Changes in Peripheral Immune Cells after the Third Dose of SARS-CoV-2 mRNA-BNT162b2 Vaccine and Disease Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors: A Prospective Analysis of the Vax-on-Third-Profile Study.

BACKGROUND: Anti-SARS-CoV-2 mRNA vaccines can deeply affect cell-mediated immune responses in immunocompromised recipients, including cancer patients receiving active treatments. The clinical implications of changes in peripheral blood lymphocyte subsets following the third dose of mRNA-BNT162b2 vaccination (tozinameran) in patients on immune checkpoint blockade are not fully understood. We conducted a prospective analysis of the Vax-On-Third-Profile study to evaluate the impact of circulating lymphocyte dynamics on disease outcomes in this subgroup of patients. METHODS: Recipients of booster dosing who had received before vaccination at least one course of an anti-PD-1/PD-L1 treatment for an advanced solid tumor were eligible. Immunophenotyping of peripheral blood was performed before the third dose of tozinameran (timepoint-1) and four weeks later (timepoint-2) to quantify the absolute counts of lymphocyte subpopulations, including CD3+CD4+ T cells, CD3+CD8+ T cells, B cells, and NK cells. Logistic regression was used to analyze the relationship between lymphocyte subsets and durable clinical benefit (DCB). The log-rank test and Cox regression model were applied to evaluate the relationship between lymphocyte subpopulations and both vaccine-related time-to-treatment failure (V-TTF) and overall survival (OS). RESULTS: We included a total of 56 patients with metastatic disease who were given a third dose of tozinameran between 23 September and 7 October 2021 (median age: 66 years; male: 71%). Most recipients had a diagnosis of lung cancer and were being treated with pembrolizumab or nivolumab. Compared to baseline, the third immunization resulted in an incremental change in the median counts of all lymphocyte subpopulations, which was statistically significant only for NK cells (p < 0.001). A significant correlation was found between NK cell counts and DCB at timepoint-2 (p < 0.001). Multivariate logistic regression analysis of DCB confirmed the predictive significance of high-level NK cell counts (p = 0.020). In multivariate Cox regression analysis, high-level NK cell counts independently predicted longer V-TTF [HR 0.34 (95% CI 0.14-0.80), p = 0.014] and OS [HR 0.36 (95% CI 0.15-0.89), p = 0.027]. CONCLUSIONS: Our data suggest expansion of NK cell counts as the most noteworthy change in circulating lymphocytes after the third dose of tozinameran in cancer patients receiving PD-1/PD-L1-targeted agents. This change correlated with enhanced therapeutic efficacy, improving the rate of disease control, and prolonging survival outcomes. Similar findings have not been previously reported, implying that they have proof-of-concept value and warrant further confirmation.

Immune-related adverse events and disease outcomes after the third dose of SARS-CoV-2 mRNA-BNT162b2 vaccine in cancer patients receiving immune checkpoint inhibitors.

BACKGROUND: The clinical implications of the third dose of coronavirus disease 2019 (COVID-19) vaccines in patients receiving immune checkpoint inhibitors are currently unknown. We performed a prospective analysis of the Vax-On-Third study to investigate the effects of antibody response on immune-related adverse events (irAEs) and disease outcomes. METHODS: Recipients of the booster dose of SARS-CoV-2 mRNA-BNT162b2 vaccine who had received at least one course of an anti-PD-1/PD-L1 treatment before vaccination for an advanced solid malignancy were eligible. RESULTS: The current analysis included 56 patients with metastatic disease (median age: 66 years; male: 71%), most of whom had a lung cancer diagnosis and were being treated with pembrolizumab- or nivolumab-based regimens. The optimal cut-point antibody titer of 486 BAU/mL allowed a dichotomization of recipients into low-responders (Low-R, < 486 BAU/mL) or high-responders (High-R, ≥ 486 BAU/mL). After a median follow-up time of 226 days, 21.4% of patients experienced moderate to severe irAEs without any recrudescence of immune toxicities preceding the booster dose. The frequencies of irAE before and after the third dose did not differ, but an increase in the cumulative incidence of immuno-related thyroiditis was observed within the High-R subgroup. On multivariate analysis, an enhanced humoral response correlated with a better outcome in terms of durable clinical benefit, which resulted in a significant reduction in the risk of disease control loss but not mortality. CONCLUSIONS: Our findings would strengthen the recommendation not to change anti-PD-1/PD-L1 treatment plans based on current or future immunization schedules, implying that all these patients should be closely monitored.

Treatment in patients with acute myeloid leukemia/high-risk myelodysplastic syndrome with hypomethylating agents: Day-hospital management compared to home care setting.

OBJECTIVES: Aim of the study was to evaluate the role of a Domiciliary Hematologic Care Unit (DHCU) compared to standard DH setting in the active frontline treatment with hypomethylating agents (HMAs) +/- venetoclax of frail patients with acute myelogenous leukemia/high-risk myelodysplastic syndromes (AML/HR-MDS). METHODS: All patients with newly diagnosed AML/HR-MDS unfit for intensive care and treated frontline with HMAs from January 2010 to April 2021 were retrospectively included. RESULTS: Among 112 patients (62 AML/50 HR-MDS), 69 (61.6%) were treated in a standard DH setting and 43 (38.4%) were followed by DHCU, allocated to DH or DHCU by responsible physician. Overall response rate was 29/69 (42.0%) in DH versus 19/43 (44.1%) in DHCU (p = .797). Median response duration was 8.7 months (95%CI 7.0-10.3) in DH versus 13.0 months (95%CI 8.3-17.6) in DHCU (p = .460). Infections were also equally reported. Median overall survival of patients treated in DH was 13.7 months (95%CI 9.9-17.4) compared to 13.0 months (95%CI 6.7-19.3) of patients managed by DHCU (p = .753). CONCLUSIONS: Home care management of HMA is feasible and effective, with results similar to standard DH setting: this approach is thus adequate to offer active therapies in frail patients with AML/HR-MDS considered up to now ineligible.

Dynamic changes in peripheral lymphocytes and antibody response following a third dose of SARS-CoV-2 mRNA-BNT162b2 vaccine in cancer patients.

The aim of this study was to evaluate the association of circulating lymphocytes profiling with antibody response in cancer patients receiving the third dose of COVID-19 mRNA-BNT162b2 vaccine. Immunophenotyping of peripheral blood was used to determine absolute counts of lymphocyte subsets, alongside detection of IgG antibodies against receptor-binding-domain (RBD) of the SARS-CoV-2 Spike protein (S1) before booster dosing (timepoint-1) and four weeks afterward (timepoint-2). An IgG titer ≥ 50 AU/mL defined a positive seroconversion response. An IgG titer ≥ 4446 AU/mL was assumed as a correlate of 50% vaccine efficacy against symptomatic infections. A total of 258 patients on active treatment within the previous six months were enrolled between September 23 and October 7, 2021. The third dose resulted in an exponential increase in median anti-RBD-S1 IgG titer (P < 0.001), seroconversion rates (P < 0.001), and 50% vaccine efficacy rates (P < 0.001). According to ROC curve analysis, T helper and B cells were significantly associated with seroconversion responses at timepoint-1, whereas only B cells were relevant to 50% vaccine efficacy rates at timepoint-2. A positive linear correlation was shown between anti-RBD-S1 IgG titers and these lymphocyte subset counts. Multivariate analysis ruled out a potential role of T helper cells but confirmed a significant interaction between higher B cell levels and improved antibody response. These findings suggest that peripheral counts of B cells correlate with humoral response to the third dose of mRNA-BNT162b2 vaccine in actively treated cancer patients and could provide insights into a more comprehensive assessment of vaccination efficacy.

Dynamic Changes of Peripheral NK Cells Predict Outcome in Patients with PD-L1 Positive Non-small-cell Lung Cancer Undergoing Immune Checkpoint Inhibitors as Second-line Therapy.

We evaluated immune cell frequencies in peripheral blood samples of 41 NSCLC patients before and after second-line therapy with anti-PD-1/PD-L1 agents. Changes in lymphocyte subsets and their correlation with clinical response, progression-free survival (PFS), and overall survival (OS) were analyzed. We observed an increase in median values of all lymphocyte subsets, being significant only for NK cells. A correlation was retrieved between higher post-treatment NK cell level and clinical benefit. On multivariate analysis, PD-L1 tumor proportion score ≥1% and higher post-treatment NK cell counts were predictive of longer PFS and OS. Co-presence of these factors was characterized by longer survival.

Peripheral lymphocyte subset counts predict antibody response after SARS-CoV-2 mRNA-BNT162b2 vaccine in cancer patients: Results from the Vax-On-Profile study.

BACKGROUND: The adaptive immune response following COVID-19 vaccination is essential for humoral immunogenicity and clinical protection against symptomatic infections. We present the results of circulating lymphocyte profiling and their correlation with antibody response in cancer patients tested serologically six months after receiving a two-dose schedule of mRNA-BNT162b2 vaccine. METHODS: Absolute counts of lymphocyte subsets were determined using peripheral blood immunophenotyping. We collected samples for flow cytometry analysis alongside quantitative detection of IgG antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S1). An IgG titer ≥ 50 AU/mL defined a positive seroconversion response. RESULTS: 311 patients were evaluable for lymphocyte profiling and serologic testing. A preliminary multivariate analysis revealed that cytotoxic chemotherapy was the most consistent factor associated with lower counts of all lymphocyte subpopulations. T helper and B cells were found to be useful in predicting the occurrence of a positive seroconversion response using ROC curve analysis. A significant positive linear correlation was shown when anti-RBD-S1 IgG titers were compared to these lymphocyte subset counts. Univariate analysis indicated that antibody titers and seroconversion rates were significantly improved in the high-level T and B cell subgroups. Multivariate analysis confirmed these significant interactions, as well as the negative predictive value of immunosuppressive corticosteroid therapy. CONCLUSIONS: These findings suggest that simple and widely available peripheral counts of T helper and B cells correlate with humoral response to mRNA-BNT162b2 vaccine in actively treated cancer patients. Upon validation, our results could provide additional insights into the predictive assessment of vaccination efficacy.

CD200 included in a 4-marker modified Matutes score provides optimal sensitivity and specificity for the diagnosis of chronic lymphocytic leukaemia.

CD200, a transmembrane type Ia glycoprotein belonging to the immunoglobulin superfamily, has been shown to have a differential expression in B-cell neoplasms. Here, we retrospectively assessed the diagnostic relevance of CD200 on 427 patients with B-cell chronic neoplasms in leukemic phase (median age, 69 y; range, 35-97 y). The final diagnosis based on the investigator's assessment was chronic lymphocytic leukaemia (CLL) in 75% of cases and non-CLL in 25% of cases. Sensitivity and specificity for the diagnosis of CLL (vs non-CLL) were calculated for the following markers: CD200, CD5, CD22, CD23, CD79b, FMC7, and SmIg. CD23 was the only marker without a statistically significant difference between the investigator assessment and the flowcytometric analysis. The other markers were unable-when individually evaluated-to discriminate between CLL and non-CLL, requiring the integration into a scoring system. The modified score no. 1 (addition of CD200) showed superimposable sensitivity and specificity compared with the Matutes score. The substitution of CD79b (modified score no. 2), surface membrane immunoglobulins (SmIg) (modified score no. 3), and CD79b and FMC7 (modified score no. 4) with CD200 showed that only the modified score no. 4 had both higher sensitivity and higher specificity compared with standard Matutes score. In conclusion, this work defines a simplified score, compared with the classical Matutes score, for the differential diagnosis of chronic B-cell leukaemia-which only requires 4 markers instead of 5 (CD5, CD23, CD200, and SmIg).

Osteoporosis and risk of fracture, analysis on a population admitted in rehabilitation post-acute.

In the context of osteoporosis the presence of a fragility fracture (vertebral or non-vertebral) constitutes a condition of severe osteoporosis; the most common fractures due to this disease are the responsibility of the proximal femur (hip), spine and wrist representing one of the leading causes of disability in the elderly population, as well as one of the greatest contributions to health care costs. By analyzing a population of patients hospitalized at a rehabilitation ward for post-acute outcomes of hip fracture fragility it was able to observe the effectiveness of preventive intervention, the risk of vertebral fractures and the importance of comorbidity.