Immune checkpoint inhibitors (ICIs) have gained popularity as a treatment option for a number of cancers, including melanoma, non-small cell lung cancer, gastrointestinal tract tumors, and head and neck tumors. ICIs work by blocking the interaction between programmed death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1). They may, however, also result in immune-related adverse events (irAEs), particularly autoimmunity against one’s own tissues
[1]. Severe polymorphic erythema and a widespread mucocutaneous response are symptoms of toxic epidermal necrolysis (TEN), a relatively uncommon condition with a 35% fatality rate
[2]. It presents a significant difficulty for clinical management. This study aims to enhance the understanding and treatment of TEN caused by ICIs therapy by reporting the clinical characteristics of a bladder cancer patient who developed TEN after ICIs treatment.
1 Case presentation
In November 2023, a 72-year-old male patient was diagnosed with bladder cancer. On April 29, 2024, he was admitted to the Third Hospital of Changsha for antitumor therapy with toripalimab (240 mg every 3 weeks) combined with a GP regimen (gemcitabine 1.4 g on day 1, cisplatin 30 mg on days 1-3). Pre-treatment assessments included the following laboratory and imaging findings: Left ventricular ejection fraction (LVEF) was 64%, N-terminal pro-brain natriuretic peptide (NT-proBNP) was 169.00 pg/mL, creatine kinase was 35 U/L, creatine kinase isoenzyme was 14.9 U/L, and lactate dehydrogenase was 165.0 U/L.
On May 26, 2024, the patient developed chest tightness and shortness of breath after physical activity. He was readmitted on May 30, 2024 for the second cycle of antitumor therapy. Due to severe myelosuppression following the previous cycle, the chemotherapy regimen was adjusted to toripalimab combined with paclitaxel (400 mg intravenously). On the second day after treatment initiation, echocardiography revealed a reduced ejection fraction (LVEF 48%) and left atrial enlargement. Laboratory tests showed elevated NT-proBNP (2 099.00 pg/mL), creatine kinase (45 U/L), creatine kinase isoenzyme (49.3 U/L), and lactate dehydrogenase (290.0 U/L). Troponin levels remained within normal limits. A diagnosis of immune-related myocarditis was considered, and the patient’s condition improved following treatment with methylprednisolone and supportive care.Following discharge, the patient’s condition remained stable.
On July 6, 2024, he commenced treatment with envafolimab (200 mg subcutaneously once weekly) in combination with a TP regimen (nab-paclitaxel 400 mg on day 1, and cisplatin 30 mg on days 1-3). A subsequent weekly dose of subcutaneous envafolimab was administered on July 13, 2024. On July 16, 2024, the patient developed a generalized rash, primarily affecting the chest. Treatment with iproniazide and diphenhydramine was ineffective, leading to the initiation of methylprednisolone (40 mg) on July 17, 2024. On July 18, 2024, erythematous patches were observed on the trunk and limbs, some of which had coalesced. The rash worsened significantly on July 22, 2024, presenting as densely distributed, partially confluent erythematous macules and patches on the face, scalp, periorbital and perioral areas, trunk, and limbs. Large blisters were evident on the inner aspects of both legs and the back (
Figure 1), involving more than 30% of the body surface area (BSA). A skin biopsy was not performed due to the presence of a characteristic rash and impaired coagulation function, following the family’s request.According to the 2024 National Comprehensive Cancer Network (NCCN) guidelines
[3] and multi-disciplinary treatment (MDT), the patient’s final diagnosis was TEN associated with ICIs. Based on the Score of TEN (SCORTEN) scale (which included age >40, malignancy, heart rate >120 min
-1, and >30% BSA skin detachment), the patient had a score of 4, estimating a mortality rate >50%. The methylprednisolone dosage was increased to 100 mg daily. On July 26, 2024, the patient’s rash improved, and rituximab (300 mg on day 1) was administered for immunomodulation.
On July 27, 2024, the generalized rash and blisters improved, and the methylprednisolone dosage was reduced. On August 4,2024, the patient began to experience pressured speech, difficulty in answering questions and communicating, and displayed pronounced crying episodes. A head CT scan showed no obvious signs of intracranial metastases. Quetiapine (25 mg) was administered orally following a neurology consultation. As the psychiatric symptoms could not be completely excluded as a steroid-related reaction, methylprednisolone was discontinued on August 9, 2024. On August 11, 2024, the patient was treated with intravenous human immunoglobulin (IVIG), and the quetiapine dose was increased to 50 mg twice daily. After active treatment, the patient was discharged on August 30, 2024, in an improved overall condition, with the rash having resolved by the time of discharge (
Figure 2).
Table 1 summarized drug administration, symptom onset, and interventions.
Informed consent from the patients has been obtained.
2 Discussion
This study presents a case of bladder cancer in which the patient developed TEN following immune-related cardiotoxicity from toripalimab and a subsequent challenge with envafolimab. The patient’s symptoms improved after management with high-dose methylprednisolone pulse therapy and supportive care. A primary limitation of this report is the absence of a skin biopsy for pathological confirmation.
Toripalimab was launched in 2018 as the first PD-1 monoclonal antibody developed in China to be approved by the Chinese National Medical Products Administration. It has been extensively used for nasopharyngeal carcinoma, urothelial carcinoma, and melanoma. Launched in 2021, envafolimab is a novel recombinant protein for subcutaneous administration. During the process of killing tumor cells, ICIs can activate the body’s immune response mechanism, which may trigger autoimmune damage in the process of targeting tumor cells. This type of damage is defined as irAEs
[4]. It consists of a humanized single-domain anti-PD-L1 antibody fused to a human immunoglobulin (Ig)G1 Fc fragment
[5]. In clinical studies
[6-7] of envafolimab, the most frequently reported drug-related adverse reactions were decreased granulocyte counts, malaise, rash, and hypothyroidism. These adverse reactions are also documented in the safety profiles of other ICIs. In this case, the decision to switch to envafolimab was primarily driven by its subcutaneous formulation, which offered enhanced convenience and accessibility for the patient. Furthermore, in the context of rechallenge, PD-L1 inhibitors, such as envafolimab, are considered to have a potentially more favorable safety profile compared to PD-1 inhibitors
[8].
The patient in this study first developed immune-related myocarditis. The clinical manifestations of ICI-associated myocarditis include asymptomatic elevation of myocardial injury markers, as well as symptoms like dyspnea and fatigue. Most cases occur within the first 3 months of starting ICI therapy
[9]. Cases of TEN induced by ICIs are rare, with an incidence of less than 1%
[10]. The mechanism by which ICIs cause these adverse reactions is not yet fully understood. The disruption of immune homeostasis by antitumor immunotherapy may lead to adverse events involving multiple organ systems.
A Meta-analysis by Gobbini, et al
[11] indicated that among patients who underwent ICIs rechallenge, 60% achieved disease control and 28% exhibited tumor shrinkage. In a case reported by Guo, et al
[12], a 60-year-old woman with melanoma developed grade 2 myocarditis 13 days after her 12th cycle of pembrolizumab. Following tumor progression, she was switched to atezolizumab, which was associated with a recurrence of myocarditis 13 days later. After a 3-month recovery period, the patient received 2 cycles of ipilimumab combined with nivolumab, which subsequently led to immune-related nephritis, necessitating permanent discontinuation of immunotherapy. Furthermore, Pollack, et al
[13] described a patient in their retrospective analysis who initially developed a G2 rash during treatment with ipilimumab plus nivolumab. Upon rechallenge, the cutaneous irAEs worsened precipitously and culminated in TEN.
A study by Dolladille, et al
[14] involved 24 079 cases of irAEs. Among these, 6 123 patients were rechallenged with ICIs, and irAEs recurred in 7.4% of these rechallenged cases. The analysis found that T-lymphocyte antigen-4 (CTLA-4), older age, and a history of colitis, pneumonitis, or hepatitis were strongly correlated with a higher irAEs recurrence rate. This suggests that older patients may be more likely to experience irAEs after rechallenge.In summary, rechallenge can be beneficial for disease control in some patients. However, patients who have previously experienced irAEs may still develop relevant adverse effects, or even severe, lethal toxicities, after resuming ICIs therapy. Consequently, a cautious approach is necessary.
In this case, the patient’s initial rash was managed with anti-allergic agents. As the eruption progressed despite this intervention, methylprednisolone (20 mg) was initiated but failed to halt the deterioration. Consequently, the methylprednisolone dose was escalated to 100 mg and combined with rituximab. When the patient subsequently developed neurological symptoms, which were attributed to high-dose corticosteroid therapy based on the drug’s prescribing information and relevant literature
[15-16], methylprednisolone was discontinued and replaced with IVIG. In addition to symptoms caused by corticosteroids, psychiatric symptoms associated with ICIs cannot be overlooked. A study
[17] based on the FDA Adverse Event Reporting System (FAERS) showed that ICIs may induce various psychiatric symptoms, such as confusion, insomnia, and anxiety. Although the reported incidence is relatively low (2.25%-3.41%), the persistent nature of these symptoms warrants clinical consideration.
For grade 3-4 immune-related cutaneous adverse events, current guidelines recommend discontinuing ICIs and initiating high-dose methylprednisolone [1-2 mg/(kg·d)]. In this case, given the severity of the presentation, we additionally employed rituximab, an agent with established efficacy in severe dermatological conditions
[18-19]. Furthermore, IVIG has been reported as a therapeutic option for TEN. This approach is supported by a case reported by Potts, et al
[20], in which a patient with renal cell carcinoma developed TEN following pembrolizumab treatment. Due to poorly controlled diabetes mellitus, glucocorticoids were discontinued, and the patient was successfully managed with a 3-day course of IVIG.
Before initiating any medication, obtaining a thorough medication history to identify past allergies and excluding drugs potentially linked to TEN is critical, as TEN is a life-threatening dermatological emergency. It must be emphasized that rechallenge with an alternative ICIs (e.g., switching from a PD-1 to a PD-L1 inhibitor) can lead to the recurrence of previous irAEs or the emergence of new, more severe toxicities. Ensuring patient safety, therefore, mandates vigilant monitoring for adverse events throughout ICI therapy, coupled with the development and proactive implementation of tailored management protocols.
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