Combination therapy (toripalimab and lenvatinib)-associated toxic epidermal necr

lNTRODUCTlON

Toripalimab, also known as JS001 or TAB001, is a humanized immunoglobulin G4 monoclonal antibody against programmed cell death-1 (PD-1)[1,2]. PD-1 inhibitors help to enhance the ability of the immune system to defeat tumor cells, but immune-related adverse events (irAEs) occur in many cases[3]. Toxic epidermal necrolysis (TEN) is a rare type of irAE caused by PD-1 inhibitors, with a mortality rate of up to 60%[4]. Lenvatinib is an antiangiogenic tyrosine kinase inhibitor (TKI) and shows synergism with PD-1 inhibitors in solid tumors[5,6]. There have been no case reports on TEN associated with toripalimab or lenvatinib[7]. However, we encountered a patient with metastatic liver cancer who developed TEN after combination therapy with toripalimab and lenvatinib. We are the first group to report this severe cutaneous adverse event following combination therapy with a PD-1 inhibitor and lenvatinib. This case report demonstrates that cautious attention should be given to rashes that develop following this combination treatment. The successful treatment of our case also demonstrated the significance of large-dose and long-course glucocorticoid application for this special type of TEN.

One day the girl said to him that now it was close on the time when he must become a fish again--the troll would soon call him home, and he would have to go, but before that he must put on the shape of the fish, otherwise he could not pass through the sea alive

CASE PRESENTATlON

Chief complaints

Erythema, blisters and erosions appeared on the face, neck, trunk and limbs 1 wk after combination therapy with toripalimab and lenvatinib.

History of present illness

Four weeks prior to presentation, a 39-year-old male began to receive combination therapy with toripalimab and lenvatinib, as well as radiotherapy, after being diagnosed with liver cancer with cervical vertebra metastasis. The oral administration dose of lenvatinib was 12 mg once daily.Toripalimab (240 mg) was administered intravenously every two weeks. One week prior to presentation, erythema, blisters and erosions began to appear on the face and neck, along with pain and fever. Rashes soon spread to the trunk and limbs, as well as the scrotum and oral mucosa. Therefore, the patient was admitted to the Dermatology Department of the Second Affiliated Hospital of Guangzhou University of Chinese Medicine.

History of past illness

The patient experienced neck pain 2 mo prior to presentation at our clinic. The diagnosis of liver cancer with cervical vertebral metastasis was ultimately confirmed by PET-CT. Hepatitis B virus (HBV)infection was diagnosed at the same time, and the patient was then treated with entecavir. The patient had no other medical history, such as diabetes or hypertension.

Personal and family history

The patient had no history of exposure to industrial poisonous substances and reported no habit of smoking or drinking alcohol. The family history was unremarkable.

Physical examination

The patient presented with typical erythema multiforme, slack bullae and epidermal peeling on the face,neck, trunk and limbs. Nikolsky’s sign was positive. Scrotal and oral mucosal erosion was observed.Skin injury covered more than 70% of the body surface area (BSA) (Figure 1A and B). The patient weighed 71 kg.

He told him his errand, and the stranger said, Then you can serve me; I am just in want of a lad like you, and I will give you good wages--a bushel of money the first year, two the second year, and three the third year, for you must serve me three years, and obey me in everything, however strange it seems to you

Laboratory examinations

Skin biopsy was performed. Prominent necrotic keratinocytes, hyperkeratosis, liquefaction of basal cells and acantholytic bullae were observed in the epidermis. Blood vessels in the dermis were infiltrated by lymphocytes and eosinophils (Figure 2A-C). Direct immunofluorescence (DIF) staining was negative.

Serum albumin decreased to 33.6 g/L. CRP and procalcitonin slightly increased to 20.9 mg/L and 0.09 ng/mL, respectively. Random blood glucose was 11.23 mmol/L. Quantitative analysis of HBV DNA yielded a value of 3.57 × 10IU/mL. The AFP value was 1497 ng/mL. The results of routine blood,blood coagulation function, liver and kidney function, routine stool, and routine urine tests, as well as of electrocardiography and chest radiography, were normal.andwere cultured from the sites of skin erosion.

FlNAL DlAGNOSlS

The diagnosis was confirmed to be TEN (associated with combination therapy with toripalimab and lenvatinib) according to the patient’s medical history, typical lesion morphologies, and typical pathological findings.

TREATMENT

The patient ceased treatment with toripalimab and lenvatinib. Methylprednisolone was administered at an initial dose of 80 mg/d. The rashes continued to worsen; thus, 3 days later, the dosage of methylprednisolone was increased to 120 mg/d. Blood pressure and blood glucose were monitored, and insulin was used to control secondary hyperglycemia. The patient received high-dose intravenous immunoglobulin (IVIG) at 0.4 g/kg/d for 5 days. Targeted antibiotic drugs, such as piperacillintazobactam and cefuroxime, were chosen in succession based on the drug sensitivity tests in pathogenic bacteria. A potassium permanganate solution bath and compound polymyxin B ointment were administered for external use. The ocular, scrotal and oral mucosa were also carefully treated with topical medication. Oxycontin was administered to relieve the cancer-related pain.

OUTCOME AND FOLLOW-UP

Interestingly, the rashes began to improve on the face and neck and progressed on the trunk and edge of the limbs at a much lower speed when the methylprednisolone dose was adjusted to 120 mg/d. This course lasted for 2 wk, and we did not reduce the dosage of methylprednisolone until we observed remarkable improvements in erythema, blisters and erosions (Figure 1C and D).

At the 2-mo follow-up for glucocorticoid therapy, the dosage of methylprednisolone was gradually reduced to 8 mg/d, and the rashes did not recur. Enhanced computed tomography (CT) scans showed that the size of the primary liver cancer focus increased, and rib metastasis and portal vein tumor thrombosis were noticed. The patient was then treated by transcatheter arterial chemoembolization(TACE).

At the 4-mo follow-up, enhanced CT scans showed that portal vein tumor thrombosis improved,while rib metastasis progressed. Thus, ultrasound-guided microwave ablation and radiotherapy were conducted in succession. Oral sorafenib was also administered, and no cutaneous adverse drug reactions were observed.

The authors declare that they have no conflicts of interest.

It is understandable that a tumor would progress rapidly after ceasing antineoplastic drugs due to severe adverse effects. Thus, it is important for patients to restart antitumor therapy as soon as the rashes are controlled. Based on the follow-up of our case, we found that different types of PD-1 inhibitors or targeted drugs do not necessarily cause the same dermatological adverse events. After weighing the pros and cons, other types of PD-1 inhibitors or targeted drugs are still worthy of investigation.

Roma sighs heavily and continues. It is hard to describe how we felt about each other-after all, we were young, and we only exchanged a few words when we could-but I can tell you, there was much love there. I assume he was killed like so many others. But I cannot bear to think that, and so I try to remember him as he was for those months we were given together.

DlSCUSSlON

TEN and Stevens Johnson syndrome (SJS) are two ends of a spectrum of rare severe adverse cutaneous drug reactions, typically with a clinical presentation of erythema multiforme, slack bullae and epidermal peeling[9]. They are distinguished only by their extent of skin detachment (＜ 10% BSA:SJS,10%-30% BSA:SJS/TEN, ＞ 30% BSA:TEN)[9]. Histopathologically, widespread necrosis in the epidermis aids in the diagnosis. DIF staining should be negative to rule out certain autoimmune blistering diseases. Specific drugs, such as allopurinol, carbamazepine, phenytoin, phenobarbital and some antibiotics, increase the risk of developing SJS/TEN[9]. The average mortality rate of TEN is 25-35%[9].

Food has a strong subconscious21 link to love, said Kathryn Zerbe, a psychiatrist22 who specializes in eating disorders23 at Oregon Health and Science University in Portland

The coffee shop had a do-it-yourself counter near the entrance. On the counter were lids, straws, and wooden stirrers. There were wraps to insulate2 your hands against the hot coffee inside the cup. There were also individual servings of sugar, sweeteners, and creamers（）. Kevin used the lids and wraps, but drank his coffee black.

Lenvatinib is an antiangiogenic TKI that is widely used in multiple solid tumors[5]. Both lenvatinib and sorafenib are recommended as the first-line treatment for unresectable hepatocellular carcinoma in the guidelines[15]. In a global randomized phase 3 trial, lenvatinib was demonstrated to be non-inferior to sorafenib for overall survival, and it led to greater improvements in progression-free survival, time to progression, objective response and quality-of-life assessments compared with sorafenib[16]. In addition, a synergistic effect has been found between lenvatinib and immune checkpoint inhibitors[6].The combination of lenvatinib/pembrolizumab is promising in several solid tumors, such as endometrial, lung, hepatocellular and gastrointestinal malignancies[5]. Thus, the patient received combination therapy with toripalimab and lenvatinib. Some dermatological adverse events associated with the application of lenvatinib have been noted, the most common of which are hand-foot skin reactions[7]. SJS/TEN induced by TKIs is rather rare, and no case of TEN associated with lenvatinib has been reported in association with any cancer condition[7,17]. However, we are the first group to report TEN, a grade 4 toxicity, after combination therapy with a PD-1 inhibitor and lenvatinib. Since this was a single case, there is still not sufficient evidence to conclude that combination therapy with a PD-1 inhibitor and lenvatinib increases the risk of TEN compared with a PD-1 inhibitor alone.

Despite the high mortality rate of the limited cases of TEN associated with checkpoint inhibitors,whether they should be managed differently from classic cases of TEN[4] (the application of corticosteroids[11]) is controversial. In our case, the rashes continued to worsen with the initial methylprednisolone dose of 80 mg/d but improved as the dosage increased later. Considering the long half-life of toripalimab, methylprednisolone was sustained for a long time, and the rashes did not recur.Successful treatment of the case above demonstrates the importance of full-dose and long-term corticosteroids in TEN associated with checkpoint inhibitors. High-dose IVIG may help to boost the immune system and prevent opportunistic infection caused by corticosteroids. Other treatments, such as antiinfection regimens, mucosal protection, anti-HBV drugs and maintaining homeostasis of the internal environment (blood glucose), also contributed to the patient’s recovery.

“ Yes, you, Michelle, and we’re so lucky,” he cheered, as he gave me a high five followed by a bear hug and a kiss to my forehead. I thought becoming a teenager would end the ritual, but it didn’t.

The patient continued taking regorafenib, and disease progression seemed to decrease. At the 10-mo follow-up, the patient was still alive.

CONCLUSlON

In conclusion, we are the first group to report TEN following combination therapy with a PD-1 inhibitor and lenvatinib. Cautious attention should be given to rashes that develop after this combination treatment. Large-dose and long-course glucocorticoid application may be crucial for the treatment of this special type of TEN.

Immune checkpoint inhibitors, including monoclonal antibodies targeting PD-1, programmed death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), represent a major breakthrough in tumor therapy[10]. Physiologically, the CTLA-4 and PD-1 immune checkpoint pathways play a central role in maintaining peripheral tolerance by downregulating T cell activation[3].However, tumor cells may take advantage of this peripheral tolerance to evade the host immune system[3]. Immune checkpoint inhibitors can restore antitumor immune responses, achieving long-term benefits for tumor treatment[3]. Pruritic maculopapular rashes, the majority of which are self-limiting,represent the most frequent cutaneous irAE, occurring in more than 1/3 of patients who receive immunotherapy[10]. There are few cases of TEN associated with PD-1 inhibitors, such as nivolumab and pembrolizumab[11-13]. Toripalimab was introduced into practice in recent years and widely adopted, especially in China, while no cases of TEN associated with toripalimab have been reported in association with any cancer condition.

Huang KK, Han SS, and Zhang CY contributed to the treatment, literature search; Huang KK,He LY and Zhen QY contributed to manuscript writing; Lin Y, Yang LL, and Liang BY contributed to the treatment and manuscript revision; Zhu ZB and Li HY provided comments to this literature; informed consent was conducted by Huang KK; all authors have read and approved the final manuscript.

Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, No. 2018B030322012.

Consent was obtained from the relatives of the patient for publication of this report and any accompanying results.

At the 6-mo follow-up, the patient reported paraplegia, which was possibly due to the intraspinal metastatic tumors revealed on the contrast-enhanced magnetic resonance imaging scan. Emission computed tomography (ECT) revealed metastasis of the occipital bone, cervical vertebra, ribs and femur. The patient was experiencing severe pain and agreed to take the risk of the rash recurring to receive additional combination treatment with immunotherapy and targeted therapy. Due to the poor therapeutic effect of sorafenib, the therapeutic regimen was adjusted to 120 mg regorafenib once daily in combination with sintilimab, another PD-1 inhibitor, in addition to toripalimab[8]. A maculopapular rash developed on the trunk 2 wk later; thus, sintilimab was stopped. The rashes were not as severe as the initial rashes and vanished after a small dose of methylprednisolone was administered.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

Recently, a systematic review summarized 5 cases of TEN-like reactions associated with checkpoint inhibitors and reported a median time to onset of 4 wk (average of 5.38 wk) from checkpoint inhibitor initiation[4]. Two patients also developed morbilliform rashes that gradually progressed for 2-4 wk before evolving into TEN, and the mortality rate reached up to 60%[4]. The incubation period in our case was approximately 3 wk, in accordance with previously reported cases. Interestingly, we found that the rashes in our case progressed/improved at different sites at the same time. This characteristic may be explained by the pharmacokinetic patterns and long half-lives of checkpoint inhibitors. For example, nivolumab and pembrolizumab have half-lives of 25 and 23 days, respectively; thus, their peak concentrations are not reached until late in the course of treatment[4]. The PD-1/PD-L1 interaction plays an important role in peripheral tolerance by sustaining Tregs and inhibiting T cell activation. Anti-PD-1 treatment allows autoreactive CD8+ T cells targeting keratinocytes to become activated and proliferate,contributing to the apoptosis of epidermal keratinocytes[14].

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So when he arrived at the Leafy Palace, more handsome and fascinating even than ever she had been led to expect, he hardly so much as glanced at the Princess, but bestowed26 all his attention upon the old Fairy, to whom he seemed to have a hundred things to say

Kai-Kai Huang 0000-0001-8010-7737; Shan-Shan Han 0000-0001-5779-8701; Li-Ya He 0000-0002-7477-5189; Lin-Lin Yang 0000-0002-7963-2777; Bao-Ying Liang 0000-0003-2824-4448; Qing-Yu Zhen 0000-0003-2866-7897; Zi-Bo Zhu 0000-0002-3295-0989; Cai-Yun Zhang 0000-0003-1841-3674; Hong-Yi Li 0000-0003-0099-5776; Ying Lin 0000-0003-2473-7851.

This store is just blocks from Humboldt State University, and this late afternoon it was overrun by students dressed in creative costumes, carrying copious1 quantities of candy, chips, and beer in anticipation2 of Halloween parties they would soon be attending

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