bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD38 x ICAM1 Bispecific Antibody Is a Novel Approach for Treating Multiple Myeloma and Lymphoma
Authors: Chen Xiaocheng , Wong Oi Kwan , Post Leonard 
Published: November 2021

Abstract
Targeting cluster of differentiation 38 (CD38) with monoclonal antibodies has resulted in outstanding responses in patients with multiple myeloma (MM). However, a significant portion of patients failed to respond and nearly all patients eventually relapsed. Furthermore, daratumumab, an anti-CD38 antibody, only showed limited monotherapy activity in relapsed/refractory Non-Hodgkin lymphoma (NHL) patients in a phase 2 study. One of the mechanisms of resistance has been partially attributed to lower CD38 expression. Intercellular adhesion molecule 1 (ICAM1), an immunoglobulin (Ig)-like cell adhesion molecule, is highly expressed in multiple myeloma and lymphoma. Antibody against ICAM1, bersanlimab (BI505, BioInvent), was well-tolerated, but only showed limited clinical efficacy in MM patients. Here, we generated bispecific CD38 x ICAM1 antibody to target ICAM1 + tumor types with low to medium CD38 expression. RNA sequencing (RNAseq) results from the Cancer Cell Line Encyclopedia (CCLE) database showed that ICAM1 is highly expressed on myeloma and lymphoma cell lines. ICAM1 expression levels for selected myeloma and lymphoma cell lines were then validated using flow cytometry. The CD38 x ICAM1 bispecific antibody was constructed by paring a novel CD38 antibody and a novel ICAM1 antibody through an asymmetric three chain knob-into-hole format. The bispecific antibody showed potent in vitro antibody-dependent cellular cytotoxicity (ADCC) activities on ICAM1 + tumor cells with medium to low CD38 levels, where daratumumab has low or minimal effect. The bispecific antibody also showed potent in vitro antibody-dependent cellular phagocytosis (ADCP) activities on cell lines with a range of CD38 expression. The CD38 x ICAM1 bispecific antibody further demonstrated potent tumor inhibition activities in in vivo myeloma and lymphoma cell line-derived xenograft (CDX) models, including cell lines with low to medium CD38 expression. We then evaluated CD38 and ICAM1 expressions in lymphoma patient-derived xenograft (PDX) samples by RNAseq. Among the 37 PDX samples, 27 of them showed ICAM1 expression above 2 5 fragments per kilobase of transcript per million map reads (FPKM). On the contrary, there is a wide range of CD38 expression levels with only 6 samples having CD38 expression above 2 5 FPKM. The ICAM1 and CD38 expressions in the selected PDX samples were further validated with IHC staining. Most importantly, the CD38 x ICAM1 bispecific antibody showed complete tumor inhibition in a rituximab-resistant lymphoma PDX model, whereas daratumumab only showed minimal efficacy. In conclusion, the CD38 x ICAM1 bispecific antibody demonstrated improved efficacy and specificity toward CD38 + and ICAM1 + tumor cells and represents a novel approach for treating multiple myeloma and lymphoma.

Disclosures
No relevant conflicts of interest to declare.
Trial in Progress: Real-World Safety and Effectiveness of Brentuximab Vedotin in Adults with CD30+ Lymphoma in China
Authors: Xu Pengpeng , Cai Mingci , Zhang Wendy , Zhao Wei Li 
Published: November 2021

Abstract

Background: Clinical trials have demonstrated the effectiveness of the CD30-targeted antibody-drug conjugate brentuximab vedotin (BV) for the treatment of classical Hodgkin lymphoma (HL) and non-Hodgkin lymphoma(e.g. ALCL, PTCL-NOS, AITL, CTCL and etc.). While clinical trials are critical for establishing efficacy, collection of real-world data outside of the controlled trial setting is important to evaluate how interventions are applied and assess the effectiveness of new treatments in routine clinical practice. Inclusion criteria are often rather restrictive compared with the patient populations seen by physicians in daily practice. There are limited real-world data related to treatment with BV in China. Our study aims to obtain timely real-world knowledge in terms of safety and effectiveness of BV in CD30+ lymphoma patients in China.
Study Design and Methods: The study (NCT04837222) is a real-world, prospective, multicenter study to evaluate the safety and effectiveness of BV in patients with CD30+ lymphoma in China. Consecutive CD30+ lymphoma patients treated with BV as a part of standard clinical practice will be enrolled. Key inclusion criteria includes adult patients undergoing treatment with BV or to be received with BV, patient/legal guardian must be able to read, understand, and sign the Informed Consent Form, CD30+ lymphoma by INV (any CD30 expression). Exclusion criteria includes patient who currently participates in or with plan to participate in any interventional clinical trial, any other reason that, in the investigator's opinion, makes the patient unsuitable to participate in this study. As CD30+ lymphoma is not a common disease and the affordability of novel treatment is limited, 1000 patients with CD30+ lymphoma will be recruited from almost 30 hematology centers. The physician will determine the treatment regimen, as well as the frequency of laboratory and clinical assessment according to her/his routine practice. All patients will be followed up per routine clinical practice and data will be documented at baseline/3/6/9/12/18/24 months unless withdrawal of Informed Consent, death or loss of follow-up, whichever comes first. Loss to follow-up will be minimized through active contact with participating patients thereafter to ensure almost all clinically relevant outcomes will be captured. The primary endpoint is serious adverse events. Secondary endpoints include adverse events, adverse drug reaction, dose adjustment, characteristics of patients receiving BV, use of BV, number of BV cycles administered, disease characteristics, time to next treatment, overall response rate, duration of response, progression free survival rate, overall survival rate, quality of life and cost-effectiveness ratio. Descriptive analysis will be performed for data analysis.

Disclosures
Zhang: Takeda Pharmaceuticals: Current Employment.
Rivaroxaban or Placebo for Extended Antithrombotic Prophylaxis after Laparoscopic Surgery for Colorectal Cancer. the PRO-LAPS II Study
Authors: Becattini Cecilia , Pace Ugo , Pirozzi Felice , Avruscio Giampiero , Donini Annibale , Rondelli Fabio , Visonà Adriana , Boncompagni Michela , De Prizio Marco , Chiari Damiano , Muratore Andrea , Guerra Francesco , De Luca Raffaele , Portale Giuseppe , Milone Marco , Righini Marc , Castagnoli Giampaolo , Persiani Roberto , Martellucci Jacopo , Frasson Stefania , Dentali Francesco , Delrio Paolo , Sciuto Antonio , Gussoni Gualberto , Agnelli Giancarlo 
Published: November 2021

Abstract
Background The clinical benefit of extending prophylaxis for venous thromboembolism (VTE) beyond hospital discharge after laparoscopic surgery for cancer is unclear. The efficacy and safety of thromboprophylaxis with direct oral anticoagulants in cancer surgery is unexplored.
Methods PROLAPS II is an investigator-initiated, prospective, randomized, double-blind study aimed at assessing the efficacy and safety of extended prophylaxis with rivaroxaban compared with placebo after laparoscopic surgery for colorectal cancer (NCT03055026). All patients received antithrombotic prophylaxis with low molecular-weight heparin for 7±2 days and were then randomized to receive rivaroxaban (10 mg once daily) or placebo for the following 3 weeks (up to day 28±2 from surgery).
The primary study outcome was the composite of symptomatic objectively confirmed VTE, asymptomatic ultrasonography-detected deep vein thrombosis (DVT) or VTE-related death within 28±2 days from laparoscopic surgery. The primary safety outcome was ISTH-defined major bleeding. By assuming an 8% incidence of primary study outcome in patients randomized to placebo and a 60% reduction with rivaroxaban, 323 patients per group were necessary to show the superiority of rivaroxaban.
Results. Patient recruitment in PROLAPS II study was preliminary closed in June 7 th, 2021 due to study drug expiry, after the inclusion of 577 patients. The main patients features are reported in the Table. Study results will be available after the last study patient will complete the 90-day follow-up (scheduled on September 7th, 2021) and will be ready to be presented at the ASH 2021 Congress.
Conclusion PROLAPS II is the first study with an oral anti-Xa agent in cancer surgery. The study has the potential to improve clinical practice by assessing the clinical benefit of extending prophylaxis after laparoscopic surgery for colorectal cancer.
Figure 1 Figure 1.

Disclosures
Becattini: Bayer HealthCare: Honoraria; Daiichi Sankyo: Honoraria; Bristol Myers Squibb: Honoraria. Dentali: Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Boehringer: Honoraria; Alfa Sigma: Honoraria. Agnelli: Bayer HealthCare: Honoraria; Daiichi Sankyo: Honoraria; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria.
Realgar Indigo Formula Plus ATRA As Postremission Treatment in an Rral and Chemo-Free Model for High-Risk Acute Promyelocytic Leukemia Patients: A Prospective, Multicenter, Phase II Study
Authors: Zhu Hong-hu , Ma Ya-fang , Chen Suning , Lu Ying , Huang Jiang , Wang Huai-Yu , Xu Xiaohua , Xie Bing-Shou , Lou Yinjun , Jin Jie 
Published: November 2021

Abstract

Background:
Low-risk patients with acute promyelocytic leukemia (APL) can be cured using only ATRA and arsenic trioxide (ATO), without chemotherapy(Lo-Coco F, et al. NEJM 2013) .Our group simplified the protocol by replacing iv ATO with oral arsenic, referred to as RIF, allowing for outpatient, oral and chemotherapy-free treatment for an increasing number of APL patients (Zhu HH, et al. NEJM 2014; 371:2239-41;Zhu HH, et al. Lancet Oncol 2018;19:871-879; Zhu HH, et al. Blood 2019;134:597-605). We also reported a promising single-center results using chemo-free postremission treatment for high-risk APL patients (Zhu HH, Blood 2018;131:2987-2989), which need to be confirmed in a well designed multi-center trial.
Objective:
To evaluate the efficacy of safety Realgar indigo formula plus retinoic acid as postremission treatment in an oral and chemo-free model for high-risk APL patients .
Design, setting and participants:
a prospective, multicenter, single-arm, phase II clinical trial conducted in the First Affiliated Hospital, Zhejiang University College of Medicine, China. Eligible patients (&gt;18 years old) with newly diagnosed APL and achieved complete remission(CR) were enrolled since May 2019, with final follow-up in July 31,2021.
Interventions:
The consolidation therapy included realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and4-week-off regimen for 4 cycles and ATRA (25 mg/m 2 daily in anoral divided dose) in a 2-week-on and 2-week-off regimen for 7 cycles. The primary endpoint was the 2-year DFS. Secondary endpoints included complete molecular remission (CMR) defined as the absence of detectable PML-RARA transcripts., event-free survival (EFS), OS, and safety.
Main outcomes and measures:
38 eligible patients were enrolled including 18 males and 20 females and the median age was 41 years old (18-77 years). The median of WBC count is 25.39（10.2-113.9）×109/L[ &gt;50×10 9/L n=10; (20-50)×10 9/L n=14，(10-20)×10 9/L n=14].All the patients achieved CMR during post-remission treatment phase (7 months). Until now, no molecular, hematologic recurrence,and central nervous system leukemia has happened with median follow-up of 13 months. What's more, this chemotherapy-free, completely oral regimen was well tolerated.
C onclusions:
These exciting results proved that RIF plus retinoic acid as postremission treatment of high-risk APL was effective, safe and convenient. The study is ongoing, and the effective of this regimen need to be evaluated by more patients and longer time.
Figure 1. The overall survival(OS) and disease-free survival (DFS) of high-risk APL patients.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Rusfertide (PTG-300), a Hepcidin Mimetic, Maintains Liver Iron Concentration in the Absence of Phlebotomies in Patients with Hereditary Hemochromatosis
Authors: Kowdley Kris V , Modi Nishit B , Valone Frank , Priego Victor M. , Ferris Christopher , Cole Frank , Gupta Suneel K 
Published: November 2021

Abstract

Introduction: Patients with hereditary hemochromatosis (HH) require continued phlebotomies to limit end-organ damage. Approximately 25% of patients in maintenance felt receiving phlebotomies was "inconvenient" or "very inconvenient" (Brisott et al, 2011). Patient compliance with phlebotomies generally declines with time (Hicken et al, 2003), and therapeutic phlebotomies may not be medically suitable for some HH patients. Rusfertide, a peptide mimetic of hepcidin, is an effective regulator of iron distribution and utilization that has demonstrated control of iron in an animal model of HH.
Methods: We conducted an open-label, dose-finding efficacy study that investigated subcutaneous rusfertide in HH patients on a stable phlebotomy regimen of 0.25 to 1 phlebotomy per month for at least 6 months. Patients with clinical laboratory abnormalities and those receiving iron chelation therapy or erythrocytapheresis were excluded. Subjects received individually titrated rusfertide doses once or twice a week to maintain transferrin saturation (TSAT) below 45% and were followed for 6 months. Study measures included TSAT, serum iron, transferrin and ferritin, liver iron concentration (LIC) measured by MRI, and adverse events (AEs).
Results: Sixteen subjects (10 male/6 female) were enrolled. Mean age and weight were 62.5 years and 88.1 kg, respectively. LIC values were maintained at pre-study levels, with minimal use of phlebotomies during the duration of the study (Figure 1A). Average pre-study phlebotomy rate was 0.27 phlebotomies/month compared to 0.03 phlebotomies/month during the study (p&lt;0.0001; Figure 1B). There was a dose- and concentration-dependent decrease in serum iron and TSAT (Figure 2A and 2B). Transferrin levels were relatively constant over the course of the study. There were no notable changes in hematological parameters such as hematocrit, erythrocytes, leucocytes, or platelets. Rusfertide was generally well tolerated. Adverse events reported in 2 or more subjects included diarrhea, fatigue, injection site reactions (erythema, induration, pain, pruritis), dizziness, and headache.
Conclusions: Rusfertide demonstrated a pharmacodynamic effect in reducing TSAT and serum iron, with corresponding significant reduction in the number of phlebotomies, and with LIC maintained at pre-study levels with minimal use of phlebotomies. These data indicate rusfertide was well tolerated in patients with HH and controls LIC, supporting development of rusfertide as a potential treatment for HH.
Figure 1 Figure 1.

Disclosures
Kowdley: PTG: Consultancy, Research Funding. Modi: Protagonist Therapeutics: Current Employment. Valone: Protagonist Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gupta: Protagonist Therapeutics: Current Employment.
Elucidating the Characteristics of Two Tumor Cell Populations in Small Cell Variant of Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma
Authors: Noguchi Kazuhiro , Ikawa Yasuhiro , Takenaka Mika , Sakai Yuta , Fujiki Toshihiro , Kuroda Rie , Wada Taizo 
Published: November 2021

Abstract
The small cell variant of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (SC-ALCL) is a subtype defined as comprising two distinct tumor cell populations in immunohistochemistry: small cells staining negative or weakly positive for ALK and CD30 protein; and large cells staining strongly positive for those proteins. Although the constitution of these two different cell populations might contribute to the poor prognosis, detailed characterization of each population by molecular-based approaches has not been done due to the difficulty of cell separation from solid tumor sample. In this paper, we have analyzed the characterization of each tumor cell population using the patient sample from SC-ALCL leukemic phase obtained from peripheral blood by molecular-based approaches. Flow cytometric analysis revealed two distinct abnormal populations. The major population comprising 74% of total leukocytes was positive for CD3 and CD8, and negative for CD4, CD5, CD25 and CD30. The minor population comprising 5% of total leukocytes was positive for CD25, CD30, CD11b and CD13. Fluorescent in situ hybridization with ALK break-apart probes and RT-PCR analysis confirmed that most of the cells including both populations were rearranged with NPM-ALK gene. To elucidate the cause underlying the distinct levels of ALK protein expression in each population, we separated those tumor cells by CD30-PE antibody and a magnetic bead separation kit, extracted DNA and RNA from each population, and compared NPM-ALK mRNA expression levels by droplet digital polymerase chain reaction. The expression level of NPM-ALK mRNA in the CD30-negative population was ten-fold less than that in the CD30-positive population (Table). This result indicated that the two tumor cell populations expressed the distinct level of NPM-ALK mRNA, although both populations possessed NPM-ALK fusion gene. To assess the effectiveness of various chemotherapies in each tumor cell population, we monitored each population in peripheral blood by flow cytometric analysis (small cell; CD30-5-8+, large cell; CD30+) over time. Intriguingly, CD30-negative population behaved as chemo-resistant cells in clinical course, however alectinib, a second-generation ALK-inhibitor, eradicated both populations inducing first complete remission. This study revealed two definitive features regarding the small CD30-negative population of SC-ALCL, with a lower expression level of NPM-ALK mRNA transcripts and chemoresistance. The cause of distinct ALK staining levels in immunohistochemistry was revealed depending on the distinct expression level of NPM-ALK mRNA transcripts. Finally, since both populations were sensitive to ALK-inhibitor, early administration of ALK-inhibitor might be the reasonable option for SC-ALCL.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
An in Depth Analysis of Factors Contributing to Diagnostic Delay in Myeloma: A Retrospective UK Study of Patients Journey from Primary Care to Specialist Secondary Care
Authors: Hossain Md Imran , Hampson Peter , Nowell Craig , Khan Shamshad , Sen Ranjoy , Sundararaman Sharadha , Adiyodi Jagdish , Basu Supratik 
Published: November 2021

Abstract
Introduction
Patients with Multiple Myeloma (MM) often have a significant delay between onset of symptoms and diagnosis of disease. As a result, a significant number of patients present via emergency routes with severe co-morbidities which affect survival rates. Timely diagnosis relies on the early recognition of symptoms and blood test results which may indicate disease.
Methods
We examined the medical records of 142 newly diagnosed MM patients (121 intact immunoglobulin and 21 light chains) across 2 UK Hospitals. Patients included had not previously been diagnosed with a plasma cell dyscrasia, including Monoclonal Gammopathy of Undetermined Significance (MGUS). Clinical symptoms and blood test results were examined from the time of initial presentation to the healthcare system with symptoms indicative of MM, to the point of diagnosis in order to highlight patterns of symptoms and blood tests results which may give an early indication of disease. Blood tests results recorded included globulin, calcium, creatinine, erythroid sedimentation rate and haemoglobin. Time to diagnosis from presentation with symptoms indicative of MM was also measured as well as the patient pathway from the point of presentation to the point of diagnosis.
Results
The median time to diagnosis from initial presentation was 77 days (range 0 - 12,986). Initial presentation was most commonly via primary care (58.1%). Urgent secondary care presentation was documented in 28.5% which included acute medical unit (15.6%), the emergency department (7.1%), and other secondary care specialities (5.7%) respectively. Multiple GP visits were common prior to haematology referral with a median of 3 visits (range 1 - 40). Initial presenting symptoms varied, but of those with data recorded (n=107) back/bone pain was the most common (58.2%) followed by anaemia (18.7%), fracture (7.5%), recurrent infection (7.5%) and renal impairment (3.7%) respectively. Interestingly, analysis of evaluable blood test results revealed a raised globulin was most often evident prior to diagnosis with 58% of patients recording an abnormal globulin a median of 140 days (range 3 - 4297) prior to diagnosis of disease.
Conclusions
Multiple GP visits prior to establishing a diagnosis of myeloma is very common. Inclusion of abnormal globulin to reflex electrophoresis request and serum free light chain assay may serve as a useful trigger for investigation when interpreted alongside presenting symptoms and other blood test results. Increased awareness of myeloma warning signs in primary care may reduce diagnostic delay and avoid presentation with severe co-morbidities in emergency settings.

Disclosures
No relevant conflicts of interest to declare.