Plinabulin and Pegfilgrastim in Combination for the Prevention of Chemotherapy-Induced Neutropenia in Patients with Breast Cancer (PROTECTIVE-2): A Randomized Trial

PurposePlinabulin is a non-granulocyte colony-stimulating factor (G-CSF) novel small molecule with both anticancer and myeloprotective effects. Single-agent plinabulin is myeloprotective in the first week of the chemotherapy cycle, and pegfilgrastim in the second week. We assessed the efficacy and safety of the combination of plinabulin and pegfilgrastim for the prevention of chemotherapy-induced neutropenia (CIN) following chemotherapy.MethodsThis randomized, open-label, Phase 2 trial enrolled patients with breast cancer. All received docetaxel 75 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 on Day 1. In the combined therapy cohort, patients received plinabulin 20 mg/m2 on Day 1 and 1.5, 3, or 6 mg pegfilgrastim on Day 2. The primary objective was to establish the recommended Phase 3 dose (RP3D). Secondary endpoints included absolute neutrophil count (ANC) nadir, relative dose intensity (RDI), and incidence of adverse events including neutropenia and bone pain.ResultsIn total, 115 patients were randomized and evaluated. The combination therapy at the RP3D (plinabulin 20 mg/m2 and pegfilgrastim 6 mg) was well-tolerated and had superior CIN prevention in terms of Grade 4 and Grade 3/4 neutropenia frequency, absolute neutrophil count (ANC) nadir, higher relative dose intensity (RDI), less bone pain, and less toxicity burden when compared with pegfilgrastim 6 mg alone.ConclusionPlinabulin combined with pegfilgrastim at the RP3D (plinabulin 20 mg/m2 Day 1 and pegfilgrastim 6 mg Day 2) had more favorable efficacy, safety, and tolerability profiles and lower bone pain incidence than did pegfilgrastim alone.Trial information Clinical Trial Registration: ClinicalTrials.gov NCT04227990Date registered: January 14, 2020 Retrospectively registered

Impact of Perioperative Absolute Neutrophil Count on Central Line-Associated Bloodstream Infection in Children With Acute Lymphoblastic and Myeloid Leukemia

BackgroundThere is lack of evidence concerning safety of placement of tunneled central venous catheters (TCVCs) in neutropenic children with acute leukemias. Here, we evaluate the impact of absolute neutrophil count (ANC) at the time of TCVC placement on development of central line-associated bloodstream infections (CLABSI) in children with lymphoblastic (ALL) or myeloid leukemia (AML).Materials and MethodsA retrospective observational study of children undergoing TCVC placement at a tertiary referral hospital between January 2000 and December 2019 was performed. Traditional and competing-risks regression models were used to estimate the effect of perioperative ANC on development of CLABSI.ResultsA total of 350 children (median age 6.4 [IQR: 3.1–10.9] years) underwent 498 consecutive TCVC implantations in neutropenic (n = 172, 34.5%) and non-neutropenic conditions (n = 326, 65.5%). The median length of observation per TCVC was 217.1 (IQR: 116.1–260.5) days with a total of 99,681 catheter days (CD). There were no differences in early (within first 30 days after TCVC placement) and overall CLABSI rates between neutropenic and non-neutropenic patients (HR 1.250, p = 0.502; HR 1.633, p = 0.143). We identified female sex (HR 2.640, p = 0.006) and the use of TCVC for treatment of relapsed leukemia (HR 4.347, p < 0.0001) as risk factors for early CLABSI and the use of double-lumen catheters (HR 2.607, p = 0.003) and use of TCVCs during leukemia relapse (HR 2.004, p = 0.005) for overall study period.ConclusionThe placement of TCVC in children with neutropenia undergoing anticancer therapy for acute leukemia is safe and not associated with an elevated rate of CLABSI.

PATTERNS OF COMPLETE BLOOD COUNTS (CBC) IN PATIENTS WITH COVID19 INFECTION

Background: COVID-19 is an ongoing pandemic caused by virus SARS-CoV-2. Many studies worldwide have documented hematological alterations in COVID-19. The present study also aimed to assess the CBC parameters in COVID-19 patients. Material And Methods: It was an observational study conducted in the Department of Pathology, Govt. Medical College, Jammu. COVID-19 patients admitted in the hospital were included in the study. Demographic details and clinical status were noted. EDTA anticoagulated blood samples received were processed on automated 5-part hematology analyzer for CBC. Various parameters obtained were evaluated and also compared with clinical severity of the patients. Results were tabulated and analysed statistically. Results: The study included 304 hospitalized COVID-19 patients. Males were 219 (72%) and females were 85 (28%). Median 6 age of patients was 55 years. Mean hemoglobin concentration was 12.05 g/dl (SD-1.93), mean RBC count was 4.21x10 /µL (SD3 3 0.69). Mean WBC count was 9.66x10 /µL (SD-4.80), mean absolute neutrophil count was 7.87x10 /µL (SD-4.63), mean absolute 3 3 lymphocyte count was 1.22x10 /µL (SD-0.77), mean absolute monocyte count was 0.52x10 /µL (SD-0.29), mean absolute 3 eosinophil count was 0.04 x10 /µL(SD-0.10). Mean NLR was 10.03 (SD-12.27), mean LMR was 2.84 (SD-2.02), mean PLR was 3 220.16 (SD-208.46). Mean platelet count was 187x10 /µL (SD-97.78). Patients with severe disease show signicantly raised WBC count and absolute neutrophil count, signicantly decreased absolute lymphocyte count, signicantly higher eosinophil count, NLR, PLR and signicantly decreased LMR with no signicant difference in absolute monocyte count and platelet count. Conclusion: Routine monitoring of CBC parameters in COVID – 19 patients during the course of illness is a simple, rapid means to assess disease severity and progression in these patients.

Low peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is associated with increased tumor T-cell infiltration and favorable outcomes to first-line pembrolizumab in non-small cell lung cancer

BackgroundAn elevated peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is a negative prognostic marker for patients with non-small cell lung cancer (NSCLC) receiving chemotherapy and immune checkpoint inhibitors. Whether dNLR is also associated with clinical outcomes to first-line pembrolizumab among patients with NSCLC and a programmed cell death ligand 1 (PD-L1) Tumor Proportion Score (TPS) of ≥50% is uncertain. How dNLR relates to the tumor immune microenvironment is also unclear.MethodsIn two participating academic centers, we retrospectively analyzed the dNLR (defined as the absolute neutrophil count/white cell count – absolute neutrophil count) prior to initiation of first-line pembrolizumab in patients with metastatic NSCLC and a PD-L1 TPS ≥50% and lacking genomic alterations in EGFR and ALK. An unbiased recursive partitioning algorithm was used to investigate an optimal dNLR cut-off with respect to objective response rate (ORR). Multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1 was performed on a separate cohort of NSCLCs to determine the immunophenotype associated with dNLR.ResultsA total of 221 patients treated with first-line pembrolizumab were included in this study. The optimal dNLR cut-off to differentiate treatment responders from non-responders was 2.6. Compared with patients with a dNLR ≥2.6 (n=97), patients with dNLR <2.6 (n=124) had a significantly higher ORR (52.4% vs 24.7%, p<0.001), a significantly longer median progression-free survival (mPFS 10.4 vs 3.4 months, HR 0.48, 95% CI 0.35 to 0.66, p<0.001), and a significantly longer median overall survival (mOS 36.6 vs 9.8 months, HR 0.34, 95% CI 0.23 to 0.49, p<0.001). After adjusting for age, sex, tobacco use, performance status, histology, serum albumin level, oncogenic driver status, and PD-L1 distribution (50%–89% vs ≥90%), a dNLR <2.6 was confirmed to be an independent predictor of longer mPFS (HR 0.47, 95% CI 0.33 to 0.67, p<0.001) and mOS (HR 0.32, 95% CI 0.21 to 0.49, p<0.001). Among advanced NSCLC samples with a PD-L1 TPS of ≥50%, those with a dNLR <2.6 had significantly higher numbers of tumor-associated CD8+, FOXP3+, PD-1 +immune cells, and PD-1 +CD8+T cells than those with a dNLR ≥2.6.ConclusionsAmong patients with NSCLC and a PD-L1 TPS ≥50%, a low dNLR has a distinct immune tumor microenvironment and more favorable outcomes to first-line pembrolizumab.

Investigation of the Neutrophil-to-lymphocyte Ratio and Platelet-to-lymphocyte Ratio in Patients with Neuromyelitis Optica Spectrum Disorders

Background: This study aimed to explore the differences in the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with neuromyelitis optica spectrum disorders (NMOSDs) as well as their relationship with the onset of the diseases.Methods: The clinical data, laboratory findings, and imaging data of patients with NMOSD admitted to Perking University Third Hospital from January 2015 to December 2020 were retrospectively analyzed. Routine blood tests of patients performed within one week of the appearance of new clinical symptoms or imaging lesions were collected to calculate the NLR and PLR. The routine blood test of the patients in remission was performed more than 6 months after the patients stopped hormone use. The NLR and PLR of patients were compared with those of 100 healthy subjects undergoing physical examinations.Results: A total of 55 patients with NMOSD were enrolled. 44 patients with NMOSD were followed up. In patients with NMOSD, the white blood cell (WBC) count, absolute neutrophil count, and NLR were significantly higher than those in patients in remission and the controls, while the absolute lymphocyte count was significantly lower than that in patients in remission and the controls. In patients with NMOSD in remission, there were no statistically significant differences in the WBC count, absolute neutrophil count, absolute lymphocyte count, or NLR compared with the controls. The PLR of patients with NMOSD in the attack stage was significantly higher than that of the controls, while the PLR of patients with NMOSD in remission was not significantly different from that of the attack stage and the controls. There were no statistically significant differences between APQ4 (+) and APQ4 (-) in patients with NMOSD at the attack stage in the WBC count, absolute neutrophil count, absolute lymphocyte count, platelet count, NLR or PLR. ROC analysis of NLR and PLR for the diagnosis of inflammatory changes in NMOSD at the attack stage and controls: The ROC curve was plotted using NLR and PLR as dependent variables. In patients with NMOSD, the AUC was 0.806 for NLR and 0.612 for PLR. ROC analysis of NLR and PLR for the diagnosis of inflammatory changes in NMOSD at the attack stage and remission stage. The AUC was 0.728 for NLR and 0.594 for PLR.Conclusion: Patients with NMOSD had significantly higher WBC counts, absolute neutrophil counts and NLRs, and elevated NLRs were correlated with inflammatory activity in NMOSD.

Association between Early Absolute Neutrophil Count and Level of D-Dimer among Patients with COVID-19 Infection in Central Taiwan

Thromboembolism is a critical event in patients with coronavirus disease (COVID)-19 infection and highly associated with neutrophil extracellular traps. D-dimer has been found to be an essential thromboembolism-associated biomarker; however, the association between absolute neutrophil count (ANC) and level of D-dimer in patients with COVID-19 infection remains unclear. In this study, we enrolled consecutive patients with COVID-19 admitted to Taichung Veterans General Hospital (TCVGH), a referral center in central Taiwan with 20 airborne infection isolation rooms. Spearman correlation was used to determine the association between ANC and level of D-dimer in distinct time periods. A total of 28 consecutive patients with COVID-19 infection were enrolled, and 32.1% (9/28) of them required mechanical ventilation. Patients requiring mechanical ventilation had a higher ANC (8225 vs. 3427/µL, p < 0.01) and levels of D-dimer (6.0 vs. 0.6 mg/L, p < 0.01) compared with those without mechanical ventilation. Notably, we identified five patients with image-proven thromboembolic events during the hospital course, with the number of patients with pulmonary embolism, venous thrombosis and acute ischemic stroke were 2, 1, and 2, respectively. We found that ANC within 4 days correlated with the level of D-dimer to a moderate level (r = 0.71, p < 0.05), and the association between ANC and D-dimer no longer exist after day 5. In conclusion, we found highly prevalent thromboembolic events among patients with severe COVID-19 infection in central Taiwan and identified the association between early ANC and D-dimer. More studies are warranted to elucidate the underlying mechanism.

COVID-19 mortality prediction model, 3C-M, built for use in resource limited settings - understanding the relevance of neutrophilic leukocytosis in predicting disease severity and mortality

In this study, a combination of clinical and hematological information, collected on day of presentation to the hospital with pneumonia, was evaluated for its ability to predict severity and mortality outcomes in COVID-19. Ours is a retrospective, observational study of 203 hospitalized COVID-19 patients. All of them were confirmed RT-PCR positive cases. We used simple hematological parameters (total leukocyte count, absolute neutrophil count, absolute lymphocyte count, neutrophil to lymphocyte ration and platelet to lymphocyte ratio); and a severity classification of pneumonia (mild, moderate and severe) based on a single clinical parameter, the percentage saturation of oxygen at room air, to predict the outcome in these cases. The results show that a high absolute neutrophil count on day of onset of pneumonia symptoms correlated strongly with both severity and survival in COVID-19. In addition, it was the primary driver of an initial high neutrophil-to-lymphocyte ratio (NLR) observed in patients with severe disease. The effect of low lymphocyte count was not found to be very significant in our cohort. Multivariate logistic regression was done using Python 3.7 to assess whether these parameters can adequately predict survival. We found that clinical severity and a high neutrophil count on day of presentation of pneumonia symptoms could predict the outcome with 86% precision. This model is undergoing further evaluation at our centre for validation using data collected during the second wave of COVID-19. We present the relevance of an elevated neutrophil count in COVID-19 pneumonia and review the advances in research which focus on neutrophils as an important effector cell of COVID-19 inflammation.