scholarly journals Complete reversibility of pembrolizumab-induced eosinophilic fasciitis without corticosteroids: A case report

2021 ◽  
Vol 9 ◽  
pp. 2050313X2110251
Author(s):  
Liane Bourcier ◽  
Ève St-Hilaire ◽  
Martin LeBlanc ◽  
Léo Picard
Keyword(s):  
Adverse Effect ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Signs And Symptoms ◽  
Eosinophilic Fasciitis ◽  
Second Line Therapy ◽  
Organ Systems ◽  
Symptom Progression ◽  
Joint Limitation

Checkpoint inhibitor immunotherapy has recently started to play a fundamental role in the management of metastatic melanoma. It is however accountable for many undesirable adverse effects involving many organ systems. Eosinophilic fasciitis is a rare immune-related adverse effect associated to checkpoint inhibitors such as pembrolizumab and nivolumab. We report the case of a 25-year-old male who received pembrolizumab as a second-line therapy for metastatic melanoma. Approximately 8 months after starting the treatment, the patient developed signs and symptoms of eosinophilic fasciitis, including edema of his hands and lower legs, as well as joint limitation. Pembrolizumab was discontinued after 15 cycles because of symptom progression. The patient experienced complete resolution of symptoms 4 months after cessation of pembrolizumab and without corticosteroids. This case illustrates the reversibility of this immune adverse effect by discontinuation of the treatment, speculating that corticotherapy may not be needed in all cases.

Analysis of metastatic melanoma treated with immune checkpoint inhibitors and the rates of adverse events of colitis and hepatitis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21591-e21591
Author(s):  
Emily Horan ◽  
Melissa Arneil ◽  
Wen Xu ◽  
Victoria Atkinson
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Complete Response ◽  
Treatment Regimens ◽  
Organ Systems ◽  
Oral Steroids ◽  
Intravenous Steroids

e21591 Background: Immune checkpoint inhibitors (CPI) are widely used in metastatic melanoma (MM), where it has markedly improved survival outcomes. ICI induced autoimmune adverse reactions (irAE) manifest in all organ systems and are due to over-activation of the immune system. Clinically relevant irAE are colitis and hepatitis as drivers of morbidity and mortality. Methods: Data was collected from a single centre (Princess Alexandra Hospital) from the electronic medical records system and immunotherapy prescribing software. Patient demographics, treatments, complications and outcomes were recorded from 2016-2019. Eligible patients had to have received immunotherapy (pembrolizumab, ipilimumab, or nivolumab) and experienced colitis or hepatitis toxicity. Trial patients were excluded. Results: The cohort of 337 patients who had received immune therapy, 18% (n = 61) had hepatitis or colitis, mean age was 56 years, 64% male. The majority were stage 4d 28% (n = 17). Braf wildtype accounted for 56% (n = 34). The highest rates of irAE occurred on combination ipilimumab and nivolumab 56% (n = 34), 10% nivolumab (n = 6), 3% (n = 2) ipilimumab, and 31% (n = 19) pembrolizumab monotherapy. Colitis affected 61% of patients (n = 37), 30% (n = 18) were grade 3 severity. Hepatitis affected 48% (n = 29), 18% (n = 32) were grade 1. The majority required oral steroids (80%, n = 49), followed by intravenous steroids (51%, n = 31), infliximab (18%, n = 11) and mycophenolate in 5% (n = 3). Hospitalisation occurred in 56% (n = 34), 20% (n = 12) requiring treatment cessation. Progressive disease occurred in 62% (n = 38), and 13% (n = 8) had a complete response. Conclusions: The findings of this analysis mirror current literature with immunotherapies used, rates and severity of irAE. The management of irAE also aligned with current guidelines. Further research is required to investigate patient factors increasing the risk of developing irAE, and ideal treatment regimens. Analysing this large cohort, the incidence of toxicity was 17%, predominantly colitis followed by hepatitis. Patients were severely impacted requiring significant interventions to manage toxicity, hospitalisation and morbidity.

Peritoneal melanosis associated with metastatic melanoma previously treated with targeted and immune checkpoint inhibitor therapy

2021 ◽  
Vol 14 (1) ◽  
pp. e238235
Author(s):  
Kwang Kiat Sim ◽  
Katie Connell ◽  
Mayank Bhandari ◽  
David Paton
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Inhibitor Therapy ◽  
Tumour Regression ◽  
Benign Condition ◽  
Checkpoint Inhibitor Therapy ◽  
Previously Treated

Peritoneal melanosis is an uncommon benign condition, the pathophysiology of which is unclear. Macroscopically, it appears as diffuse dark brown or black pigmentation within the peritoneum, mimicking more sinister conditions such as metastatic melanoma. It has been described in a variety of contexts, but only exceedingly rarely in association with metastatic melanoma, with only two previous published case reports. We present a case of peritoneal melanosis associated with metastatic melanoma involving the spleen, previously treated with targeted and immune checkpoint inhibitor therapy. With increasing reports of melanoma regression manifesting as cutaneous tumorous melanosis in patients treated with immune checkpoint inhibitors, we postulate that, similarly, immunotherapy and tumour regression might have a role to play in the pathogenesis of the peritoneal pigmentation in this case.

Behcet’s-like syndrome following pembrolizumab: An immune-related adverse event associated with programmed death receptor-1 inhibitor therapy

2019 ◽  
Vol 26 (4) ◽  
pp. 995-999 ◽  
Author(s):  
Steffi Thomas ◽  
Chay Bae ◽  
Tabanor Joy-Ann ◽  
William Traverse
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Programmed Death ◽  
Organ Systems ◽  
Wide Range ◽  
The Right

Introduction The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system. Case report We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations. Management and outcome Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer. Discussion Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet’s disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet’s-like syndrome presentation.

scholarly journals Immune checkpoint inhibitor induced autoimmune encephalitis in a patient with metastatic melanoma

2020 ◽  
Vol 7 (3) ◽  
pp. 1
Author(s):  
Nivedita Sudhekar ◽  
Binoy Yohannan ◽  
Mark Feldman
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Combined Therapy ◽  
Autoimmune Encephalitis ◽  
The Body

Background: Immune checkpoint inhibitors have changed the therapeutic milieu for patients with metastatic melanoma. However, their use may promote autoimmunity in virtually any organ in the body due to the blockade of intrinsic immune down regulators such as cytotoxic T-lymphocyte antigen- 4 (CTLA-4), programmed cell death 1 (PD1) or its ligand (PDL1). Immune mediated adverse neurological events are rare with these agents, however, and are seen in < 1% of treated patients. We report a patient with immune checkpoint inhibitor associated autoimmune encephalitis, with complete clinical recovery after treatment.Case Report: A 49-year-old female with metastatic melanoma currently on nivolumab therapy but recently on ipilimumab/nivolumab combined therapy presented with a new headache. She also reported associated confusion, loss of balance, personality changes and language difficulty. Magnetic resonance imaging of the brain did not reveal any evidence of metastasis, infarct, meningitis, or encephalitis. Lumbar puncture revealed an elevated protein level and pleocytosis, with a normal glucose level. She was started on empiric glucocorticoid therapy with a presumptive diagnosis of immune checkpoint inhibitor associated autoimmune encephalitis. She improved considerably by day 3 of treatment with complete resolution of neurological symptoms by day 5.Conclusion: Immune checkpoint inhibitors are increasingly important in cancer immunotherapy as they can cause sustained remissions in patients with metastatic melanoma and other malignancies. Because these drugs block immune-regulatory targets, they can lead to enhanced activation of immune system resulting in immune-related adverse events. Autoimmune encephalitis is a rare immune-related adverse event associated with immune checkpoint inhibitors. The incidence of autoimmune encephalitis is higher with combination or sequential CTLA-4 (ipilimumab) and PD1(nivolumab) inhibitor therapy than with monotherapy. With more widespread use of immunotherapy, it is important for clinicians to be aware of this rare and reversible cause of encephalitis. Early recognition and prompt initiation of immunosuppressive therapy with glucocorticoids is essential to enhance neurological recovery.

scholarly journals 6. Treatment resistant ulcerating dermatomyositis in metastatic melanoma treated with checkpoint inhibitor therapy

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Lucy Parker ◽  
Philippa Coull ◽  
Fotini Soliotis
Keyword(s):  
Metastatic Melanoma ◽  
Skin Disease ◽  
Conflicts Of Interest ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Muscle Disease ◽  
Solid Tumours ◽  
Ivig Treatment ◽  
Underlying Malignancy ◽  
Facial Swelling

Abstract Introduction Paraneoplastic dermatomyositis is a well-recognised clinical entity, and should prompt investigation for an underlying malignancy. Immunosuppressive treatment can be effective in control of both skin and muscle disease. The effect of checkpoint inhibitors for control of solid tumours on autoimmune paraneoplastic phenomena is yet to be fully understood. Case description A 49-year-old female with a background of melanoma on the left thigh 2014 (Breslow thickness 1.9mm, treated with wide local excision only) presented with classical features of dermatomyositis; facial erythema, V-sign, Gottron’s papules, muscle weakness and elevated creatine kinase (CK) at 711 IU/L. An MRI of the upper arms was consistent with myositis. Myositis ENA panel was negative. She was initially treated with high dose oral prednisolone and weekly methotrexate. At presentation, there was no clinical or radiographic evidence of recurrent melanoma, but unfortunately after 7 months she developed a lump in the left groin which proved to be metastatic melanoma (stage IV M1a). She was treated with 3 months palliative pembrolizumab, but this was discontinued due to lack of clinical response, when an interval CT scan showed increasing volume of disease (progressive left pelvic, retroperitoneal and left supra-clavicular fossa lymphadenopathy). Her skin disease remained painful despite 20mg PO prednisolone and 25mg of subcutaneous methotrexate weekly, so she was treated with intravenous immunoglobulin (IVIG) 2g/kg planned to be given over 5 days. On day 3, she was found to be pyrexial at 38.2 degrees celcius prior to commencement of the infusion. Treatment was delayed by 2 days. On day 6 she was again apyrexial and the IVIG treatment was completed with IV paracetamol and 100mg IV hydrocortisone given alongside. Following the IVIG, she has developed areas of painful localised ulceration over the dorsi of her feet, limbs and forehead. Her skin disease remains active with facial swelling and erythema, florid Gottron’s papules and periungual erythema. The ulcerated areas are discrete from the areas of known metastasis, and are considered to be secondary to severe dermal inflammation which is being treated with betnovate ointment, with a plan to introduce hydroxychloroquine if there is no clinical improvement. Discussion The use of checkpoint inhibitors to treat solid tumours is increasing. The autoimmune side effects of this group are well documented, and pembrolizumab is known to trigger dermatitis as a treatment related adverse event. However, the implications for checkpoint inhibitor use in an existing paraneoplastic autoimmune phenomenon is not yet understood. Key learning points Thorough investigation for underlying malignancy is paramount in new dermatomyositis. Patients treated with checkpoint inhibitors should be monitored closely for disease activity. Conflicts of interest The authors have declared no conflicts of interest.

Corticosteroids for the management of immune-related adverse events in patients receiving checkpoint inhibitors

2017 ◽  
Vol 25 (3) ◽  
pp. 544-550 ◽  
Author(s):  
Kiersten J Williams ◽  
Dennis W Grauer ◽  
David W Henry ◽  
Michelle L Rockey
Keyword(s):  
Adverse Effect ◽  
Adverse Effects ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Total Duration ◽  
Inhibitor Therapy ◽  
Related Adverse Effect ◽  
Starting Dose ◽  
Checkpoint Inhibitor Therapy

Introduction Due to enhanced T-cell activity, immune checkpoint inhibitors cause immune-related adverse effects. Corticosteroids are the mainstay of immune-related adverse effect management but the optimal strategy has not been determined, putting patients at risk for steroid-related adverse effects and potentially decreased efficacy of immunotherapy. This study aims to characterize the use of corticosteroids for the management of immune-related adverse effect. Methods and materials A retrospective, single-center evaluation of patients receiving checkpoint inhibitors was conducted. The primary objective was to evaluate corticosteroid use for immune-related adverse effects, including starting dose, taper strategy, total duration, and resumption of immunotherapy. Secondary objective was to describe the incidence and significance of hyperglycemia. Results One hundred and three patients met inclusion criteria and experienced 123 immune-related adverse effects. Prednisone was used most commonly (67%) at an average starting dose of 0.88 mg/kg (range 0.07–17.0). On average, steroid tapers began 9.2 days after initiation (range 0–89) and were continued for a total of 84.2 days (range 3–693). In 21.1% of cases, checkpoint inhibitor therapy was not delayed and 68.6% resumed checkpoint inhibitors, while the patient was taking steroids (30.4 mg prednisone on average, range 5–80). On average, checkpoint inhibitor therapy was resumed 18.6 days after detection of immune-related adverse effect (range 0–150). Clinically relevant hyperglycemia occurred in 8.9%. Conclusion Utilization of steroids for immune-related adverse effect at our institution is highly variable. The majority of patients received prolonged courses of steroids and resumed checkpoint inhibitor therapy with concomitant steroids above recommended doses. Additional monitoring for hyperglycemia and other steroid associated adverse effects should be considered.

scholarly journals 20. MELANOMA CELL INTRINSIC GABAA RECEPTOR ENHANCEMENT POTENTIATES RADIATION AND IMMUNE CHECKPOINT INHIBITOR RESPONSE BY PROMOTING DIRECT AND T CELL-MEDIATED ANTI-TUMOR ACTIVITY

2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii3-ii3
Author(s):  
Soma Sengupta ◽  
Tahseen Nasti ◽  
Milota Kaluzova ◽  
Laura Kallay ◽  
Johannes Melms ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Melanoma Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Tumor Volume ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Expression Of Genes ◽  
Melanoma Patients ◽  
Anti Tumor Activity

Abstract Most metastatic melanoma patients exhibit poor and variable response to radiotherapy and targeted therapies, including immune checkpoint inhibitors. There is a need for therapeutics that can potentiate existing treatments to positively impact clinical outcomes of metastatic melanoma patients. We reanalyzed melanoma TCGA transcriptomes and identified, as linked to previously defined molecular subgroups, enhanced expression of genes coding for subunits of the Type A GABA receptor (GABAAR), a chloride ion channel and major inhibitory neurotransmitter receptor. Using whole-cell patch clamp electrophysiology, we find that melanoma cells possess GABAARs that control membrane permeability to anions. Select benzodiazepines, by enhancing GABAAR mediated anion transport, depolarize melanoma cell mitochondrial membrane potential and impair cell viability in vitro. Using a syngeneic melanoma mouse model, we find that a benzodiazepine promotes reduction in tumor volume when administered alone and potentiated radiation or immune checkpoint inhibitor α-PD-L1. When a benzodiazepine is combined with concurrent α-PD-L1 and a sub-lethal radiation dose, there is near complete loss of tumor, beyond what is observed for benzodiazepine with radiation or α-PD-L1. Mechanistically, benzodiazepine with radiation or α-PD-L1 results in ipsilateral and an abscopal tumor volume reduction commensurate with enhanced infiltration into the tumor milieu of polyfunctional CD8 T-cells. There is also an increased expression of genes with roles in the cytokine-cytokine receptor and p53 signaling pathways. This study provides evidence for melanoma cell GABAARs as a therapeutic vulnerability with benzodiazepines promoting both direct and immune-mediated anti-tumor activity.

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

2021 ◽  
Vol 5 (2) ◽  
pp. 108-117
Author(s):  
Anagha Bangalore Kumar ◽  
Alan Bryce ◽  
Prakash Vishnu ◽  
Svetomir Markovic ◽  
Marian McEvoy
Keyword(s):  
Adverse Effect ◽  
Adverse Effects ◽  
Clinical Response ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Logistic Regression Models ◽  
Related Adverse Effect ◽  
Dermatologic Toxicity ◽  
Objective Clinical Response ◽  
Melanoma Patients

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.

scholarly journals Examining the Relationship between Circulating CD4− CD8− Double-Negative T Cells and Outcomes of Immuno-Checkpoint Inhibitor Therapy—Looking for Biomarkers and Therapeutic Targets in Metastatic Melanoma

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 406
Author(s):  
Sabino Strippoli ◽  
Annarita Fanizzi ◽  
Antonio Negri ◽  
Davide Quaresmini ◽  
Annalisa Nardone ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Metastatic Melanoma ◽  
Immune Cells ◽  
Lymphocyte Count ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Double Negative ◽  
Double Negative T Cells

Background: The role of circulating CD4−/CD8− double-negative T cells (DNTs) in the immune response to melanoma is poorly understood, as are the effects of checkpoint inhibitors on T cell subpopulations. Methods: We performed a basal and longitudinal assessment of circulating immune cells, including DNTs, in metastatic melanoma patients treated with checkpoint blockade in a single-center cohort, and examined the correlations levels of immune cells with clinical features and therapy outcomes. Results: Sixty-eight patients (48 ipilimumab, 20 PD1 inhibitors) were enrolled in the study. Our analysis indicated that better outcomes were associated with normal LDH, fewer than three metastatic sites, an ECOG performance status of 0, M1a stage, lower WBC and a higher lymphocyte count. The increase in lymphocyte count and decrease of DNTs were significantly associated with the achievement of an overall response. The median value of DNT decreased while the CD4+ and NK cells increased in patients that responded to treatment compare to those who did not respond to treatment. Conclusions: DNT cells change during treatment with checkpoint inhibitors and may be adept at sensing the immune response to melanoma. The complementary variation of DNT cells with respect to CD4+ and other immune actors may improve the reliability of lymphocyte assessment. Further investigation of DNT as a potential target in checkpoint inhibitor resistant melanoma is warranted.

scholarly journals Immune checkpoint inhibitor-related hypogonadism and infertility: a neglected issue in immuno-oncology

2021 ◽  
Vol 9 (2) ◽  
pp. e002220
Author(s):  
Berna C Özdemir
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Systematic Investigation ◽  
Gonadal Function ◽  
Organ Systems ◽  
Adults And Children ◽  
Potential Impact ◽  
Secondary Hypogonadism

Despite a significant amount of data on incidence and therapy of immune-related adverse events affecting virtually all organ systems, the potential impact of immune checkpoint inhibitors (ICIs) on gonadal function has not been sufficiently studied. The limited evidence available suggests that ICI-related primary hypogonadism due to orchitis as well as secondary hypogonadism due to hypophysitis are a potential risk for infertility. A systematic investigation of gonadal function under ICIs is warranted given the increasing application of ICIs in the adjuvant setting, among young adults and children and the possible influence of sex hormone levels on the efficacy and toxicity of ICIs.

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