Decreased Lymphocyte Count Research Articles

A phase Ib study of endogenous T cell therapy using SLC45A2-specific CD8 T cells for patients with metastatic uveal melanoma.

9588 Background: Overall survival (OS) for patients (pts) with advanced uveal melanoma (UM) is poor compared with outcomes in cutaneous melanoma. Roughly half of all pts with UM will develop distant metastatic disease despite effective treatment of the primary tumor. Antigen-specific endogenous T cells (ETC) can be expanded and infused successfully in pts with many different types of cancer. Our group has identified epitopes of SLC45A2, a melanosomal transport protein, which are highly expressed in UM and are present at low levels in normal melanocytes. In vitro, we showed that cytotoxic T cells against SLC45A2 were able to kill HLA-matched UM cell lines. In vivo, we hypothesize that infused ETC can traffic to tumor sites. Methods: Between 6/2017 and 12/2022, we conducted a single-center, IRB-approved, first-in-human phase 1b dose escalation study of ETC targeting SLC45A2 in pts with metastatic UM (NCT03068624). Eligible pts with metastatic UM who express HLA-A*02:01 or A*24:02 underwent apheresis to collect peripheral T cells which were then selected and expanded (Turnstile 1). For Turnstile 2, conditioning with low-dose cyclophosphamide (300 mg/m2) occurred on Day -2. For pts in the radiation cohort, radiation occurred between Day -7 and Day -1. Infusion of ETC was done via hepatic arterial or central venous catheter on Day 0 followed by low dose subcutaneous interleukin-2 (IL-2) twice daily for 14 days +/- ipilimumab. The study utilized a 3+3 design with a starting dose level of 3.3 x 109 cells/m2 of ETC alone. The primary objective was to evaluate the safety and tolerability of infusing ETC targeting SLC45A2. Secondary objectives were to evaluate the in vivo persistence and anti-tumor efficacy of this regimen. Results: With a median age of 58 years (30-77), 34 pts were enrolled, 16 (47%) men and 18 (53%) women. 33 (97%) pts underwent apheresis and 11 (32%) received infusion of ETC. One dose limiting toxicity (DLT) thought to be unrelated to treatment or underlying cancer (cardiac disorder Grade 5) occurred at the starting dose level with no additional DLTs. The maximum tolerated dose was established as 1 x 1010 cells/m2. The most common treatment-related grade 3 and 4 toxicities were lymphocyte count decrease 9 (82%), hyponatremia 1 (9%), and hypophosphatemia 1 (9%). Per immune-related response criteria (irRC), 4 (36%) pts had stable disease (SD), 6 (55%) had progression of disease (PD), and 1 (9%) was not evaluable for best response. Median overall survival (OS) was 8.9 weeks (wks). OS was 91% at 4 wks, 55% at 8 wks and 46% at 13 wks. Median progression-free survival was 5.9 wks. In the 4 patients with stable disease, the median duration of SD was 5.7 months. Conclusions: ETC targeting SLC45A2 is safe and well-tolerated in pts with metastatic UM. Further analyses are underway to evaluate T cell trafficking and persistence. Clinical trial information: NCT03068624 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: Cancer is a recognized condition of secondary immunosuppression. Lymphoma patients often show a decrease in absolute lymphocyte counts and in peripheral blood gamma-globulin levels. However, less is known about how NK cells are altered in lymphoma patients. The aim of this study was to evaluate the patterns of circulating NK cell dysfunction in lymphoma patients. Methods: We performed a cross-sectional study of patients with a recent diagnosis of nodal lymphoproliferative disorder. Patients with active anticancer treatment or steroid use were excluded. Peripheral blood samples in EDTA were analyzed by multicolor flow cytometry. A custom panel of 30 markers was applied to all samples to test for major subpopulations, maturation, and functional markers. Results were compared to healthy controls. Clinical data were obtained from the electronic database. This study was approved by the institutional IRB and Clinical Ethics Committee. Results: A total of 30 patients were examined between October 2021 and November 2022. The median age was 62 years (range 15–88) and 45.7% were female (16). Patients had the following subtypes: large B-cell lymphoma (LBCL; 9), follicular lymphoma (FL; 9), Hodgkin lymphoma (HL; 5), mantle cell lymphoma (MCL; 4), marginal zone lymphoma (MZL; 2), Waldenström macroglobulinemia (WM; 1). Most patients had advanced stage disease (20). Compared to healthy controls (n = 10), lymphoma patients showed a significant decrease in absolute NK cell counts (ANKC, 319.7 vs. 131.1 cells/mm3; p < 0.0001). MCL patients had the lowest ANKC (68.8) and Hodgkin patients the highest (165.6). Advanced stage disease correlated with lower ANKC compared to localized disease (99.85 vs. 148.9; p = ns). The pattern of maturation was altered in lymphoma patients compared to controls (p = 0.0092). Patients had a higher proportion of immature CD56-bright NK cells (4.97% vs. 2.88%) and lower levels of CD16 expression in the mature CD56-dim subpopulation (68.12% vs. 85.94%). Lymphoma patients also showed dysfunctional expression of receptors and activation markers (Figure). There was a significant increase in the levels of FAS-L, IFNg, CD49b, CD57, CD96, and CD107a, while the levels of TIGIT and NKG2D were significantly decreased. Differences in the expression of immune checkpoints (PD-1, LAG-3, TIM-3), as well as additional activating, inhibitory, and chemokine receptors were not significant. 22 of 30 patients (73.3%) achieved a complete response. All patients with ANKC above 135 cells/mm3 at diagnosis achieved sustained complete remission. The research was funded by: Fondecyt 11200805 Clínica Alemana de Santiago ID1025 Keyword: diagnostic and prognostic biomarkers No conflicts of interests pertinent to the abstract.

Temsirolimus (T) in patients (pts) with solid tumors with PIK3CA mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

3117 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in cohorts of pts with breast cancer (BC) and other solid tumors with PIK3CA mut treated with T are reported. Methods: Eligible pts had BC or other solid tumors, measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. After antihistamine pre-tx, 25 mg of T was infused over 30-60 minutes once weekly until disease progression. Primary endpoint was disease control (DC), defined as complete or partial (PR) response, or stable disease of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. For the BC cohort, Simon’s optimal 2-stage design with null DC rate of 15% vs. 35% (power=0.85, α=0.10) was used with stage 1 (n=10) stopping for futility if &lt; 2/10 pts had DC. Low accruing histology-specific cohorts with PIK3CA and T tx were collapsed into 1 histology-pooled (HP) cohort. For the HP cohort, the hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test with α=0.10. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: 12 pts with PIK3CA mut with BC and 29 pts with PIK3CA mut in other solid tumors (across 9 tumor types) were enrolled. 2 pts (1 in each cohort) were found to be ineligible after enrolling and were not included in efficacy analyses. Demographics and outcomes for each cohort are shown. At the end of stage 1 in the BC cohort, 1 PR was observed for DC and OR rates of 9%; the cohort was closed for futility (p=0.83). For the HP cohort, 3 PR and 5 SD16+ were observed for DC rate of 29% (p=0.049) and OR rate of 11%; the null hypothesis was rejected. Cancer types in pts with OR or SD16+ included cervical, ovarian and head/neck; most common muts were H1047R/L (3), E545K (2) and E542K (2). 1 pt with ovarian and H1047R has ongoing PR at 86 wks. 11/41 pts had ≥1 tx-related grade 3-4 adverse or serious adverse event, including anemia, headache, hyperglycemia, hypertension, hypertriglyceridemia, mucositis oral, lymphocyte, neutrophil or platelet count decrease, pneumonitis, and sepsis. Conclusions: Although T does not appear to have antitumor activity in pts with BC with PIK3CA mut, it does show antitumor activity in pts with other solid tumors with PIK3CA mut and warrants further study. Clinical trial information: NCT02693535 . [Table: see text]

Fatal dermatophytic pseudomycetoma in a patient with non-HIV CD4 lymphocytopenia

ABSTRACT Dermatophytic pseudomycetoma is a rare invasive infection, involving both immunocompetent and immunocompromised individuals. Since the discovery of inherited immune disorders such as the impairment of CARD9 gene, extended dermatophyte infections are mostly ascribed to any of these host factors. This study is to present and explore the potential causes in a fatal dermatophytic pseudomycetoma patient. We present a chronic and deep pseudomycetoma caused by the common dermatophyte Microsporum canis which ultimately led to the death of the patient. Mycological examination, genetic studies and host immune responses against fungi were performed to explore the potential factors. The patient had decreased lymphocyte counts with significantly reduced CD4+ T cells, although all currently known genetic parameters proved to be normal. Through functional studies, we demonstrated that peripheral blood mononuclear cells from the patient showed severe impairment of adaptive cytokine production upon fungus-specific stimulation, whereas innate immune responses were partially defective. This is, to our knowledge, the first report of fatal dermatophytic pseudomycetoma in a patient with non-HIV CD4 lymphocytopenia, which highlights the importance of screening for immune deficiencies in patients with deep dermatophytosis.

Acute Kidney Injury in Hospitalized Patients with COVID-19: Risk Factors and Serum Biomarkers.

AKI is one of the COVID-19 complications with high prognostic significance. In our research, we studied the prognostic role of several biomarkers that could help us understand AKI pathogenesis in patients with COVID-19. We evaluated the medical data of 500 patients hospitalized with COVID-19 in Tareev Clinic from 5 October 2020 to 1 March 2022. The diagnosis of COVID-19 was confirmed with positive RNA PCR in nasopharyngeal swabs and/or typical radiological findings on CT scans. Kidney function was assessed in accordance with KDIGO criteria. In the selected 89 patients, we evaluated serum levels of angiopoetin-1, KIM-1, MAC, and neutrophil elastase 2 and their prognostic significance. The incidence of AKI in our study was 38%. The main risk factors for kidney injury were male sex, cardiovascular diseases, and chronic kidney disease. High serum angiopoetin-1 levels and a decrease in blood lymphocyte count and fibrinogen level also increased the risk of AKI. AKI is an independent risk factor for death in patients with COVID-19. We propose the prognostic model of AKI development, which includes the combination of serum levels of angiopoetin-1 and KIM-1 on admission. Our model can help to prevent AKI development in patients with coronavirus disease.

Abstract CT098: A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced IDH-mutant cholangiocarcinoma and other solid tumors

Abstract Background: Isocitrate dehydrogenase 1/2 (IDH1/2) is mutated in a subset of cholangiocarcinoma (CCA), gliomas, and other solid tumors. LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 study of oral LY3410738 in patients (pts) with IDH1/2m CCA, and IDH1m glioma or other solid tumors. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in advanced IDHm CCA and other solid tumors (NCT04521686). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 80 pts including 42 with CCA (33 IDH1m, 9 IDH2m), 27 with glioma (IDH1m), and 11 other tumor types (IDH1m) received LY3410738 dosed at 25-600 mg QD or 300 mg BID. Pts were median 52 years of age (range, 23-80) with a median of 2 prior therapies (range, 1-7). 19% of CCA pts had received prior IDH1 inhibitor. Median time on treatment was 3.7 months (range, 0.1-19). No DLTs or treatment related deaths were observed; the MTD was not reached. Treatment emergent adverse events (TEAEs) ≥15% included nausea (35%), vomiting (21%), and decreased appetite (19%) and were mostly grade 1-2. Most frequent grade ≥3 TEAEs &amp;gt;2% were anemia (4%), cholangitis (3%), headache (3%), decreased lymphocyte count (3%), and hyponatremia (3%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels, including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Among the 42 pts with R/R CCA, the best response included 1 PR and 22 SD. Of the 22 glioma pts with contrast enhancing tumors, best response included 3 PR and 9 SD. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1/2m advanced solid tumors. Consistent with the expectations for IDH inhibitor monotherapy in this setting, CCA and glioma pts exhibited prolonged stable disease. RP2D evaluation is ongoing. Updated data on LY3410738 monotherapy will be presented at the meeting. Citation Format: Jordi Rodon, Lipika Goyal, Teresa Macarulla Mercade, Masafumi Ikeda, Shunsuke Kondo, Do-Youn Oh, Li-Yuan Bai, Makoto Ueno, Antoine Italiano, Kyriakos Papadopoulos, David Spigel, Sani H. Kizilbash, Rasha Cosman, Joon Oh Park, Li-Tzong Chen, Tomoya Yokota, Anita A. Turk, Chih-Yi Liao, Rachna Shroff, Anthony El-Khoueiry, Taroh Satoh, Antoine Hollebecque, Mitesh J. Borad, Nilofer Azad, Kurt A. Jaeckle, Herbert H. Loong, Jorge Adeva, Wei Peng Yong, Junjie Zhao, Hui Liu, Anna M. Szpurka, Ivelina Gueorguieva, Kamnesh R. Pradhan, Xiaojian Xu, James J. Harding. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced IDH-mutant cholangiocarcinoma and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT098.

Safety and immunogenicity of a ChAdOx1 vaccine against Rift Valley fever in UK adults: an open-label, non-randomised, first-in-human phase 1 clinical trial

Rift Valley fever is a viral epidemic illness prevalent in Africa that can be fatal or result in debilitating sequelae in humans. No vaccines are available for human use. We aimed to evaluate the safety and immunogenicity of a non-replicating simian adenovirus-vectored Rift Valley fever (ChAdOx1 RVF) vaccine in humans. We conducted a phase 1, first-in-human, open-label, dose-escalation trial in healthy adults aged 18-50 years at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Participants were required to have no serious comorbidities or previous history of receiving an adenovirus-based vaccine before enrolment. Participants were non-randomly allocated to receive a single ChAdOx1 RVF dose of either 5 × 109 virus particles (vp), 2·5 × 1010 vp, or 5 × 1010 vp administered intramuscularly into the deltoid of their non-dominant arm; enrolment was sequential and administration was staggered to allow for safety to be assessed before progression to the next dose. Primary outcome measures were assessment of adverse events and secondary outcome measures were Rift Valley fever neutralising antibody titres, Rift Valley fever GnGc-binding antibody titres (ELISA), and cellular response (ELISpot), analysed in all participants who received a vaccine. This trial is registered with ClinicalTrials.gov (NCT04754776). Between June 11, 2021, and Jan 13, 2022, 15 volunteers received a single dose of either 5 × 109 vp (n=3), 2·5 × 1010 vp (n=6), or 5 × 1010 vp (n=6) ChAdOx1 RVF. Nine participants were female and six were male. 14 (93%) of 15 participants reported solicited local adverse reactions; injection-site pain was the most frequent (13 [87%] of 15). Ten (67%) of 15 participants (from the 2·5 × 1010 vp and 5 × 1010 vp groups only) reported systemic symptoms, which were mostly mild in intensity, the most common being headache (nine [60%] of 15) and fatigue (seven [47%]). All unsolicited adverse events reported within 28 days were either mild or moderate in severity; gastrointestinal symptoms were the most common reaction (at least possibly related to vaccination), occurring in four (27%) of 15 participants. Transient decreases in total white cell, lymphocyte, or neutrophil counts occurred at day 2 in some participants in the intermediate-dose and high-dose groups. Lymphopenia graded as severe occurred in two participants in the 5 × 1010 vp group at a single timepoint, but resolved at the subsequent follow-up visit. No serious adverse events occurred. Rift Valley fever neutralising antibodies were detectable across all dose groups, with all participants in the 5 × 1010 vp dose group having high neutralising antibody titres that peaked at day 28 after vaccination and persisted through the 3-month follow-up. High titres of binding IgG targeting Gc glycoprotein were detected whereas those targeting Gn were comparatively low. IFNγ cellular responses against Rift Valley fever Gn and Gc glycoproteins were observed in all participants except one in the 5 × 1010 vp dose group. These IFNγ responses peaked at 2 weeks after vaccination, were highest in the 5 × 1010 vp dose group, and tended to be more frequent against the Gn glycoprotein. ChAdOx1 RVF was safe, well tolerated, and immunogenic when administered as a single dose in this study population. The data support further clinical development of ChAdOx1 RVF for human use. UK Department of Health and Social Care through the UK Vaccines Network, Oak Foundation, and the Wellcome Trust. For the Swahili translation of the abstract see Supplementary Materials section.

Demographic Features and Laboratory Parameters Among Hospitalized Vaccinated Patients With COVID-19 in Istanbul, Turkey

Background The number of COVID-19 cases has been decreasing recently, and the restrictions are waived in many countries. The data about vaccine efficacy are essential to be prepared for the future even if the pandemic ends and the disease becomes endemic. Aims The aim of this study was to define demographic and laboratory data for disease severity among vaccinated COVID-19 cases who were hospitalized. Study Design This is a retrospective cohort study. Methods SARS-CoV-2 polymerase chain reaction–positive patients who were fully vaccinated (2 doses of vaccines and 3 doses of vaccines) and had been hospitalized at least 15 days after the last vaccine dose were enrolled in this study. Patients' data including laboratory parameters were retrieved, and descriptive statistics and comparison of variables were calculated. Results Between September 1, 2021, and February 28, 2022, 685 patients (mean age, 67.84 years; 50.8% female) were hospitalized. Inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac) had been administered to 467 of the patients (68.4%), BNT162b2 mRNA vaccine (Pfizer-Pfizer-BioNTech) had been administered to 107 of the patients (15.6%), and to 111 of the patients (16%), a combination of 2 vaccines had been administered. At least 1 comorbidity was present in 160 participants (23%) and more than 4 comorbidities in 46 patients (6.6%). The most common comorbidity was hypertension (349, 50.2%). The presence of comorbidities was significantly higher in patients having 3 doses of vaccine. Increased ferritin levels were determined in 56.4% of the patients, increased D-dimer levels in 69.9% of the patients, increased C-reactive protein levels in 79.7% of the patients, and increased procalcitonin levels in 61.5% of the patients. A total of 36.4% of the patients had decreased lymphocyte counts, 20% had low lymphocyte/monocyte ratio, and 22% had decreased neutrophil/lymphocyte ratio. The only parameter that was significantly higher in patients having 3 vaccine doses was procalcitonin. Mean duration of hospitalization was 9.68 ± 7.29 days. In the CoronaVac and Pfizer-BioNTech groups, 68.5% and 21.4%, respectively, of the patients were older than 65 years. Seventeen (3.6%) patients in the CoronaVac group, 6 (5.4%) patients in the combination group, and 3 (2.8%) patients in Pfizer-BioNTech group had been admitted to the intensive care unit. Mortality rate was 0.3% (2 of 685 patients). Conclusions The incidence of severe COVID-19 disease among fully vaccinated patients is low even in the presence of comorbidities, older age, and presence of abnormal laboratory parameters, regardless of the vaccine type.

Effects of COVID-19 and vaccination on the human immune system: cases of lymphopenia and autoimmunity

Effects of COVID-19 and vaccination on the human immune system: cases of lymphopenia and autoimmunity

The comparison of systemic inflammatory response markers and Doppler ultrasound parameters between pregnancies with intrahepatic cholestasis and control cases

Objective: This study aims to detect a relationship between inflammatory markers, ductus venosus (DV) pulsatility index (PI), middle cerebral artery (MCA) PI, and umbilical artery (UA) systole to diastole ratio (S/D) and PI between pregnancies with intrahepatic cholestasis and control cases. Methods: This prospective study included 82 cases having intrahepatic cholestasis of pregnancy (ICP) and 80 gestational age-matched healthy control cases. The Doppler measurements (DV PI, MCA PI, and UA S/D and PI), inflammatory markers (neutrophil to lymphocyte ratio [NLR], platelet to lymphocyte ratio [PLR], mean platelet volume [MPV], and red blood cell distribution width [RDW]), and fetal and maternal outcomes were compared. Results: Patients with ICP had increased PLR value (p=0.019) and decreased lymphocyte count (p=0.004) compared to control cases. Also, there was a positive correlation between PLR value and the presence of ICP (χ2=5.774, p=0.016). There were no significant differences between ICP and control groups concerning NLR, RDW, MPV, and UA PI values. We found higher UA S/D, and DV PI values and lower MCA PI values in pregnancies with ICP compared to controls (p&lt;0.001, p=0.026, and p=0.003, respectively). Conclusion: In ICP cases, the PLR value was significantly increased than the controls, but the NLR, RDW, MPV, and UA PI values were found to be similar to control cases. The UA S/D, and DV PI values were increased, and MCA PI was significantly decreased in the ICP group compared to healthy pregnancies. However, we could not demonstrate the benefit of Doppler measurements in predicting neonatal outcomes in ICP cases.

Role of neutrophils to lymphocytes ratio in identification of bacterial infection in adult population

Background: Bacterial infection are difficult to distinguish from viral infection. Neutrophils are the first cells mobilize to infectious site caused by bacteria and also apoptosis of lymphocytes in response to cell mediated immunity hence raised in neutrophils and decrease in lymphocyte count. The goal of this study is to determine the neutrophil to lymphocyte ratio in patient with positive blood culture for bacteria in patients admitted in hospital.&#x0D; Patients and methods: This cross-sectional study was conducted at Department of Pathology, Hamdard University Karachi, Pakistan from 1st January to 31st June 2022. Total 123 adult patients with positive blood cultures admitted in ward or ICU were enrolled in the study. CBC Samples were collected from patients admitted in ward or ICU and blood culture were already sent due to clinical condition, the organism isolated in blood culture were recorded As blood culture is a gold standard investigation to detect bacterial infection .In this study we will record neutrophil to lymphocyte ratio in patients admitted with positive blood culture for bacteria. Age less than 15 years, pregnant female, OPD patients, negative blood cultures and patients on antibiotic therapy were excluded. Complete blood count (CBC) was performed in Beckman coulter model DxH 520 made by Germany. Age and ward of patient, organism isolated from blood culture, CRP.&#x0D; Results: A total of 123 patients with positive blood culture were enrolled in the study. Out of 123 patients 61.8% (n=76) were male and 38.2% (n=47) were female. Mean NLR was 5.9± 13.1. Total 45.5% patients presented with high NLR. Mean CRP was 58.5± 68.7. &#x0D; Conclusion: High NLR was seen in 45.5% which shows NLR is an important indicator of bacterial infection. More studies are needed to define true significance of NLR in all ages and negative blood cultures. &#x0D;

Efficacy and safety of levilimab in combination with methotrexate in patients with active rheumatoid arthritis: 56-week results of phase III randomized double-blind placebo-controlled trial SOLAR

Background. Previously, 24-week results of phase III double-blind, placebo-controlled randomized clinical study (SOLAR) of levilimab in subjects with active rheumatoid arthritis (RA) proved a superiority of levilimab over placebo. Here we present 1-year efficacy and safety data of the SOLAR study.Objective – to evaluate the efficacy and safety of levilimab in combination with methotrexate (MTX) in subjects with MTX resistant active RA.Methods. The study was conducted at 21 clinical sites in Russia and Belarus. All randomized subjects have completed the study between November 2019 and October 2021.154 adults, aged ≥18 years with confirmed diagnosis of RA were randomly assigned (2:1) to receive either levilimab (162 mg, SC, QW) + MTX (n=102) or placebo + MTX (n=52).After W24 of the study all subjects continued to receive open label levilimab. Subjects who have achieved DAS28-CRP≤2.6 at W24 were switched to maintenance (Q2W) regimen of levilimab at W28 (LVL QW/Q2W and PBO/LVL Q2W arms). Those with DAS28-CRP&gt;2.6 at W28 continued with QW regimen (LVL QW and PBO/LVL QW arm). The PBO/LVL Q2W arm contained only one subject, thus not included in the analysis. The efficacy analysis was done in a population of all randomized subjects. Those with missing data due to study discontinuation or rescue therapy prescription were considered non-responders. Otherwise, the analysis was performed on complete cases.Safety was assessed through monitoring of adverse events (AEs) in a population of those, who received at least on dose of LVL (n=152).Results. Better response to treatment was observed in LVL QW/Q2W as it composed of those who reach DAS28-CRP≤2.6 at W24. At this time point 15/27 (55.6%) of them achieved ACR70; 23/27 (85.2%) achieved DAS28-CRP remission (&lt;2.6) and 7/27 (25.9%) achieved ACR/EULAR 2011 remission of RA. After switching to LVL Q2W, rates of ACR70 and DAS28-CRP&lt;2.6 did not significantly changed until W52: 17/27 (63.0%) and 21/27 (77.8%), respectively, yet the proportion of subject with ACR/EULAR 2011 remission further increased and reached 12/27 (44.4%).LVL QW arm was diminished by subjects who achieved high response to treatment at W24 and composed LVL QW/Q2W arm. Thus, ACR70, and remissions rate in this arm was close to zero at W24. However, continuation of LVL QW in those who not achieved DAS28-CRP≤2.6 at W24 induced ACR70 response in 37/75 (36.0%), DAS28-CRP remission in 35/75 (46.7%) and ACR/EULAR 2011 remission in 8/75 (10.7%) at W52.The most common adverse events (reported in ≥5% of subjects) were blood cholesterol increase (30.3%), ALT increase (23.0%), lymphocyte count decrease (17.1%), ANC decrease (16.4%). blood triglycerides increase (13.8%), bilirubin increase (11.2%), AST increase (9.9%), WBC decrease (9.9%), IGRA with Mycobacterium tuberculosis antigen positive (7.2%) and injection site reactions (5.9%). No deaths were occurred.Conclusions. Open label period confirmed the lasting efficacy and safety of levilimab in combination with MTX in subjects with MTX resistant active RA and suggested the possibility of switching to maintenance (Q2W) regimen in those who achieved remission of RA at week 24.

Hematological and Biochemical Responses of Donkeys (Equus asinus) to Packing and Trekking During the Hot-Dry Season.

The study aimed to evaluate effects of packing (load-carrying) and trekking on hematological and biochemical parameters in donkeys during the hot-dry season. Ten pack donkeys, aged 2-3 years, weighing 93 ± 2.7 kg were enrolled in the study and randomly divided into two groups of five animals each. Group 1 donkeys were subjected to packing+trekking while group 2 trekked only. All the donkeys trekked 20 km thrice, 1-day apart. Blood was collected before and after packing or trekking for hematological evaluation; and serum analyzed for electrolyte concentrations, and aspartate aminotransferase, creatine kinase and lactate dehydrogenase activities. Temperature-humidity index pre and postpacking was 70.00 ± 0.1 and 79.67 ± 0.3, respectively. The packed cell volume (30.93 ± 1.1%) was higher (P < .05) before packing than postpacking value (27.83 ± 0.7%) in group 1 donkeys. Hemoglobin concentration (9.01 ± 0.3 g/dL) decreased (P < .05) after trekking (7.81 ± 0.1 g/dL) in group 2 donkeys. Neutrophil count increased (P < .05) in group 1 donkeys after packing (from 8.63 ± 0.9×109/L to 10.59 ± 1.2×109/L). Lymphocyte count (8.58 ± 0.8×109/L) decreased (P < .05), compared to postpacking (5.23 ± 0.5×109/L) in group 1 donkeys. Postpacking neutrophil/lymphocyte ratio in group 1 donkeys (2.33 ± 0.4) was higher (P < .05) than in group 2 donkeys (1.31 ± 0.3). Electrolyte concentrations and enzyme activities did not change significantly. In conclusion, packing+trekking was more stressful to the donkeys than trekking only, evidenced by postpacking increased neutrophil count, neutrophil/lymphocyte ratio and phosphate ion concentration, but decreased lymphocyte count. If this stress is not mitigated, the performance of pack donkeys during hot-dry season may not be optimum.

Abstract P4-01-21: Phase 2 Study of the CDK4/6 Inhibitor FCN-437c in Combination With Fulvestrant or Letrozole and Goserelin in Patients With HR+, HER2– Advanced Breast Cancer

Abstract Background: FCN-437c is a second-generation CDK4/6 inhibitor. Phase 1b clinical results indicated improved antitumor activity in patients (pts) with HR+, HER2– advanced breast cancer (ABC), treated with FCN-437c + letrozole. Methods: This Phase 2, multicenter, open-label clinical study evaluated the antitumor activity, pharmacokinetics (PK), and safety of FCN-437c + fulvestrant in post-menopausal pts (Cohort 1, treatment-naïve or 2L), FCN-437c + letrozole + goserelin in pre-menopausal pts (Cohort 2, treatment-naïve). Pts received FCN-437c (200 mg QD) in a 21-day-on and 7-day-off schedule either in combination with fulvestrant (500 mg D1) or letrozole (2.5 mg QD) + goserelin (3.6 mg once per cycle) in 28-day cycles. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), overall survival (OS), PK, and safety. Results: At study cutoff (Feb 7, 2022), 36 pts were enrolled in Cohort 1 and 31 pts were in Cohort 2; 42 (62.7%) pts had visceral metastases and 9 (13.4%) pts had bone-only metastases. In Cohort 1, 18 pts were treatment-naïve, 15 pts had received 1L treatment, and 3 pts had received ≥2L treatment. In Cohort 2, 25 pts were treatment-naïve and 6 pts had received 1L treatment. Overall, 27 pts in the per-protocol set achieved partial response (PR), resulting in an ORR of 40.9% (95% CI, 29.0-53.7). Median follow-up was 12.8 months, and median PFS (mPFS), OS, and DOR were not reached. However, at 12 months, the PFS rate was 67.7% (95% CI, 53.2-78.6) and the OS rate was 95.9% (95% CI, 84.5-99.0); the 6-month DOR rate was 96.0% (95% CI, 74.8-99.4). In Cohort 1 (n=35), 11 pts achieved PR: the ORR was 31.4% (16.9-49.3%) and mPFS was 12.9 months (95% CI, 9.2-NR); the 6-month DOR rate was 100%. In Cohort 2 (n=31), 16 pts achieved PR: the ORR was 51.6% (95% CI, 33.1-69.9%). mPFS, OS, and DOR were not reached; the 6-month DOR rate was 92.9% (95% CI, 59.08-98.96) (Table). Treatment-emergent adverse events (TEAEs) were observed in all pts. Majority of AE were G1 or 2 except for hematological TEAE. 58 (86.6%) pts reported grade ≥3 TEAEs, mainly neutropenia (74.6%), leukopenia (49.3%), hypertriglyceridemia (6.0%), lymphocyte count decrease (4.5%), and γ-glutamyltransferase increase (3.0%): most were reversed through dose interruption and symptomatic therapy. Steady-state PK parameters were analyzed after 15-21 days of QD administration: Cohort 1: median Tmax was 3 h, geomean T1/2 was 44.6 h, geomean Cmax was 1650.7 ng/mL, and geomean AUC0-24h was 29,148.08 h*ng/mL; the geomean accumulation ratios of AUC0-24h and RCmax were 2.18 and 1.74, respectively, compared with first dose. Cohort 2: median Tmax was 4 h, geomean T1/2 was 35.7 h, geomean Cmax was 1314.34 ng/mL, and geomean AUC0-24h was 22,889.96 h*ng/mL; the geomean accumulation ratios of AUC0-24h and RCmax were 1.95 and 1.63, respectively, compared with first dose. Conclusion: FCN-437c in combination with fulvestrant or letrozole + goserelin demonstrates antitumor activity and safety and is well tolerated in pts with HR+, HER2– ABC. This combination therapy will be further investigated in 2 ongoing Phase 3 trials (NCT05438810 and NCT05439499). Clinical trial number: NCT05004142. Research Sponsor: Avanc Pharmaceutical Co., Ltd Table. Clinical outcomes for patients in the per-protocol set. Citation Format: JiaJie Shi, Wei Li, Zhongsheng Tong, Aimin Zang, Xiaohua Zeng, Shui Wang, Tao Huang, Ying Wang, Yanqiu Song, Lihua Kang, Zheng Lv, Yehui Shi, Hua Yang, Jing Wu, Yongmei Yin, Yan Liang, Jie Tan, Jie Ming, Yaping Yang, Simin Luo, Xiujuan Gui, Ai-Min Hui, Zhuli Wu, Ling Tian, Yuchen Yang, Lei Diao, Wenjing Zhang, Yongjiao Zhang, Yunjiang Liu. Phase 2 Study of the CDK4/6 Inhibitor FCN-437c in Combination With Fulvestrant or Letrozole and Goserelin in Patients With HR+, HER2– Advanced Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-21.

Distribution and clinical features of lymphomas involving skin in Taiwan.

A wide variety of primary and secondary lymphoma types involves the skin. However, reports with comparisons between both groups are limited in Taiwan. We retrospectively enrolled all cutaneous lymphomas and evaluated their clinicopathologic features. There were 221 cases of lymphoma: 182 (82.3%) primary and 39 (17.7%) secondary. Mycosis fungoides was the most common primary T-cell lymphoma, 92 (41.7%) cases, followed by CD30-positive T-cell lymphoproliferative disorders including lymphomatoid papulosis (n=33, 14.9%) and cutaneous anaplastic large cell lymphoma (n=12, 5.4%). The most frequent primary B-cell lymphomas were marginal zone lymphoma (n=8, 3.6%) and diffuse large B-cell lymphoma (DLBCL), leg type (n=8, 3.6%). DLBCL including variants was the most common secondary lymphoma involving skin. Most primary lymphomas presented at low-stage (T-cell, 86%; B-cell, 75%), whereas the majority of secondary lymphomas presented at high-stage (T-cell, 94%; B-cell, 100%). Patients with secondary lymphomas had an older mean age, more frequent B symptoms, lower serum albumin and hemoglobin, and a higher frequency of atypical lymphocytes in blood than those with primary lymphomas. In primary lymphomas, older age, lymphoma types, decreased lymphocyte counts and atypical lymphocytes in blood were poorer prognostic factors. In secondary lymphoma patients, lymphoma types, high serum lactate dehydrogenase and low hemoglobin levels predicted poorer survival. We found that the distribution of primary cutaneous lymphomas in Taiwan mirrors that of other Asian countries but shows some differences as compared with Western countries. Primary cutaneous lymphomas have a better prognosis than secondary lymphomas. Histologic classification of lymphomas highly correlated with disease presentation and prognosis.

Stereotactic Ablative Radiation Therapy in 3 Fractions Induces a Favorable Systemic Immune Cell Profiling in Prostate Cancer Patients

ABSTRACT The impact of radiotherapy (RT) on immune cell status in prostate cancer (PCa) is only partially determined. The aim of this study was to assess the effect of different RT strategies on peripheral B, T, and Natural killer (NK) lymphocytes at precise longitudinal time-points in PCa. 18 patients treated with stereotactic body radiation therapy (SBRT) (40 Gy/3FRX), definitive moderate-hypofractionation (62 Gy/20FRX), or post-operative conventional-fractionation RT (66–69 Gy/30FRX) were prospectively evaluated for the immune cell profile in terms of immune cell composition, differentiation stage, cytokine production and inhibitory receptor (IR) expression. The immune-monitoring of the 18 patients revealed that RT affects the balance of systemic immune cells, with the main differences observed between SBRT and conventionally fractionated RT. SBRT favorably impacts immune response in term of increased B cells, central-memory and effector-memory CD8+ T cells, along with decreased Treg cells after treatment. On the contrary, conventional fractionated RT had a long-term negative effect on the systemic immune profile, including a decrease of total lymphocyte counts accompanied by an increase of neutrophils-to-lymphocytes ratio. Total B and T cells decreased and Treg-to-CD8+ ratio increased. Functionality of T lymphocytes were not affected by any of the 3-fractionation schedules. Interestingly, SBRT significantly up-regulates the expression of V-domain immunoglobulin suppressor of T-cell activation (VISTA) in CD8+ T cells in the absence of other IRs. Our results indicate the relevance of systematic immunomonitoring during RT to identify novel immune-related target to design trials of combined radio-immunotherapy as a promising strategy in the clinical management of PCa.

Incidence, predictors and prognosis of acute kidney injury in acute ST-segment elevation myocardial infarction patients undergoing emergent coronary angiography/primary percutaneous coronary intervention.

Acute kidney injury (AKI) after coronary angiography (CAG) and primary percutaneous coronary intervention (PPCI) is frequently observed, and often interpreted as contrast induced-AKI. This study aimed to investigate the incidence, predictors and outcomes of AKI in acute ST-segment elevation myocardial infarction (STEMI) patients undergoing emergent CAG/PPCI using the control group of STEMI patients who were not exposed to contrast agents within the first 72 h. We performed a retrospective analysis of 1670 STEMI patients. Of them, 673 patients underwent emergent CAG/PPCI, and 997 patients treated with thrombolysis or no reperfusion therapy who were not exposed to contrast material during the first 72 h. AKI was defined as an increase of serum creatinine ≥ 44.2 mmol/L or ≥ 25% from baseline within 72 h. Patents were then followed up for the occurrence of all-cause mortality for 40 months (interquartile range: 24-55 months). After propensity score matching, 505 pairs of patients were matched. Overall, the incidence of AKI was 27.4%, and AKI rates were not significantly different in patients with and without emergent CAG/PPCI procedure (27.5% vs. 27.3%, P = 0.944). Multivariate logistic regression analysis identified that the independent predictors of AKI were female, elevated interleukin-6 level, decreased lymphocyte count, left ventricular ejection fraction < 50% and use of diuretics in patients with emergent CAG/PPCI. Patients with AKI than those without AKI experienced higher incidence of acute heart failure with Killip class III (9.4% vs. 3.3%, P = 0.005; 15.2% vs. 6.8%, P = 0.003, respectively) and mortality (5.8% vs. 1.4%, P = 0.014; 12.3% vs. 4.6%, P = 0.002, respectively) in patients with and without emergent CAG/PPCI. Multivariate Cox regression analysis confirmed that AKI was independently associated with long-term mortality rate at 40 months follow-up in patients with and without emergent CAG/PPCI (HR = 1.867, 95% CI: 1.086-3.210, P = 0.024; HR = 1.700, 95% CI: 1.219-2.370, P = 0.002, respectively). Approximately 27.0% of STEMI patients experience AKI, which is strongly associated with an increased short- and long-term mortality regardless of emergent CAG/PPCI procedure. The development of AKI is mainly related to female gender, inflammation reaction, heart failure and use of diuretics in STEMI patients undergoing emergent CAG/PPCI.

Anlotinib combined with TQB2450 (PD-L1 blockade) as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, multicenter, open-label phase II clinical trial.

377 Background: PD-1 blockades combined with chemotherapy in first-line setting exhibited encouraging efficacy for patients with ESCC recently. However, the safety profile of conventional chemotherapy was still disappointing. Therefore, the chemotherapy-free regimen might be a promising strategy. And it had been proved that PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) in second-line treatment for advanced ESCC showed potential efficacy and manageable toxicity. As a novel multitarget TKI mainly targeting VEGFR1-3, anlotinib was a potential first-line combination therapy and second-line monotherapy for patients with ESCC in China. TQB2450 was a novel PD-L1 blockade developed by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (Nanjing, China), which is currently undergoing several clinical studies in China, involving ESCC and other solid tumors. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with TQB2450 as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC, whose age was between 18 and 75 years, with ECOG PS of 0 or 1 and life expectancy of more than 3 months were eligible as the inclusion criteria. Eligible patients were administered with anlotinib (12mg, po, d1~14, q3w) plus TQB2450 (1200mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 and iRECIST using CT scans every 2 cycles for the first 6 cycles, and every 3 cycles thereafter. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 46. The primary endpoint was ORR. Secondary endpoints included safety, PFS, DCR, DoR and OS. Results: From Mar 2022 to Aug 2022, a total of 36 patients were enrolled, 23 patients included in per-protocol set. In best overall response assessment, there were 14 PR (60.9%), 8 SD (34.8%) and 1 NE (4.4%). In consequence, the preliminary ORR was 60.9% (95%CI: 38.5%~80.3%), DCR was 95.7% (95%CI: 78.1%~99.9%). No patients had disease progression at the date of data cutoff. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-related adverse events in 36 patients with the incidence &gt;10% were hypertension (33%), fatigue (17%), decreased white blood cell count (14%), hyperthyroidism (11%) and decreased neutrophil count (11%). The common grade ≥3 treatment-related adverse events were decreased platelet count (3%) and decreased lymphocyte count (3%). Conclusions: Preliminary results suggested that anlotinib combined with TQB2450 as first-line therapy in advanced ESCC exhibited encouraging efficacy and manageable adverse events. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: NCT05038813 .

P558 Etrasimod for the treatment of ulcerative colitis: analysis of infection rates from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 clinical trials

Abstract Background Infections are an important safety concern in patients with IBD and may be due to its therapies, such as corticosteroids. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). The biologic effect of etrasimod leads to selective and reversible lymphocyte retention in lymph nodes with a decrease in peripheral lymphocyte count. We report the infection events from the phase 3 ELEVATE programme. Methods Infection events were evaluated in the pivotal UC pooled safety analyses set comprising two phase 3 studies: ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369). Subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). We report the n (%) and exposure-adjusted incidence rate (EAIR) of infections including serious infections, severe infections, opportunistic infections (including tuberculosis), and herpes infections. Infections were considered adverse events of special interest (AESI) if they were severe (≥ CTCAE Grade 3), were opportunistic infections, or were herpes zoster or herpes simplex infections. Results From the pooled ELEVATE UC 12 and ELEVATE UC 52 trials, 527 subjects received ≥1 dose of etrasimod 2 mg (265.6 subject-years of exposure) and 260 subjects were randomised to PBO (103.0 subject-years of exposure). Infections were similar between treatment groups (etrasimod: 99 [18.8%], EAIR=0.41; PBO: 46 [17.7%], EAIR=0.52). The most frequent infections in both groups were COVID-19, urinary tract infections, and nasopharyngitis (Table 1). Serious infections occurred in 3 (0.6%) subjects in the etrasimod arm (EAIR=0.01) and 5 (1.9%) in PBO arm (EAIR=0.05). Two cases of herpes zoster were reported in each treatment group (etrasimod: 0.4%, EAIR&amp;lt;0.01; PBO: 0.8%, EAIR=0.02); these were localised and nonserious. One opportunistic infection was reported in each arm (etrasimod: subject withdrew from the study on day 20, the AE of Cytomegalovirus infection [Grade 2] was reported on day 36; PBO: tuberculosis [Grade 2]). Overall, 3 cases of infection led to discontinuation: 2 in the etrasimod arm (both mild) and 1 in the PBO arm (Table 2). No subject with an absolute lymphocyte count &amp;lt;0.2×109/L subsequently reported a serious/severe or opportunistic infection. There were no deaths. Conclusion In these trials, etrasimod-treated subjects reported no increase in infections relative to PBO. Serious infections and herpes zoster were more commonly reported in the PBO-treated group. Longer-term follow-up data from the ongoing 5-year open-label extension will further characterize the etrasimod safety profile.

Safety of upadacitinib in Latin American patients with rheumatoid arthritis: an integrated safety analysis of the SELECT phase 3 clinical program

Introduction/objectivesRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by ongoing inflammation and degradation of synovial joints. The oral JAK inhibitor, upadacitinib, is approved for RA. We conducted an integrated safety analysis of upadacitinib 15 mg once daily (QD) in patients from Latin America (LATAM) versus the rest of the world (RoW).MethodsTreatment-emergent adverse events (AEs) and laboratory data from six phase 3, randomized controlled trials, adjusted for upadacitinib 15 mg QD use in RA, were analyzed.ResultsOverall, 3209 patients received upadacitinib 15 mg QD for 7024 patient-years (PY). LATAM patients (n = 725) had a mean upadacitinib exposure of 1518 PY. Baseline characteristics were generally similar between LATAM and RoW populations. AE rates (including serious/opportunistic infections, tuberculosis, and herpes zoster) and deaths were comparable between populations. LATAM patients had lower serious AE rates per 100 PY (9.4 vs 14.0 E/100 PY) and discontinuation-related AEs (3.9 vs 6.0 E/100 PY) versus RoW. Rates of cardiovascular events were low (≤ 0.5 E/100 PY) and similar between populations. Malignancies, excluding non-melanoma skin cancer, were less common in the LATAM population versus RoW (0.2 vs 1.0 E/100 PY). Laboratory abnormalities were similar between populations, with decreases in hemoglobin, lymphocyte, and neutrophil counts, and elevations in liver enzymes and creatine phosphokinase. Mean change from baseline in low- and high-density lipoprotein cholesterol was generally comparable between LATAM and RoW populations.ConclusionUpadacitinib 15 mg QD demonstrated a consistent safety profile across LATAM and RoW patient populations, with no new safety risks observed.Trial registration numbersSELECT-EARLY, NCT02706873; SELECT-NEXT, NCT02675426; SELECT-COMPARE, NCT02629159; SELECT-MONOTHERAPY, NCT02706951; SELECT-BEYOND, NCT02706847; SELECT-CHOICE, NCT03086343.Key Points• This study assessed the safety of upadacitinib 15 mg in patients with rheumatoid arthritis from Latin America compared with patients from the rest of the world participating in the SELECT phase 3 program.• Safety was generally similar between the two groups, including serious and opportunistic infections, tuberculosis, herpes zoster, and cardiovascular events. Malignancy, major adverse cardiovascular events, and venous thromboembolic events were infrequent in the Latin American patients.• Consistent with the known safety profile of upadacitinib, serious infections, herpes zoster, and laboratory abnormalities were the most common safety events in the Latin American population.