Current Perspective
Drug-induced sarcoidosis-like reaction in adjuvant immunotherapy: Increased rate and mimicker of metastasis

https://doi.org/10.1016/j.ejca.2020.02.024Get rights and content

Highlights

  • Potentially higher rate of sarcoidosis-like reactions (SLR) in patients who receive adjuvant immunotherapy than in patients with metastatic disease.

  • Differentiation between SLR and progression of disease in most cases only possible with biopsy.

  • No clinical symptoms of the SLR in our patients, no steroid treatment required.

  • No progression of the SLR after continuation of treatment.

  • Patients that developed SLR and patients that did not had an equal relapse rate (20%).

Abstract

Background

Anti-[programmed cell death protein 1 (PD-1)] antibodies nivolumab and pembrolizumab were approved for adjuvant treatment of melanoma as they demonstrated improved relapse-free survival. Currently, combined anti-PD-1 plus anti-[cytotoxic T-lymphocyte-associated protein 4 (CTLA4)] blockade is being investigated in adjuvant and neoadjuvant trials. Sarcoidosis-like reactions have been described for immune checkpoint inhibitors and are most likely drug-induced. The reported rate of sarcoidosis/sarcoidosis-like reactions within clinical melanoma trials is <2%. We observed that a remarkably higher number of melanoma patients (10/45 patients, 22%) treated with immune checkpoint inhibitor (ICI) within an adjuvant clinical trial-developed drug induced sarcoidosis-like reaction (DISR) mimicking metastasis.

Case presentation

Of 45 stage III melanoma patients who were treated at our institute with adjuvant ICI (either nivolumab alone or in combination with ipilimumab) within a two-armed, blinded clinical trial, ten developed a DISR. Three of the ten patients were men, median age was 52 years (range, 32–70 years). DISRs were asymptomatic and generally detected radiographically at first radiographic imaging after the start of therapy (median time, 2.8 months) and described as a differential diagnosis to tumour progression. In one patient, DISR was only apparent 13.1 months after start of therapy and 4 weeks after the end of ICI treatment. DISR presented as mediastinal/hilar lymphadenopathy in 8/10 patients (as only site or in addition to lung, skin and/or bone involvement), one patient had only lung and cutaneous, one patient only cutaneous DISR. Biopsies from lymph nodes, skin and bone were taken in 8/10 patients, and histology confirmed sarcoidosis-like reactions (SLRs). As patients were asymptomatic, no treatment for DISR was required, and study treatment was stopped for DISR in only one patient due to bone involvement. DISRs have resolved or are in remission in all patients. At a median follow-up time of 15.3 months (range, 12–17.6 months), two patients experienced melanoma relapse.

Conclusions

In most cases, sarcoidosis could only be differentiated from melanoma progression on biopsy. Treating physicians as well as radiologists have to be aware of the potentially higher rate of DISR in patients receiving adjuvant ICI. A thorough interdisciplinary workup is required to discriminate from true melanoma progression and to decide on continuation of adjuvant ICI treatment.

Section snippets

Background

Immune checkpoint inhibitors (ICIs) and kinase inhibitors have become the standard-of-care treatments for patients with advanced melanoma [1]. Recently, anti-[programmed cell death protein 1 (PD-1)] antibodies nivolumab and pembrolizumab as well as [proto-oncogene B-Raf (BRAF)]-inhibitor dabrafenib plus [mitogen-activated protein kinase kinase enzyme (MEK)]-inhibitor trametinib have been approved for the adjuvant treatment of patients with high-risk melanoma [[2], [3], [4]].

Sarcoidosis is a

Discussion and conclusions

As the exact pathophysiology of sarcoidosis itself is still unknown, it can only be speculated whether ICIs are inducing a DISR syndrome very similar to sarcoidosis or are truly inducing sarcoidosis [6]. The temporal relationship with initiation of ICI treatment as well as the improvement after ICI treatment discontinuation as described in our patients speak for DISR.

Sarcoidosis-like reactions/sarcoidosis induced by ICI has been reported for both anti-CTLA4-and anti-PD1-blocking agents [8,12].

Ethics approval and consent to participate

Not applicable.

Consent for publication

Is available on request.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

Authors' contributions

EC, TK, DS and EL analyzed and interpreted the patient data and were a major contributor in writing the manuscript. Eva Hadaschik and Dirk Theegarten performed the histological examinations, Eva Hadaschik further performed the PD-L1 staining of the tumour- and SLR-material. All authors read, gave their recommendations and approved the final manuscript.

Conflict of interest statement

E.C.: reports travel support from Bristol-Myers Squibb, MSD SHARP & DOHME and Novartis.T.K.: reports travel support from Novartis, Amgen, Celgene, Lilly and Pierre-Fabre.

L.Z.: served as consultant and/or has received honoraria from Roche, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, Pierre Fabre, Sanofi, and travel support from MSD, BMS, Amgen, Pierre Fabre and Novartis.

E.H.: reports no conflict of interest.

S.U.: reports grants, personal fees and non-financial support from

Acknowledgements

The authors are indebted to all patients and their relatives and would like to thank Antje Sucker and Julia Kretz from the Dept. of Dermatology, University Hospital Essen, for the laboratory assistance including PD-L1 staining.

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