Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life. METHODS: We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations). RESULTS: The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash. CONCLUSIONS: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244).

Cancer type and histology influence cutaneous immunotherapy toxicities: a multi-institutional cohort study.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) are the most common toxicities to occur in the setting of immune checkpoint inhibitor (ICI) therapy. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. OBJECTIVES: To investigate the influence of cancer type and histology on the development of cirAEs in the setting of ICI therapy and survival outcomes. METHODS: This retrospective cohort study included patients recruited between 1 December 2011 and 30 October 2020. They received ICI from 2011 to 2020 with follow-up of outcomes through October 2021. We identified 3668 recipients of ICI therapy who were seen at Massachusetts General Brigham and Dana-Farber. Of these, 669 developed cirAEs. Records that were incomplete or categories of insufficient sample size were excluded from the study cohort. Multivariate Cox proportional hazards models were used to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI initiation, and year of ICI initiation. Time-varying Cox proportional hazards modelling was used to examine the impact of cirAE development on mortality. RESULTS: Compared with other nonepithelial cancers (neuroendocrine, leukaemia, lymphoma, myeloma, sarcoma and central nervous system malignancies), cutaneous squamous cell carcinoma [cSCC; hazard ratio (HR) 3.57, P < 0.001], melanoma (HR 2.09, P < 0.001), head and neck adenocarcinoma (HR 2.13, P = 0.009), genitourinary transitional cell carcinoma (HR 2.15, P < 0.001) and genitourinary adenocarcinoma (HR 1.53, P = 0.037) were at significantly higher risk of cirAEs in multivariate analyses. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma (HR 0.37, P < 0.001) and cSCC (HR 0.51, P = 0.011). CONCLUSIONS: The highest rate of cirAEs and subsequent survival benefits were observed in cutaneous malignancies treated with ICI therapies. This study improves our understanding of patients who are at highest risk of developing cirAEs and would, therefore, benefit from appropriate counselling and closer monitoring by their oncologists and dermatologists throughout their ICI therapy. Limitations include its retrospective nature and cohort from one geography.

Cutaneous immune-related adverse events (cirAEs) are the most common complications to occur for oncology patients treated with immune checkpoint inhibitors (ICIs). cirAEs can lead to increased use of healthcare resources and significant morbidity. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. In this study, we aimed to investigate the influence of cancer organ system and histology on the development of cirAEs and survival outcomes. To do this, we included a cohort of patients retrospectively between 1 December 2011 and 30 October 2020. We identified 3668 ICI recipients who were seen at Massachusetts General Brigham and Dana-Farber in Boston, Massachusetts. Of these, 669 people developed cirAEs. Multivariate Cox proportional hazards models were used to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI start, and year of ICI initiation. Time-varying Cox proportional hazards modelling was used to examine the impact of cirAE development on mortality. We found that, compared with other nonepithelial cancers, patients with cutaneous squamous cell carcinoma (cSCC) and melanoma were at significantly higher risk of cirAEs. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma and cSCC. This study improves our understanding of patients who are at highest risk of developing cirAEs ­ those with melanoma and cSCC. Therefore, many patients could benefit from appropriate counselling and close monitoring by their oncologists and dermatologists throughout ICI therapy.

Evaluation of anticancer therapy-related dermatologic adverse events: Insights from Food and Drug Administration's Adverse Event Reporting System dataset.

BACKGROUND: New anticancer therapies have improved patient outcomes but associated dermatologic adverse events (AEs) may cause morbidity and treatment discontinuation. A comprehensive estimation of associations between cancer drugs and skin AEs is lacking. METHODS: This study utilized the Food and Drug Administartion (FDA)'s Adverse Event Reporting System database (January 2013-September 2022), with 3,399,830 reports involving 3084 drugs and 16,348 AEs. A nearest neighbor matching model was employed to select 10 controls for each case report, utilizing the cosine similarity of demographic and AE severity factors to minimize false positives/negatives. RESULTS: There were 10,698 unique anticancer drugs (n = 212) to skin AE (n = 873) pairs, of which 676 had significant reporting odds ratios (ROR) > 1, comprising 113 drugs and 144 AEs. The minimum ROR was 1.25, and 50% of associations displayed a ROR >10. The most common were rash (51 agents) and dry skin (28 drugs). Methotrexate induced the most distinct AEs (34), then mechlorethamine (33), and vemurafenib (24). Targeted therapies accounted for 49% of pairs, cytotoxic chemotherapies for 35.9%, and immunotherapies for 11%. CONCLUSIONS: A total of 113 anticancer drugs were identified as significantly associated with skin AEs, most frequently rash and dry skin. Data are likely under-reported but enable quick postmarketing identification of skin toxicity signals.

Drug-Induced and Malignancy-Associated Neutrophilic Dermatoses in Patients with Hematologic Malignancies: A Single Institution Experience.

INTRODUCTION: Neutrophilic dermatoses (NDs) often occur secondary to inflammatory conditions, medication exposure, and hematologic malignancy. While malignancy-associated NDs (MA-NDs) have been well reported among those with hematologic cancers, little is known about drug-induced NDs (DI-NDs) within this population. The objective of this study was to compare the presentations and outcomes of patients with hematologic malignancies who developed MA-NDs and DI-NDs. METHODS: Cases of ND occurring between 2013 and 2023 among those with hematologic malignancies were identified from the electronic medical records of our institution. Patient characteristics, recent medication exposures, cancer mutations, and disease outcomes were reviewed. Patients were categorized with DI-ND if they were recently exposed to one of four medications known to be commonly associated with ND or were otherwise categorized with MA-ND. We report a descriptive analysis of cases of DI-ND and MA-ND. RESULTS: We identified 52 patients with ND and co-occurring hematologic malignancy including 16 cases of DI-ND (30.8%) and 36 cases of MA-ND (69.2%). The most common ND in both groups was Sweet's syndrome. Chronic underlying conditions including solid tumors, inflammatory disorders, chronic viral infection, and tobacco use were more common among those with MA-ND. Among those with DI-ND, tyrosine kinase inhibitors were the most commonly associated drugs (43.8%). The most common cancer mutation among those with DI-ND was FLT3 (43.8%), while the most common mutation among those with MA-ND was TP-53 (19.4%). Among those who had died at the time of data collection, 90.0% of those with DI-ND and 66.7% of those with MA-ND died within 1 year of ND diagnosis. CONCLUSION: Most cases of ND occurring with hematologic malignancies develop secondary to cancer rather than drug exposure. Different cancer mutations may predispose to DI-ND and MA-ND. Further research is needed to establish diagnostic criteria for DI-ND and to determine the pathogenic role of specific cancer mutations, particularly FLT3, in the development of ND.

Cutaneous immune-related adverse events: incidence rates, risk factors and association with extracutaneous toxicity - a prospective study of 189 patients treated with checkpoint inhibitors at a Spanish tertiary care hospital.

BACKGROUND: Clinicians are increasingly prescribing immune checkpoint inhibitors (ICIs) to treat cancer, but the real-world incidence, characteristics and risk factors of cutaneous immune-related adverse events (cirAEs) are unclear. OBJECTIVES: To determine the incidence, features and risk factors of cirAEs and to measure their possible association with extracutaneous toxicity. METHODS: We conducted a prospective observational study in a Spanish tertiary care hospital, including people who started an ICI between March 2020 and May 2022. We used a survival analysis and a log-rank test to obtain and compare incidence rates, and a multivariate Cox model to detect risk factors for cirAEs. RESULTS: We included 189 patients, 82 (43.4%) of whom presented cutaneous toxicity. The incidence of cirAEs was 75.0 per 100 person-years, with a 50.0% probability of the appearance of a cirAE at 10 months of follow-up. The most frequent cirAE category was inflammatory dermatoses, and the most frequent types were pruritus, eczema and maculopapular eruptions. ICI combination therapy, a family history of psoriasis and rheumatological and pulmonary immune-related adverse events increased the risk of cirAEs. CONCLUSIONS: We found a high incidence of cirAEs, and they occurred early in the follow-up period. Dermatologists should be involved in the management of cirAEs, especially in people with risk factors.

Oral Antibiotics and Risk of Serious Cutaneous Adverse Drug Reactions.

Importance: Serious cutaneous adverse drug reactions (cADRs) are potentially life-threatening drug hypersensitivity reactions involving the skin and internal organs. Antibiotics are a recognized cause of these reactions, but no studies have compared relative risks across antibiotic classes. Objectives: To explore the risk of serious cADRs associated with commonly prescribed oral antibiotics, and to characterize outcomes of patients hospitalized for them. Design, Setting, and Participants: Nested case-control study using population-based linked administrative datasets among adults aged 66 years or older who received at least 1 oral antibiotic between 2002 and 2022 in Ontario, Canada. Cases were those who had an emergency department (ED) visit or hospitalization for serious cADRs within 60 days of the prescription, and each case was matched with up to 4 controls who did not. Exposure: Various classes of oral antibiotics. Main Outcomes and Measures: Conditional logistic regression estimate of the association between different classes of oral antibiotics and serious cADRs, using macrolides as the reference group. Results: During the 20-year study period, we identified 21 758 older adults (median age, 75 years; 64.1% female) who had an ED visit or hospitalization for serious cADRs following antibiotic therapy and 87 025 matched controls who did not. In the primary analysis, sulfonamide antibiotics (adjusted odds ratio [aOR], 2.9; 95% CI, 2.7-3.1) and cephalosporins (aOR, 2.6; 95% CI, 2.5-2.8) were most strongly associated with serious cADRs relative to macrolides. Additional associations were evident with nitrofurantoin (aOR, 2.2; 95% CI, 2.1-2.4), penicillins (aOR, 1.4; 95% CI, 1.3-1.5), and fluoroquinolones (aOR, 1.3; 95% CI, 1.2-1.4). The crude rate of ED visits or hospitalization for cADRs was highest for cephalosporins (4.92 per 1000 prescriptions; 95% CI, 4.86-4.99) and sulfonamide antibiotics (3.22 per 1000 prescriptions; 95% CI, 3.15-3.28). Among the 2852 case patients hospitalized for cADRs, the median length of stay was 6 days (IQR, 3-13 days), 9.6% required transfer to a critical care unit, and 5.3% died in the hospital. Conclusion and Relevance: Commonly prescribed oral antibiotics are associated with an increased risk of serious cADRs compared with macrolides, with sulfonamides and cephalosporins carrying the highest risk. Prescribers should preferentially use lower-risk antibiotics when clinically appropriate.

Cutaneous lichenoid drug eruptions: A narrative review evaluating demographics, clinical features and culprit medications.

Cutaneous lichenoid drug eruptions (LDE) are adverse drug reactions (ADR) characterized by symmetric, erythematous, violaceous papules reminiscent but rarely fully characteristic of lichen planus (LP). We aimed to analyse the literature describing cases of LDE within the last 20 years to provide additional insight into culprit drugs, typical latency to onset of the eruption, the spectrum of clinical presentations, severity and management. A literature search was conducted in MEDLINE between January 2000 and 27 January 2021. The keywords 'lichenoid drug rash' and 'lichenoid drug eruption' were used. Cases were included if LDE diagnosis was made, and culprit drugs were identified. A total of 323 cases with LDE were identified from 163 published case reports and studies. The mean patient age was 58.5 years (1 month to 92 years), and 135 patients (41.8%) were female. Checkpoint inhibitors (CKI) were the most frequently reported culprit drugs (136 cases; 42.1%), followed by tyrosine kinase inhibitors (TKI) (39 cases; 12.0%) and anti-TNF-α-monoclonal antibodies (13 cases; 4.0%). The latency between initiation of the drug and manifestation was 15.7 weeks (range: 0.1-208 weeks). After discontinuing the culprit drug, the median time to resolution was 14.2 weeks (range: 0.71-416 weeks). One hundred thirty-six patients (42.1%) were treated with topical, and 54 patients (16.7%) with systemic glucocorticoids. Overall, we conclude that, albeit rare, LDE is challenging to diagnose ADR induced by mostly CKI, TKI, and biologics. Treatment modalities resemble that of lichen planus, and the culprit drugs had to be discontinued in only 26%, which is low compared with other types of adverse drug reactions. This is probably due to the low risk of aggravation (e.g. toxic epidermal necrolysis) if the drug is continued and the benefit/risk ratio favouring the drug, as is often the case in cancer therapy.

Malignancy-associated generalised exfoliative dermatitis: A retrospective study in a single-centre Asian cohort.

BACKGROUND: Erythroderma is an inflammatory skin condition that causes extensive erythema and skin scaling amounting ≥90% of the body surface area. This retrospective cohort study describes the prevalence of malignancy-associated erythroderma in a single centre where there was concerted effort to systematically offer malignancy screens to all adult erythroderma patients above the age of 65 years. METHODS: Clinical charts were reviewed for all adult inpatients and outpatients with erythroderma who attended the National University Hospital (NUH) from 1 July 2019 to 31 December 2021. Data collected included patient demographics, clinical findings, laboratory investigations, disease-specific investigations such as endoscopic procedures and biopsies, follow-up duration and mortality data. RESULTS: Seventy-four patients were analysed. The median age of the patients was 73 years old (interquartile range: 59-81 years old). An underlying dermatosis was the most common cause of erythroderma-63 patients having atopic dermatitis/asteatotic eczema or psoriasis. Three patients had erythroderma from drug eruptions, and 1 patient had chronic actinic dermatitis. Four patients had associated malignancies (5.4%). Half of our patients completed further evaluation for malignancy (52.7%). The rest had either declined or were eventually unable to complete the investigations. There was a higher prevalence of associated malignancy (7.8%) in elderly patients above 65 years old. CONCLUSION: When compared to existing literature, our cohort reflects a higher observed occurrence of malignancy in association with erythroderma. As delays in evaluation for underlying malignancy could result in potentially deleterious outcomes, it is prudent to consider systematic screening for malignancy in high-risk populations such as elderly erythroderma patients.

An Analysis of Risk Factors for the Development of Acneiform Eruptions in Patients on Monoclonal Antibody Epidermal Growth Factor Receptor Inhibitors.

Acneiform eruptions occur frequently and early in patients on epidermal growth factor receptor inhibitors (EGFRi). Identification of baseline patient risk factors would prompt earlier referral to dermatology to optimize prevention and management. The primary objective of this retrospective study is to determine the association between clinical and demographic characteristics and the development of acneiform eruptions. A retrospective chart review was conducted on patients diagnosed with colon and head and neck cancers who started EGFRi between January 2017 and December 2021. Patients were followed until death or September 2022. Baseline demographic and clinical parameters were documented and patients were followed from the time of diagnosis to most recent visit for the development and management of an acneiform eruption. Regression analyses were performed to determine the association between baseline characteristics and the development of acneiform eruptions. A total of 66 patients were treated with cetuximab or panitumumab between 2017-2021 were included in the analysis. Forty-seven of the sixty-six patients developed an acneiform eruption while on EGFRi therapy (71.2%). Combination cancer therapy with another chemotherapeutic agent was associated with a lower risk of acneiform eruption (OR 0.03, P = .027). No other baseline features were statistically associated with a lower risk of acneiform eruption. Acneiform eruptions are a common cutaneous adverse event of EGFRi therapy. Ongoing research is required to elucidate risk factors for the development of acneiform eruptions, to improve the quality of life of oncology patients.

Epidemiology and risk factors for the development of cutaneous toxicities in patients treated with immune-checkpoint inhibitors: A United States population-level analysis.

BACKGROUND: A variety of dermatoses have been reported in the growing number of patients treated with immune-checkpoint inhibitors (ICIs), but the current understanding of cutaneous immune-related adverse events (irAEs) is limited. OBJECTIVE: To determine the cumulative incidence, distribution, and risk factors of cutaneous irAEs after ICI initiation. METHODS: This was a retrospective cohort study of patients in a national insurance claims database including cancer patients treated with ICIs and matched controls. RESULTS: The study included 8637 ICI patients and 8637 matched controls. The overall incidence of cutaneous irAEs was 25.1%, with a median onset time of 113 days. The ICI group had a significantly higher incidence of pruritus, mucositis, erythroderma, maculopapular eruption, vitiligo, lichen planus, bullous pemphigoid, Grover disease, rash, other nonspecific eruptions, and drug eruption or other nonspecific drug reaction. Patients with melanoma and renal cell carcinoma and those receiving combination therapy were at a higher risk of cutaneous irAEs. LIMITATIONS: Retrospective design without access to patient chart data. CONCLUSIONS: This study identifies cutaneous irAEs in a real-world clinical setting and highlights patient groups that are particularly at risk. The results can aid dermatologists at the bedside in the diagnosis of cutaneous irAEs and in formulating management recommendations to referring oncologists regarding the continuation of ICI therapy.

Adverse reactions of targeted therapy in cancer patients: a retrospective study of hospital medical data in China.

BACKGROUND: The adverse reactions (ADRs) of targeted therapy were closely associated with treatment response, clinical outcome, quality of life (QoL) of patients with cancer. However, few studies presented the correlation between ADRs of targeted therapy and treatment effects among cancer patients. This study was to explore the characteristics of ADRs with targeted therapy and the prognosis of cancer patients based on the clinical data. METHODS: A retrospective secondary data analysis was conducted within an ADR data set including 2703 patients with targeted therapy from three Henan medical centers of China between January 2018 and December 2019. The significance was evaluated with chi-square test between groups with or without ADRs. Univariate and multivariate logistic regression with backward stepwise method were applied to assess the difference of pathological characteristics in patients with cancer. Using the univariate Cox regression method, the actuarial probability of overall survival was performed to compare the clinical outcomes between these two groups. RESULTS: A total of 485 patients were enrolled in this study. Of all patients, 61.0% (n = 296) occurred ADRs including skin damage, fatigue, mucosal damage, hypertension and gastrointestinal discomfort as the top 5 complications during the target therapy. And 62.1% of ADRs were mild to moderate, more than half of the ADRs occurred within one month, 68.6% ADRs lasted more than one month. Older patients (P = 0.022) and patients with lower education level (P = 0.036), more than 2 comorbidities (P = 0.021), longer medication time (P = 0.022), drug combination (P = 0.033) and intravenous administration (P = 0.019) were more likely to have ADRs. Those with ADRs were more likely to stop taking (P = 0.000), change (P = 0.000), adjust (P = 0.000), or not take the medicine on time (P = 0.000). The number of patients with recurrence (P = 0.000) and metastasis (P = 0.006) were statistically significant difference between ADRs and non-ADRs group. And the patients were significantly poor prognosis in ADRs groups compared with non-ADRs group. CONCLUSION: The high incidence of ADRs would affect the treatment and prognosis of patients with cancer. We should pay more attention to these ADRs and develop effective management strategies.

Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far. METHODS: The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE. RESULTS: Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were "weight change", "difficulty to grip things", "bloody or mucous stool" and "insomnia". Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire. CONCLUSION: Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on "weight change" and "insomnia" may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03453892 . Registered on 05 March 2018.

Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of 414 cases.

BACKGROUND: Cutaneous reactions after messenger RNA (mRNA)-based COVID-19 vaccines have been reported but are not well characterized. OBJECTIVE: To evaluate the morphology and timing of cutaneous reactions after mRNA COVID-19 vaccines. METHODS: A provider-facing registry-based study collected cases of cutaneous manifestations after COVID-19 vaccination. RESULTS: From December 2020 to February 2021, we recorded 414 cutaneous reactions to mRNA COVID-19 vaccines from Moderna (83%) and Pfizer (17%). Delayed large local reactions were most common, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions. Forty-three percent of patients with first-dose reactions experienced second-dose recurrence. Additional less common reactions included pernio/chilblains, cosmetic filler reactions, zoster, herpes simplex flares, and pityriasis rosea-like reactions. LIMITATIONS: Registry analysis does not measure incidence. Morphologic misclassification is possible. CONCLUSIONS: We report a spectrum of cutaneous reactions after mRNA COVID-19 vaccines. We observed some dermatologic reactions to Moderna and Pfizer vaccines that mimicked SARS-CoV-2 infection itself, such as pernio/chilblains. Most patients with first-dose reactions did not have a second-dose reaction and serious adverse events did not develop in any of the patients in the registry after the first or second dose. Our data support that cutaneous reactions to COVID-19 vaccination are generally minor and self-limited, and should not discourage vaccination.

Cutaneous reactions in children treated with MEK inhibitors, BRAF inhibitors, or combination therapy: A multicenter study.

BACKGROUND: Treatment with BRAF inhibitors (BRAFI) and MEK inhibitors (MEKI) causes cutaneous reactions in children, limiting dosing or resulting in treatment cessation. The spectrum and severity of these reactions is not defined. OBJECTIVE: To determine the frequency and spectrum of cutaneous reactions in children receiving BRAFI and MEKI and their effects on continued therapy. METHODS: A multicenter, retrospective study was conducted at 11 clinical sites in the United States and Canada enrolling 99 children treated with BRAFI and/or MEKI for any indication from January 1, 2012, to January 1, 2018. RESULTS: All children in this study had a cutaneous reaction; most had multiple, with a mean per patient of 3.5 reactions on BRAFI, 3.7 on MEKI, and 3.4 on combination BRAFI/MEKI. Three patients discontinued treatment because of a cutaneous reaction. Treatment was altered in 27% of patients on BRAFI, 39.5% on MEKI, and 33% on combination therapy. The cutaneous reactions most likely to alter treatment were dermatitis, panniculitis, and keratosis pilaris-like reactions for BRAFI and dermatitis, acneiform eruptions, and paronychia for MEKI. CONCLUSIONS: Cutaneous reactions are common in children receiving BRAFI and MEKI, and many result in alterations or interruptions in oncologic therapy. Implementing preventative strategies at the start of therapy may minimize cutaneous reactions.

Incidence of Adverse Cutaneous Reactions to Epidermal Growth Factor Receptor Inhibitors in Patients with Non-Small-Cell Lung Cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are routinely used in advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, their use is associated with gastrointestinal and cutaneous toxicities, including acneiform eruptions, pruritus, xerosis, nail and hair changes. Aside from reducing patients' quality of life, such cutaneous reactions have a considerable impact on the oncologic treatment given that dose reduction or even drug discontinuation may be necessary, especially for the severe forms. OBJECTIVES: To assess the incidence, impact on treatment and management of EGFR inhibitor-related cutaneous reactions in patients with NSCLC. METHODS: We conducted a prospective observational study on 87 consecutive patients with advanced NSCLC treated with EGFR-tyrosine kinase inhibitors from January to December 2019. Patients who developed mucocutaneous reactions were evaluated and treated by both oncologists and dermatologists, and underwent dermatologic follow-up until resolution of the cutaneous reaction. Demographic and clinical data were collected for each patient, and the severity of the cutaneous reaction was graded using the Common Terminology Criteria for Adverse Events. RESULTS: Seventy-one patients (81.6%) developed cutaneous reactions. The number of cutaneous reactions per patient was 1 in 37%, 2 in 41% and 3 or more in 22%. The most common cutaneous reactions included acneiform eruptions (56.3%), xerosis ± asteatotic eczema (48.3%), nail changes (39.1%), mucositis (29.9%), pruritus (24.1%) and hair changes (12.6%). Afatinib was associated with a higher rate of nail changes and mucositis (p < 0.01 and p < 0.005, respectively) compared to other agents, while no patient-related predictive factors were identified. Dose reduction was performed in 18% of patients. Multidisciplinary management involving dermatologists allowed to resume the drug in all patients who had discontinued it due to the cutaneous reactions. CONCLUSIONS: A multidisciplinary approach to EGFR inhibitor-related cutaneous reactions is advantageous and can reduce the need to discontinue oncologic treatment.

Immune checkpoint inhibitor-related dermatologic adverse events.

Immune checkpoint inhibitors have emerged as a pillar in the management of advanced malignancies. However, nonspecific immune activation may lead to immune-related adverse events, wherein the skin and its appendages are the most frequent targets. Cutaneous immune-related adverse events include a diverse group of inflammatory reactions, with maculopapular rash, pruritus, psoriasiform and lichenoid eruptions being the most prevalent subtypes. Cutaneous immune-related adverse events occur early, with maculopapular rash presenting within the first 6 weeks after the initial immune checkpoint inhibitor dose. Management involves the use of topical corticosteroids for mild to moderate (grades 1-2) rash, addition of systemic corticosteroids for severe (grade 3) rash, and discontinuation of immunotherapy with grade 4 rash. Bullous pemphigoid eruptions, vitiligo-like skin hypopigmentation/depigmentation, and psoriasiform rash are more often attributed to programmed cell death-1/programmed cell death ligand-1 inhibitors. The treatment of bullous pemphigoid eruptions is similar to the treatment of maculopapular rash and lichenoid eruptions, with the addition of rituximab in grade 3-4 rash. Skin hypopigmentation/depigmentation does not require specific dermatologic treatment aside from photoprotective measures. In addition to topical corticosteroids, psoriasiform rash may be managed with vitamin D3 analogues, narrowband ultraviolet B light phototherapy, retinoids, or immunomodulatory biologic agents. Stevens-Johnson syndrome and other severe cutaneous immune-related adverse events, although rare, have also been associated with checkpoint blockade and require inpatient care as well as urgent dermatology consultation.

Cutaneous adverse reactions to anti-PD-1 treatment-A systematic review.

The use of the humanized monoclonal anti-programmed cell death 1 antibodies pembrolizumab and nivolumab as potent anticancer therapies is rapidly increasing. However, since their approval, numerous cases of cutaneous reactions have been reported. Cutaneous adverse reactions to these agents have yet to be fully characterized and range from nonspecific eruptions to recognizable skin manifestations, which may be localized and vary from mild to life threatening. This systematic review article provides an overview of the various adverse cutaneous reactions to pembrolizumab and nivolumab therapy and offers suggestions for their management.

Characterizing the adverse dermatologic effects of hydroxychloroquine: A systematic review.

BACKGROUND: Hydroxychloroquine is associated with myriad adverse dermatologic effects, most of which are poorly characterized by the literature, with unknown frequencies and risk factors. OBJECTIVE: To conduct a systematic review of the adverse dermatologic effects and predisposing factors of hydroxychloroquine toxicity. RESULTS: The review included 94 articles comprising 689 dermatologic adverse effects. A total of 21 unique dermatologic reactions were reported, most commonly drug eruption or rash (358 cases), cutaneous hyperpigmentation (116), pruritus (62), acute generalized exanthematous pustulosis (27), Stevens-Johnson syndrome or toxic epidermal necrolysis (26), hair loss (12), and stomatitis (11). Almost all underlying conditions were rheumatologic or autoimmune in nature, composed primarily of lupus erythematous (72% of all cases) and rheumatoid arthritis (14%). The range of reported mean cumulative dosages was wide, with some adverse reactions found after as little as 3 g or as much as 2500 g. LIMITATIONS: Dermatologic adverse events and primary diagnoses related to the use of hydroxychloroquine may be under-reported as only case reports and clinical trials that reported at least 1 dermatologic adverse effect were included. CONCLUSION: Although hydroxychloroquine is generally well tolerated, dermatologic adverse effects involving the skin, hair, or nails are a frequent and significant complication. Most of these reactions occurred after treatment of autoimmune conditions, often manifesting on the skin after a wide range of cumulative dosages.

Analysis of cutaneous allergic reactions in clinical trials of eslicarbazepine acetate.

OBJECTIVES: To evaluate cutaneous allergic reactions in clinical trials of adjunctive eslicarbazepine acetate (ESL) for focal seizures. MATERIALS AND METHODS: Data were analyzed from three phase III randomized, double-blind, placebo-controlled studies of adjunctive ESL in adults (placebo, n = 426; ESL, n = 1021) and two randomized, double-blind, placebo-controlled studies (and open-label extensions [OLEs]) of adjunctive ESL in children aged 4-17 years (placebo, n = 160; ESL, n = 202; OLE, n = 337). RESULTS: Adult studies: Rash (ESL 1.9%, placebo 0.9%) and pruritus (ESL 1.2%, placebo 0.9%) were the most frequent rash-related treatment-emergent adverse events (TEAEs). Most rash-related TEAEs were mild or moderate in severity. Incidence of rash increased with increasing ESL dose, but was not higher for patients who initiated treatment with higher ESL doses. Pediatric studies: Allergic dermatitis (ESL 3.0%, placebo 0) and rash (controlled studies: ESL 1.0%, placebo 1.3%; OLE periods: ESL ≤1.2%) were the most frequent rash-related TEAEs. There was one case of DRESS in the ESL group. Most rash-related TEAEs were mild or moderate in severity and judged as not related to treatment with ESL. CONCLUSIONS: Serious skin rashes were rare during adult and pediatric clinical trials of ESL. Although the incidence of rash with ESL was low, it is important for patients/caregivers to be made aware of the potential signs and symptoms associated with serious skin rashes.

Skin toxicity following treosulfan-thiotepa-fludarabine-based conditioning regimen in non-malignant pediatric patients undergoing hematopoietic stem cell transplantation.

TBC regimens are considered as "reduced toxicity" and are increasingly employed in pediatric HSCT. In our center, we commonly use the combination of treosulfan-thiotepa-fludarabine and ATG for pediatric non-malignant diseases. As we often observe acute skin toxicities following this conditioning regimen, we conducted a prospective observational study to describe and characterize these toxicities. Fifteen pediatric patients undergoing HSCT for non-malignant diseases who were treated at Hadassah-Hebrew University Medical Center during 2015 were enrolled. A thorough dermatological assessment was done on days 0, 1, 7, and 14 from treatment initiation and included description of cutaneous reactions, measurement of BSA of affected skin, and response to local treatment. All the fifteen enrolled patients developed some degree of acute skin reaction. Cutaneous manifestations were variable and included erythematous patches in inguinal area and genitalia (80%), in neck and axillae (40%), diffuse hyperpigmentation (73%), erosions in inguinal area and buttock (47%), and xerosis and desquamation (40%). Average affected BSA reached 71.8%. Erosions were more prevalent in children younger than 2 years of age. The eruptions resolved without sequela in all patients and did not necessitate treatment other than topical agents. Observed extracutaneous toxicities included oral mucositis (40%), diarrhea (47%), and elevated liver enzymes (47%). TBC combined with thiotepa is highly toxic to the skin with various cutaneous manifestations. The toxicity resolves with no long-term sequela.