bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is Anaemia Another Bleeding Risk in Cancer-Associated-Thrombosis?
Authors: Janus Nicolas 
Published: November 2020

INTRODUCTION AND AIMS:
Anaemia is very common in cancer patients. However, the impact of anaemia in venous thromboembolic (VTE) patients on the risk of bleeding is not well-known. Consequently, the question of the impact of anaemia in cancer-associated-thrombosis (CAT) patients is important.
METHODS:
All the literature (PubMed) was reviewed about the potential links between cancer, CAT and anaemia. However, there were no dedicated studies on this topic. Furthermore, the WHO definition of anaemia was the one used in most of the publications
RESULTS:
Several studies investigated about all the risks of bleeding/VTE in atrial fibrillation and VTE patients, including anaemia. Most of them reported that anaemia exposed VTE patients to a higher risk of bleeding. The COMMANDER study, evaluated the influence of anaemia in VTE patients and reported that VTE patients with mild and moderate/severe anaemia had higher risk for major bleeding and that the risk for major bleeding increased according to the severity of anaemia. The RIETE (Registro Informatizado Enfermedad Tromboembólica) reported that anaemia was found in 57% of the patients with cancer and in 28% without cancer (odds ratio 3.46; 95% CI 3.33-3.60), exposing to a higher risk of major bleeding. The same registry reported also that in CAT patients, anaemia had a two-fold higher rate of major bleeding and fatal bleeding than CAT patients without anaemia. This link between anaemia and bleeding in cancer patients are multifactorial. Indeed, there are both quantitative and qualitative changes in red blood cells that could affect bleeding and thrombosis, as well as interactions of red blood cells with cellular and molecular components of the haemostatic system. Indeed, for example, low haematocrits are associated with bleeding. Finally, it is interesting to notice that there is a gap between the definition of anemia in CAT patients when compared to not CAT cancer patients. Indeed, WHO definition is quite common in VTE and CAT patients but EORTC/NCCN are used in cancer patients for several reasons. As a consequence, it could be important to align on this point.
CONCLUSIONS:
Anaemia, cancer and thrombosis are closely linked. It is important to screen and manage both anaemia in CAT patients because of the increased risk of bleeding. Consequently, it is important to consider this bleeding risk in CAT patients before initiating an anticoagulants treatment or prophylaxis in cancer patients.

Disclosures
Janus: Bayer:Honoraria, Research Funding;Pierre Fabre Oncology:Research Funding;Novartis:Honoraria;Gilead:Honoraria, Research Funding;Vifor Pharma:Honoraria, Research Funding;Fresenius Medical Care:Honoraria;Amgen:Honoraria, Research Funding;B-Braun:Honoraria;Guerbet:Research Funding;TEVA:Research Funding;IPSEN:Honoraria;Pfizer:Consultancy, Honoraria;Roche:Honoraria, Research Funding;Daichii-Sankyo:Honoraria, Research Funding;LEO Pharma A/S:Current Employment, Honoraria.
SGN-CD30C, an Investigational CD30-Directed Camptothecin Antibody-Drug Conjugate (ADC), Shows Strong Anti Tumor Activity and Superior Tolerability in Preclinical Studies
Authors: Ryan Maureen , Lyski Ryan , Bou Lauren , Heiser Ryan , Grogan Bryan , Meyer Dave , Jin Steven , Simmons Jessica , Conerly Melissa , Senter Peter , Jeffrey Scott 
Published: November 2020

SGN-CD30C, an investigational CD30-directed ADC, utilizes a potent novel camptothecin derivative as the cytotoxic payload. SGN-CD30C targets the same antigen as brentuximab vedotin (BV), though the payload has a different mechanism of action, namely inhibiting topoisomerase I rather than disrupting microtubules. Unlike monomethyl auristatin E, camptothecin-based therapies do not cause peripheral neuropathy clinically, suggesting that SGN-CD30C may have the potential to avoid one of the most common adverse events associated with BV.
In preclinical studies, SGN-CD30C demonstrated strong monotherapy activity, inducing durable tumor regressions in multiple lymphoma models and eliciting cures in a BV-resistance tumor model (Figure 1). Moreover, SGN-CD30C exhibits many of the desirable attributes associated with BV, notably, bystander activity and CD30+ T regulatory cell (Treg) depletion. Using an admixed model of CD30+ and CD30-tumor cells, SGN-CD30C demonstrated robust anti-tumor activity in vivo, confirming SGN-CD30C can induce bystander killing of antigen-negative tumor cells in CD30-heterogeneous tumors. Additionally, SGN-CD30C depleted CD30+ Treg cells in vitro (Figure 2), suggesting it has the potential to exert activity through multiple mechanisms of action.
SGN-CD30C was well-tolerated in non-human primate toxicology studies and demonstrated ~6-fold higher maximum tolerated dose when compared to BV. The primary toxicity for SGN-CD30C in non-human primates (NHP) studies was anemia due primarily to bone marrow suppression of erythropoiesis. SGN-CD30C had no effect on neutrophil counts and caused only minimal to mild decreases in platelets. The lack of significant neutropenia seen with SGN-CD30C contrasts with BV, indicating the two ADCs may have non-overlapping dose limiting toxicities. Hematology parameters show SGN-CD30C is tolerated at a 10-fold higher dose than BV with weekly dosing, suggesting SGN-CD30C may offer the potential for increased dose density.
In summary, our data show SGN-CD30C is a compelling therapeutic candidate for CD30-positive malignancies. The distinct mechanism of action, strong anti-tumor activity, and enhanced tolerability provide a strong rationale to clinically investigate SGN-CD30C across the CD30-expressing lymphoma landscape. A Phase 1 clinical trial is planned to investigate SGN-CD30C in relapsed and refractory lymphoma.

Disclosures
Heiser: Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Grogan:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Jin:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Conerly:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company.
Novel Germline TRAF3IP3 Mutation in a Dyad with Familial Acute B Lymphoblastic Leukemia
Authors: Pommert Lauren , Burns Robert , Furumo Quinlan , Pulakanti Kirthi , Brandt Jon , Burke Michael J , Rao Sridhar 
Published: November 2020

Acute lymphoblastic leukemia (ALL) is the most common single malignancy in children, representing 25% of all new cancer diagnoses. Advances in genomic sequencing has demonstrated that inherited genetic risk factors play a larger role in leukemia development than previously appreciated. We identified a father-daughter dyad with childhood B cell acute lymphoblastic leukemia (B-ALL) and obtained their diagnostic bone marrow samples from the Children's Oncology Group (COG) bank in addition to germline samples via remission marrow (daughter) or buccal swab (father). Whole Exome Sequencing (WES) was performed and compared to a panel of normal to identify large genomic changes and single nucleotide variants. In parallel, RNA-sequencing (RNA-seq) was performed on the diagnostic marrows. We discovered a novel germline chromosomal structural variant in chromosome 1q32.2 within the TRAF3IP3 gene. TRAF3IP3 regulates B cell lymphopoiesis and this mutation likely resulted in a predisposition to leukemia by causing expansion of immature B-cell precursors which are highly vulnerable to secondary somatic mutations. This mutation has not been previously described in ALL, however based on the function of TRAF3IP3 in B cell lymphopoiesis, we conclude this likely represents a mutation predisposing to the development of leukemia. WES revealed this dyad had no shared SNVs that are associated with leukemia in the literature and that they had only a few shared SNVs within the leukemia samples, none of which were identified as clinically significant; which suggests the spectrum of their somatic mutations were distinctly different. Given the lack of concordance in their somatic mutational spectrum, we wondered if the two leukemia samples would exhibit a shared transcriptome, implying convergent leukemogenic pathways were altered within the two specimens since they were both clinically reported as hyperdiploid. In comparing the leukemia gene expression profiles identified by RNA-seq to 216 cases of sporadic B-ALL from the TARGET database (The Therapeutically Applicable Research to Generate Effective Treatments program), we discovered that these two leukemia samples did not cluster together but did cluster with other cases of childhood B-ALL. We suspect that this germline TRAF3IP3 mutation increased this dyad's susceptibility to leukemia development but that the somatic mutational spectrum drove the leukemia development and dictated its phenotype. This research may have identified a novel gene involved in leukemogenesis which may also be involved in de novo cases of ALL. Additional studies are needed to further characterize this TRAF3IP3 structural variant, the co-occurring somatic mutations within these leukemia samples and their combined role in leukemogenesis.

Disclosures
No relevant conflicts of interest to declare.
Rapamycin (Sirolimus) and Rap-536 Increase Red Blood Cell Parameters through Distinct Mechanisms in Wild-Type and Thalassemic Mice
Authors: Acar Melih , Jupelli Madhulika , MacBeth Kyle , Schwickart Martin 
Published: November 2020

Luspatercept, a fusion protein composed of a modified activin receptor type-2B (ActRIIB) and IgG1 Fc, is a novel erythroid maturation agent that has been shown to increase red blood cell (RBC) and hemoglobin (Hb) levels. Luspatercept binds to and sequesters several endogenous transforming growth factor-beta superfamily ligands, thereby diminishing Smad2/3 signaling. RAP-536, the murine analog of luspatercept, has been shown to induce erythroblast maturation and increase RBC, Hb, and hematocrit levels in wild-type (WT) mice and in murine disease models of beta-thalassemia and myelodysplastic syndromes. Previous studies have shown that rapamycin (sirolimus), an mTOR inhibitor, improved anemia in a mouse model of beta-thalassemia by activating the autophagy pathway.
In this study, rapamycin was tested in combination with RAP-536 by treating WT mice and th3/+ mice (a beta-thalassemia disease model; B6.129P2-Hbb-b1tm1Unc Hbb-b2tm1Unc/J) with vehicle, RAP-536 10 mg/kg twice weekly, rapamycin 4 mg/kg daily, or RAP-536 plus rapamycin for 2 weeks.
Single-agent dosing with either RAP-536 or rapamycin increased RBC, Hb, and hematocrit levels significantly compared with vehicle treatment in both WT and th3/+ mice (Figure). The percentage increase in RBC, Hb, and hematocrit levels upon RAP-536 or rapamycin administration was substantially higher in th3/+ mice than in WT mice. Interestingly, much higher and significant increases in RBC and Hb levels in both WT and th3/+ mice, and in hematocrit levels in th3/+ mice, were observed with RAP-536 plus rapamycin, when compared with the single agents. For example, in th3/+ mice, the increase in Hb levels compared with vehicle control was 19.2% with RAP-536 alone, 13.0% with rapamycin alone, and 44.7% with RAP-536 plus rapamycin (Figure). In th3/+ mice, RAP-536 plus rapamycin treatment also significantly reduced spleen enlargement compared with vehicle (P &lt; 0.001). RAP-536 increased and rapamycin decreased overall reticulocyte levels and immature reticulocyte relative percentages in whole reticulocyte populations in the blood of WT mice, suggesting that RAP-536 and rapamycin have different mechanisms of action through which they increase RBC and Hb levels.
Altogether, these preclinical results provide a rationale for combining rapamycin, and potentially other mTOR inhibitors, with luspatercept to treat anemia associated with beta-thalassemia.

Disclosures
Acar: Bristol Myers Squibb: Ended employment in the past 24 months. Jupelli:Bristol Myers Squibb: Current Employment. MacBeth:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Schwickart:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.
DAC+CAG Compared with the Standard 3+7 Regimen for Induction of the Medically Fit Elderly Acute Myeloid Leukemia: An Open-Label, Multicenter, Randomized, Phase III Trial
Authors: Liu Miaomiao , Zhang Yu , Zheng Weiyang , Liu Qifa 
Published: November 2020

Background :Elderly subjects with acute myeloid leukemia have a very poor prognosis,only 40%-60% achieving a complete remission(CR) with intensive chemotherapy. Hypomethylating agents such as decitabine show activities in elderly AML cases. Method:This multicenter, open-label, randomized phase III trial compared the outcomes between decitabine combined with modified CAG regimen (DAC+CAG) and standard daunorubicin or idarubicin plus cytarabine (3+7) for medically fit elderly AML patients.Patients were randomly assigned to the two group in 1:1 ratio approximately. Results:A total of 110 newly diagnosed AML patients selected according to age (range 60-75), performance status (PS≤2), Charlson Comorbidity Index (CCI≤2) were analyzed.CR rate was 58.2% and 61.8% after the first cycle(P=0.963), and 70.9% and 69.1% after two cycles(p=0.780), respectively,in the DAC+CAG group and 3+7 group. There was no statistically difference of ORR after two cycles between the two groups (74.5% vs 76.4%,P=1.000).With a median follow-up of 18 months, the 1-year,3-year OS was 67.4% (95% CI:53.7-81.1%),38.9% (95% CI:16.8-61%) and 55.7%(95% CI:42-69.4%),37.6% (95% CI:20-54.8%) in the DAC+CAG and 3+7 group,respectively(p=0.383).And the 1-year,3-year LFS was 66.8% (95% CI:51.9-81.7%),34.2% (95% CI:22.2-64.2%) and 55.7% (95% CI:40-69.4%),35.8% (95% CI: 19.2-52.4%) in the two groups,respectively(p=0.255). Grade 3 or worse adverse events ,such as neutropenia (38 [69.1%] vs 46 [83.6%]), thrombocytopenia (38 [69.1%] vs 46 [83.6%]),infections(17 [30.9%] vs 25 [45.5%]) and septicemia(3[5.5%] vs 11 [20%]) are more common in 3+7 group than DAC+CAG group.The 8-week cumulative incidence of induction chemotherapy-related mortality(iTRM) were 5.5% and 12.7% (p=0.069) in DAC+CAG and 3+7 groups, respectively.Multivariate analysis revealed that allo-HSCT(p=0.004,HR=0.327,95%CI:0.152-0.703) and after first cycle achieved CR(CR1)(p=0.005,HR=0.348,95%CI:0.166-0.732) were favourable factors for OS,and the latter was also identified as a favourable factor for LFS (p=0.013,HR=0.480,95%CI:0.173-1.331). Conclusion: DAC+CAG regimen showed a similar CR rate and encouraging survival compared with the 3+7 regimen,it seems be a safe and effective regimen for medically fit older patients with AML.
Keywords:Acute myeloid leukemia, Elderly, DAC+CAG regimen, 3+7 regimen,medically fit patients

Disclosures
No relevant conflicts of interest to declare.
Is Absolute Lymphocyte Count at Time of Diagnosis a Predictor of Overall Survival in Non-Hodgkin Lymphoma Patients?
Authors: Zatreh Mallak , Kaur Anahat , Albawaliz Anas , Bulchandani Sheetal , Khan Ghazal 
Published: November 2020

Introduction:The prognostic significance of absolute lymphocyte count (ALC) has been an area of debate in non-Hodgkin-lymphoma (NHL). Several studies have reported that lymphocyte count during and after chemotherapy independently predict outcome in patients with acute myelocytic lymphoma (AML), follicular lymphoma and diffuse large B-cell lymphoma (DLBCL). Furthermore, lymphocytopenia is a poor prognostic marker in initial staging of NHL and in relapsed DLBCL. Therefore, we aimed to investigate whether ALC at time of diagnosis is an independent predictor of overall survival (OS) in NHL.
Methods:We retrospectively reviewed patients with aggressive NHL who were seen at hospitals affiliated with Saint Luke's Health System from January 2000 to December 2017 with at least 2 year longitudinal follow up after diagnosis. We retrieved 447 patients with histopathological diagnosis of DLBCL, Burkitt's Lymphoma, Follicular Lymphoma Grade IIIB, primary Effusion Lymphoma, B-cell Lymphoma unclassifiable, and high-grade B cell lymphoma. Through chart review we determined pathological and clinical characteristics of these patients, calculated the ALC at time of diagnosis, studied the treatment patterns, response to therapy and survival in our center. ALC at time of diagnosis was obtained on 358 patients based on data availability.
Results:A multivariate analysis was conducted to see if ALC at time of diagnosis is a predictor of OS by correcting for age at diagnosis, gender, race, stage at diagnosis, international prognostic index (IPI), central nervous system involvement, histopathological diagnosis and type of chemotherapy. ALC at diagnosis after controlling all variables was not a significant predictor of OS (P: 0.7126).
Conclusion:We found that ALC at time of diagnosis did not have a statistically significant effect on OS. We believe that prospective large-scale studies are needed to determine whether ALC at time of diagnosis affects OS in NHL patients.
Table

Disclosures
No relevant conflicts of interest to declare.
Plasma Exchange for COVID-19 Thrombo-Inflammatory Disease
Authors: Thomas Mari , Arulkumaran Nishkantha , Brearley David , Alwan Ferras , Singh Deepak , Lunn Michael P , Welch Anna , Clark Samuel , Raith Eamon , Reddy Ugan , Low Ryan , Leverett David , Singer Mervyn , Scully Marie 
Published: November 2020

Introduction
Severe COVID-19 disease is associated with a hyperinflammatory, pro-thrombotic state and a high mortality. A thrombotic phenotype rather than a coagulopathy is suggested and we undertook plasma exchange to determine its effects on organ function and thrombo-inflammatory markers.
Methods
Plasma exchange was carried out in seven critically ill adults with severe COVID-19 respiratory failure (PaO2:FiO2 ratio &lt;200 mmHg) requiring invasive or non-invasive ventilatory support and elevated thrombo-inflammatory markers (LDH&gt;800 IU/L and D dimer&gt;1000 µg/L (or doubling from baseline). Patients received a daily single volume 3 litre plasma exchange for a minimum of five days. No other immunomodulatory medications were initiated during this period. Effects on organ function, thrombo-inflammatory markers and complications were monitored. Seven patients matched for age and baseline biochemistry were a comparator group.
Results
Coagulation screening revealed no evidence of coagulopathy. However, von Willebrand Factor (VWF) activity, antigen and VWF antigen:ADAMTS13 ratio, Factor VIII and D-dimers were all elevated. Following five days of plasma exchange, plasma levels of all the above, and ferritin levels, were significantly reduced (p&lt;0.05, Figure 1) while lymphocyte count normalized (p&lt;0.05). The PaO2:FiO2 ratio increased from a median(IQR) of 11.6 (10.8- 19.7) kPa to 18.1 (16.0-25.9) kPa (p&lt;0.05). Similar improvements were not observed in controls. Acute kidney injury (AKI) occurred among 5 patients in the control arm but not in patients who underwent plasma exchange.
Conclusion
Plasma exchange was associated with an improvement in oxygenation, decreased incidence of AKI, normalisation of lymphocytes and reduction in circulating thrombo-inflammatory markers including D-Dimer and VWF Ag:ADAMTS13 ratio.

Disclosures
Thomas: Ablynx: Honoraria, Other: Advisory Board; Bayer: Honoraria, Speakers Bureau; Sanofi: Honoraria, Other: Advisory Board. Scully:Takeda: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Shire/Takeda: Other: Advisory Board, Research Funding, Speakers Bureau; Novartis: Other: Advisory Board, Speakers Bureau; Takeda: Speakers Bureau; Ablynx/Sanofi: Consultancy, Other: Advisory Board, Speakers Bureau.
In Hemophilia Α Plasma Treated with Emicizumab, Factor IXa in Activated Prothrombin Complex Concentrates Is the Dominant Contributor to Enhanced Thrombin Generation
Authors: Monroe Dougald , Ezban Mirella , Hoffman Maureane 
Published: November 2020

Background. Recently a novel bifunctional antibody (emicizumab) that binds both factor IXa and factor X has been used to treat hemophilia A. Emicizumab has proven remarkably effective as a prophylactic treatment for hemophilia A; however there are patients that still experience bleeding. An approach to treating this bleeding in hemophilia A patients with inhibitors is to give an activated prothrombin complex concentrate (APCC; FEIBA) (disfavored in NHF MASAC #255). APCC contains a number of coaguation factors including prothrombin, factor X (FX), and factor IX (FIX). APCC also contains activated factor X (FXa) and factor IX (FIXa). Previous work has shown that when APCCs are added to hemophilia A plasma containing emicizumab there is a significant increase in thrombin generation [J Thromb Haemost 2018;16:1580-1591]. The goal of this work was to study thrombin generation in hemophilia A plasma with emicizumab and to examine the role of the zymogen and activated components of an APCC in the increased thrombin generation.
Methods. In hemophilia A plasma, thrombin generation assays were done using 100 µM lipid and 420 µM Z-Gly-Gly-Arg-AMC with or without emicizumab at 55 µg/mL which is the clinical steady state level. The reactions were initiated with low (1 pM) tissue factor (TF). The components of APCC were studied at concentrations that should mimic the levels seen in the plasma of a patient given a dose of 50 U/kg: prothrombin 1800 nM; FX 130 nM; FIX 90 nM; and FIXa 0.4 nM.
Results. When initiated with low TF, hemophilia A plasma alone had essentially no thrombin generation. As expected, adding emicizumab enhanced thrombin generation. The addition of zymogen coagulation factors, prothrombin, FIX, and FX, separately or together gave a small increase in thrombin generation. However, addition of FIXa to emicizumab gave a large increase in peak thrombin. In hemophilia A plasma with emicizumab and FIXa, addition of prothrombin further increased thrombin generation and specifically increased the peak level of thrombin. Further addition of FX or FIX, separately or together, only minimally increased thrombin generation.
Discussion. The strong contribution of factor IXa to the effects of APCCs on thrombin generation in hemophilia A plasma depends on the presence of emicizumab. In the absence of emicizumab, a study of the individual components of APCC showed that a combination of FXa and prothrombin at levels found in APCCs had the major effect on thrombin generation [Haemophilia. 2016;22:615-24]. That study found that FIXa did not increase thrombin generation. However, in the presence of emicizumab, despite the weak solution phase affinity of the bifunctional antibody for FIXa, small amounts of FIXa were the most significant contributor to thrombin generation.

Disclosures
Monroe: Novo Nordisk:Research Funding.Ezban:Novo Nordisk:Current Employment.Hoffman:Novo Nordisk:Research Funding.