Novel Hemorrhagic Dermatologic Toxicity Associated with Bruton's Tyrosine Kinase Inhibitor Therapy

Background: Bruton Tyrosine Kinase inhibitors (BTKi), including ibrutinib and acalabrutinib, are an integral part of the treatment paradigm for many B-cell malignancies including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom macroglobulemia (WM). Dermatologic toxicities associated with drugs in this class including petechiae, easy bruising, panniculitis, folliculitis, and aphthous ulcerations have been previously documented (Sibaud et al Am J Clin Dermatol. 2020). The ecchymotic lesions noted in this recent review by Sibaud et al were noted to mimic solar purpura with discrete areas of bruising or hematoma. In the present case series, we present a cohort of patients experiencing an array of skin toxicities during treatment with ibrutinib or acalabrutinib including instances of striking confluent ecchymotic skin lesions. Methods: A retrospective chart review was conducted on patients treated within our health system who had received ibrutinib, acalabrutinib or zanubrutinib treatment. IRB approval was obtained prior to collection of clinical data. Patients who had a dermatologic toxicity including petechiae, ecchymoses, hematoma or vasculitis were identified. Patients were excluded if they were receiving BTKi for graft versus host disease or an indication other than CLL or lymphoma, or if there were insufficient records. Data collection included the BTKi agent and dosing utilized, the age at onset of dermatologic toxicity, the time from initiation of BTKi therapy to the development of dermatologic toxicity, and subsequent treatments following BTKi cessation (if any). Data was compiled and descriptive statistics were obtained. Results: Patients had a median age of 73; five patients were male and two female. Diagnoses included CLL (n = 3), MCL (n = 3), and WM (n = 1). Three were treated with acalabrutinib while 4 received ibrutinib. Two patients received combination therapy with ibrutinib, one with ublituximab and one with ixazomib. The average time to onset of skin toxicity was sooner in those taking acalabrutinib (63 days) versus ibrutinib (642 days). Two of the acalabrutinib-related events were documented within 1 month of therapy initiation. Skin biopsy on one patient treated with acalabrutinib revealed vascular ectasia with non-occlusive thrombotic vasculopathy. Following development of these skin toxicities, therapy with the BTKi was discontinued in only 2 of 7 patients. Three patients were transitioned to an alternative BTKi and two were continued on therapy without modification and without further clinical deterioration. Conclusion: While dermatologic toxicity associated with use of ibrutinib and acalabrutinib has been previously described, this cohort represents, to our knowledge, the first documentation of large confluent BTKi- associated ecchymoses. While several patients in this cohort were transitioned to an alternative BTKi or to a different therapeutic class entirely at the onset of dermatologic toxicity, two continued on the implicated BTKi without alteration in therapy. As demonstrated by these varied approaches, management of BTKi therapy following development of dermatologic toxicity is not standardized, with optimal management determined on an individualized basis through discussion and joint decision making with the patient. Figure 1 Figure 1. Disclosures Williams: Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding. Flowers: Venthera: Current Employment.

812 Erythema nodosum-like toxicity in an immunotherapy treated patient is accompanied by oligoclonal memory activated CD4 T cells

BackgroundImmune checkpoint inhibitors (ICIs) are increasingly used to treat advanced malignancy but can be associated with immune related adverse events (irAE). Here we present a case report of a rare dermatologic toxicity occurring in a melanoma patient with isolated brain metastasis. After surgical resection, the patient was treated with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination therapy followed by single agent nivolumab with ongoing, excellent response. During nivolumab, the patient developed an erythema nodosum (EN)-like irAE. The condition resolved after potassium iodine treatment and nivolumab therapy was resumed. To understand the pathogenesis of this irAE, we examined samples from this patient's blood, brain metastasis and tissue biopsy of the EN toxicity.MethodsRNA and T cell receptor (TCR) sequencing on the patient's brain metastasis and site of irAE were performed. We also performed RNA sequencing on 3 non-ICI EN patients. RNA in situ hybridization (RNAish) for CD4, CD8 and granzyme B, and the most abundant TCR identified was conducted on the patient's site of toxicity. Single cell RNA/TCR sequencing was carried out on the patient's peripheral blood mononuclear cells (PBMC) at baseline, 3 weeks after ipilimumab and nivolumab combination therapy, during EN toxicity and after resolution.ResultsRNAish showed that the most abundant TCR (20% of total TCR sequencing reads at the site of toxicity) colocalized with CD4 at the site of toxicity. According to CIBERSORT deconvolution, the site of toxicity had high memory activated CD4 T cells and low M2 macrophage infiltration, which is different from the brain metastasis and non-ICI-induced EN cases. Compared to non-ICI EN, the EN skin biopsy was also enriched for interferon response and inflammation related genes. In the peripheral blood, cytotoxic CD8 T cells clonally expanded during EN toxicity, accompanied by a decrease in naïve/memory CD4 T cells. The TCR repertoire in the site of toxicity did not overlap with that in the tumor or PBMC.ConclusionsWe found oligoclonal memory activated CD4 T cells are enriched at the site of toxicity, suggesting their association with EN toxicity. The unique TCR repertoire, gene expression profile and immune cell composition at the site of toxicity could indicate that the EN toxicity is distinct from the anti-tumor immunity and analogous non-ICI autoimmunity. Future work will focus on determining the antigen for this irAE and determining its relevancy to other skin toxicities and EN autoimmune conditions.Ethics ApprovalIRB 100178 and 161485ConsentApproval under IRB 100178

Case Report: A Rare Case of Pembrolizumab-Induced Bullous Pemphigoid

The programmed cell death protein 1 inhibitor pembrolizumab, an immune checkpoint inhibitor, has subsequently been approved for the treatment of a wide variety of malignant tumors. Compared with conventional chemotherapy, immunotherapy is associated with a unique set of immune reactions, known collectively as immune-related adverse events. Although often mild, dermatologic toxicity can occasionally be high grade and potentially life-threatening. Here we describe a rare case of bullous pemphigoid (BP) associated with pembrolizumab. A 79-year-old male patient presented with scattered erythema, papules, blisters, and pruritus after pembrolizumab treatment. Then, the rash gradually aggravated and spread to the whole body. The extensive edematous erythema, blisters, bullae, and blood blisters were loose and easy to rupture, forming an erosive surface and with pruritus and obvious pain. The hemidesmosomal protein BP180 (type XVII collagen) was detectable in the serum, and the histological examination diagnosis was bullous pemphigoid. After 10 days of glucocorticoid (methylprednisolone, iv, 80 mg/day) treatment, new blister formation ceased. We need to increase the awareness on and facilitate the earlier identification of the cutaneous adverse effects of BP with immunotherapy so that treat can begin early in order to limit the duration and severity of toxicity.

LGG-08. TREATMENT OUTCOMES AND TOLERABILITY OF TRAMETINIB IN PROGRESSIVE CIRCUMSCRIBED LOW-GRADE GLIOMAS

Circumscribed low-grade gliomas comprise roughly one-third of pediatric CNS tumors. Most of these tumors are caused by activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Drugs targeting the MAPK pathway are effective in other cancers and are being utilized in low-grade gliomas. We describe treatment outcomes and toxicities in a series of thirteen low-grade glioma patients treated with trametinib. We performed a retrospective chart review to evaluate response on T2/FLAIR MRI images per updated RANO criteria, visual outcomes, tolerability, and durability of response in progressive low-grade glioma patients treated with trametinib. Thirteen patients age 22 months to 34 years were included. Best radiographic response on therapy included 2/13 partial response, 3/13 minimal response, 5/13 stable disease, and 3/13 progressive disease. Diagnoses included pilocytic astrocytoma (n=6), desmoplastic infantile ganglioglioma (DIG; n=1), and low-grade glial neoplasms (n=2). Molecular drivers included BRAF:KIAA1549 fusion (n=3), V600E mutation (n=1), and somatic NF1 mutation (n=1). Three patients had germline NF1. In patients with partial or minimal response, best response was seen after longer durations of therapy; 4 of 5 best responses occurred after at least 12 months on therapy. Five patients completed prescribed therapy. Three patients remain stable off therapy at 6, 12, and 21 months; two patients recurred at 1 and 10 months off therapy. Skin manifestations were the predominant form of toxicity. This was more severe in older males, and symptoms improved with intermittent dosing. All patients with optic pathway tumors showed at least stable vision throughout treatment, with some patients having dramatic improvement. Trametinib is effective and well-tolerated in patients with low-grade glioma. Dermatologic toxicity can be mitigated by intermittent dosing. Best responses tended to occur later in therapy, sometimes after relatively stable MRIs. Patients with optic pathway lesions showed stable to improved vision even in the absence of significant radiographic response.

Long-term follow-up outcomes and treatment among patients previously treated with Zizao Yangrong granules (ZYG) for egfris–related skin xerosis.

e24054 Background: Traditional Chinese medicine (TCM) has broad prospects in the treatment of targeted drugs–related dermatologic toxicity. In our previous study (ChiCTRIOR-17013498), Zizao Yangrong granules (ZYG) made effect on EGFRIs-related xerosis and improve the quality of life. However, some people still doubt that TCM could affect therapeutic benefit for patients treated with EGFRIs. Methods: Patients with EGFRIs related xerosis who underwent ZYG and vitamin E ointment from May 2016 to January 2018 were retrospectively reviewed. Survival data and quality of life data analysis were performed. Besides, patients who used ZYG for more than 8 weeks were also summarized, followed by telephone follow-up and questionnaire survey. Results: Of 68 participates randomly assigned, 54 patients were successfully followed up. Median PFS in Vitamin E Ointment plus ZYG group was 41.6 months, and that in Vitamin E Ointment group was 40.9 months, with no statistical difference (HR 0.85, 95% CI 0.48 to 1.51, P = 0.586). Subsequently, 19 patients who used ZYG for longer than 8 weeks were also included. 2 patients reported complete response, 14 patients reported partial response, and 3 patients reported no response. The overall effective rate was 84.2%. The total DLQI score of patients with long-term intervention of ZYG was 4.47±3.10. Compared with baseline DLQI score (7.00±2.91), the DLQI of patients after ZYG intervention has been significantly improved (P = 0.000). During the continuous use of ZYG treatment, incidence of adverse effects was 57.9%. Treatment-related adverse reactions were mostly mild, with no grade 3/4 adverse events. Conclusions: ZYG did not affect progression free survival of patients treated with EGFRIs. And long time-scale ZYG intervention could continuously relieve EGFRI-related xerosis and significantly improve the quality of life of patients without serious adverse effects. Clinical trial information: ChiCTRIOR-17013498.

Refractory dermatitis contributed by pityriasis versicolor: a case report

Background Dermatologic toxicity is a very common immune-related adverse event (irAE) for patients with melanoma who are receiving immune checkpoint inhibitor therapy (ICI). Concurrent skin infection, such as in the case of pityriasis versicolor reported here, can mimic and/or exacerbate dermatologic toxicity from irAE. Case presentation A 58-year-old Caucasian man with a history of pityriasis versicolor infection and metastatic melanoma received ICI therapy. He developed progressively worsening pruritic maculopapular lesions 22 weeks into his treatment that ultimately covered 40% of his body. He was diagnosed with dermatologic toxicity due to ICI therapy with concurrent pityriasis versicolor. He was initially started on topical steroid and topical antifungal cream but achieved minimum improvement. His treatment was then escalated to oral prednisone, but it only achieved modest control of his dermatitis. All subsequent attempts to wean him from oral prednisone resulted in worsening of his dermatitis. Eventually he was started on oral fluconazole in combination with prednisone, which led to rapid resolution of his dermatitis. Conclusion We report a case of dermatological toxicity due to an irAE with concurrent pityriasis versicolor. The steroid treatment for irAE was likely exacerbating the underlying fungal infection, and the fungal infection was in term mimicking the symptoms of irAE. This patient’s severe dermatitis was only brought under control after receiving a more potent antifungal therapy in combination with a steroid. It is vital to look beyond the irAE when managing dermatitis in patients receiving ICI therapy.

Associations of Cutaneous Immune-Related Adverse Effects of Immunotherapy With Treatment Response in Patients With Metastatic Melanoma

Background: Dermatologic toxicity is the most common immune-related adverse effect of cancer immunotherapy. Methods: We retrospectively reviewed the health records of adult (≥18 years) melanoma patients who received ipilimumab, nivolumab, or pembrolizumab from January 1, 2011, through September 15, 2017, at Mayo Clinic. The χ2 test was used to assess the association between development of a cutaneous immune-related adverse effect and antitumoral response to the immune checkpoint inhibitors. Odds ratios were calculated with logistic regression models and were adjusted for sex and immunotherapeutic drugs. We described the various cutaneous immune-related adverse effects and assessed the response to immunotherapy (each patient’s objective clinical response was categorized as favorable [complete or partial response] or unfavorable). We then determined whether development of a cutaneous immune-related adverse effect was associated with the clinical response. Results: Of 690 melanoma patients, 232 (33.6%) had a cutaneous immune-related adverse effect. The most common effects were dermatitis (21.4%), pruritus (5.5%), and vitiligo (4.2%). Median (range) time to onset of dermatitis was 3 (0-7) weeks; lichenoid dermatitis, 12 (6-18) weeks; and vitiligo, 40 (12-96) weeks. Development of a cutaneous immune-related adverse effect was significantly associated with favorable clinical response. Conclusions: Development of cutaneous immune-related adverse effects is associated with favorable responses to nivolumab, ipilimumab, pembrolizumab, and ipilimumab plus nivolumab therapy in patients with metastatic melanoma.

Case Report: Enfortumab Vedotin for Metastatic Urothelial Carcinoma: A Case Series on the Clinical and Histopathologic Spectrum of Adverse Cutaneous Reactions From Fatal Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis to Dermal Hypersensitivity Reaction

Enfortumab vedotin is a Nectin-4 directed antibody-drug conjugate approved in metastatic urothelial carcinoma following progression on a platinum-containing chemotherapy and immune checkpoint blockade. On-target dermatologic toxicity may occur from Nectin-4 expression in the skin. We highlight a case of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis following enfortumab infusions that was ultimately fatal. The second case describes an erythema multiforme-like rash with interface dermatitis related to enfortumab. Dermatologic findings, immunohistochemistry studies, and immune profiling are detailed. These cases demonstrate the potentially catastrophic outcomes in some patients treated with enfortumab. Patients must be monitored for cutaneous toxicities with early involvement of dermatology and dermatopathology.

Acute interstitial nephritis: New agents for an old entity

A 73-year-old male diagnosed with metastasized malignant melanoma was started on combined therapy with dabrafenib and trametinib, but soon admitted with gastrointestinal intolerance. Blood tests revealed toxic hepatitis and acute kidney injury. Renal duplex Doppler ultrasound ruled out urinary and vascular obstruction and apart from a positive antinuclear antibody, other tests for acute kidney injury assessment were unremarkable. Urinary sediment microscopy showed dysmorphic red blood cells, in addition to yellow-pigmented casts. Kidney biopsy revealed signs of acute tubular necrosis and acute interstitial nephritis. Kidney function declined further, prompting the need for urgent hemodialysis. Treatment with dabrafenib and trametinib was stopped and corticosteroids were initiated, with a rapid beneficial effect on both the kidney function and liver toxicity. Hemodialysis was stopped after four sessions with a full recovery after 2 months of corticosteroids, with the dose being slowly tapered. Unfortunately, the patient died a few months later due to melanoma progression. Dual therapy with the combination of a B-Raf proto-oncogene inhibitor with a mitogen-activated protein kinase kinase inhibitor improves response rates and has been recently approved by the U.S. Food and Drug Administration, and while dermatologic toxicity is a common adverse effect, the association with acute renal failure has seldom been reported. To the best of our knowledge, there are only two published case reports of acute kidney injury in patients treated with combination of dabrafenib and trametinib and only one of them is biopsy proven. Further studies evaluating the incidence of acute kidney injury with the combination of B-Raf proto-oncogene and mitogen-activated protein kinase kinase inhibitors are warranted, and may provide new insights into the mechanisms underlying renal toxicity.