Nivolumab Hypersensitivity Reactions a Myth or Reality in Solid Tumors—A Systematic Review of the Literature

Immune-checkpoint inhibitors (ICIs) are the most effective treatments nowadays. Nivolumab was the second ICI used for treating solid tumors with amazing results. Patients treated with Nivolumab may react differently to this treatment. Some people tolerate this treatment very well without experiencing any adverse reactions, whilst some may have mild symptoms and a part of them can present severe reactions. In our research, we sought to identify the answers to four questions: 1. what type of cancer has more severe hypersensitivity reactions to Nivolumab, 2. what is the time frame for developing these severe reactions to Nivolumab, 3. whether it is best to continue or stop the treatment after a severe hypersensitivity reaction to Nivolumab and 4. what severe hypersensitivity reactions are the most frequent reported along Nivolumab treatment. This review also highlights another problem with regard to the usage of concomitant and prior medications or other methods of treatment (e.g., radiation therapy), which can also lead to severe reactions. Treatment with Nivolumab is very well tolerated, but patients should also be warned of the possibility of severe hypersensitivity reactions for which they should urgently see a doctor for a personalized evaluation. There are some options for individuals with severe hypersensitivity reactions, for eg. switching the medication or applying a desensitization protocol.

A hypersensitivity reaction is an inappropriate or exaggerated immune response to either an antigen or allergen. The hypersensitivity reactions can be divided into two subgroups of immediate reactions (<1 h) or delayed reactions (>1 h) [11]. Immediate reactions are type I and include pruritus, edema, urticaria, and anaphylactic shock [12]. The delayed ones are type IV reactions, mediated by T-cells, and include drug-induced agranulocytosis (DIA), drug-induced skin disorders (DISI), drug-induced liver injury (DILI), and drug-induced renal injury (DIRI) [11]. The DISI group contains contact allergy, fixed drug eruption (FDE), acute, generalized exanthematic pustulosis (AGEP), maculopapular rash (MPR), Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) [11,13]. The hypersensitivity reactions may be regarded as a subcategory of irAEs in patients receiving ICIs [14].

Materials and Methods
This review has been conducted meeting the guidelines of Preferred Reporting Items for Systematic Reviews (PRISMA 2020). The registration number: no 41482 and the date of approval is 9 August 2022.

The Review Questions
Are there many severe hypersensitivity reactions to Nivolumab described in the literature? What type of cancer has the most severe hypersensitivity reactions to Nivolumab? What is the time frame for developing severe hypersensitivity reactions to Nivolumab? How are Nivolumab hypersensitivity reactions managed through the literature search? What types of severe hypersensitivity reactions are more frequently reported?

Literature Search
The literature search was performed in the electronic database of PubMed, and the following combination has been researched: "Nivolumab hypersensitivity reaction". The search was performed between 2013 and September 2022. The relevant articles related to the questions of this review were identified and only those that met the eligibility criteria were assessed. The inclusion and exclusion criteria are provided in Table 1.

Data Extraction and Presentation
Using the aforementioned combination of keywords, we searched for the articles published in PubMed. The search yielded a total of 129 articles, of which 104 of them were irrelevant or duplicated. Among the 25 articles relevant to this review, only 18 studies met the eligibility criteria and were included in this systematic review. The flow chart of the research is presented in Figure 1.

Data Extraction and Presentation
Using the aforementioned combination of keywords, we searched for the articles published in PubMed. The search yielded a total of 129 articles, of which 104 of them were irrelevant or duplicated. Among the 25 articles relevant to this review, only 18 studies met the eligibility criteria and were included in this systematic review. The flow chart of the research is presented in Figure 1.

Results
This research included only 18 articles. These articles are case reports of severe hypersensitivity reactions to Nivolumab. We excluded from this study the cases with nonsevere reactions, grade 1 or 2 according to CTCAE v 5.0, November 2017 [15], and erythema nodosum, lichen planus, morphea, lichen sclerosus et atrophicus. All the included studies are summarized in Table 2.
Most of the dirAEs are low to moderate grades according to the CTCAE v 5.0, November 2017 [15]. In grade 1 and 2 dirAEs, the treatment consists of topical corticosteroids with moderate or high potency and supportive care. Severe dirAEs (grade 3 and grade 4) require the administration of high-dose systemic corticosteroid treatment, intense supportive care management, and wound management. In some cases, it is a must to administer tumor necrosis factor alpha (TNF-α) inhibitors (Infliximab or Etanercept), Mycophenolate mofetil, Cyclosporin, and even plasmapheresis [34,36] These reactions require a definitive interruption of immunotherapy [38][39][40].
In our study, we found nineteen cases of severe hypersensitivity reactions to Nivolumab: nine cases of female patients, seven cases of male patients, and three cases without the sex of the patient mentioned in the article. Regarding the solid tumor's distribution, there were 6/19 patients with gastrointestinal cancers (31.58%), 5/19 lung cancer patients (26.32%), 4/19 melanoma patients (21.05%), 3/19 renal cancer patients (15.79%) and 1/19 patients with head and neck cancer (5.26%) who have developed severe hypersensitivity reactions to Nivolumab. It appears that Nivolumab hypersensitivity reactions are more frequent in patients with gastrointestinal cancers. This may be due to the fact that the gut microbiome is considered responsible for the modulation of immune responses. Lu Y highlighted in his review that the gut microbiome can generate increased responses to ICIs by adjusting the CD8+ T cells, T helper 1, and tumor-associated myeloid cell proportions [41]. In a study of fecal microbial transplantation, the mouse who received the transplant had an increased level of CD8+ T cells [42]. In another review article, Pierrard J. et al. showed that the development of irAEs in mouse models can be influenced by the composition and modifications in the gut microbiome [43]. Patients with Bifidobacterium longum, Collinsella aerofaciens and Enterococcus faecium present in gut microbiome show good responses to anti-PD-1 therapy. In some studies, the Ruminococaceae family of the Firmicutes phylum is responsible for the development of irAEs [44,45].
Most of the hypersensitivity reactions were present in the first week after starting the treatment with Nivolumab and only four of the authors reported different times for the development of the adverse reactions. P. Basu [25].
In recent studies, the efficacy of ICIs has been related to the development of irAE in NSCLC patients [45,46]. In NSCLC patients it has been demonstrated by Hussaini [47,48]. In melanoma patients, the development of dirAE, especially vitiligo, is associated with the efficacy of ICI treatment in stages III and IV [49][50][51]. Other reports, sustain that the development of irAE was associated with a higher objective response rate (ORR), but not with progression-free survival (PFS) [52].
It is very essential to know the patient previous medications used to treat their cancers or if the patient was exposed to radiation therapy. We should check this information on the hospital networks or hospital records. In our research, five authors reported severe hypersensitivity reactions after Nivolumab was stopped. Yasushige Takeda et al. documented a case of SJS after two cycles of S-1 and Docetaxel for gastric cancer, the author mentioned that the patient received Nivolumab before the start of the first cycle of S-1 and Docetaxel [20]. Takayoshi Komatsu-Fujii et al. reported a case of SJS in a patient receiving tegafur/gimeracil/oteracil (TS-1) who was previously treated with Nivolumab for his disease [53]. Yi-Tsz Lin et al. showed a case of SJS induced by treatment with Esomeprazole in a patient who received Nivolumab for advanced lung cancer [23]. M Arenbergerova et al. related a case of TEN induced by Vemurafenib after discontinuation of Nivolumab [54]. Maximova N et al. presented another patient diagnosed with DRESS induced by Vemurafenib administration after Nivolumab, who responded very well to the administration of Tocilizumab and Infliximab [29]. Also, there are some reports of SJS syndrome induced by radiation in patients receiving Nivolumab [24,55] or anticonvulsant drugs like phenytoin [56], phenobarbital [57], and amifostine [58].
Only two cases in our research of the literature continued desensitization to Nivolumab as an alternative to continuing therapy: a 57 years old female with kidney cancer who developed an infusion reaction to Nivolumab during her third cycle and another patient with kidney cancer [22,31]. In one of the 19 cases Nivolumab was switched with Pembrolizumab and in another one, the combination of Vemurafenib and Cobimetinib was changed to Trametinib and Dabrafenib. The patients stopped showing signs of adverse reactions [16,28]. The combination of chemotherapy, antibiotics and antiretroviral therapy brings more adverse reactions than the treatment with just Nivolumab [45,[59][60][61].
Although our research has only a limited number of studies, the distribution of the severe hypersensitivity reactions to Nivolumab was the following: 42 [17,19,23,25,26]. Only 5.26% of the patients (1/19 patients) had a complete response to Nivolumab treatment after DRESS and 15.79% of the patients (3/19 patients) had stable disease [9,22,28,31].
Our review has some limitations. We could include in our study only 18 articles on severe hypersensitivity reactions to Nivolumab. We focused our search only on solid tumors and did not include hematological malignancies. Furthermore, our findings need to be extended to include the hematological malignancies treated with Nivolumab.

Conclusions
The treatment with Nivolumab is very effective and very well tolerated by most patients without developing any irAE. It is crucial to recognize the prodromal symptoms of severe reactions to the Nivolumab treatment and to promptly intervene. As our research of the literature showed, switching the medication or applying a desensitization protocol are options for severe reactions to Nivolumab.

Conflicts of Interest:
The authors declare no conflict of interest.