Development of a Strategic Initiative at MD Anderson Cancer Center to Improve Outcomes in Immune-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for many cancer types. The clinical use of ICIs is increasing rapidly, including in combinations associated with increased risk of toxicities, termed "immune-related adverse events" (irAEs). Therefore, MD Anderson Cancer Center (MDACC) in Houston, Texas has proactively responded by developing a priority endeavor known as the Immuno-Oncology Toxicity (IOTOX) initiative. This strategic initiative aims to facilitate the seamless integration of key domains: (1) standardized clinical practice and innovative decision toolsets; (2) patient and provider education; and (3) a comprehensive clinical and translational research platform. The ultimate goal of this initiative is to develop and disseminate clinical best practices and biologic insights into irAEs to improve outcomes of patients with irAEs at MDACC and in the wider oncology community.

Cutaneous toxicities of mitogen-activated protein kinase inhibitors in children and young adults with neurofibromatosis-1.

PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. However, cutaneous adverse events (CAEs) are common and may hinder patients' abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS: We reviewed institutional medical records of patients under 30 years with a diagnosis of "NF1," "NF2," or "other neurofibromatoses" on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS: Our cohort consisted of 40 patients with NF1 (median age, 14 years). Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi. There was no significant association between CAE presence and tumor response (p = 0.39). CONCLUSIONS: Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

Cutaneous adverse events in 155 patients with metastatic melanoma consecutively treated with anti-CTLA4 and anti-PD1 combination immunotherapy: Incidence, management, and clinical benefit.

BACKGROUND: In response to the increased use of combination checkpoint inhibitors (CPIs) and the resulting increased cutaneous adverse events (CAEs), this study reviewed patients with melanoma treated with combination CPIs to characterize CAE features and their clinical impact, correlation to adverse events in other organs, and correlation to tumor response. METHODS: Patients from the authors' institutional database who received at least 1 dose of ipilimumab in combination with either nivolumab or pembrolizumab between January 1, 2012, and December 31, 2017, for stage IV or unresectable stage III melanoma were identified. The time to next treatment (TTNT) was calculated from the start of CPI therapy to the start of the next treatment or death, and the development of CAEs was tested in a time-dependent Cox regression to identify associations with TTNT. RESULTS: Eighty-one patients (52.3%) experienced a total of 92 CAEs, including eczematous dermatitis (25.0%), morbilliform eruption (22.8%), vitiligo (12.0%), and pruritus without rash (8.7%). The median times to the onset and resolution of CAEs were 21 days (range, 0-341 days) and 50 days (range, 1-352 days), respectively. Most CAEs resolved after patients entered the CPI maintenance phase and treatment with oral antihistamines with or without topical steroids. CPI discontinuation occurred in 4 patients (2.6%) because of CAEs, in 49 (31.6%) because of other immune-related adverse events, and in 20 (12.9%) because of melanoma progression or death. For patients definitively treated with CPIs (n = 134; 86.5%), TTNT was significantly longer with CAEs than without CAEs (hazard ratio, 0.567; 95% CI, 0.331-0.972; P = .039). CONCLUSIONS: CAEs were mostly reversible and rarely required therapy discontinuation. The development of CAEs was associated with a longer TTNT, and this suggested a possible clinical benefit.

Clinical activity of checkpoint inhibitors in angiosarcoma: A retrospective cohort study.

BACKGROUND: Systemic treatments for angiosarcoma remains an area of unmet clinical need. The authors conducted this retrospective study to assess the clinical activity of checkpoint inhibitors in patients with angiosarcoma. The primary objective was to assess the objective response rate, and the secondary objective was to assess the progression-free and overall survival durations and disease control rate. METHODS: Patient data were obtained using The University of Texas MD Anderson Cancer Center Tumor Registry database. The final study population was refined to only include patients who had undergone pembrolizumab monotherapy. The objective response rate was evaluated using RECIST/irRECIST version 1.1. Progression-free survival and overall survival were defined as the time from the initiation of immunotherapy to disease progression or recurrence, death, or last follow-up and to death or last follow-up, respectively. RESULTS: The final cohort comprised 25 patients. Most patients had metastatic disease (72%) and had undergone at least two lines of systemic therapy (80%) before starting pembrolizumab. The objective response rate was 18%, whereas the disease control rate was 59%. The median progression-free survival duration was 6.2 months and was not significantly different between the cutaneous (4.7 months) and visceral angiosarcoma (6.2 months) groups (p = .42). The median overall survival duration was 72.6 months. Toxicities were recorded for eight patients, with fatigue, anemia, constipation, and rash being the most common. CONCLUSIONS: Pembrolizumab shows durable clinical activity in angiosarcoma. These findings suggest that checkpoint inhibition as monotherapy or combination therapy is likely to have a high probability of success.© 2022 American Cancer Society. LAY SUMMARY: This is the largest retrospective study to assess the clinical activity of checkpoint inhibitor monotherapy in angiosarcomas. The study includes an adequate number of patients with visceral angiosarcoma that enabled to obtain meaningful clinical insights that were previously unavailable. Our findings indicate an improvement in progression-free survival with pembrolizumab that is comparable to other active agents in angiosarcoma. Pembrolizumab monotherapy in angiosarcomas also has a favorable tolerability profile. Our findings emphasize the need for prospective studies to evaluate the activity of pembrolizumab monotherapy and combination therapy.

Management of Dermatologic Events Associated With the Nectin-4-directed Antibody-Drug Conjugate Enfortumab Vedotin.

Enfortumab vedotin is a first-in-class Nectin-4-directed antibody-drug conjugate approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic urothelial cancer (la/mUC) previously treated with a platinum-based chemotherapy and a programmed death receptor-1/programmed death-ligand 1 (PD-1/L1) inhibitor, or patients with la/mUC who are ineligible for cisplatin-based chemotherapy and have previously received one or more prior lines of therapy. Enfortumab vedotin is the only drug to have demonstrated survival benefit versus chemotherapy in a randomized controlled trial in patients with la/mUC previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor. The development of dermatologic events following the administration of enfortumab vedotin is anticipated given the expression of Nectin-4 in epidermal keratinocytes and skin appendages (eg, sweat glands and hair follicles). There is the potential for rare but severe and possibly fatal cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrosis, as described in the boxed warning of the US prescribing information for enfortumab vedotin. This manuscript describes the presumed pathophysiology and manifestations of dermatologic reactions related to enfortumab vedotin, and presents recommendations for prevention and treatment, to provide oncologists and other healthcare providers with an awareness of these potential adverse events to best anticipate and manage them.

Severe de novo pustular psoriasiform immune-related adverse event associated with nivolumab treatment for metastatic esophageal adenocarcinoma.

Breakthrough targeted therapies have produced significant improvements in survival for cancer patients, but have a propensity to cause cutaneous immune-related adverse events (irAEs). Psoriasiform irAEs, representing about 4% of dermatologic toxicities associated with immune checkpoint inhibitor (ICI) therapy, are usually mild, occur in older patients and present as an exacerbation of existing psoriasis after several doses of ICI therapy. We report a case of a 58-year-old woman with metastatic esophageal adenocarcinoma and no prior history of psoriasis who developed a pustular psoriasiform irAE, beginning 3 days after initiation of nivolumab and progressing to confluent erythroderma with pustules over 2 weeks despite topical steroid use. She had concurrent acrodermatitis enteropathica, clinically diagnosed and confirmed with a low serum zinc level, that improved with supplementation. Her psoriasiform irAE was refractory to systemic steroids and acitretin, prompting discontinuation of nivolumab and treatment with ustekinumab and concomitant slow taper of acitretin and prednisone. Pustular psoriasiform irAE is a rare but severe dermatologic toxicity resulting from ICI therapy. Given the diverse morphologic types of cutaneous irAEs that can occur during ICI therapy, a clinical and histopathologic examination of dermatologic toxicities is critical to identify patients who may benefit from biologic therapy.

Acneiform eruptions with combination targeted cancer therapy in colorectal cancer patients.

PURPOSE: Epidermal growth factor receptor inhibitors (EGFRI) can be used with pathway inhibitors, including mitogen-activated protein kinase kinase inhibitors (MEKIs), BRAF inhibitors (BRAFIs), and checkpoint inhibitors such as programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) to treat colorectal cancer. These can precipitate treatment-resistant acneiform eruptions, prompting dose modification or discontinuation. Predicting the likelihood of severe rash development and crafting effective treatments may promote adherence to life-saving chemotherapy. METHODS: An Institutional Review Board-approved retrospective chart review of patients with colorectal cancer treated with EGFRI or MEKI in combination with HER2, BRAF, PI3K, or checkpoint inhibitors between January 1, 2016, and January 1, 2020, was performed. Surrogates for rash severity were investigated, including lower extremity involvement, utilization of oral steroids or retinoids, dose modification, and incidence of superinfection. RESULTS: Of 122 patients treated with combination therapy, 105 developed a rash, and 87 developed an acneiform eruption. Common combinations included MEKI/PD-LI, EGFRI/MEKI, and MEKI/PD-1I. Patients treated with EGFRI/MEKI developed the most severe rashes (p = 0.02). Lower extremity involvement was more frequent with EGFRI/MEKI compared to alternative combinations (p = 0.05). Drug holiday correlated with all rash severity surrogates, including rash grade, lower extremity involvement, oral steroid or retinoid use, and incidence of superinfection. Use of oral steroids or retinoids was associated with development of superinfection (p = 0.002). Prophylactic tetracycline use did not impact rash severity or rash incidence. CONCLUSION: This is the first descriptive analysis to characterize acneiform eruptions for patients with colorectal cancer on combination cancer therapy. Approximately 85% of patients developed a cutaneous toxicity with what appears to be synergistic effects of EGFRI and MEKI combination therapy causing the most severe eruptions. Superinfection rate correlated to systemic therapy use beyond oral tetracyclines. Further investigation into the utility of prophylactic oral tetracyclines in this population is needed.

Biologic therapies for checkpoint inhibitor-induced cutaneous toxicities: a single-institution study of 17 consecutively treated patients.

PURPOSE: Treatment options for corticosteroid-refractory and/or high-grade checkpoint inhibitor (CPI)-induced cutaneous adverse events (CAEs) are limited; however, anecdotal reports of biologic therapies have been successful. We aim to characterize the appropriate treatment scenarios and safety and efficacy profiles of biologics used to treat patients with CPI-induced CAEs at a single institution. METHODS: This is a retrospective case series of patients from January 1st, 2015 to October 20th, 2020, with CPI-induced CAEs who were treated with biologics at a single cancer center. Patients were identified using institutional electronic medical record who underwent CPI therapy with subsequent CAEs that necessitated biologic therapy. Diagnostic criteria utilized for CAEs were based on documentation by four board-certified dermatologists, in combination with detailed chart reviews and pathology findings. Primary study outcome measurements include CAE response, tumor response, and adverse events during biologics treatment. RESULTS: We identified 17 patients who fit study criteria. Sixteen patients experienced some degree of CAE improvement on biologics, with 10 of 10 patients reaching CAE resolution at 6 months post biologics. Eight patients needed new systemic treatment post biologics treatment, while 9 patients received no further treatment or stayed on the CPI. Thirteen patients tolerated biologics well with no significant adverse events or blood abnormalities, with only 2 patients experiencing biologic dose delays. CONCLUSION: In our cohort, biologics appear to be extremely efficacious in the treatment of severe-grade and/or steroid refractory CAEs. They also appeared to be well-tolerated without overtly negative effects on tumor response. In patients with limited cancer treatment options and good tumor response to CPIs, biologics should be considered for severe-grade and/or refractory CAEs.

Application of least absolute shrinkage and selection operator logistic regression for the histopathological comparison of chondrodermatitis nodularis helicis and hyperplastic actinic keratosis.

BACKGROUND: The distinction between chondrodermatitis nodularis helicis (CNH) and hyperplastic actinic keratosis (HAK) on the ear can pose a diagnostic challenge. We aimed to identify histopathological characteristics that could distinguish between CNH and HAK on routine sections using penalized least absolute shrinkage and selection operator (LASSO) logistic regression analysis. METHODS: Cases of CNH (n = 80) and HAK (n = 28) were analyzed for selected histopathological characteristics. Fisher's exact test and LASSO regression were performed. RESULTS: In univariate analyses, the following were significantly associated with CNH: ulceration, acanthosis, granular layer in the majority of the lesion, hypergranulosis at the periphery of the lesion, hyperkeratosis at the periphery of the lesion, hyperparakeratosis at the periphery of the lesion, fibrosis, increased blood vessels, vertically oriented blood vessels, and fibrin. A LASSO model excluding atypia found that fibrin, fibrosis, presence of granular layer, ulceration, and vertically oriented blood vessels were most predictive of CNH. Keratinized strap cells were not a significant predictor. CONCLUSION: We have identified features that may aid in differentiating these entities and demonstrated that a LASSO regression model can identify predictors that may improve diagnostic accuracy. Our results indicate that the highest diagnostic accuracy in this dilemma is dependent on obtaining biopsy specimens with visible dermis.

Surgical Intervention for Paronychia Induced by Targeted Anticancer Therapies.

BACKGROUND: Paronychia is a common toxicity associated with targeted anticancer therapies. Antibiotics and steroids are the standard treatments for severe paronychia, yet they are often inadequate, prolonging the patient's suffering and resulting in changes to effective cancer therapy. OBJECTIVE: This article describes the clinical course of drug-induced paronychia and attempts to identify circumstances under which nail surgery may be beneficial. MATERIALS AND METHODS: This is a retrospective case series from a single institution's electronic medical record for patients on paronychia-inducing anticancer therapies with nail disease visit diagnosis codes. RESULTS: The authors identified 36 nail procedures performed on 12 patients, all of whom were managed with conservative steroid and antibiotic therapy with varying degrees of improvement; however, no further improvement was seen after 90 days. Partial matricectomy, nail avulsion, debridement/clipping, and incision and drainage were performed with resolution rates of 100% (11/11), 38.5% (5/13), 12.5% (1/8), and 0% (0/4), respectively. The average time to surgical intervention was 196 days, and the average time to resolution was 268 days. CONCLUSION: This series highlights the prolonged course of severe drug-induced paronychia and the importance of surgical intervention to reduce pain and impact on cancer treatment. Partial matricectomy should be considered for paronychia unresponsive to conservative therapy by 3 months.

Skin Reactions to Immune Checkpoint Inhibitors.

Due to the novelty of immune checkpoint inhibitors, their cutaneous adverse events (AEs) have only been recently characterized. This, along with the substantial rate of cutaneous reactions, has left many clinicians without sufficient familiarity to diagnose and treat cutaneous AEs. Pruritus and rash are among the top five immune-related AEs reported in clinical trials for this class of therapy. Incidence varies between 35 and 60% for cutaneous AEs among the seven FDA-approved drugs used as monotherapy or combination therapy. Although only 2% are reported as grade 3 or 4 events with monotherapy, the incidence can be as high as 6-9% for combination therapy and the impact on quality of life can be significant for these patients. Of ipilimumab patients, 43.5% have a cutaneous AE, and, at our institution, 20% of them had a dose interruption as a result. This means potentially 9% of patients have dose interruption of ipilimumab because of their cutaneous AEs. In the following chapter, we review the categories of these drugs, common cutaneous effects, their grading, and management options.

Disseminated atypical mycobacterial infection in an allogeneic stem cell transplant recipient.

Nontuberculous mycobacteria are pathogens with diverse manifestations in immunocompromised hosts. The lesser-known Mycobacterium haemophilum usually causes cutaneous infection. Diagnosis is challenging but is aided by molecular testing and multidisciplinary communication. We present an immunocompromised patient with disseminated cutaneous mycobacterial infection with digital tenosynovitis.

Racial characteristics of alopecia areata in the United States.

BACKGROUND: Epidemiologic studies on the association between race and alopecia areata (AA) are limited. OBJECTIVE: To characterize racial differences of AA in the United States. METHODS: Cross-sectional study of self-registered AA patients and noncases in the National Alopecia Areata Registry (NAAR). We evaluated odds of AA and its subtypes for 5 ethnic/racial groups using logistic regression. A sex-stratified analysis and a sensitivity analysis among dermatologist-confirmed cases were also performed. RESULTS: We identified 9340 AA patients and 2064 noncases. Compared with whites, African Americans had greater odds of AA (odds ratio, 1.77; 95% confidence interval, 1.37-2.28) and Asians had lower odds (odds ratio, 0.40; 95% confidence interval, 0.32-0.50) of AA. The results were consistent in AA subtypes, dermatologist-confirmed cases, and by sex. LIMITATIONS: Residual confounding due to limited number of covariates. Recall or recruitment bias not representative of the entire disease spectrum. Also, outcome misclassification was possible because not all AA cases in the registry were confirmed by dermatologists. CONCLUSION: Our findings suggest higher odds of AA in African Americans and lower odds in Asians compared with whites. Future studies examining racial disparity in AA from clinical and genetic perspectives are warranted for a better understanding of the disease pathogenesis.

Twelve cases of acneiform eruptions while on anti-CTLA4 therapy.

We present the first detailed report of acneiform eruptions in patients on CTLA-4 inhibitor therapy. Acneiform eruptions commonly occur (up to 75-100%) as a cutaneous adverse event associated with EGFR inhibition; however, acneiform eruptions have not been highly reported as a cutaneous adverse event associated with CTLA-4 inhibitor therapy. We conducted a retrospective chart review of our institution's database to assess cutaneous adverse events associated with ipilimumab and tremelimumab, identifying 12 patients with acneiform eruptions (2 on tremelimumab and 10 on ipilimumab). The median time to onset of rash was 3 weeks after starting CTLA-4 inhibitor therapy, ranging from 0.7-45 weeks. Median time to cutaneous resolution was 6 weeks, ranging from 2 to 282 weeks. Treatment included oral and topical antibiotics, antihistamines, and oral or topical corticosteroids with four patients receiving no treatment. Acneiform eruptions are seen less commonly with CTLA-4 inhibitors than other cancer therapies, but awareness that it does occur is important for clinical practice. Better description is a necessary help to aid in early diagnosis and intervention. While EGFR inhibitor-associated acneiform eruptions are associated with clinical benefit, our sample size is too small to determine whether CTLA-4 inhibitor associated acneiform eruptions display the same correlation.

Skin Reactions to Immune Checkpoint Inhibitors.

Due to the novelty of immune checkpoint inhibitors, their cutaneous adverse events (AEs) have only been recently characterized. This, along with the substantial rate of cutaneous reactions, has left many clinicians without sufficient familiarity to diagnose and treat cutaneous AEs. Pruritus and rash are among the top five immune-related AEs reported in clinical trials for this class of therapy. Incidence varies between 35 and 50% for cutaneous AEs among the eight FDA-approved drugs. Although only 2% are reported as grade 3 or 4 events, the impact on quality of life can be significant for these patients and is best described and most severe in ipilimumab trials. Of ipilimumab patients, 43.5% have a cutaneous AE and, at our institution, 20% of them had a dose interruption as a result. This means potentially 9% of patients have dose interruption of ipilimumab because of their cutaneous AEs. In the following chapter, we review the categories of these drugs, common cutaneous effects, their grading, and management options.

Dermatomyositis associated with nivolumab therapy for melanoma: a case report and review of the literature.

We present a rare case of dermatomyositis associated with nivolumab therapy for melanoma. Nivolumab is an immune checkpoint inhibitor that blocks the programmed death-1 (PD1) receptor and has a number of associated immunotherapy related adverse events. Although most are T-cell mediated, some are antibody mediated mimics of classical autoimmune diseases. We review the characteristics of other cases of anti-PD1 associated dermatomyositis and the recent literature to better understand how to classify and treat this challenging immunotherapy related adverse event.

Unusual presentation of Kaposi sarcoma in an HIV-negative woman.

Kaposi sarcoma typically presents as violaceous macules and papules in immunocompromised, specifically HIV-positive, patients. Its distinct clinical features often facilitate rapid diagnosis. In this article, we report a case of Kaposi sarcoma presenting as a concerning yet nondescript lesion in an HIV-negative woman. Although Kaposi sarcoma is frequently part of the differential diagnosis for skin lesions affecting HIV-positive patients, it is less frequently considered in HIV-negative individuals. Additionally, this case differs from the classic clinical presentation of Kaposi sarcoma by resembling a squamous cell carcinoma or superficial basal cell carcinoma. Therefore, it illustrates the importance of suspicious lesion biopsies to ensure accurate diagnosis and appropriate treatment.

A case of new-onset vitiligo in a patient on tofacitinib and brief review of paradoxical presentations with other novel targeted therapies.

With recent advancements in the understanding of vitiligo pathogenesis, Janus kinase (JAK) inhibitors have emerged as a promising new treatment modality, but their effects remain incompletely elucidated. Tofacitinib, an oral JAK 1/3 inhibitor approved for the treatment of rheumatoid arthritis, has previously been shown to induce significant re-pigmentation in vitiligo. However, as with other novel targeted therapies, cutaneous adverse effects have been observed. We report a 36-year-old woman with a history of rheumatoid arthritis, refractory to multiple pharmacotherapies, who was initiated on tofacitinib and subsequently developed progressive depigmented patches consistent with new-onset vitiligo. Although definitive causation cannot be established in this case without additional studies, it is important to note that many targeted therapies have the potential to induce paradoxical effects, that is, the occurrence or exacerbation of pathologic conditions that have been shown to respond to these medications. Paradoxical findings with other targeted therapies include the occurrence of melanoma during treatment with BRAF inhibitors, keratoacanthomas with PD-1 inhibitors, vitiligo and psoriasis with TNF-alpha inhibitors, and hidradenitis suppurativa with various biologic agents. Although JAK inhibitors hold therapeutic promise in the treatment of inflammatory skin disorders, further research is warranted to more fully comprehend their effects.

Surgical site identification with personal digital device: A prospective pilot study.

BACKGROUND: Various means to facilit ate accurate biopsy site identification have been proposed. OBJECTIVE: To determine the accuracy of biopsy site identification by using photographs taken with a patient's digital device by a dermatologist versus professional medical photography. METHODS: Photographs of circled biopsy sites were taken with personal digital devices by the principal investigator (PI). Another set of photographs was taken by a professional photographer. Secondary photographs were taken of the biopsy site location pointed to by the staff and PI on the basis of the personal digital device image and professional medical photography, respectively. On the basis of secondary photographs, 2 independent dermatologists determined whether the skin biopsy locations pointed out by the staff were consistent with the ones pointed out by PI. RESULTS: Per dermatologist A, the staff correctly identified all 53 biopsy sites. Per dermatologist B, the staff were correct on 51 of 53 observations. Dermatologist C, the final arbiter, concurred with dermatologist A on the 2 cases in which dermatologist B was not certain of the location of the biopsy site. LIMITATIONS: The mean interval from initial biopsy to reidentification of the site was 36.2 days. CONCLUSION: Utilizing patients' personal digital devices is a cost-effective, Health Insurance Portability and Accountability Act-compliant, and readily available means to identify skin biopsy sites.