Real-world management practices and characteristics of patients with advanced melanoma initiated on immuno-oncology or targeted therapy in the first-line setting during the period 2015-2018 in Greece. The 'SUMMER' study: a retrospective multicenter chart review project.

This study primarily aimed to generate real-world evidence (RWE) on the profile and first-line treatment (1LT) patterns of patients with advanced (unresectable Stage III/metastatic) cutaneous melanoma initiated on immuno-oncology (IO)- or targeted therapy (TT)-based 1LT between 1 January 2015 and 1 January 2018 (index period), in routine settings of Greece. This was a multicenter, retrospective chart review study. Eligible consented (unless deceased, for whom consent was waived by the hospital) patients were consecutively included by six oncology clinics. The look-back period extended from informed consent or death to initial melanoma diagnosis. Between 9 Junuary 2021 and 9 February 2022, 225 eligible patients (all Caucasians; 60.4% male; 35.6% diagnosed with de novo advanced melanoma) were included. At 1LT initiation, median age was 62.6 years; 2.7/6.7/90.7% of the patients had Stage IIIB/IIIC/IV disease and 9.3% were unresected. Most frequent metastatic sites were the lung (46.7%), non-regional nodes (33.8%), and liver (20.9%). Among patients, 98.2% had single primary melanoma, 45.6% had disease localized on the trunk, and 63.6% were BRAF-mutant. Of the patients, 45.3% initiated 1LT with an IO-based, 53.3% with a TT-based regimen, and three patients (1.3%) received TT-based followed by IO-based or vice versa. Most common 1LT patterns (frequency ≥10%) were BRAFi/MEKi combination (31.6%), anti-PD-1 monotherapy (25.3%), BRAFi monotherapy (21.8%), and anti-CTLA-4 monotherapy (17.8%). Most frequent regimens were Dabrafenib+Trametinib in 25.3%, and monotherapies with Pembrolizumab/Ipilimumab/Vemurafenib/Dabrafenib in 23.6/17.8/11.1/10.7% of patients, respectively. SUMMER provides RWE on 1LT strategies and profile of patients initiated 1L IO- or TT-based therapy in Greece during the 3-year index period.

Cytomegalovirus Infections in Patients Treated With Immune Checkpoint Inhibitors for Solid Malignancies.

Cytomegalovirus (CMV) infection/disease has been repeatedly reported in patients treated with immune-checkpoint inhibitors (ICIs) and most commonly involves patients with relapsed/refractory (R/R) immune-related adverse events (irAEs). In the current study, we present a patient with melanoma who developed CMV gastritis during treatment with pembrolizumab in the absence of irAEs and without previous or current immunosuppression. Moreover, we review the literature regarding CMV infection/disease in patients treated with ICIs for solid malignancies. We present the currently available data on the pathogenesis, clinical characteristics, endoscopic findings, and histologic features and highlight the potential differences among cases complicating R/R irAEs versus those occurring in patients who are immunosuppression naive. Finally, we discuss the currently available data regarding potential useful diagnostic tools as well as the management of these patients.

COVID-19 in Patients with Melanoma: A Single-Institution Study.

We conducted a single-center, non-interventional retrospective study of melanoma patients with COVID-19 (1 March 2020 until 17 March 2023). The cohort was further divided into three groups according to the periods of SARS-CoV-2 variant dominance in Greece. We recorded demographics, comorbidities, vaccination data, cancer diagnosis/stage, types of systemic melanoma treatments, date of COVID-19 diagnosis and survival. We identified 121 patients. The vast majority (87.6%) had advanced disease (stages III or IV). A total of 80.1% of the patients were receiving immune checkpoint inhibitor-based therapies, 92.5% had asymptomatic/mild COVID-19 and 7.4% had moderate/severe/critical disease, while 83.5% contracted COVID-19 during the third period of the pandemic. Sixteen patients (13.2%) were hospitalized for COVID-19 with a median length of stay of 12 days (range: 1-55 days). Advanced age, heart failure, number of comorbidities (≤1 vs. >1), vaccination status and the time period of the infection correlated with more severe COVID-19, whereas only heart failure and time period were independently correlated with severity. The 30-day mortality rate after COVID-19 was 4.2%. With a median follow-up of 340 days post-COVID-19, 17.4% of patients were deceased. In this cohort of melanoma patients with COVID-19, the 30-day mortality rate was low. There was no association between melanoma stage, treatment receipt and type of treatment with COVID-19 severity.

Immunogenicity and Safety of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Melanoma Treated with Immunotherapy.

The BNT162b2 vaccine against SARS-CoV-2 has a proven efficacy and a favorable safety profile. In cancer patients under immunotherapy in the form of immune-checkpoint inhibitors (ICIs), the efficacy of the vaccine has not been thoroughly studied, while a theoretical concern has also been raised about triggering immune-related adverse events (irAEs) by the vaccine. We conducted a prospective, non-interventional study on the immunogenicity and safety of the BNT162b2 vaccine in patients with advanced or metastatic melanoma treated with ICIs. Blood samples were obtained 0-4 days before the first dose and 12-21 days after the second dose of the vaccine for the quantification of the SARS-CoV-2 anti-spike antibody using an ELISA and immunophenotyping of the T and myeloid cell subpopulations. The active recording of AEs for a two-month period was conducted. Forty patients were included in the study. All but one (97.3%) achieved seroconversion after two doses of the vaccine and no correlations of the antibody titers with any of the studied parameters (age, gender, stage and duration of the disease, type of ICI, previous treatment, etc.) were found. Moreover, no differences in the subpopulations of the T cells (including the T-regulatory cells) or the myeloid cells were found pre- and post-vaccination. All AEs were low-grade, while one case of arthritis exacerbation was noted. The seroconversion rate in the studied population was high and was comparable to that of healthy subjects, while no major safety issues were raised during the safety follow-up. Finally, no derangements in the subpopulations of T cells or myeloid cells were noted. This is the first study focusing on the immunogenicity, safety, and effect of anti-SARS-CoV-2 vaccines on the blood-cell immunophenotype status of patients with melanoma treated with ICIs.

Regulatory T-cell Transcriptomic Reprogramming Characterizes Adverse Events by Checkpoint Inhibitors in Solid Tumors.

Immune checkpoint inhibitors (ICI), which target immune regulatory pathways to unleash antitumor responses, have revolutionized cancer immunotherapy. Despite the remarkable success of ICI immunotherapy, a significant proportion of patients whose tumors respond to these treatments develop immune-related adverse events (irAE) resembling autoimmune diseases. Although the clinical spectrum of irAEs is well characterized, their successful management remains empiric. This is in part because the pathogenic mechanisms involved in the breakdown of peripheral tolerance and induction of irAEs remain elusive. Herein, we focused on regulatory T cells (Treg) in individuals with irAEs because these cells are vital for maintenance of peripheral tolerance, appear expanded in the peripheral blood of individuals with cancer, and abundantly express checkpoint molecules, hence representing direct targets of ICI immunotherapy. Our data demonstrate an intense transcriptomic reprogramming of CD4+CD25+CD127- Tregs in the blood of individuals with advanced metastatic melanoma who develop irAEs following ICI immunotherapy, with a characteristic inflammatory, apoptotic, and metabolic signature. This inflammatory signature was shared by Tregs from individuals with different types of cancer developing irAEs and individuals with autoimmune diseases. Our findings suggest that inflammatory Treg reprogramming is a feature of immunotherapy-induced irAEs, and this may facilitate translational approaches aiming to induce robust antitumor immunity without disturbing peripheral tolerance.

Systemic mastocytosis accompanied by a non-secretory plasma cell dyscrasia and nephrotic syndrome-level proteinuria in a 76-year-old patient.

We report here the interesting case of a 76-year-old man with severe proteinuria who was diagnosed with systemic mastocytosis accompanied by a clonal non-mast-cell lineage haematological disorder (a non-secretory plasma cell dyscrasia). This is a unique report of systemic mastocytosis with a non-secretory plasma cell dyscrasia and nephrotic syndrome. The pathophysiological relevance between these entities along with the probability of occult amyloidosis is discussed.

Evidence for regulation of oxidative stress by latent membrane protein 1 oncoprotein in patients with low-grade leukemic B cell lymphoma with latent Epstein-Barr virus infection.

The role of latent Epstein-Barr virus (EBV) infection in the pathogenesis of low-grade B cell non-Hodgkin lymphoma (B-NHL) has not been studied. We therefore investigated the incidence of latent EBV infection in a group of patients with leukemic low-grade B-NHL, as well as the incidence of viral latent membrane protein 1 (LMP1) oncoprotein expression in the same patient group. Furthermore, in an attempt to elucidate the role of this viral oncoprotein in non-EBV-related lymphomas, we correlated the expression of LMP1 with the level of oxidative stress, a parameter related to apoptosis. In the present study we detected lower levels of oxidative stress in the sera of LMP1-positive patients. This possibly implies an anti-apoptotic role of this viral oncoprotein in low-grade B cell lymphomas. However, LMP1 expression status did not affect expression of the major anti-apoptotic gene BCL-2.

Rituximab in the treatment of EBV-positive low grade B-cell lymphoma.

BACKGROUND: Following infection of B lymphocytes by Epstein Barr virus (EBV), the viral genome remains in the nucleus, and a latency phase is established, during which only a small proportion of the viral genes are expressed. Among them, LMP1 is essential for transformation. Rituximab is a potent agent used in the treatment of low grade B-cell lymphomas and is also widely used for the treatment of post-transplant lymphoproliferative disorders caused by EBV. The effect of rituximab treatment on the latent EBV infection in non-transplant patients with lymphoproliferative disorders has never been studied to our knowledge. PATIENTS AND METHODS: We studied, the effect of rituximab-based immunochemotherapy on the EBV status of 44 patients with leukemic low grade B-cell lymphoma. RESULTS: After three cycles of rituximab-based treatment, only 1/17 patients was still positive for EBV. DISCUSSION: Our results suggest that rituximab used in the treatment of EBV-positive low-grade lymphoma is efficient in eradicating the virus from the peripheral blood, a fact with potential implications in the course and prognosis of the disease.