Radiation myelitis after pembrolizumab administration, with favorable clinical evolution and safe rechallenge: a case report and review of the literature

Abstract

BackgroundNeurologic complications as myelitis are very rare but extremely deleterious adverse effects of both immunotherapy and radiotherapy. Many recent studies have focused on the possible synergy of these two treatment modalities due to their potential to enhance each other’s immunomodulatory actions, with promising results and a safe tolerance profile.Case presentationWe report here the case of a 68-year-old man with metastatic non-small-cell lung cancer (NSCLC) who developed myelitis after T12-L2 vertebral radiotherapy, with motor deficit and sphincter dysfunction, while on treatment with pembrolizumab (an immune checkpoint inhibitor). The spinal abnormalities detected by magnetic resonance imaging (MRI), suggestive of myelitis, faithfully matched the area previously irradiated with 30 Gy in 10 fractions, six and a half months earlier. After immunotherapy discontinuation and steroid treatment, the patient rapidly and completely recovered. On progression, pembrolizumab was rechallenged and, after 8 cycles, the patient is on response and there are no signs of myelitis relapse.ConclusionThe confinement within the radiation field and the latency of appearance are suggestive of delayed radiation myelopathy. Nevertheless, the relatively low dose of radiation received and the full recovery after pembrolizumab discontinuation and steroid therapy plead for the contribution of both radiotherapy and immunotherapy in the causality of this complication, as an enhanced inflammatory reaction on a focal post-radiation chronic inflammatory state. In the three previously described cases of myelopathy occurring after radiotherapy and immunotherapy, a complete recovery had not been obtained and the immunotherapy was not rechallenged. The occurrence of a radiation recall phenomenon, in this case, can not be excluded, and radiation recall myelitis has already been described with chemotherapy and targeted therapy. Safe rechallenges with the incriminated drug, even immunotherapy, have been reported after radiation recall, but we describe it for the first time after myelitis.

Neurological immune‐related adverse events associated with immune checkpoint inhibitors: A review of the literature

“…We searched PubMed for ICIs‐related myelitis cases and identified 11 patients (Tables 2 and S4), 26,82‐91 seven (63.7%) of whom were males. The median onset age was 63 years (IQR: 51.5‐68; range: 35‐75).…”

Central Nervous System Demyelination Associated With Immune Checkpoint Inhibitors: Review of the Literature

“…Articles included in this review contained 23 case reports of patients who developed CNS demyelination after ICI administration. Of these cases, patients were classified as having the following syndromes: 7 with myelitis (19,(34)(35)(36)(37)(38)(39), four isolated optic neuritis (40)(41)(42)(43), one NMOSD (44), three had a relapse from a previously diagnosed MS (21,23,24), and two evolved from a radiologically isolated syndrome (RIS) to MS (22,45). Six patients had atypical demyelination (14,25,(46)(47)(48)(49).…”

“…Anti-aquaporin4 (anti-AQP4) antibodies were tested in four patients and were positive in one; a paraneoplastic panel was assessed in nine patients, with a positive result in two of them (anti-Hu and anti-CRMP5); one patient was negative for anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibodies. ICI treatment was at least temporarily discontinued in 20 of 23 patients because of the nirAE; in two patients, ICI treatment was maintained because of good oncologic response and benefits overweighting the risks (23,45); in two cases, ICI treatment was reinstituted after the resolution of nirAE without the development of new irAE (22,36). Treatment of demyelination included systemic steroids (21/23), plasma exchange (PLEX) (5/23), intravenous immunoglobulin (IVIg) (4/23), infliximab (2/23), interferon (2/23), cyclophosphamide (2/23), glatiramer (1/23), and mycophenolate mofetil (1/23); two patients received no systemic treatment other than discontinuation of ICI, and in one patient treatment was not reported.…”

“…We found seven case reports of myelitis associated with ICI. In four of them (34)(35)(36)(37), patients were exposed to radiotherapy on the cervical spine for bone metastases before (cases 7, 8, and 11) or during (case 10) ICI treatment. In all cases, delayed radiation myelopathy (DRM) was considered, but some features implicated an immune etiology, at least superimposed.…”

Inflammatory Myeloradiculitis Secondary to Pembrolizumab: A Case Report and Literature Review

“…Four cases received plasmapheresis [ 21 , 23 , 24 , 27 ], and two received intravenous immunoglobulin [ 21 , 27 ]. Four of the six included cases demonstrated significant improvement in their symptoms [ 20 , 21 , 23 , 27 ]. A summary of reported myelitis cases secondary to PD-1 inhibitor therapy is provided in Table 1 .…”