumumab, obinutuzumab, ibrutinib, rituximab, bendamustin or alemtuzumab, in patients with previously untreated CLL. Efficacy outcome measures included progression-free survival (PFS) at 18 months and best overall response rate (ORR), which consists of both complete and partial response rates. Bayesian NMA method was used to conduct this NMA that pools evidence from direct and indirect comparisons to facilitate simultaneous inference regarding all treatments used.
Results: Five trials were identified, enrolling 2,113 newly diagnosed CLL patients with a median age ranging from 60 to 73. NMA demonstrated superiority of obinutuzumab plus chlorambucil over other mAb combinations and ibrutinib, and had the highest probability of achieving PFS at 18 months when compared to ibrutinib with risk ratio (RR) of 2.41 (credible interval [CrI] 0.89 to 5.29) and ofatumumab plus chlorambucil with RR of 7.11 (CrI 3.31 to 13.8). Table-1 depicts the results of NMA for PFS at 18 months. It also had the highest probability of achieving ORR, followed by ibrutinib ranking the second.
Conclusion: Obinutuzumab plus chlorambucil has higher probability of achieving efficacy compared to other mAb combinations or ibrutinib, in terms of better ORR and better PFS rates, followed by ibrutinib. The certainty in the evidence is low because of indirectness, which is a limitation in this NMA, however our results parallel the evidence based practice. Although no head to head clinical trials compared first-line treatments for CLL, our NMA showed that obinutuzumab plus chlorambucil and ibrutinib had better efficacy profile. NMA is not a substitute for well conducted RCTs investigating direct comparisons.
Abbreviations: CrI, credible intervals; PFS, progression free survival. *Treatments are ranked according to their probability of achieving comparative effectiveness.

Disclosures
No relevant conflicts of interest to declare.