Efficiency of Nicotinamide-based Supportive Therapy in Lymphopenia for Patients With COVID-19: A Randomized Controlled Trial

Background: The purpose of this study was to investigate the efficiency of nicotinamide-based supportive therapy in lymphopenia for patients with coronavirus disease-2019 (COVID-19). Methods: 24 patients diagnosed with the COVID-19 were randomly divided into two groups (n=12) during hospitalization in the ratio of 1:1. Based on the conventional treatment, the treatment group was given 100mg nicotinamide, five times a day. The control group only received routine treatments. The primary endpoint was the change in absolute lymphocyte counts. The secondary endpoints included both the in-hospital death and the composite endpoint of aggravation, according to upgraded oxygen therapy, improvement of nursing level, and ward rounds of superior physicians for changes of conditions. Results: The full blood counts before and after receiving the nicotinamide were comparable in each group (all P>0.05). Before and after receiving the nicotinamide, mean absolute lymphocyte counts were similar between the two groups ([0.94±0.26]*109/L versus [0.89±0.19]*109/L, P=0.565; [1.15±0.48]*109/L versus [1.02±0.28]*109/L, P=0.445, respectively). Therefore, there was no statistically significant difference in the lymphocyte improvement rate between the two groups (23.08±46.10 versus 16.52±24.10, P=0.67). There was also no statistically significant difference for the secondary endpoints between the two groups.Conclusion: Among patients with COVID-19, there was no statistically significant difference in change of full blood counts and the absolute lymphocyte counts before and after intervention in both groups. Therefore, no new evidence was found for the effect of niacinamide on lymphopenia in patients with COVID-19.Trial registration: ClinicalTrials.gov, NCT04910230. Registered 1 June 2021-retrospectively registered.

The impact of lymphopenia during chemoradiotherapy using photons or protons on the clinical outcomes of esophageal cancer patients

We assessed the development of lymphopenia during concurrent chemoradiotherapy (CRT) using X-ray versus proton beams and the impact on survival in patients with esophageal cancer. Among patients with esophageal cancer who were administered concurrent CRT with a curative intent at our institute from 2014 to 2018, 69 (15 receiving X-ray radiotherapy (XRT) and 54 receiving proton beam therapy [PBT]) who underwent weekly blood testing during treatment were enrolled. The absolute lymphocyte counts (ALC) at 1, 5 and 6 weeks were significantly higher in the patients who received PBT than in those who received XRT (p = 0.002, p = 0.006 and p = 0.009, respectively), and a similar trend in the neutrophil-to-lymphocyte ratio (NLR) was observed (p = 0.003 at 5 weeks). The 2-year overall survival (OS) and progression-free survival (PFS) rates tended to be higher in the patients who maintained an ALC ≥200 compared with those who did not (p = 0.083 and p = 0.053, respectively), and similar trends were observed in the NLR (p = 0.061 and p = 0.038, respectively). Dose–volume analysis revealed significant correlations between volumes of the thoracic bones irradiated by 5–50 Gy and minimum ALCs and maximum NLR. These findings suggested that PBT prevented the development of lymphopenia during CRT by reducing the irradiated volume of the thoracic bone, and the maintained lymphocyte count is possibly one of the early predictors for survival in patients with esophageal cancer.

The association between platelet-to-lymphocyte ratio with mortality among patients suffering from acute decompensated heart failure

Background Platelet-to-lymphocyte ratio (PLR) is an inflammation index suggested to have the prognostic capability in heart failure (HF). We sought to investigate the association of PLR with cardiovascular disease (CVD) mortality and creatinine (Cr) rise among Iranian individuals suffering from acute decompensated HF (ADHF). Methods This retrospective cohort study was in the context of the Persian Registry Of cardioVascular diseasE/Heart Failure (PROVE/HF) study. 405 individuals with ADHF admitted to the emergency department were recruited from April 2019 to March 2020. PLR was calculated by division of platelet to absolute lymphocyte counts and categorized based on quartiles. We utilized the Kaplan–Meier curve to show the difference in mortality based on PLR quartiles. Cr rise was defined as the increment of at least 0.3 mg/dl from baseline. Cox proportional hazard ratio (HR) was used to investigate the association of PLR with CVDs mortality. Results Mean age of participants was 65.9 ± 13.49 years (males: 67.7%). The mean follow-up duration was 4.26 ± 2.2 months. CVDs mortality or re-hospitalization was not significantly associated with PLR status. Multivariate analysis of PLR quartiles showed a minimally reduced likelihood of CVDs death in 2nd quartile versus the first one (HR 0.40, 95% confidence interval (CI) 0.16–1.01, P = 0.054). Cr rise had no remarkable relation with PLR status in neither model. Conclusion PLR could not be used as an independent prognostic factor among ADHF patients. Several studies are required clarifying the exact utility of this index.

Indeterminate QuantiFERON Gold Plus results reveal deficient IFN-γ responses in severely ill COVID-19 patients

Background: SARS-CoV-2 is a novel positive-sense single stranded RNA virus that has caused a recent pandemic. Most patients have a mild disease course, while approximately 20 percent have moderate-to-severe disease, often requiring hospitalization and, in some cases, care in the intensive care unit. Results: By investigating a perceived increased rate of indeterminate QuantiFERON®-TB Gold Plus results in hospitalized COVID patients, we demonstrate that severely ill COVID-19 patients have at least a 6-fold reduction of interferon-gamma (IFN-γ) levels compared to control patients. What is more, over sixty percent of these severely ill COVID-19 patients’ peripheral T-cells were found to be unable to produce measurable IFN-γ when stimulated with phytohemagglutinin (PHA), a potent IFN-γ mitogen, reflected by an indeterminate QuantiFERON®-TB Gold Plus. This defect of IFN-γ production was independent of absolute lymphocyte counts and immunosuppressive therapy. It was associated with increased levels of IL-6, which was a predictor of patient outcomes for our cohort when measured early in the course of disease. Finally, in a subset of COVID-19 patients, we found elevated IL-10 levels, in addition to IL-6 elevation. Conclusions: In addition to finding a significant limitation of IGRA testing severely ill COVID-19 patients, these data provide evidence that many of these patients demonstrate a focused Th2 immune response with inhibition of IFN-γ signaling and, in many cases, significant elevations of IL-6.

Absolute Lymphocyte Counts After Lenalidomide Initiation may Predict the Prognosis of Patients With Relapsed or Refractory Multiple Myeloma

Background/Aim: We assessed the prognosis of patients with refractory or relapsed multiple myeloma (RRMM) by focusing on the change in absolute lymphocyte counts (ALCs) after lenalidomide and dexamethasone (Ld) initiation. Patients and Methods: In total, 72 patients with RRMM were treated with Ld. ALCs were evaluated before treatment and at 1, 2, and 3 months after Ld initiation. The median ALCs in the entire cohort before and at 1, 2, 3 months after Ld initiation were 1,131, 1,059, 1,222, and 1,162/μl, respectively. Results: ALCs before Ld initiation did not affect time to next treatment (TNT) or overall survival (OS). However, the patients with ALCs equal to or greater than the median at 3 months showed relatively better TNT than those with lower lymphocyte counts, with a significant difference. OS was also significantly longer in patients with higher ALCs. Conclusion: Immunomodulation by lenalidomide may improve prognosis in patients with RRMM.

Study of Absolute Lymphocyte Count as a Marker of COVID 19 Disease Severity in Tertiary Care Centre, Suryapet

BACKGROUND The World Health Organization (WHO) has declared Coronavirus disease 2019 (COVID - 19) as a global public health pandemic. Clinical and laboratory biomarkers to predict the severity of corona virus 2019 are essential in this pandemic. Lymphocyte count has been a marker of interest in order to investigate the association of lymphocyte count and severity of COVID-19. We would like to analyse the relationship between absolute lymphocyte count (ALC) & COVID-19 disease severity. METHODS We performed a retrospective study on patients admitted to Government general hospital, Suryapet for COVID-19 illness from September 1st 2020 to September 16th 2020. Age, gender and complete blood count of patients admitted in the hospital was collected. Haemoglobin, total leucocyte count (TLC), absolute neutrophilic count (ANC), absolute lymphocyte count (ALC) and platelet counts were compared between ICU and Non-ICU groups and comparison of absolute lymphocyte counts in each group - ICU alive, ICU death and non-ICU groups was carried out. RESULTS 134 patients who were admitted in the hospital were analysed. Mean age and gender were compared between ICU and Non-ICU groups. We compared ALC between ICU alive, ICU death and non-ICU groups. Mean ALC in ICU death group was 0.81, in ICU alive group 1.04 and in non-ICU as 1.75. We found that patients with disease severity have lower absolute lymphocyte counts. In addition to this we also found that there was neutrophilia and lower haemoglobin levels in ICU patients. CONCLUSIONS We conclude that lymphopenia, defined as absolute lymphocyte count less than 1.1 x 109 /L may be useful in predicting the severity of COVID-19 illness. KEYWORDS COVID-19, Absolute Lymphocyte Count (ALC), Lymphopenia, SARS COV2

First-in-human study of lisaftoclax (APG-2575), a novel BCL-2 inhibitor (BCL-2i), in patients (pts) with relapsed/refractory (R/R) CLL and other hematologic malignancies (HMs).

7502 Background: The BCL-2i venetoclax is active in certain HMs but can increase the risk of tumor lysis syndrome (TLS), requiring a 5-week dose ramp-up for CLL patients. Cases of severe neutropenia with venetoclax treatment have also been reported. Lisaftoclax is a novel, potent, selective BCL-2i that is active against HMs and is under clinical development. Methods: This first-in-human global phase I dose study assessed the safety, PK, PD, efficacy, and MTD/RP2D of lisaftoclax in patients with R/R CLL and other HMs. Lisaftoclax was orally administered daily in a 28-day cycle. Patients with CLL or intermediate-high TLS risk were initiated on a daily ramp-up schedule until the assigned dose before the study cycles. Results: On January 7, 2021, 35 pts had been enrolled and treated with lisaftoclax at doses ranging from 20 to 1,200 mg, with a median (range) of 2 (1-13) prior lines of treatment, and had diagnoses of R/R CLL or SLL (n = 15), MM (n = 6), FL (n = 5), WM (n = 4), and either AML, MCL, DLBCL, MDS, or HCL (n = 1 each). No DLT has been observed, even though 1,200 mg was considered as the highest dose treated. The MTD has not been reached, and no laboratory or clinical TLS has been reported. Any grade TRAEs in > 10% of pts included neutropenia (22.9%) and anemia (17.1%; hematologic), and fatigue (28.6%), diarrhea (17.1%), and nausea (11.4%; nonhematologic). Grade >3 TRAEs were neutropenia (14.3%) and thrombocytopenia, leukopenia, lymphopenia, fatigue, and nausea (2.9% of pts each). In CLL/SLL pts, grade 3-4 TRAEs included neutropenia (13.3%) and thrombocytopenia (6.7%), which did not cause treatment-related discontinuation. In all, 12 of 35 pts (34.3%) had non-treatment-related SAEs, and only two pts experienced > 1 SAE. With a median (range) treatment of 7 (3-20) cycles, 12 of 14 evaluable R/R CLL/SLL pts achieved PR, for an ORR of 85.7% and a median (range) time to response of 3 (2-7) cycles. Absolute lymphocyte counts (ALCs) were reduced at lisaftoclax doses as low as 20 mg/day. The preliminary PK profile showed that exposures increased with lisaftoclax doses from 20 to 1,200 mg (average half-life: 4-5 hours). On BH3 profiling, lisaftoclax rapidly triggered changes in BCL-2 complex in CLL/SLL pt samples, which were consistent with rapid clinical reductions in ALCs. Conclusions: Lisaftoclax was well tolerated up to 1,200 mg/day. No TLS was observed, even with the daily ramp-up schedule. There were no significant new or unmanageable safety findings, and the ORR in R/R CLL/SLL pts was 85.7%. Grade 3-4 TRAEs were infrequent, even at dose levels of 800 mg and above. BCL-2i lisaftoclax offers a treatment alternative for patients with R/R CLL/SLL and other HMs, with a daily ramp-up schedule that may be more pt “user friendly” and a favorable preliminary safety profile. Internal study identifier APG2575-001. Clinical trial information: NCT03537482.

Prediction of survival after eribulin chemotherapy for breast cancer by absolute lymphocyte counts and progression types

Background In the RECIST diagnostic criteria, the concepts of progression by pre-existing disease (PPL) and progression by new metastases (PNM) have been proposed to distinguish between the progression types of cancer refractory to treatment. According to the tumor biology of cancer progression forms, the "PPL" form indicates invasion and the "PNM" form indicates metastasis. On the other hand, recent studies have focused on the clinical importance of inflammatory markers as indicators of the systemic tumor immune response. In particular, absolute lymphocyte counts (ALC) is an indicator of the host’s immune response. Thus, we developed a new measure that combined progression form with ALC. In this study, we clinically validated the combined assessment of progression form and ALC in eribulin chemotherapy. Methods From August 2011 to April 2019, a total of 486 patients with locally advanced or metastatic breast cancer (MBC) underwent treatment. In this study, only 88 patients who underwent chemotherapy using eribulin were included. The antitumor effect was evaluated based on the RECIST criteria, version 1.1. To measure ALC, peripheral blood samples collected before eribulin treatment were used. The cut-off value for ALC in this study was 1,500 /µL, based on previous studies. Results The PPL group (71 patients, 80.7%) had significantly longer PFS (p = 0.022, log-rank) and OS (p < 0.001, log-rank) than the PNM group (17 patients,19.3%). In the 51 patients with ALC < 1500/µl, the PPL group had a significantly better prognosis than the PNM group (PFS: p = 0.035, OS: p < 0.001, log-rank, respectively). On the other hand, in the 37 patients with ALC ≥ 1500/µl, the PPL group had a better OS compared to the PNM group (p = 0.055, log-rank), but there was no significant difference in PFS between the two groups (p = 0.541, log-rank). Furthermore, multivariate analysis that validated the effect of OS showed that high ORR and “high-ALC and PPL” were factors for a good prognosis (p < 0.001, HR = 0.321) (p = 0.036, HR = 0.290). Conclusions In breast cancer patients with eribulin chemotherapy, good systemic immune status, such as ALC ≥ 1500/µl, was associated with less progression, particularly metastasis, and better prognosis. Furthermore, the biomarker "high-ALC and PPL" was particularly useful as a prognostic marker following eribulin chemotherapy.

Abnormal Thyroid Function Is Associated With Lymphopenia in Bacterial Sepsis and COVID-19

Background: Lymphopenia is a key feature of immune dysfunction in bacterial sepsis and COVID-19 patients and is associated with poor clinical outcomes, but the cause is largely unknown. These severely ill patients may also present with thyroid function abnormalities, so-called non-thyroidal illness syndrome (NTIS), and several studies have suggested that TSH, thyroxin (T4) and triiodothyronine (T3) play a crucial role in the homeostatic regulation and function of lymphocyte populations. Aim: The purpose of this study was to test the hypothesis that abnormal thyroid function correlates with lymphopenia in severly ill patients with bacterial sepsis or COVID-19. Methods: Retrospective analysis of absolute lymphocyte counts and circulating TSH, T4, FT4, T3, albumin and inflammatory biomarkers was performed in two independent cohorts of bacterial sepsis (n=224) and hospitalized COVID-19 patients (n=35). Results: Only T3 correlated (rho=0.252, p-value: &lt;0.001) with lymphocyte counts in the bacterial sepsis population and lower concentrations were found in severe lymphopenic compared to non-lympopenic patients (p-value: &lt;0.001; n=56 per group). Severe lymphopenic COVID-19 patients (n=17) showed significantly lower plasma concentrations of TSH, T4, FT4 and T3 (p-value: 0.026, &lt;0.001, 0.001, &lt;0.001, respectively) compared to patients withouth lymphopenia (n=18), and demonstrated significantly increased values of the inflammatory parameters IL-6, C-reactive protein and ferritin (p-value: &lt;0.001, 0.023, and 0.008, respectively). Remarkable, after one week follow-up, the majority of (12/15) COVID-19 patients showed quantitative recovery of their lymphocyte numbers, while TSH and thyroid hormones remained mainly disturbed. Conclusions: Abnormal thyroid function correlates with low lymphocyte counts in severe sepsis and COVID-19 patients, but future studies need to establish whether a causal relationship is involved.