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• W2608329604 abstract "To date, there are only a few reports on adverse events encountered in patients treated with kinase inhibitors following immune checkpoint blockade. Some of these were of high severity implying a yet unknown inflammatory hyperactivation which may be potentially fatal if left unrecognized [1.Johnson D.B. Wallender E.K. Cohen D.N. et al.Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy.Cancer Immunol Res. 2013; 1: 373-377Crossref PubMed Scopus (86) Google Scholar, 2.de Maleissye M.-F. Nicolas G. Saiag P. Pembrolizumab-induced demyelinating polyradiculoneuropathy.N Engl J Med. 2016; 375: 296-297Crossref PubMed Scopus (70) Google Scholar]. A 45-year-old woman was diagnosed with AJCC stage IV melanoma of the perianal skin in January 2016 (initial 5 mm Breslow depth with ulceration [pT4b] with in-transit and macrometastases in the lymph nodes [pN3]). Molecular analysis revealed BRAF V600K mutation. After surgical removal of the metastases and radiotherapy she was put on ipilimumab in February 2016 for two infusions. She switched to pembrolizumab in April 2016 and received five infusions until June 2016. Therapy-related complications consisted of pneumonitis and autoimmune thyroiditis, later requiring therapy with l-thyroxin (albeit not fully substituted). ACTH/cortisol axis was assessed monthly and did not show any signs of impairment. Disease progression was evident in June 2016, prompting the therapy switch to dabrafenib and trametinib in July 2016. Four weeks later, the patient presented in our emergency room with fever >39 °C, chills and fatigue. Astonishingly, her performance status was very good, despite low blood pressure (72/37 mmHg) and tachycardia (116/min). Her medical history was not suggestive of an antecedent infection. She was hospitalized for further investigation and monitoring. Changes in peripheral blood parameters are shown in Figure 1A and B. Blood and urine cultures were taken and an empiric i.v. therapy with amoxicillin–clavulanic acid initiated. Shortly after admission her hypotension worsened to 38/26 mmHg. In spite of aggressive fluid replacement (6 l), the hypotension persisted. The patient became anuric and was transferred to an intensive care unit. She was diagnosed with systemic inflammatory reaction with multiorgan dysfunction syndrome. She was treated for sepsis, with intermittent use of noradrenalin and broad spectrum antibiotics. In addition, systemic hydrocortisone therapy was initiated. On the third day, the patient became stable, renal and hepatic function recovered. She was transferred back to our in-patient ward. Hydrocortisone was switched from i.v. to oral prednisone taper. One week after initial worsening the patient was started on vemurafenib and cobimetinib, which she tolerated well. The patient was discharged from hospital after a total of 11 days. No pathogen could be detected in blood and other tissue cultures taken at admission. The patient has been on vemurafenib and cobimetinib since and has shown complete response of extracranial metastases. New brain metastases were detected in March 2017. A 48-year-old woman was diagnosed with AJCC stage IV melanoma on her left heel in September 2016 (initial Breslow tumor thickness of 8 mm without ulceration [pT4a], with in-transit and macrometastases in the lymph nodes [pN3]). Molecular profiling revealed a BRAF V600E mutation. Following surgical removal of the primary tumor and lymph node metastases, she received radiotherapy of the left groin. She was started on pembrolizumab in April 2016 and received seven infusions until September 2016. She developed autoimmune thyroiditis in August 2016, requiring substitution therapy with l-thyroxin. Due to disease progression in September 2016, she was started on vemurafenib and cobimetinib. Eight days later, she developed face swelling (including eyes and lips) and a diffuse pruritic eruption, composed of erythematous and violations macules and papules (supplementary Figure S1A and B, available at Annals of Oncology online). This rash was accompanied by hypotension, tachycardia and fever >39 °C. There was no evidence of blisters, skin fragility or mucosal involvement. She denied any symptoms, suggesting an antecedent infection. Changes in blood and chemistry parameters are shown in Figure 1C and D. The constellation of rash and systemic symptoms led to the diagnosis of hypersensitivity syndrome (or DRESS; drug rash with eosinophilia and systemic symptoms) and the patient was admitted to hospital. Eosinophilia appeared several days later, completing the diagnosis. The patient was put on systemic steroid therapy with methyl-prednisolone and has had a prompt recovery of skin and organ function (supplementary Figure S1C and D, available at Annals of Oncology online). Blood and urine cultures were negative. She was discharged from the hospital after 9 days. Four days later in October 2016, she was re-exposed to vemurafenib and cobimetinib in an in-patient setting, showing no signs of intolerance. She continued this therapy until she succumbed to progressing melanoma in January 2017. BRAF inhibitors have been shown to modify immune-tumor interactions by increasing the abundance of intratumoral CD8+ T cells, by modulating tumor cell immunogenicity and by changing the tumor immunological microenvironment [3.Knight D.A. Ngiow S.F. Li M. et al.Host immunity contributes to the anti-melanoma activity of BRAF inhibitors.J Clin Invest. 2013; 123: 1371-1381Crossref PubMed Scopus (225) Google Scholar]. A previous treatment with an immunomodulator would be expected to increase efficacy; however, combination with immune checkpoint inhibitors was reported to cause severe cutaneous and neurologic toxicity during vemurafenib administration after anti-PD-1 therapy [1.Johnson D.B. Wallender E.K. Cohen D.N. et al.Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy.Cancer Immunol Res. 2013; 1: 373-377Crossref PubMed Scopus (86) Google Scholar]. Two reported patients showed severe hypersensitivity reactions (DRESS criteria were not met) with variable organ involvement, with one patient developing an acute inflammatory demyelinating polyneuropathy. An additional report of two cases with demyelinating polyradiculoneuropathy after treatment pembrolizumab followed [2.de Maleissye M.-F. Nicolas G. Saiag P. Pembrolizumab-induced demyelinating polyradiculoneuropathy.N Engl J Med. 2016; 375: 296-297Crossref PubMed Scopus (70) Google Scholar]. These and other data underline the complexity of immune effects triggered by anti-PD-1 therapy. BRAF inhibitors may provide additional boost due to their paradoxical ability to increase T-cell activation through up-regulation of ERK signaling and increase in gene expression of pro-inflammatory cytokines and cytotoxic factors [4.Callahan M.K. Masters G. Pratilas C.A. et al.Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor.Cancer Immunol Res. 2014; 2: 70-79Crossref PubMed Scopus (86) Google Scholar, 5.Liu L. Mayes P.A. Eastman S. et al.The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4.Clin Cancer Res. 2015; 21: 1639-1651Crossref PubMed Scopus (304) Google Scholar]. Intricate interactions occurring during sequential therapy with immune checkpoint and kinase inhibitors may provoke an ‘immunological storm’ leading to hypersensitivity or other devastating inflammatory syndromes. Their frequency is unknown and is thought to be rare. Our cases illustrate the intensity of such reactions and should sensitize clinicians to maintain a high level of suspicion for these dangerous toxicities. Re-challenge with related drugs can be undertaken under close monitoring of vital signs and organ functions. None declared." @default.
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• W2608329604 title "Systemic inflammatory reaction syndrome during combined kinase inhibitor therapy following anti-PD-1 therapy for melanoma" @default.
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