Romidepsin and azacitidine synergize in their epigenetic modulatory effects to induce apoptosis in CTCL

Purpose Cutaneous T cell lymphomas (CTCL) are a heterogeneous group of malignancies that despite available therapies commonly relapse. The emergences of combination epigenetic therapies in other hematologic malignancies have made investigation of such combinations in CTCL a priority. Here, we explore the synergistic anti-proliferative effects of romidepsin, an HDAC inhibitor, and azacitidine, a demethylating agent, combination in CTCL. Experimental Design The growth inhibition under combination treatment and single agent was explored by the MTT cell viability assay and the Annexin V/ Propidium Iodide apoptosis assay in different CTCL cell lines and tumor cells derived from Sézary syndrome patients. Quantitative analysis of dose-effect relationship of romidepsin and azacitidine was done by the CompuSyn software. Investigation of mechanism of action was performed by flow cytometry, immunoblotting, qRT-PCR arrays and chromatin immunoprecipitation. Global CpG methylation-sequencing was utilized to study genome methylation alteration under the treatment modalities. Results The combination of romidepsin and azacitidine exerts synergistic anti-proliferative effects and induction of apoptosis involving activation of the caspase cascade in CTCL. We identified genes that were selectively induced by the combination treatment, such the tumor suppressor gene RhoB that is linked to enhanced histone acetylation at its promoter region in parallel with pronounced expression of p21. Global CpG methylation-sequencing in a CTCL cell line and tumor cells demonstrated a subset of genes with a unique change in methylation profile in the combination treatment. Conclusions The synergistic anti-proliferative effects of romidepsin and azacitidine combination treatment justify further exploration in clinical trials for advanced CTCL

Cutaneous drug eruptions associated with the use of new oncological drugs

There is a variety of adverse effects and toxicities of newer and older chemotherapeutic agents which emerge in the skin, mucosa and adnexa. Common skin reactions while undergoing chemotherapy include alopecia, changes in skin pigmentation, palmoplantar erythrodysesthesia, nail dystrophies and stomatitis. Extravasation injuries or hypersensitivity reactions may be severe. New oncologic agents have led to the development of different, class-specific cutaneous side effects. Epidermal growth factor receptor (EGFR) inhibitors induce papulopustular rashes in a high percentage of patients as well as, to a smaller degree, xerosis cutis, hair and nail changes, hyper pigmentation and enhancement of radiation dermatitis. Multikinase inhibitors will often cause hand-foot syndrome, but may also induce facial erythema, subungual splinter hemorrhages and other less frequent skin changes. BRAF inhibitors can lead to rash and development of cutaneous keratinocytic neoplasias for which patients should be closely monitored. Finally, MEK/ERK inhibitors induce similar skin toxicities to EGFR inhibitors such as papulopustular rashes, xerosis cutis and paronychia. Our chapter will focus on the clinical picture, histopathology and treatment options of these new class-specific cutaneous side effects

Real-life experience with pegylated interferon and conventional interferon in adjuvant melanoma therapy

Interferon (IFN) is the most studied and the only approved adjuvant therapy for melanoma. There are 2 formulations of IFN, conventional IFN and pegylated IFN (peg-IFN), which have been investigated in multiple randomized clinical trials. We have compared the feasibility and tolerability of low-dose conventional IFN and peg-IFN in real life, outside the controlled settings of clinical trials. In this study, we analyzed 99 patients with resected melanoma, who were treated with either conventional IFN (n=48) or with peg-IFN (n=51), retrospectively. The median treatment duration in conventional IFN group was 13.3 versus 16.5 months in peg-IFN (P=0.52). Moreover, patients with peg-IFN tended to have dose reduction or treatment discontinuation due to adverse events (AE) significantly more often. In addition, neutropenia occurred significantly more often in peg-IFN group versus IFN group (n=2; 5% conventional vs. n=16; 36.4% peg-IFN, P=0.00). More than 90% of these patients developed only grade 2 neutropenia and there were no reported infections. We conclude that the 100 µg flat dose peg-IFN, which is commonly referred to as "low-dose," actually represents a higher dose of IFN, which consequently results in more frequent dose reductions and discontinuation of treatment. The use of peg-IFN is certainly more convenient for the patient in terms of application, thus close monitoring, early medical interventions, and dose adjustments to avoid treatment discontinuation are crucial for compliance

Acute progression of the leukemic phase in mycosis fungoides and Sézary syndrome

Keywords: CTCL classifications; CTCL, cutaneous T-cell lymphoma; LDH, lactate dehydrogenase; MF, mycosis fungoides; SS, Sézary syndrome; Sézary syndrome; T cell; WBC, white blood cell; clinical cases; leukemic progression; lymphoma; medical dermatology; mycosis fungoides. Conflict of interest statement Dr Dummer reports intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp and Dhome, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, and Alligator outside the submitted work. Dr Ramelyte reports intermittent, project-focused consulting and/or advisory relationships with Amgen, Novartis, Sanofi, Pierre Fabre, and Sun Pharma outside the submitted work. Dr Kim reports grants and personal fees from Actelion and 10.13039/501100009754Galderma; personal fees from Helsinn and Almirall; and grants from 10.13039/501100004628MedImmune, Kyowa Kirin, and Soligenix outside the submitted work. Drs Maredia, Cozzio, and Rozati have no conflicts of interest to declare

Melanoma immunotherapy: historical precedents, recent successes and future prospects

The idea of cancer immunotherapy has been around for more than a century; however, the first immunotherapeutic ipilimumab, an anti-CTLA-4 antibody, has only recently been approved by the US FDA for melanoma. With an increasing understanding of the immune response, it is expected that more therapies will follow. This review aims to provide a general overview of immunotherapy in melanoma. We first explain the development of cancer immunotherapy more than a century ago and the general opinions about it over time. This is followed by a general overview of the immune reaction in order to give insight into the possible targets for therapy. Finally, we will discuss the current therapies for melanoma, their shortcomings and why it is important to develop patient stratification criteria. We conclude with an overview of recent discoveries and possible future therapies

Association of Cardiovascular Disease in Patients with Mycosis Fungoides and Sézary Syndrome Compared to a Matched Control Cohort

Mycosis fungoides/Sézary syndrome (MF/SS) produces a low-grade chronic inflammatory state that may be associated with an increased risk of cardiovascular (CV) events, as seen in other chronic, systemic dermatologic diseases. To assess this association, a retrospective, cross-sectional study was designed in which 421 patients with a biopsy-proven diagnosis of MF/SS were compared with a control cohort of 4,210 age-, gender-, and race-matched patients randomly selected from the National Health and Nutritional Evaluation Survey database. The MF/SS cohort had a 14% prevalence of CV events, which was not statistically different from the control population’s prevalence of 13%. In the MF/SS cohort, a multivariable logistic regression model showed that older patients (OR = 1.05 for each year of age, 95% confidence interval = 1.02–1.07) and those diagnosed with hypertension (OR = 3.40, 95% confidence interval = 1.71–6.75) had a higher risk of a CV event (P < 0.001). Risk factors such as gender, race, smoking, diabetes, and obesity were not significantly associated with CV events. Findings suggest that in the MF/SS population, advancing age and hypertension are risk factors for CV events, requiring clinical recognition and management. In addition, further research is needed to understand the complex interplay of how chronic inflammation in MF/SS impacts the immune development of CV disease