Lymphopenia In Patients Research Articles

The adverse effects of trastuzumab-containing regimes as a therapy in breast cancer: A piggy-back systematic review and meta-analysis.

Trastuzumab is a valuable therapy option for women with ERBB2(HER2)+ breast cancer tumours, often used in combination with chemotherapy and alongside other therapies. It is known to have adverse effects, but these have proved difficult to separate from the effects of other concurrent therapies patients are usually taking. This study aims to assess the adverse effects specifically attributable to trastuzumab, and whether they vary by patient subgroup or concurrent therapies. As registered on PROSPERO (CRD42019146541), we used previous systematic reviews as well as the clinicaltrials.gov registry to identify randomised controlled trials in breast cancer which compared treatment regimes with and without trastuzumab. Neoadjuvant, adjuvant and metastatic settings were examined. Data was extracted from those which had, as of July 2022, reported adverse events. Risk of bias was assessed using ROB2. Primary outcomes were adverse events of any type or severity (excluding death). A standard random-effects meta-analysis was performed for each outcome independently. In order to ascertain whether adverse effects differed by individual factors such as age or tumour characteristics, or by use of trastuzumab concurrently with hormone therapy, we examined individual-level patient data for one large trial, HERA. 79 relevant trials were found, of which 20 contained comparable arms of trastuzumab-containing therapy and corresponding matched therapy without trastuzumab. This allowed a comparison of 8669 patients receiving trastuzumab versus 9556 receiving no trastuzumab, which gave a list of 25 statistically and clinically significant adverse effects related to trastuzumab alone: unspecified pain, asthenia, nasopharyngitis, skin disorders (mainly rash), dyspepsia, paraesthesia, infections (often respiratory), increased lacrimation, diarrhoea, myalgia, oedema (limb/peripheral), fever, nose bleeds, cardiac events, insomnia, cough, back pain, dyspnoea, chills, dizziness or vertigo, hypertension, congestive heart failure, increased levels of aspartate aminotransferase, gastrointestinal issues and dehydration. Analysis of individual patient-level data from 5102 patients suggested that nausea is slightly more likely for women taking trastuzumab who are ER+ /also taking hormone therapy than for those who are ER-/not taking hormone therapy; no other potential treatment-subgroup interactions were detected. We found no evidence for significantly increased rates of neutropenia, anaemia or lymphopenia in patients on trastuzumab-containing regimes compared to those on comparable regimes without trastuzumab. This meta-analysis should allow clinicians and patients to better identify and quantify the potential adverse effects of adding trastuzumab to their treatment regime for breast cancer, and hence inform their decision-making. However, limitations include serious risk of bias due to heterogeneity in reporting of the outcomes and the open-label nature of the trials.

Opportunities for correction of immunosuppression in patients with COVID-19

Here, we review thematic publications in available literature sources of the databases PubMed, Scopus, Web of Science, eLibrary, 49 of which were dated of the years 19972022. Analysis of such reports is aimed at assessing features of cytokine storm-induced hyperinflammatory reaction with signs of immunosuppression accompanied by pronounced lymphopenia and lowered count of CD4+T helpers during severe COVID-19. The prognostic factor for unfavorable prognosis was based on the marker of systemic inflammatory reaction correlating with the disease severity the soluble IL-2 receptor as well as the neutrophil-to-lymphocyte ratio and the lymphocyte subset imbalance. An immunosuppressive therapy of severe forms of COVID-19, aimed at weakening the inflammatory response, exacerbates immune dysfunction by suppressing the T cell function, mainly due to Th1 lymphocytes involved in recognizing and eliminating intracellular pathogens particularly viruses. Upon that, cell-mediated immunity becomes compromised that relies on cytotoxic T-lymphocytes, natural killer cells and macrophages. Timely and targeted immunocorrection is required to prevent or reduce the immunosuppression that accompanies a severe disease course and leads to serious and prolonged complications, as well as to association of secondary infections. In fight against the cytokine storm, it is important not to miss a time point of developing immunosuppressive condition that transitions into immunoparalysis as follows from recent publications covering the tactics of treating immune-mediated complications of coronavirus infection. The review discusses opportunities for immunosuppressive therapy along with glucocorticosteroids and monoclonal antibodies blocking IL-6 or cognate receptors. Studies using mesenchymal stem cells (MSCs) to reduce systemic inflammatory response at COVID-19 are outlined in the review. The use of antigen-specific Treg and their combinations with antagonists of tumor necrosis factor- (TNF), interferon- (IFN) as well as low-dose IL-2 in patients with SARS-CoV-2 infection were analyzed. The prognostic perspectives for CAR-T cells and CAR-NK cells technology have been considered as novel therapeutic approaches aimed at training effector cells to recognize the surface SARS-CoV-2 virus spike-like (S) protein. The feasibility of a therapeutic approach is also emphasized by comparatively analyzed of efficacy of using IL-7 or IL-15 during lymphopenia in patients with COVID-19. Here, side effects complicating immunocorrection come to the fore. Critical evaluation of corrected immunosuppressive conditions in patients with COVID-19 in the post-COVID-19 period by using low-dose IL-2 therapy revealed its ability to repair cellular immune response. As a result, a low-dose IL-2 therapy is recommended as a cytokine replacement therapy in such patients with COVID-19 during hyper-to-hypo-inflammatory phase transition in immune response.

Radiation-Induced Lymphopenia in Patients with Breast Cancer after Mastectomy: Results from Chinese POTENTIAL Trial

<h3>Purpose/Objective(s)</h3> POTENTIAL is an ongoing prospective, multicenter, phase III, randomized trial investigating whether internal mammary nodal irradiation (IMNI) improves prognosis in high-risk breast cancer with positive axillary nodes after mastectomy. This study aimed to assess the incidence and risk factors of radiation-induced lymphopenia (RIL) in patients from the POTENTIAL trial, and the trends of lymphocyte recovery from RIL were also evaluated. <h3>Materials/Methods</h3> Eligible patients were randomly assigned to receive IMNI (IMNI group) or not (no IMNI group). The prescribed dose is either 50 Gy in 25 fractions (conventional fractionated radiation therapy, CFRT) or 43.5 Gy in 15 fractions (hypofractionated radiation therapy, HFRT). Peripheral lymphocyte count (PLC) tests were performed before radiation therapy (RT), weekly during RT, at 1, 2 weeks, 3, 6 months and 1 year after RT. The lowest PLC (nadir-PLC) during RT or within two weeks after RT was graded according to CTCAE version 5.0. PLCs were summarized as means ± standard deviation and compared by the t test. <h3>Results</h3> A total of 431 patients treated in 15 Chinese institutions were prospectively evaluated, including 214 (49.7%) patients in IMNI group and 217 (50.3%) in no IMNI group. 291 (67.5%) patients received HFRT and 140 (32.5%) received CFRT. Chest wall ± IMN was irradiated with intensity-modulated RT (IMRT) in 397 (92.1%) patients and electrons in 34 (7.9%) patients. Supra/infraclavicular axillary nodal region was irradiated with IMRT technique in 431 (100%) patients. All patients received a median of 8 cycles of chemotherapy, including neoadjuvant chemotherapy in 153 (35.5%) patients. 52 (12.1%) patients had ≥ Grade 1 lymphopenia before RT. A total of 417 (96.8%) patients developed RIL during RT or within two weeks after RT, grade 1 in 37 (8.6%) patients, grade 2 in 190 (44.1%) patients, grade 3 in 187 (43.4%) patients, and grade 4 in 3 (0.7%) patients. Mean PLC at 1 year after RT was still significantly lower than mean baseline PLC (1.35±0.32 vs. 1.58±0.46, P=0.001). Among 187 patients who had grade ≥ 3 RIL, most (118/122, 96.7%) of them recovered with grade ≤ 2 lymphopenia at 3 months after RT. The mean nadir-PLC was significantly higher in the no IMNI group than in the IMNI group (0.58±0.23 vs. 0.52±0.19, p=0.005). The incidence of grade ≥ 3 RIL was similar in the IMNI and no IMNI group (48.6% vs. 45.3%, p=0.061). In both HFRT and CFRT groups, the PLC declined steadily during RT but started to recover at 1 week after RT. The mean nadir-PLC was significantly higher in the HFRT group than in the CFRT group (0.57±0.22 vs. 0.51±0.18, p=0.011), and the incidence of grade ≥ 3 RIL was significantly higher in the CFRT than in the HFRT group (53.6% vs. 39.50%, p=0.006). Left-sided tumors, low baseline PLC, CFRT and IMRT techniques were risk factors for developing grade ≥ 3 RIL. <h3>Conclusion</h3> The incidence of RIL was high in breast cancer patients receiving IMRT after mastectomy. The risk of grade ≥ 3 RIL is lower with HFRT than with CFRT. IMNI may not increase the risk of grade ≥ 3 RIL.

Severe Radiation-Induced Lymphopenia during Concurrent Chemoradiotherapy for Lung Cancer: External Validation of Two Prediction Models

<h3>Purpose/Objective(s)</h3> Severe radiation-induced lymphopenia in patients undergoing chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is associated with detrimental survival outcomes and decreased efficacy of subsequent immunotherapy. This impact provides a strong incentive to identify patients at high risk who could benefit from lymphopenia-mitigating strategies. At The Christie, a prediction model for grade ≥3 lymphopenia was developed in lung cancer patients. At MDACC, a model for grade 4 lymphopenia was developed in esophageal cancer patients. The aim of this study was to validate both models for predicting grade ≥3 and grade 4 lymphopenia during concurrent CRT in patients with stage III NSCLC. <h3>Materials/Methods</h3> Consecutive patients who underwent concurrent CRT for stage III NSCLC at our comprehensive cancer center between 2019 and 2020 were included. Mildly hypofractionated radiotherapy was administered (24 × 2.75 Gy to primary tumor and 24 × 2.42 Gy to involved lymph nodes). Chemotherapy consisted of daily low-dose cisplatin. The primary outcomes of grade ≥3 and grade 4 lymphopenia were defined as absolute lymphocyte count (ALC) nadirs during CRT of <0.5 and <0.2 K/mL, respectively. Predictors of the Christie model included age, baseline ALC, mean heart and lung doses, and thoracic vertebrae V20Gy. Predictors of the MDACC model were age, baseline ALC, and PTV in interaction with BMI. The prediction models' performance was assessed in terms of discrimination and calibration. <h3>Results</h3> A group of 68 patients was studied in which 51 patients (75%) developed grade ≥3 lymphopenia during CRT, with grade 4 lymphopenia in 9 patients (13%). For prediction of grade ≥3 lymphopenia, application of the Christie and MDACC models yielded c-statistics of 0.82 (95%CI: 0.71-0.94) and 0.85 (95%CI: 0.73-0.97), respectively. For prediction of grade 4 lymphopenia, the Christie and MDACC models yielded c-statistics of 0.68 (95%CI: 0.51-0.86) and 0.78 (95%CI: 0.62-0.94), respectively. Calibration (adjusted for the a-priori risk) demonstrated moderate agreement between the observed and predicted risk for grade ≥3 and grade 4 lymphopenia using the Christie model (Table 1). Good calibration was found using the MDACC model for both grade ≥3 and grade 4 risk predictions. <h3>Conclusion</h3> The MDACC prediction model for severe radiation-induced lymphopenia demonstrated superior external performance in the setting of concurrent CRT in patients with stage III NSCLC as compared with the Christie prediction model. As such, the prediction model may aid in identifying thoracic cancer patients at high risk for severe lymphopenia.

EP05.01-010 External Validation of Two Prediction Models for Severe Radiation-induced Lymphopenia during Concurrent Chemoradiotherapy for Lung Cancer

Severe radiation-induced lymphopenia in patients undergoing chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is associated with detrimental survival outcomes and decreased efficacy of subsequent immunotherapy. This impact provides a strong incentive to identify patients at high risk who could benefit from lymphopenia-mitigating strategies. At The Christie, a prediction model for grade ≥3 lymphopenia was developed in lung cancer patients. At MDACC, a model for grade 4 lymphopenia was developed in esophageal cancer patients.

Prevalence of lymphopenia in patients with Fontan circulation without protein losing enteropathy

BackgroundLymphopenia without protein losing enteropathy (PLE) is found in patients with Fontan circulation on long term follow up. Fontan associated liver disease (FALD) is a serious complication in these patients. ObjectiveThe objective of this study is to assess the prevalence of asymptomatic lymphopenia in patients with Fontan circulation and its associations with other hematological and liver function parameters. MethodsRetrospective cohort study involving 48 patients with Fontan circulation. All patients had yearly complete blood count and liver function tests performed during their routine follow up. Patients with PLE were excluded. Lymphopenia defined as absolute lymphocyte count (ALC) < 1000 cells/μL and its correlation with other hematological and liver enzymes were studied. ResultsLymphopenia was present in 9 (18.75 %) patients and was found after 10 years of post Fontan duration in 7 patients, at 5.5 years in 1 patient, and at 6.7 years in 1 patient. The mean ALC of patients with and without lymphopenia was 748 ± 190.8 versus 2053 ± 844.9 cells/μL (P = 0.002). Patients with lymphopenia had lower total white blood cell count (3.9 ± 1.9 versus 6.02 ± 2.1 × 109/L, P = 0.006) and platelet counts (180.7 ± 94.6 versus 253.6 ± 80.3 × 109/L, P = 0.02). Lymphopenia correlated with elevated aspartate transaminase (AST) (43.2 ± 9 versus 29.8 ± 6.98 IU/L, P = 0.006), Gamma glutamyl transpeptidase (GGTP) (69.5 ± 61 versus 29.8 ± 6.98 IU/L, P = 0.04) and AST – platelet ratio index (APRI) (0.7 ± 0.5 versus 0.3 ± 0.1, P = 0.001). ConclusionAsymptomatic lymphopenia is common in patients with Fontan circulation. Identification of lymphopenia with associated thrombocytopenia, elevated AST, GGTP, and APRI are necessary as these are the markers of hepatic fibrosis. Further investigations, such as MRI and liver biopsy, can be considered in these patients.

SP2.2.5 Sarcopenia and lymphopenia in patients undergoing chemotherapy and surgery for oesophageal cancer. Can prehabilitive exercise be used to reverse the decline?

Abstract Introduction Studies have demonstrated that sarcopenia and lymphopenia are associated with poor oncological and survival outcomes in patients with oesophageal cancer. Neo-adjuvant chemotherapy (NAC) for oesophageal cancer is associated with muscle wasting and sarcopenic obesity. Lymphocytes are essential component of anti-tumour immunity. This study assesses the body composition and peripheral blood markers in patients undergoing a structured exercise program, during neo-adjuvant chemotherapy, as part of a non-randomised trial. Methods A prospective non-randomised trial compared a standard care pathway to a structured prehabilitation exercise programme undertaken before and during NAC and surgery for oesophageal cancer. CT determined body composition analysis and peripheral blood markers were collected at multiple timepoints. Results Comparison of the Intervention (n=21) and Control (n=19) showed Fat Free Mass increased during NAC in the intervention group (16.1 to 17.3 kg/m2; control 15.4 vs. 14.8 kg/m2, p=0.056) and Fat Mass Index to Fat Free Mass Index ratio (-5.51% Intervention, 10.74% control p=0.043) decreased in the treatment group. Lymphocyte subsets showed a marked increase in the intervention group after chemotherapy (CD3 10.92% vs 84.92% p=0.015, CD4 13.27% vs 107.75% p=0.0147, CD8 12% vs 69% p=0.033). Conclusion A structured exercise programme prior to neoadjuvant chemotherapy reverses levels of sarcopenia, reduces visceral adiposity and increases levels of lymphocytes in patients with oesophageal cancer. Further studies will be needed to assess the oncological and clinical implications.

Efficacy of Thymosin α1 in Management of Radiation Pneumonitis in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiotherapy: A Phase 2 Clinical Trial (GASTO-1043)

To evaluate the efficacy of thymosin α1 in management of radiation pneumonitis (RP) in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with concurrent chemoradiotherapy (CCRT). This phase 2, single-arm trial enrolled patients with unresectable LANSCLC of 18 to 75 years' old and an Eastern Cooperative Oncology Group performance status of 0 to 1. Eligible patients received definitive CCRT and weekly thymosin α1 from the start of CCRT until 2 months after CCRT. Patients were administered 51 Gy in 17 daily fractions or 40 Gy in 10 daily fractions in the first course followed by a re-evaluation and those patients without disease progression had an adaptive plan of 15 Gy in 5 daily fractions or 24 Gy in 6 daily fractions as a boost. Concurrent chemotherapy consisted of weekly docetaxel (25 mg/m2) and nedaplatin (25 mg/m2) during radiation therapy. The primary endpoint was the incidence of Grade (G) ≥2 RP. Secondary endpoints included the incidence of late pulmonary fibrosis, total lymphocyte count (TLC), serum C-reactive protein (CRP) levels, and the composition of gut microbiota. TLC and CRP data were collected at baseline, 2 to 3 weeks during CCRT, the end of CCRT, 2 and 6 months after CCRT. Fecal samples were collected at baseline and the end of CCRT. Patients treated with CCRT but without thymosin α1 intervention during the same period were selected as the control group by the propensity score matching method. Sixty-nine patients were enrolled in the study, and another 69 patients were selected as the control group. The incidence of G≥2 RP was lower in the study group compared with control cases (36.2% vs 53.6%, P=.040). G1 late pulmonary fibrosis occurred in 2 (3.7%) patients of the control group compared with no event in the study group (P=.243). Compared with the control group, the incidence of G3 to G4 lymphopenia (19.1% vs 62.1%, P < .001) was lower, and the median TLC nadir (0.51 k/µL vs 0.30 k/µL, P < .001) was higher in the study group. The proportion of patients with maximum CRP ≥100 mg/L was lower in the study group (13.8% vs 29.7% P=.029). The diversity and community composition of the gut microbiota were not significantly different between the 2 groups. Administration of thymosin α1 during and after CCRT was associated with significant reductions in G≥2 RP and G3 to G4 lymphopenia in patients with LANSCLC compared with historic controls.

Potential Determinants for Radiation-Induced Lymphopenia in Patients With Breast Cancer Using Interpretable Machine Learning Approach.

Radiation-induced lymphopenia is known for its survival significance in patients with breast cancer treated with radiation therapy. This study aimed to evaluate the impact of radiotherapy on lymphocytes by applying machine learning strategies. We used Extreme Gradient Boosting (XGboost) to predict the event of lymphopenia (grade≥1) and conduced an independent validation. Then, we induced feature attribution analysis (Shapley additive explanation, SHAP) in explaining the XGboost models to explore the directional contribution of each feature to lymphopenia. Finally, we implemented the proof-of-concept clinical validation. The results showed that the XGboost models had rigorous generalization performances (accuracies 0.764 and ROC-AUC 0.841, respectively) in the independent cohort. The baseline lymphocyte counts are the most protective feature (SHAP = 5.226, direction of SHAP = -0.964). Baseline platelets and monocytes also played important protective roles. The usage of taxane only chemotherapy was less risk on lymphopenia than the combination of anthracycline and taxane. By the contribution analysis of dose, we identified that firstly lymphocytes were sensitive to a radiation dose less than 4Gy; secondly the irradiation volume was more important in promoting lymphopenia than the irradiation dose; thirdly the irradiation dose promoted the event of lymphopenia when the irradiation volume was fixed. Overall, our findings paved the way to clarifying the radiation dose volume effect. To avoid radiation-induced lymphopenia, irradiation volume should be kept to a minimum during the planning process, as long as the target coverage is not compromised.

Do Low-Density Granulocytes Induce Lymphopenia in Patients with COVID-19?

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CD47-SIRPα Controls ADCC Killing of Primary T Cells by PMN Through a Combination of Trogocytosis and NADPH Oxidase Activation

Immunotherapies targeting the “don’t eat me” myeloid checkpoint constituted by CD47 SIRPα interaction have promising clinical potential but are limited by toxicities associated with the destruction of non-tumor cells. These dose-limiting toxicities demonstrate the need to highlight the mechanisms of anti–CD47-SIRPα therapy effects on non-tumor CD47-bearing cells. Given the increased incidence of lymphopenia in patients receiving anti-CD47 antibodies and the strong ADCC (antibody-dependent cellular cytotoxicity) effector function of polymorphonuclear cells (PMNs), we investigated the behavior of primary PMNs cocultured with primary T cells in the presence of anti-CD47 mAbs. PMNs killed T cells in a CD47-mAb–dependent manner and at a remarkably potent PMN to T cell ratio of 1:1. The observed cytotoxicity was produced by a novel combination of both trogocytosis and a strong respiratory burst induced by classical ADCC and CD47-SIRPα checkpoint blockade. The complex effect of the CD47 blocking mAb could be recapitulated by combining its individual mechanistic elements: ADCC, SIRPα blockade, and ROS induction. Although previous studies had concluded that disruption of SIRPα signaling in PMNs was limited to trogocytosis-specific cytotoxicity, our results suggest that SIRPα also tightly controls activation of NADPH oxidase, a function demonstrated during differentiation of immature PMNs but not so far in mature PMNs. Together, our results highlight the need to integrate PMNs in the development of molecules targeting the CD47-SIRPα immune checkpoint and to design agents able to enhance myeloid cell function while limiting adverse effects on healthy cells able to participate in the anti-tumor immune response.

013 An exploration of risk factors for dimethyl fumarate-induced lymphopenia in patients with multiple sclerosis

Dimethyl fumarate (DMF) is a commonly used first-line immunomodulatory drug used for the treatment of relapsing-remitting multiple sclerosis. It has been found to cause lymphopenia in a proportion of patients, and the incidence of several cases of progressive multifocal leukoencephalopathy in patients taking DMF has given rise to concerns regarding its safety.The purpose of this study was to identify risk factors for DMF-induced lymphopenia.: We performed ret- rospective analysis of 323 patients prescribed DMF in our NHS Lothian MS clinic in Edinburgh since the drug was introduced in 2014.Older age (&gt;45), and lower baseline absolute lymphocyte count (ALC) both increased the risk of devel- oping grade 2 lymphopenia, with the latter also increasing the risk of severe, grade 3 lymphopenia. We also found that the decline in ALC happens within the first 6 months of DMF treatment, and after this point it no longer declines but has a tendency to rise.Increased vigilance with ALC monitoring is required in the first 6 months, especially in those who are older and have a low baseline ALC. By knowing the risk factors for DMF-induced lymphopenia, clinicians will be able to make more informed decisions when choosing a drug to start a patient on with multiple sclerosis.s1504225@sms.ed.ac.uk

Lymphopenia in patients affected by SARS-CoV-2 infection is caused by margination of lymphocytes in large bowel: an [18F]FDG PET/CT study

BackgroundTo investigate the cause of lymphopenia in patients with newly diagnosed COVID-19, we measured [18F]FDG uptake in several tissues, including the ileum, right colon, and caecum at diagnosis and after recovery and correlated these measurements with haematological parameters.MethodsWe studied, by [18F]FDG PET/CT, 18 newly diagnosed patients with COVID-19. Regions of interest were drawn over major organs and in the terminal ileum, caecum, and right colon, where the bowel wall was evaluable. Five patients were re-examined after recovery, and three of them also performed a white blood cell scan with 99mTc-HMPAO-WBC on both occasions. Complete blood count was performed on both occasions, and peripheral blood lymphocyte subsets were measured at diagnosis. Data were analysed by a statistician.ResultsPatients had moderate severity COVID-19 syndrome. Basal [18F]FDG PET/CT showed focal lung uptake corresponding to hyperdense areas at CT. We also found high spleen, ileal, caecal, and colonic activity as compared to 18 control subjects. At recovery, hypermetabolic tissues tended to normalize, but activity in the caecum remained higher than in controls. Regression analyses showed an inverse correlation between CD4 + lymphocytes and [18F]FDG uptake in the caecum and colon and a direct correlation between CD8 + lymphocytes and [18F]FDG uptake in lungs and bone marrow. WBC scans showed the presence of leukocytes in the caecum and colon that disappeared at recovery.ConclusionsThese findings indicate that lymphopenia in COVID-19 patients is associated with large bowel inflammation supporting the hypothesis that CD4 + lymphocytes migrate to peripheral lymphoid tissues in the bowel.

123: SEVERE LYMPHOPENIA ACQUIRED DURING CHEMORADIOTHERAPY FOR ESOPHAGEAL CANCER: INCIDENCE AND EXTERNAL VALIDATION OF A PREDICTION MODEL

Abstract Background and aim The incidence of grade 4 lymphopenia in patients treated with chemoradiotherapy (CRT) according to Chemoradiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) regimen is unclear. The primary aim was to determine the incidence of grade 4 lymphopenia during CROSS for esophageal cancer. Secondary aims were to externally validate a prediction model for grade 4 lymphopenia and compare overall survival between patients with and without grade 4 lymphopenia. Methods Patients who underwent CRT for esophageal cancer between 2014 and 2019 were eligible for inclusion. Patients with a planned radiation dose of 41.4 Gy (CROSS) or 50.4 Gy (‘extended-CROSS’) and concurrent carboplatin and paclitaxel were included. The primary outcome was the incidence of grade 4 lymphopenia during CRT defined according to Common Terminology Criteria for Adverse Events version 5.0 (i.e. lymphocyte count nadir &amp;lt;0.2 μL). The secondary outcome measures were the prediction model’s external performance (i.e. discrimination and calibration). Overall survival for patients with versus without grade 4 lymphopenia was compared using Kaplan–Meier analysis. Results A total of 219 patients were included of whom 176 patients (80%) underwent CROSS and 43 patients (20%) extended-CROSS. The incidence of grade 4 lymphopenia was 11% in CROSS and 33% in extended-CROSS (P &amp;lt; 0.001). External discrimination yielded a c-statistic of 0.80 (95% confidence interval: 0.70–0.89). External calibration of the model was poor in CROSS but fair in extended-CROSS. Adjusted calibration using intercept correction (adjusted for the lower a-priori risk for grade 4 lymphopenia in CROSS) showed fair agreement between the observed and predicted risk for grade 4 lymphopenia. Median overall survival in patients with versus without grade 4 lymphopenia was 12.7 versus 42.5 months (P = 0.045). Conclusion The incidence of grade 4 lymphopenia is significantly higher in esophageal cancer patients receiving extended-CROSS compared to those receiving CROSS. The prediction model demonstrated good external performance in the setting of the CROSS-regimen and could be used to identify patients at high-risk for grade 4 lymphopenia who might be eligible for lymphopenia–mitigating strategies.

The Relationship between Severity of Lung Involvement Based on High-Resolution Computed Tomography (HRCT) Findings and Lymphopenia in Patients with COVID-19

Background: Lymphopenia may reflect the degree of lung injury in patients with coronavirus disease 2019 (COVID-19). Given that few studies have been conducted in this regard, this study aimed to evaluate the association between severity of lung involvement based on high-resolution computed tomography (HRCT) findings and lymphocyte count in patients with COVID-19. Materials and Methods: This descriptive-analytical study was conducted on 123 patients with COVID-19 from March 2020 to April 2020 in Shahid Sadoughi hospital, Yazd, Iran. Data including age, gender, hospitalization ward, lymphocyte count, and computed tomography (CT) scan findings were extracted from medical records. Results: The mean lung involvement score was 36.8±22.34. The mean lymphocyte count in these patients was 1229.25±536.80 µL. Lymphopenia was observed in 79 patients (64%). No relationship was seen between HRCT findings and lymphopenia in patients with COVID-19 (P=0.31). Although a significant relationship was seen between HRCT findings and lymphopenia in females (P&lt;0.05), there was no relationship between HRCT findings and lymphopenia, regarding age, male gender, and hospitalization wards (P&gt;0.05). Conclusion: There was no significant relationship between HRCT and lymphopenia findings, and parameters such as age and inpatient ward in patients with Covid-19. However, there was an interesting relationship between lymphopenia and lung involvement in women; therefore, more studies are needed to prove this hypothesis.

Reduced Counts of Various Subsets of Peripheral Blood T Lymphocytes in Patients with Severe Course of COVID-19.

This study was intended to define T lymphocyte subsets in different clinical groups of COVID-19-infected patients to explore the interaction between T cell-mediated immune response and the severity of COVID-19 course. Lymphopenia in patients with severe COVID-19 was found. In patients with severe COVID-19 course, the absolute counts of CD3+, CD4+, and CD8+ T lymphocytes at admission were lower than on day 14 after discharge. Further analysis showed that the older were the patients with COVID-19, the more likely they developed severe infection. The results confirmed the significance of T lymphocytes in the clearance of the COVID-19.

Risk of Bacterial, Viral, and Fungal Infections in Patients With Solid Malignant Tumors Treated With Curative Intent Radiation Therapy

PurposeThe incidence, etiology, and association of infections with radiation therapy (RT)–induced lymphopenia in patients with solid tumors is not well elucidated. Methods and MaterialsWe identified possible, probable, and definite infections caused by bacteria, fungi, and viruses, combining data on medication, microbiology, and diagnoses. Definite infections had either a diagnosis or a positive microbiological isolation. We analyzed the incidence and adjusted incidence-rate ratio of infections in the year after the start of RT among patients who received RT plus chemotherapy and RT monotherapy, by type of infection and according to the degree of RT-induced lymphopenia. ResultsA total of 4450 of 6334 (70.3%) patients experienced 11264 infections overall; 1424 (22.5%) patients developed 2104 definite infections in the first year after RT. Infections were more frequent among patients who received RT plus chemotherapy (2590 of 3469; incidence: 16.5 [95% confidence interval {CI}, 16.1-17.0], per 100 patient-years) compared with patients who received RT monotherapy (1860 of 2865; incidence: 12.7 [95% CI, 12.3-13.2]). The incidence of infection was highest in the first 3 months overall (28.2 vs 18.0 in patients who received RT plus chemotherapy compared with those who received RT monotherapy) and for definite infections (4.7 vs 3.8). The proportion of specific bacterial infections were similar among patients who received RT plus chemotherapy versus those who received RT monotherapy. Urinary tract infections were the most frequent (51.2% vs 56.2%), followed by pneumonias (24.1% vs 22.4%). Viral and fungal infections were more frequent among patients who received RT plus chemotherapy, but they were uncommon. In multivariable analyses, patients who received RT plus chemotherapy with a lymphopenia grade of 1-2 or ≥3 versus no lymphopenia at end of RT had an increased risk of bacterial infections 0 to 3 months after RT (incidence rate ratio, 1.45 [95% CI, 1.06-1.97] and 1.71 [95% CI, 1.26-2.34], respectively). Limiting to definite bacterial infections, the incidence rate ratio for lymphopenia grade ≥3 versus no lymphopenia was 2.66 (95% CI, 1.40-5.03). ConclusionsThe incidence of bacterial infections 0 to 3 months after RT plus chemotherapy for solid tumors was high, especially among patients with RT-induced lymphopenia grade 1-2 and ≥3.

Immunological Predictors of Dimethyl Fumarate-Induced Lymphopenia.

Treatment with dimethyl fumarate (DMF) leads to lymphopenia and infectious complications in a subset of patients with multiple sclerosis (MS). Here, we aimed to reveal immune markers of DMF‐associated lymphopenia. This prospective observational study longitudinally assessed 31 individuals with MS by single‐cell mass cytometry before and after 12 and 48 weeks of DMF therapy. Employing a neural network‐based representation learning approach, we identified a CCR4‐expressing T helper cell population negatively associated with relevant lymphopenia. CCR4‐expressing T helper cells represent a candidate prognostic biomarker for the development of relevant lymphopenia in patients undergoing DMF treatment. ANN NEUROL 2022;91:676–681

Early predictive risk factors for dimethyl fumarate-associated lymphopenia in patients with multiple sclerosis

BackgroundLymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy. A pronounced reduction in absolute lymphocyte counts (ALCs) early after treatment initiation has been suggested to be associated with the occurrence of lymphopenia thereafter. ObjectivesTo identify risk factors for DMF-induced lymphopenia and evaluate whether the degree of decrease in the ALCs three months after initiation of DMF treatment is a predictor of the subsequent development of lymphopenia. MethodsIn this real-world Spanish prospective multicenter study conducted in MS patients who started DMF between 2014 and 2019, we analyzed the association between DMF-related lymphopenia and the percentage of early ALCs decline using regression models, considering both, significant lymphopenia (grades 2 + 3) and severe lymphopenia (grade 3). The cutoff values of early ALCs declines were obtained using the ROC curve. ResultsAmong 532 MS patients treated with DMF, 193 (36.3%) developed any grade of lymphopenia. Older age and lower ALCs at treatment onset predicted the risk for lymphopenia but the best predictive risk factor was the reduction of ALCs within the three first months of treatment. Specifically, a reduction in ALCs≥21.2% was associated with a 6.5-fold higher risk of developing significant lymphopenia, and a decrease in ALCs≥40.2% with a 12.7-fold higher risk of developing severe lymphopenia. ConclusionsA pronounced reduction in ALCs early after initiation of DMF in MS patients is the best predictive risk factor for the subsequent development of significant lymphopenia.

Dosimetric Modeling of Lymphopenia in Patients With Metastatic Cancer Receiving Palliative Radiation and PD-1 Immune Checkpoint Inhibitors

PurposeRadiation therapy (RT)–associated lymphopenia may adversely affect treatment outcomes, particularly in the era of immunotherapy. We sought to determine dosimetric factors correlated with lymphopenia after palliative RT in a cohort of patients with advanced cancer treated with anti-PD-1 immune checkpoint inhibitors. Methods and MaterialsWe included patients with metastatic lung cancer, melanoma, or renal cell carcinoma who were treated with either pembrolizumab or nivolumab and received palliative RT to an extracranial site. Baseline and nadir absolute lymphocyte counts (ALCs) within 6 weeks of RT were recorded. Dosimetric factors were extracted from the corresponding dose-volume histograms and also used to model the dose to circulating lymphocytes via a whole-body blood flow model that simulates the spatiotemporal distribution of blood particles in major organs during RT. ResultsWe analyzed 55 patients who underwent 80 total courses of palliative RT; most (94%) were treated with 3-dimensional conformal RT. Doses to the whole body, bone, and large blood vessels (LBVs) were negatively correlated with the ALC nadir, with the strongest correlations seen at V15 (rs, –0.38, –0.43, and –0.37, and P = .0004, .0001, and .0008, respectively). Doses to other organs were not significantly correlated with the ALC nadir. The modeled dose to circulating lymphocytes was also negatively correlated with the ALC nadir and percent ALC change (for D2%, rs, –0.31 and –0.44, and P = .005 and .0001, respectively). Grade ≥3 lymphopenia was associated with LBV V15 (odds ratio [OR], 1.16; 95% CI, 1.07-1.26; P < .001), bone V15 (OR, 1.04; 95% CI, 1.01-1.08; P = .03), body V15 (OR, 1.003; 95% CI, 1.001-1.006; P = .008), and modeled lymphocyte dose (OR, 1.45; 95% CI, 1.16-1.82; P < .001). ConclusionsThe RT dose to the whole body, bone, and LBVs and the modeled dose to circulating lymphocytes were correlated with lymphopenia in patients treated with palliative RT and anti-PD-1 immune checkpoint inhibitors. These findings may inform future radiation planning in this setting.