Safety and Tolerability of an Ad26.RSV.preF-based Vaccine in a Phase 2b Study in Older Adults

Respiratory syncytial virus (RSV) may cause severe lower respiratory tract disease in older adults and there is currently no approved vaccine. We assessed the safety and reactogenicity of an Ad26.RSV.preF-based vaccine in a randomized, double-blind, placebo-controlled Phase 2b proof-of-concept trial in adults aged ≥65 years (CYPRESS; NCT03982199). Prior to the RSV season, participants were randomized 1:1 to receive an Ad26.RSV.preF-based vaccine or placebo. Solicited adverse events (AEs; fatigue, headache, nausea, myalgia, fever, injection site reactions) and unsolicited AEs were assessed from time of vaccination to Day 8 and Day 29, respectively, in a safety subset of 695 participants (vaccine, n=348; placebo, n=347). All participants were followed for serious AEs (SAEs) until the end of the RSV season or 6 months after vaccination, whichever occurred later. A total of 5728 participants were randomized and received vaccine or placebo (n=2891 in each group). In the safety subset, the frequency of solicited AEs and Grade ≥3 solicited AEs was 51.4% and 3.2% in the vaccine group and 20.2% and 0.6% in the placebo group, respectively. The most frequent solicited AEs in the vaccine group were fatigue, myalgia, headache, and injection site pain/tenderness. The rates of unsolicited AEs and Grade ≥3 unsolicited AEs were similar between the vaccine (16.7% and 1.7%) and placebo (14.4% and 1.4%) groups. In the overall study population, the rate of SAEs was similar between groups (vaccine, 4.6%; placebo, 4.7%); none were considered related to the vaccine. The Ad26.RSV.preF-based vaccine was safe and well tolerated in adults aged ≥65 years.

GM-CSF secreting leukemia cell vaccination for MDS/AML after allogeneic HSCT: a randomized double blinded phase 2 trial

Vaccination using irradiated, adenovirus transduced autologous myeloblasts to secrete GM-CSF (GVAX) early after allogeneic hematopoietic stem cell transplantation (HSCT) can induce potent immune responses. We conducted a randomized phase II trial of GVAX after HSCT for MDS-EB or relapsed/refractory AML. Myeloblasts were harvested before HSCT to generate the vaccine. Randomization to GVAX vs. placebo (1:1) was stratified by disease, transplant center, and conditioning. GVHD prophylaxis included tacrolimus and methotrexate. GVAX or placebo started between day +30-45 if there was engraftment and no GVHD. Vaccines were administered SC/ID weekly x 3, then q2 wks x 3. Tacrolimus taper began after vaccine completion. 123 patients enrolled, 92 proceeded to HSCT, and 57 (GVAX 30, Placebo 27) received at least 1 vaccination. No CTC grade ≥ 3 vaccine related adverse events were reported, but injection site reactions were more common after GVAX (10 vs. 1, p=0.006). With a median follow up of 39 months (range, 9-89), 18-month PFS, OS and relapse incidence were 53% vs 55% (p=0.79), 63% vs. 59% (p= 0.86), and 30% vs. 37% (p=0.51) for GVAX and placebo, respectively. NRM at 18 months was 17% vs. 7.7% (p=0.18), Grade II-IV aGVHD at 12 months 34% vs. 12% (p=0.13), and cGVHD at 3 years 49% vs. 57% for GVAX and placebo, respectively, p=0.26. Reconstitution of T, B, and NK cells were not decreased or enhanced by GVAX. There were no differences in serum MICA/B or other immune biomarkers between GVAX and placebo. GVAX does not improve survival after HSCT for MDS/AML. (Clinicaltrials.gov identifier: NCT01773395)

Herpes zoster infection following mRNA COVID-19 vaccine in a patient with ankylosing spondylitis

Since the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) pandemic outbreak, vaccines gained a growing role. Possible vaccine-related side effects range from minor local events to more prominent systemic manifestations up to anaphylactic reactions. A heterogeneous spectrum of cutaneous reactions has been reported, ranging from local injection site reactions to urticarial and morbilliform eruptions, pernio/chilblains and zoster flares. Here, we describe a case of varicella zoster virus reactivation following mRNA coronavirus 2019 vaccine and discuss the available literature upon the topic published so far.

Randomized, Double-Blind, Phase III Study of Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: CONSOLE

PURPOSE We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone. PATIENTS AND METHODS Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, –10% for the difference in the overall CR rate). RESULTS Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, –2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% ( P < .001) and 0.3% versus 3.6% ( P < .001), respectively. CONCLUSION FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.

Safety and preliminary efficacy of the Gam-COVID-Vac vaccine and outcomes of SARS-CoV-2 infection in Russian patients with genitourinary malignancies

Background To our knowledge, there is no clinical data pertaining to COVID-19 outcomes and safety of COVID-19 vaccination in Russian patients with genitourinary (GU) malignancies. Aim of our analysis was to describe the characteristics of the COVID-19 infection course as well as preliminary safety and efficacy of Gam-COVID-Vac vaccine in patients with active GU malignancies. Methods Patients were retrospectively identified at nine cancer centers in different regions. Patients were included if COVID-19 was diagnosed by a polymerase chain reaction. Data from additional patients with GU cancers who had no positive SARS-CoV-2 RT-PCR test before vaccination and who received two doses of Gam-COVID-Vac (Sputnik V) between 11 February and 31 August 2021 were collected for safety assessment. Anonymized data were collected through an online registry covering demographics, treatments, and outcomes. Results The Gam-COVID-Vac vaccine was well tolerated; no grade 3–5 toxicities were reported in 112 vaccinated metastatic GU cancer patients. The most common grade 1 adverse events (81%) were injection site reactions (76%), flu-like illness (68%), and asthenia (49%). Five patients experienced grade 2 chills (4.5%) and 3 patients had grade 2 fever (2.7%). With median follow-up of 6.2 months, two COVID-19 cases were confirmed by RT-PCR test in the vaccine group (of 112 participants; 1.8%). Eighty-eight patients with COVID-19 disease were included in the analysis. The average age as of the study enrollment was 66 (range 39–81) and the majority of patients were male with renal cell carcinoma (RCC). Thirty-six patients (41%) had evidence of metastatic disease, of these 22 patients were receiving systemic therapy. More than half of patients required hospitalization. Fifty-four patients (61%) experienced complications. Sixteen patients who developed COVID-19 pneumonia required mechanical ventilator support. Sixteen patients (18%) died in a median of 23.5 days after the date of COVID-19 diagnosis was established. The 3-month survival rate was 82%. Clinical and/or radiographic progression of cancer during COVID-19 infection or the subsequent 3 months was observed in 10 patients (11.4%). Conclusion Patients with GU malignancies are at increased risk of mortality from COVID-19 infection when compared to the general population. Vaccination could be safe in GU cancer patients. Trial registration: retrospectively registered.

Phase 2 dose-ranging study of the virologic efficacy and safety of the combination COVID-19 antibodies casirivimab and imdevimab in the outpatient setting

Background: The monoclonal antibody combination casirivimab and imdevimab (REGEN-COV®) reduced viral load, hospitalisation, or death when administered 1:1 as an intravenous (IV) dose ≥1200 mg in a phase 3 COVID-19 outpatient study. Availability of subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients. Methods: This is a double-blind, placebo-controlled study of SARS-CoV-2-infected outpatients who were asymptomatic, or symptomatic but without risk factors for severe COVID-19. Patients were randomised to single IV dose (517 patients) of REGEN-COV 300, 600, 1200 or 2400 mg or placebo; or a single SC dose (286 patients) of REGEN-COV 600 or 1200 mg or placebo. The primary endpoint was time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative to SARS-CoV-2 at baseline. Findings: All REGEN-COV treatments showed significant (p<0.001 versus pooled placebo) virologic reduction through day 7. Least-squares mean differences in TWACB viral load for the treatments versus placebo ranged from –0·56 to –0.71 log10 copies/mL. Each REGEN-COV treatment showed significant (p<0.001 versus pooled placebo) and similar virologic reduction through day 7. There were no safety concerns, dose-related safety findings, grade ≥2 infusion related/hypersensitivity reactions, grade ≥3 injection-site reactions, nor fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported. Interpretation: In asymptomatic and low-risk symptomatic SARS-CoV-2-infected outpatients seronegative for antibodies against SARS-CoV-2 at baseline, REGEN-COV significantly and comparably reduced viral load at all IV and SC doses.

Psoriasis: Anti-IL-17-Antikörper vorbehaltlos auch beim älteren Menschen einsetzbar

Anti-interleukin-17 agents have recently been developed for the treatment of psoriasis. This study evaluated the tolerance and effectiveness of anti-interleukin-17 agents for psoriasis in elderly patients in daily practice. A multicentre, retrospective study was performed, involving psoriatic patients aged ≥65 years who had received an anti-interleukin-17 agent, including secukinumab, ixekizumab or brodalumab. A total of 114 patients were included: 72 received secukinumab, 35 ixekizumab, and 7 brodalumab. Treatment was stopped in 32 patients (28.9%), because of relapses in 14 patients (41.2%), primary failures in 11 patients (32.4%), or adverse events in 7 patients (20.6%). The 3 most frequently reported adverse events were injection site reactions (n = 4), oral candidiasis (n = 3), and influenza-like illness (n = 3). Regarding effectiveness, 80 patients (70%) reached a Physician Global Assessment score of 0/1, 6 months after treatment initiation. In conclusion, anti-interleukin-17 therapy appears to be an effective and safe therapeutic option for psoriasis treatment in patients aged ≥ 65 years.

Cutaneous adverse reactions of COVID-19 vaccines: a systematic review

Background: Numerous vaccines are implementation for the prevention of severe course and lethal outcome of coronavirus disease 2019 (COVID-19).Objective: This systematic review aims to summarize and integrated the findings of studies regarding cutaneous side effects of COVID-19 vaccines. Methods: This systematic review conducted by searching the scientific databases of PubMed, Scopus, Science direct, and Web of knowledge from the beginning of the COVID-19 to10/5/2021. Articles were reviewed and analyzed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.Results: Seventeen studies were included after the screening of search results based on to the eligibility criteria. The results showed that injection site reactions and delayed large local reactions were the most common side effects arising from all vaccine types. Most cutaneous reactions occurred in middle-aged women, after the first dose of vaccine, and 1-21 days after vaccination. Most cutaneous reactions were self-limiting, need little or no therapeutic intervention, and were not regarded as a barrier to injecting a second dose.Limitations:Conclusion: In certain groups such as patients with allergies and a history of local injection reactions, pre-vaccination counseling and the use of appropriate medications may be helpful. However, more studies are needed to investigate the side effect profile of all COVID-19 vaccines.

Herpes zoster following mRNA-1273 COVID-19 vaccination

Sir, Skin rashes have been associated with COVID-19 and studies suggest the inclusion of skin diseases in the list of COVID-19 symptoms. Skin eruptions are also associated with the mRNA-1273 COVID-19 vaccine. Findings by Baden et al. [1] describe immediate injection-site reactions observed in 84.2% of participants after the first dose, with delayed onset reactions—on or after day eight—occurring much more infrequently, 0.8% after the first dose and 0.2% after the second dose. Blumenthal et al. [2] discuss twelve cases of delayed vaccine reactions, with all patients experiencing reactions in the vaccination site. Herein, we describe two cases of herpes zoster within days of receiving their first mRNA-1273 vaccine. Both cases presented to the same dermatology clinic. A 77-year-old male presented with a bumpy, itchy, red rash on the upper right arm and axilla three days following an mRNA-1273 vaccine injection. The symptoms continued to worsen and the patient was clinically diagnosed with herpes zoster and treated with valacyclovir (Fig. 1). Another patient, also a 77-year-old male, complained of a rash located on the right upper arm and axilla. It was a red, itchy, bumpy rash that the patient developed two days after an mRNA-1273 vaccine injection (Fig. 2). Both rashes demonstrated a similar distribution pattern and both patients responded well to valacyclovir with the resolution of the erythema; however, one patient did have residual post-herpetic neuralgia.

Evaluation of subcutaneous daratumumab injections in the ambulatory care setting

Introduction Subcutaneous daratumumab is non-inferior to intravenous daratumumab for the treatment of multiple myeloma and significantly reduced incidence of systemic reactions. However, manufacturer for subcutaneous daratumumab has not provided guidance regarding optimal methods for monitoring for hypersensitivity reactions following subcutaneous daratumumab administration. Methods A retrospective analysis was performed in two cohorts of patients who received at least two doses of subcutaneous daratumumab for the treatment of plasma cell disorders: patients with previous exposure to intravenous daratumumab (dara-exposed) and patients without history of intravenous daratumumab (dara-naïve). The primary outcome was incidence of systemic and injection-site reactions following first dose of subcutaneous daratumumab. Secondary analysis included time to systemic and injection-site reactions, grading of adverse reaction, and incidence of second systemic reaction. Results Thirty-one patients were dara-naïve and 49 patients were dara-exposed. Differences in incidence of systemic (dara-naïve: 9.7% vs dara-exposed: 6.1%, p = 0.67) and injection-site reactions (dara-naïve: 12.9% vs dara-exposed: 14.3%, p = 0.99) did not reach statistical significance. Difference in median time to systemic reaction (dara-naïve: 3 h vs dara-exposed: 12 h, p = 0.18) was clinically important but did not reach statistical significance. Median time to injection-site reactions (dara-naïve: 6 h vs dara-exposed: 24 h, p = 0.03) was shorter in the dara-naïve cohort. No clinically meaningful difference was observed for incidence of second systemic reaction. Conclusion Most reactions were mild and did not require medical intervention. Following first subcutaneous daratumumab dose, monitoring for 3 h for dara-naïve patients and no monitoring time for dara-exposed patients for hypersensitivity reactions may be a safe and reasonable practice.