Rapid recovery of postnivolumab vemurafenib-induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome after tocilizumab and infliximab administration

Abstract

BackgroundImmune checkpoint inhibitors such as nivolumab and targeted BRAF inhibitors have dramatically altered the treatment outcomes of metastatic melanoma over the past few years. Skin toxicity is the most common adverse event (AE) related to the commonly used BRAF inhibitor vemurafenib, affecting more than 90% of patients. Vemurafenib-related severe AEs with early onset are reported in patients who were previously treated with anti-programmed cell death-1 (anti PD-1) antibodies. A prolonged administration of systemic steroids is the first-line treatment of severe or life-threatening AEs. We report the case of a woman suffering from vemurafenib-related severe, rapidly worsening Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome, resolved in a few hours after single-dose administration of a combination of TNF-α antagonist infliximab with interleukin (IL)-6 receptor antagonist tocilizumab.Case presentationA 41-year-old woman treated with single-agent nivolumab presented with a melanoma progression. Biopsy samples were revised, revealing a BRAF V600E mutation. The patient was started on vemurafenib and cobimetinib treatment only 10 days after the last administration of nivolumab. On the third day of anti-BRAF therapy, profound lymphopenia was detected, and maculopapular eruption appeared afterward. Subsequently, the clinical conditions deteriorated further, and the woman was admitted on an emergency basis with high fever, respiratory and cardiocirculatory failure, diffuse rash, generalized edema, and lymphadenopathy. Diagnosis of DRESS syndrome with overexpressed capillary leakage was made. A single dose of tocilizumab was administered with an improvement of cardiocirculatory and renal function in a few hours. Because of worsening of liver function, skin lesions and mucositis, a single dose of infliximab was prescribed, and dramatic improvement was noted over the next 24 hours. Dabrafenib and trametinib were initiated, and coinciding with washout of infliximab from the patient’s blood, the drug toxicity recurred.ConclusionAnti-IL-6 and anti-TNF-α target treatment of very severe AEs may afford an immediate resolution of potentially life-threatening symptoms and reduce the duration and the costs of hospitalization. Maintenance of therapeutic infliximab blood concentrations permits an early switch to dabrafenib after vemurafenib-related AEs.

Systematic review of BRAF/MEK inhibitors‐induced Severe Cutaneous Adverse Reactions (SCARs)

“…Dabrafenib was reported twice ( n = 2; 3%) as the causative drug of two DRESS cases (one after switching from a vemurafenib‐DRESS‐induced case) 20,21 . All the remainder ( n = 30; 98%) were caused by vemurafenib, which was related with melanoma in all of the cases 12–14,16,20–33 . A total of 64.5% ( n = 20) cases were related to the combination of vemurafenib and cobimetinib; 20,22,27–29 however, when an actual assessment of the culprit drug was performed (Naranjo scale, ALDEN score, patch test and/or in vitro analysis of lymphocyte reactivity), vemurafenib was the solo cause of the SCAR 15,25,27 .…”

“…All the remainder ( n = 30; 98%) were caused by vemurafenib, which was related with melanoma in all of the cases 12–14,16,20–33 . A total of 64.5% ( n = 20) cases were related to the combination of vemurafenib and cobimetinib; 20,22,27–29 however, when an actual assessment of the culprit drug was performed (Naranjo scale, ALDEN score, patch test and/or in vitro analysis of lymphocyte reactivity), vemurafenib was the solo cause of the SCAR 15,25,27 . Interestingly, 45.2% ( n = 14) of the cases received prior immunotherapy, some of them more than one drug (8 cases received nivolumab, 5 pembrolizumab and 4 ipilimumab) 20,22,27–29,32 .…”

“…Sixteen cases (51.6%) were treated with systemic corticosteroids 12,16,20,21,24–26,28,29,32,33 . Dabrafenib was a common‐used therapy after vemurafenib‐induced SCAR ( n = 16; 51.7%), 15,20–22,24–27,29,31 and no other SCAR was subsequently reported except in one case 21 …”

“…We found two reports of dabrafenib‐induced SCARs; 20,21 however, it is worth noting that one was not an established DRESS but a maculopapular rash accompanied with hypereosinophilia that appeared six hours after dabrafenib intake in a patient with a previous well‐defined vemurafenib‐induced DRESS 21 . Moreover, in thirteen reported cases dabrafenib was the selected therapy for those who suffered a vemurafenib‐induced SCAR (follow‐up of at least 10.1 to 24 weeks, in cases with provided data) 22,24,25,29 . This switching seems to be a safe alternative for these patients, although larger studies are still lacking.…”

“…Regarding DRESS, the most remarkable feature was the short interval (mean of 11.4 days) between vemurafenib intake and DRESS onset, which is definitively shorter than for classic DRESS (2–6 weeks) 3,51 . Time of onset of DRESS may differ depending on the medications involved; however, these data suggest vemurafenib‐induced DRESS seems to occur within the first 15 days of treatment 16,20,21,26–29,52 . Similarly, non‐specific skin rash due to BRAF/MEKi usually occurs early, within the first two weeks of treatment 36 .…”