Case of the Month

51-year-old patient with durvalumab-induced erythema multiforme

Medical history
  • 01/2021 non-small-cell lung cancer (adenocarcinoma)
    • Initial stage: cT2N0cM0, IIB, PD-L1 expression 10%
Oncological Therapy
  • 01/2021 – 03/2021 Radiochemotherapy with cisplatin, vinorelbine and radiation 66,6 Gy
    • Partial response
  • 05/2021 - 02/2022 Immunotherapy with durvalumab 10 mg/kg bw every 2 weeks (19 doses)
    • Partial response
Immune-related adverse event

After 9 months (and 19 doses) of immunotherapy with the anti-PD1 antibody durvalumab 10 mg/kg bw every 2 weeks, the patient developed a “rash”. Initially, the immunotherapy was discontinued and the patient treated with topical steroids and systemic prednisolone 60 mg p.o. for 10 days, which led to an initial improvement of the skin condition. While tapering the steroids, there was another exacerbation and 150 mg prednisolone i.v. were administered. Since there was no improvement under this therapy, the patient was referred to the department of Dermatology.

The patient presented with erythema and erythematous plaques covering approximately 18% of the body surface area, predominantly on the distal extremities. There was also lamellar desquamation and blistering, particularly on the hands. Histology showed vesicular detachment at the level of the basement membrane zone, a perivascular lymphocytic infiltrate, single-cell apoptosis and single eosinophils. The fluorescence pattern was non-specific. In summary, the findings corresponded to an erythema multiforme (EM)-like drug reaction.

How we proceeded

The dose of corticosteroids was increased to 250 mg prednisolone i.v. for 3 days and then reduced to 80 mg p.o. The steroids were then tapered very slowly, but had to be increased again twice. In parallel, topical therapy with mometason cream was carried out. Due to the steroid-refractory or steroid-dependent course, secondline immunosuppression (therapy with intravenous immunoglobulins (IVIG) as well as extracorporal photophereses) was discussed.

Could we continue the immunotherapy?

Four months after the onset of the erythema multiforme, currently, a cortisone dose of 30 mg is required. Secondline immunosuppression was not started and the checkpoint inhibitor therapy was not yet re-initiated.

Background

Cutaneous side effects are observed in 46-62% of patients on checkpoint inhibitor therapy and occur after a median of 2-3 weeks, but also up to two years after the start of immunotherapy. Rash, pruritus, and vitiligo-like lesions are the most common; lichenoid reactions, blistering reactions, psoriasis, and sarcoid-like lesions are less common. In 90% of cases, cutaneous irAE are mild and can be treated with topical therapy. Serious and potentially fatal cutaneous adverse events include DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), Stevens-Johnsons Syndrome, toxic epidermal necrolysis, bullous skin lesions, and dermatitis herpetiformis (Heinzerling et. al, Dtsch Arztebl, 2019; Belum et. al., Eur J Cancer, 2016). The literature on erythema multiforme under immunotherapy is limited to individual case reports. Cases have been reported with ipilimumab, nivolumab and pembrolizumab. Treatment was mostly with systemic steroids, in one case also with IVIG. EM often led to discontinuation of immunotherapy (Zimmer, L et al, J Transl. Med, 2015; Jour et. al., J Cutan Pathol., 2016; Sundaresan et. al., Dermatol Online J., 2017; Utsunomiya et. al., Case Rep Dermatol., 2018; Yano et. al., Trends in Immunotherapy, 2021; Hashimoto et al, J Clin Med., 2021; Ambur et. al., Cureus, 2021).

Our conclusion

Cutaneous irAEs are often mild but can be severe, requiring discontinuation of immunotherapy and initiation of systemic therapy. Dermatologists should be involved in managing cutaneous side effects, since specific skin findings may require varying treatments.

56-year-old patient with bilateral vestibulopathy

Medical history
  • 01/2021 melanoma of unknown primary (MUP)
    • Initial stage: pTxNxM1c(0), IV (AJCC 2017), BRAF wild-type
    • Metastases in lungs, liver, duodenum, gastric corpus, esophagus, and peritoneal carcinosis
Oncological Therapy
  • 02/2021 Combination immunotherapy with ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw, every three weeks (3 doses in total)
  • 05/2021 - 04/2022 Immunotherapy with nivolumab 240 mg, every 2 weeks
Immune-related adverse event

After three doses of combination immunotherapy with ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw, the patient developed visual impairment due to iritis that was treated topically with cortisone eye drops. Shortly thereafter, the patient reported dizziness, tinnitus, hearing impairment and balance disorder. An ENT examination showed caloric near-areflexia on both sides and a videooculographically pathological Halmagyi head impulse test. The ability to hear in the high-frequency range was limited in the audiogram. A bilateral vestibulopathy was diagnosed.

How we proceeded

The patient received three bilateral intratympanic cortisone injections. The imbalance disorder improved significantly on the right and slightly on the left. The hearing ability in the high-frequency range improved. Subjectively, the patient also reported a significant improvement in gait and mobility stability.

Could we continue the immunotherapy?

After the patient’s general condition improved, we continued immunotherapy with nivolumab monotherapy. There was no exacerbation of the vestibulopathy, but the patient developed irColitis and also Uveitis and Vitiligo, suggesting Vogt-Koyanagi-Harada disease. With regard to the melanoma, the course of the disease remained stable.

Our conclusion

Vestibulopathies are rare immune-mediated side effects and have been described with various immunotherapies (nivolumab, ipilimumab+nivolumab, ipilimumab and pembrolizumab). Both with and without therapy, patients often show little or no improvement in vestibular symptoms (Voskens et al., J Clin Oncol, 2012; Mendis et al. Eur J Canc, 2021; Lemasson et al., Eur J Canc, 2019; Koch et al., J Immuother, 2021; Stürmer et al., J Immunother, 2021). Intratympanical cortisone application is an alternative to systemic cortisone administration (Salt et al., Drug Discov Today, 2005). A correlation between the time from the onset of vestibulopathy to the start of therapy and the response is probable. Therefore, physicians should be aware of immune-mediated vestibulopathy and conduct a prompt ENT consultation in suspected cases.

61-year-old patient with steroid-refractory irColitis and 2nd line therapy with infliximab, vedolizumab (α₄β₇ integrin blocker) and extracorporeal photopheresis (ECP)

Medical History
  • 04/2021 melanoma of unknown primary (MUP)
    • Initial stage: pTxNxM1d(0), IV (AJCC 2017), BRAF wild-type
    • Cerebral metastases
Oncological Therapy
  • 06/2021: Stereotactic radiosurgery of cerebral metastases
  • 06/2021: Combination immunotherapy with ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw, every three weeks
  • 09/2021: Stereotactic radiosurgery of cerebral metastases
  • 09/2021: Chemotherapy with temozolomide 200 mg/m²
  • 10/2021: Re-Immunotherapy with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw (flip dose), every three weeks
  • 10/2021: Stereotactic radiosurgery of cerebral metastases
  • 01/2022: Chemotherapy with gemcitabine 1000 mg/m² and treosulfan 3500 mg/m²
Immune-related adverse event and how we proceeded:

After one dose of ipilimumab + nivolumab, irHepatitis grade 1 (CTCAE) and irColitis grade 1 (CTCAE) occurred. The immunotherapy was interrupted. Initial therapy:

  • Methylprednisolone 1 mg/kg bw

During an attempt to taper off the steroids, irColitis grade 2 (CTCAE) developed with diarrhea up to 7 times per day. Therapy:

  • Methylprednisolone 1.5 mg/kg bw
  • Infliximab 5 mg/kg bw i.v.

After this therapy, the patient was initially symptom-free. But when the steroids were tapered off, there was a recurrence of irColitis (grade 2) on 10 mg prednisolone. The patient had to be admitted to the hospital. Therapy:

  • Methylprednisolone 1 mg/kg bw
  • 2nd Dose of infliximab 5 mg/kg bw i.v.
  • Start of extracorporeal photopheresis (ECP)

Initially, there was a further deterioration of the irColitis. The patient developed severe diarrhea, some with blood, fecal incontinence and dehydration (irColitis grade 4). Therapy:

  • Methylprednisolone 2 mg/kg bw
  • Continuation of extracorporeal photopheresis (weekly)
  • Vedolizumab 300 mg i.v.

With this therapy, the symptoms improved over time. A second dose of vedolizumab was administered. The intervals of the ECP could be extended to every 2 weeks. Due to cerebral progress, stereotactic radiosurgery was repeated and chemotherapy with temozolomide 200 mg/m² was initiated.

Could we continue the immunotherapy?

Due to renewed significant cerebral tumor progression, the decision was made to reinitiate a combined immunotherapy with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw (flip dose), every three weeks after a risk-benefit assessment and thorough patient information. Stereotactic radiosurgery was performed again. Unfortunately, the colitis symptoms returned. Tumor therapy was switched to chemotherapy with gemcitabine and treosulfan.

Our conclusion

For the treatment of steroid-refractory irColitis, most guidelines recommend therapy with infliximab as the first step for patients who do not show any improvement within 3-5 days with steroids (Thompson et. al, J Natl Compr Canc Netw., 2020; Brahmer et. al., J Clin Oncol., 2018).
The integrin antagonist vedolizumab may be considered in infliximab-refractory irColitis according to ESMO-, NCCN- and ASCO guidelines for the management of immune-related adverse events. In a study from 2017, vedolizumab relieved symptoms in 6 of 7 patients with steroid-dependent or steroid-refractory irColitis; no side effects were reported (Bergqvist et. al., Cancer Immunol Immunother., 2017).  

Extracorporeal Photophoresis (ECP) as treatment for steroid-refractory irAE

ECP consists of the three steps of leukapheresis, photoactivation and reinfusion and has immunomodulatory effects (modulation of dendritic cells, change in cytokine profile, induction of T cell subpopulations). Indications are currently the treatment of Sézary syndrome, Graft-versus-host disease (GvHD), organ transplant rejection and systemic scleroderma. Importantly, there is no attenuation of the anti-tumor response as far as reported from lymphoma patients in contrast to potential effects of immunosuppression with drugs. Apostoleva et. al. reported on a case of a 29-year-old patient with steroid-refractory irColitis who showed only slight improvement or recurrence after administration of infliximab and ciclosporin, and in whom combined drug therapy with ECP was able to achieve freedom from symptoms and recurrence (N Eng J Med., 2020). This indicates that an off-label use of ECP for the treatment of irAE is possible and promising.

Anti-PD-1 rechallenge after irHepatitis grade 3 and irPneumonitis grade 1 during combined anti-CTLA-4 / anti-PD-1 immunotherapy

Medical History
  • 05/2021 acrolentiginous melanoma of the left foot
    • Initial stage: T4bN3bM1b, IV (AJCC 2017), BRAF wild-type
    • Inguinal and iliac lymph node metastases
    • One metastasis in small pelvis
Oncological therapy
  • 06/2021 – 08/2021: Combination immunotherapy with ipilimumab (3 mg/kg bw) and nivolumab (1 mg/kg bw) every three weeks
  • 08/2021 – 11/2021: Interruption of immunotherapy due to irPneumonitis grade 1 and irHepatitis grade 3
  • 11/2021 – 01/2022: Nivolumab 240 mg every two weeks
Immune-related adverse event

After 4 doses of combination immunotherapy with ipilimumab and nivolumab, a chest CT performed for staging showed a nonspecific interstitial pneumonia (NSIP)-pattern. The patient was completely asymptomatic (no dyspnoea, malaise, cough or fever). We diagnosed irPneumonitis grade 1 (CTCAE). In the follow-up laboratory check, AST and ALT were elevated > 5 x ULN. Therefore, in addition irHepatitis grade 3 (CTCAE)  was diagnosed.

How did we proceed?

The immunotherapy was interrupted. Therapy with methylprednisolone 1.5 mg/kg bw for three days was initiated and tapered over the following weeks. The transaminases declined and the pulmonary radiological findings clearly improved. The patient remained asymptomatic at all times.

Could we continue the immunotherapy?

After normalization of transaminases, we reinitiated monotherapy with nivolumab 240 mg every two weeks. To date, the patient has received five doses of nivolumab and has remained asymptomatic. The transaminases remained within the normal range.

Our conclusion

A rechallenge with immunotherapy carries the risk of reexacerbation of the irAE but may be indicated in certain circumstances.

Pollack et al. studied 80 patients who had to interrupt combined immunotherapy due to an irAE. Of those patients 39% experienced recurrent (18%) or clinically significant distinct (21%) irAE with anti-PD-1 monotherapy resumption. In this study, recurrence of irAE was independent of the duration of steroid taper, use of other immunosuppressants in addition to steroids, and the severity of the initial irAE. Under rechallenge with anti-PD1 monotherapy, a complete or partial response was observed in 70% of the patients, a stable disease in 19% and a progressive disease in 11% (Pollack et al, Ann Oncol., 2018).

Patients who are rechallenged show a reexacerbation in about a third of the cases if challenged with the same immunotherapy (Abu Seibh et al, J Clin Oncol., 2019) and 18% if challenged with monotherapy after combination immunotherapy. Thus, a rechallenge with immunotherapy can be considered in side effects that are not life-threatening, as there is a high probability of good efficacy. Patients have to be informed about the risk of reexacerbation. Clinicians should use critical judgement and extreme caution in resuming immunotherapy in patients with life-threatening irAE such as myocarditis.

In our case, the rechallenge with nivolumab has been well tolerated so far.

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