bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Rituximab on the Clinical Outcomes of Primary Central Nervous System Lymphoma (PCNSL) When Added to Combination Chemotherapy: A Comprehensive Meta-Analysis
Authors: Haddad Philip A , Hammoud Dalia , Gallagher Kevin M. 
Published: November 2020

Introduction:
PCNSL is a rare diffuse large B-cell lymphoma (DLBCL) confined to the central nervous system accounting for approximately 2-5% of all primary brain tumors. Although there is no standard combination of chemotherapy, high-dose methotrexate is considered the backbone of all PCNSL chemotherapy regimens. Rituximab, an anti-CD20 antibody, has been a standard component of non-CNS DLBCL combinations since it improves progression-free (PFS) and overall survival (OS). However, the role of Rituximab in the treatment of PCNSL has been controversial with contradictory results. A meta-analysis conducted in 2019 found no associated survival advantage for Rituximab when added to chemotherapy. However, this meta-analysis was small and included only 2 studies. The purpose of this meta-analysis is to evaluate in a more comprehensive way the impact of Rituximab-based chemotherapy combinations on the clinical outcomes of patients with PCNSL incorporating all available comparative studies.
Methods:
A review of the medical literature was conducted using online databases. Inclusion criteria consisted of PCNSL diagnosis, English language, and studies reporting OS and PFS with hazard ratios (HR) or Kaplan-Meier curves that compared similar regimens with and without Rituximab. A meta-analysis using an inverse variance method with a random-effects model was conducted.
Results:
Four comparative studies with a total of 467 patients were included in this meta-analysis. Two of these studies were retrospective comparative studies and two were randomized phase II trials. When added to chemotherapy, Rituximab was found to significantly improve the OS and PFS (HROS 0.75, 95%CI: 0.59-0.96, p=0.02; HRPFS 0.67, 95%CI: 0.53-0.85, p=0.001) with a heterogeneity estimate, I2=0%.
Conclusions: This is the first meta-analysis to show that adding Rituximab to chemotherapy is associated with OS and PFS in patients with PCNSL. In the absence of randomized clinical trials, this meta-analysis represents the most compelling data supporting the routine use of Rituximab combinations in PCNSL.

Disclosures
No relevant conflicts of interest to declare.
Gls-010, a Novel Anti-PD-1 Mab in Chinese Patients with Relapsed or Refractory Classical Hodgkin Lymphoma: Preliminary Impressive Results of a Phase II Clinical Trial
Authors: Song Yuqin , Zhu Jun , Lin Ningjing , Zhang Mingzhi , Bai Hai , Liu Hui , Cui Jie , Ke Xiaoyan , Zhang Huilai , Liu Lihong , Yan Dongmei , Jiang Yongsheng , Zang Aimin , Qi Junyuan , Wang Li , Liu Zhuogang , Xu Bing , Zhang Ying , Zhang Zhihui , Meng Haijin 
Published: November 2020

Introduction: Classical Hodgkin lymphoma (cHL) is characterized by genetic alterations in 9p24.1, leading to overexpression of PD-L1 ligand. GLS-010 is a novel fully human anti-PD-1 monoclonal antibody (mAb) and exhibited favorable results in previous Phase I study. The aim of this study was to evaluate the safety and efficacy profile of GLS-010 in Chinese patients (pts) with relapsed or refractory cHL.
Methods: In this multi-center, single-arm Phase II clinical trial, pts with relapsed or refractory cHL after at least 2 lines of prior systemic chemotherapies were enrolled and treated with GLS-010 240mg every 2 weeks until disease progression, death, unacceptable toxicity or withdraw from the study. Efficacy was assessed with the primary endpoint of objective response rate (ORR) by independent review committee (IRC) per Lugano 2014. Adverse events (AEs) were graded by NCI CTCAE v4.03.
Results: As of April 18, 2020, a total of 85 pts with relapsed or refractory cHL received a median of 14.5 treatment cycles (1 cycle include 2 injections). The pretreatment characteristics of the pts are shown in Table 1. At a median follow-up of 15.8 months, 28.2% (24/85) of pts discontinued treatment. As shown in Table 2, treatment-related adverse events (TRAEs) of any grade occurred in 79 (92.9%) of 85 patients, most of which were Grade 1-2. The most common TRAEs were fever (27/85, 31.8%), neutrophil count decreased (17/85, 20%) and alanine aminotransferase (ALT) increased (17/85, 20%). Grade ≥3 TRAEs occurred in 25 (29.4%) pts, most commonly, hepatic function abnormal (5/85, 5.88%) and hyperuricaemia (4/85, 4.71%). For all the 85 pts, ORR was 90.59% (77/85, 95%CI: 82.30-95.85) with 32.9% (28/85) of patients achieving a CR and 57.6% (49/85) of patients achieving a PR (Table 3). Median duration of response (DoR) and progression free survival (PFS) were not reached yet.
Conclusions: GLS-010 showed impressive anti-tumor activity (ORR=90.59%) and manageable safety profile in Chinese patients with relapsed or refractory cHL, and could be a new safe and effective treatment option.

Disclosures
Meng: Guangzhou Gloria Biosciences Co., Ltd.: Current Employment.
In-Silico Transcriptome Analyses of Hemostasis Triggers in Inflamed Vs Normal Mucosa of IBD Patients
Authors: Branca Enrica , Carrà Giovanna , Russo Isabella , Terzolo Massimo , Guerrasio Angelo , Morotti Alessandro 
Published: November 2020

Background:inflammatory bowel disease (IBD) is characterized by chronic inflammation associated with an increased tendency to thrombosis and thromboembolic complications. The underlying mechanisms of VTE are not yet fully understood. Several studies reported different expressions of circulating procoagulant factors or fibrinolysis inhibitors in IBD. Others linked podoplanin overexpression with thrombosis, hypercoagulability, and increased risk of VTE. Here, we aimed to identify, among genes able to trigger thrombosis, those aberrantly expressed in IBD samples as compared with matched normal mucosa.
Methods:we analyzed the transcriptome of matched normal and inflamed lesions in 168 patients with Adult Crohn Disease (CD) and 245 pediatric IBD using publicly available datasets. We intentionally assessed the expression levels of triggers and inhibitors of the coagulation system (Tissue Factor, TFI), the fibrinolytic system (PLAU, PLAT, PAI-1/2/3, TAFI, PN-1, SERPINF2, A2M, SNX1, SERPINC1) and platelets activation (podoplanin). Analyses were finally performed using additional datasets with 219 ulcerative colitis (UC) adult patients, 198 IBD patients and compared to normal colon transciptome.
Results:in all datasets, when compared to matched normal mucosal transcriptome, CD and UC inflamed tissues over-expressed Podoplanin mRNA (p=2.46e-25). TF mRNA was also consistently up-regulated in inflamed mucosal of IBD patients, even if paralleled with up-regulation of TFPI as well, questioning on the functional role of TF in IBD. Among the regulators of the fibrinolytic system the urokinase-activator of the plasminogen is consistently deregulated in inflamed areas.
Conclusion: our in-silico analyses on gene expression profiles, using matched normal and pathological mucosa of the same patients, suggested that IBD inflamed mucosa favors platelets activation due to podoplanin over-expression. These observations require further studies to assess the biological role of podoplanin in IBD patients and opens new insights on how to perform antithrombotic prophylaxis in IBD patients.

Disclosures
No relevant conflicts of interest to declare.
Impact of Human T-Cell Lymphotropic Virus Infection on Survival Following Stem Cell Transplantation
Authors: Gupta Vishal K , El-Jawahri Areej , Janakiram Murali , Johnson Mariam H , Weinberg Janice , Goodrich Courtney B , Okoev Grigori , Sloan John Mark 
Published: November 2020

Human T-Cell Lymphotropic Virus (HTLV) Types 1 or 2 are delta retroviruses that may lead to complications including adult T-cell leukemia-lymphoma (ATLL) and HTLV-1-associated myelopathy (HAM). There is concern that immunosuppression may result in progression from an asymptomatic carrier state to ATLL or HAM. Data on the safety of stem cell transplantation (SCT) in patients with HTLV-1/2 infection are lacking. The Center for International Blood and Marrow Transplant Research (CIBMTR) was queried for all patients who tested positive for HTLV infection in the pre-transplantation workup and underwent either autologous SCT (AutoSCT) or allogeneic SCT (AlloSCT) between 2008-2017. The primary outcome was overall survival up to four years post-SCT, assessed using the Kaplan-Meier statistic. All analyses were univariate and did not adjust for differences in disease, disease stage or patients characteristics. In those who underwent AutoSCT, 54 (0.5%) patients were HTLV-positive and 9,837 were HTLV-negative. In those who underwent AlloSCT, 126 (0.7%) patients were HTLV-positive and 18,084 were HTLV-negative. In the HTLV-negative group, a larger proportion underwent AlloSCT for acute myeloid leukemia in the HTLV-negative group, while Non-Hodgkin lymphoma/other leukemia was more common in the HTLV-positive group (P&lt;0.001). Additional patient demographics are listed in Table 1. No difference in overall survival (p=0.661) or non-relapse mortality (p=0.522) was noted following AutoSCT based on HTLV status. Following AlloSCT, univariate analysis showed the HTLV-positive patients had a statistically significant lower overall survival (Figure 1; p=0.013) and higher non-relapse mortality at year four (Figure 2; p=0.023). In conclusion, survival after AutoSCT seems unaffected by HTLV status. While the underlying indications for AlloSCT differed in HTLV-infected patients, decreased overall survival and increased non-relapse mortality were seen in HTLV-positive patients. Reasons for increased non-relapse mortality may include increased infectious complications or graft-versus-host disease. Further studies are needed to understand the relative contributions of these factors.

Disclosures
Janakiram: Takeda, Fate, Nektar: Research Funding. Sloan:Stemline: Consultancy; Abbvie: Consultancy.
An Immune Risk Score Predicts Survival of Patients with Myelodysplastic Syndrome
Authors: Liang Yang , Hu Fang , Dai Yu-Jun , Wang Yun , Li Huan 
Published: November 2020

Background: Myelodysplastic syndrome (MDS) was characterized as ineffective hematopoiesis, increased transformation to acute myeloid leukemia (AML), and accompanied by immune system dysfunction. However, the immune signature of MDS remains elusive.
Methods: The clinical data (age, sex, international prognostic score system (IPSS), hemoglobin, blast, RBC transfusion dependence, and corresponding subject-level survival) as well as expression profiles of MDS (CD34+ cells) were obtained from Gene Expression Omnibus (GEO: GSE 58831; GSE 114922). A robust prognosis model of immune genes was constructed by the least absolute shrinkage and selection operator (LASSO) regression analysis. Survival analysis for prognostic model was carried out through the Kaplan-Meier curve and Log-rank test. The receiver operating characteristic (ROC) curves and area under the curve (AUC) were used to assess the accuracy of prognostic models. Immune score for different subtype were calculated further by single sample gene set enrichment analysis (ssGSEA).
Result: A novel robust immune gene prognostic model indicate that subtype with lower risk score were longer overall survival (OS) than subtype with higher risk score in training cohort (Figure1 A, C). The model was further verified by the validation cohort (Figure1 B, D). The multivariate Cox regression analysis demonstrated the model was an independent prognostic factor for OS prediction with hazard ratios of 56.694 (95% CIs: 9.038−355.648), 3.009 (95% CIs: 1.042−8.692) both in train cohort and external validation cohort respectively (Figure1 G, H). The AUC of 5- year were 0.92 (95% CIs: 0.86 - 0.97) and 0.7 (95% CIs: 0.51 - 0.89) for OS respectively in training cohort and validation cohort (Figure1 E, F). Furthermore, ssGSEA showed higher risk score subtype was significantly associated with higher immune score of check point, human leukocyte antigen (HLA), T cell co-inhibition and type I interferon (IFN) response (Figure1 K-N), which indicating that the poor outcome might be caused by tumor-associated immune response dysfunction partly.
Conclusion: We constructed a robust immune gene prognostic model, which have a potential prognostic value for MDS patients and may provide evidence for personalized immunotherapy.
Figure

Disclosures
No relevant conflicts of interest to declare.
Retrospective Analysis of the Efficacy of Solvent/Detergent Treated Pooled Plasma As Compared to Fresh Frozen Plasma in Thrombotic Thrombocytopenic Purpura: A Single Center Experience
Authors: Klapheke Catherine A , Milito Chelsea , McRae Hannah L , Blumberg Neil , Refaai Majed A 
Published: November 2020

Background : Plasma exchange is the primary treatment for acute episodes of Thrombotic Thrombocytopenic Purpura (TTP), a rare condition characterized by the formation of thromboses in small blood vessels, resulting in thrombocytopenia, hemolytic anemia and multi-organ failure. Plasma exchange replacement fluids in TTP include Fresh Frozen Plasma (FFP) and solvent/detergent treated pooled plasma (SDP), such as Octaplas. SDP is a virus-inactivated, pooled human plasma product with standardized plasma protein content, including ADAMTS13, that has been used in the treatment of TTP. This study evaluates the effectiveness of SDP as compared to FFP in the treatment of acute TTP episodes.
Study Design and Methods : A retrospective analysis was conducted comparing SDP- to FFP-treated patients with suspected acute TTP episodes as a primary admitting diagnosis between December 2014 and December 2019. A total of 16 patients were included in this study. The FFP group consisted of 9 patients (6M/3F, median age 44 years), three of whom had relapsed TTP. The SDP cohort had 7 patients (2M/5F, median age 38 years), one of whom had relapsed TTP. The primary outcomes measured included reported thromboembolic and major bleeding events. Secondary outcomes included number of plasma exchange procedures, adverse effects including neurological changes, transfusion of other blood products, ICU and hospital length of stay (LOS), and changes in laboratory values.
Results : There were no adverse transfusion reactions reported in either group. 12 bleeding events were reported from 6 patients in the FFP group and 8 bleeding events from 4 patients in the SDP group (p=0.397). No significant differences were detected in ICU stay, hospital LOS, number of plasma units transfused, daily percentage of change of laboratory values, or changes in neurological status.
Conclusions:These data confirm the previously reported efficacy of SDP for treating suspected/confirmed TTP.There were no significant differences in thromboembolic or bleeding events between patients who received FFP as compared to SDP. The non-significant differences observed in laboratory values throughout the duration of plasma exchange procedures as well as adverse reactions and clinical outcomes between both groups confirm the safety of SDP when used interchangeably with FFP for the treatment of TTP.
Table

Disclosures
Blumberg: CSL Behring: Consultancy. Refaai:CSL Behring: Consultancy; Octapharma: Research Funding; Instrumentation Laboratory: Research Funding; iLine Microsystems: Research Funding; Diagnostica Stago: Consultancy.
A Systemic Review on Efficacy of Ibrutinib-Based Regimens for the Treatment of Waldenstrom Macroglobulinemia
Authors: Khurshid Qasim , Dar Abdul Jabbar , Mirza Muhammad Ali , Ahmad Muhaddis Ejaz , Jaan Ali , Aamir Sobia , Abdullah Syed Maaz , Kashyap Richi , Khan Israr , Khan Waqas , Ali Sundas , Akbar Arshia , Javed Saad , Qamar Fazeel , Anwer Faiz 
Published: November 2020

Introduction:
Ibrutinib works by inhibiting downstream signaling after the interaction between the mutated MYD88 (Leu265Pro) protein and BTK. In 2015, Ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), was approved by the U.S Food and Drug Administration (FDA) for patients with symptomatic Waldenstrom Macroglobulinemia (WM).
Methods:
We performed a comprehensive literature search following PRISMA guidelines. Beginning with articles published after April 2015, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library, and Web of Science. A total of 580 articles were identified initially, and after a detailed screening, we finalized 4 studies involving 248 WM patients.
Results:
The total number of patients who received Ibratunib based regimens were 248. The dose ranged from 140-560 mg. The overall response rate ranged from 90-92%, very good partial response ranged from 13-23%, and the partial response ranged from 36-75%.
1) Ibtrutunib +Rituximab:
In a study by Dimopoulos et al., (N=150), the overall response rate (ORR) was 92% vs 47% in control vs placebo respectively. The progression-free survival (PFS) of 30 months was 82% vs 28% respectively.
2) Ibrutinib alone:
In a study by Dimopoulos et al., with (N=31), ORR was 90%, a very good progression rate (VGPR) was 13 %, and the partial response (PR) was 58%. In a study by Treon et al., (N=63) ORR was observed in Treon et al. at 90.50%, VGPR was 15%, PR was 36%, no response (NR) was 57%, with overall survival (OS) was 24 months. In a study by Richard et al., (N=4), PR was noted at 75%.
Conclusion:
Ibtrutunib used for the treatment of WM showed an overall response rate of 92%. Infections, cytopenia, bleeding, hypertension and atrial fibrillation were major side effects reported. However, due to the recent FDA approval of the drug to be used for the patients of WM there is very limited studies on Ibrutinib. We recommend future randomized prospective trials to understand the efficacy and safety profile of Ibrutinib for WM treatment.

Disclosures
Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.
Anlotinib Induced Apoptosis and Regulated the Chemosensitivity and Immune-Related Properties of Leukemia Stem Cells By Inhibiting JAK2-STAT3/5 Signaling
Authors: Liu Long , Jiang Long Yue , Xu Bing 
Published: November 2020

Acute myeloid leukemia (AML) is derived from small populations of leukemia stem cells (LSCs) characterized by the self-renewal and chemoresistant properties. Residual LSCs after chemotherapy remain as the critical barriers to cure. Clearance of LSCs might rationally lead to an improvement of clinical outcome. Recently studies showed that JAK/STAT signaling play an important role in the self-renewal of AML-LSCs due to increased growth factor (GF) receptor expression such as c-kit, FLT3, CD123 and altered GF signaling by activating tyrosine kinases. Therefore, targeting such tyrosine kinases might be a strategy to eliminate LSCs. Anlotinib displayed its anti-tumor activity in lung cancer by targeting tyrosine kinase of VEGFR, FGFR, PDGFR and c-kit. However, whether anlotinib could inhibit the GF receptor-related tyrosine kinase overactivation and its downstream JAK-STAT signaling, and subsequently kill LSCs or regulate LSCs biology remains largely unknown.
To explore whether anlotinib could exert effective ani-LSCs activity, we treated LSC like cell lines (CD34+CD38-KG-1 and Kasumi-1) with anlotinib, and found anlotinib could effectively induce apoptosis of LSC-like cells in a dose- and time-dependent manner. Similar results were observed in primary CD34+CD38-AML LSCs; notably, anlotinib did not significantly kill normal CD34+ cells in vitro. Additionally, the anti-LSC activity of anlotinib was further confirmed in the xenograft mouse model by injection of Kasumi cells (LSC-like cell line) into irradiated female BALB/c nude mice.
To determine whether anlotinib could inhibit the over activation of the GF receptor-related tyrosine kinase, we performed western blot at 12h after anlotinib treatment when LSC-like cells did not showed significant apoptosis. As a result, anlotinib inhibit c-kit phosphorylation and JAK2 activation. Intriguingly, unlike JAK2 inhibitors, anlotinib could not only the inhibit phosphorylation of STAT3 and STAT5 but also downregulate their expression.
Chemoresistance and immune evasion were the key features of LSCs, JAK2-STAT3/5 signaling was reported to involved in chemoresistance by upregulating anti-apoptotic proteins such as Bcl-2 ,Mcl-1 and also involved in immune escape by inducing immune suppressive molecules such as PD-L1 ,TGF-β.Thus we evaluated Bcl-2 expression and found a significant decrease in LSC-likes cells after anlotinib treatment. Similarly, PD-L1 and TGF-β were also significantly downregulated after anlotinib treatment.
In conclusion, anlotinib not only displayed the effective anti-LSCs activity but also might regulate the chemoresistance and immune evasion of LSC by downregulating the anti-apoptotic proteins and suppressive molecules such as PD-L1, TGF-β respectively. Consequently, anlotinib might has the potential to contribute to a deeper clearance of LSCs by combining with chemotherapy or immunotherapy.

Disclosures
No relevant conflicts of interest to declare.
The Prognostic Impact of Dynamic Changes of Genetic Risk Stratification in Multiple Myeloma
Authors: Fan Huishou , Liu Jiahui , Yuan Chenglu , Mao Xue-Han , LI Xiaoqing , Du Xin , Li Zengjun , Hao Mu , Yan Yuting , Deng Shuhui , Du Chenxing , Li Chengwen , Zhao Jiawei , Yi Shuhua , Zou Dehui , Zhao Yaozhong , Zhan Fenghuang , Tai Yu-Tzu , Wang Jianxiang , Anderson Kenneth , Qiu Lugui , An Gang 
Published: November 2020

Purpose: Most data on the prognostic impact of cytogenetic abnormalities come from the setting of newly diagnosed multiple myeloma, it remains unclear whether the dynamic changes of cytogenetic aberrations affect the prognostic evaluation in multiple myeloma.
Methods: We analyzed the prognostic impact of dynamic changes of cytogenetic abnormalities with a cohort consisting of 80 paired patients with consecutive cytogenetic data both at diagnosis and recurrence among 568 patients with newly diagnosed multiple myeloma.
Results : Three patterns of recurrence were established from 80 paired patients: Pattern A (40%) consisted of 32 patients without new cytogenetic abnormalities at the time of progression. Pattern B (15%) consisted of 12 patients harboring new standard risk (SR) cytogenetic aberrations. Pattern C (45%) consisted of 36 patients with new high-risk (HR) cytogenetic abnormalities. The median overall survival (mOS; P &lt;0.001) and median progression-free survival (mPFS; P =0.013) differed significantly among three patterns. Four groups including 60 paired patients were further established according to genetic risk stratification changes. There were 15 patients who kept SR in group 1 (25%); 12 SR patients who evolved into HR group in group 2 (20%); 17 HR patients without new HR cytogenetic abnormalities in group 3 (28%); and 16 HR patients harboring new HR cytogenetic aberrations in group 4 (27%). The mOS (P=0.001) also differed significantly among these four groups.
Conclusions: Dynamic cytogenetic changes significantly affected prognostic evaluation in multiple myeloma. Patients harboring new HR cytogenetic abnormalities and escalated genetic risk stratification at relapse had worse outcomes.
Figure 1

Disclosures
Anderson: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.