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LETTER TO EDITOR
Year : 2018  |  Volume : 66  |  Issue : 2  |  Page : 509-511

Severe polyradiculoneuritis associated with the combination of ipilimumab and pembrolizumab in a lung cancer patient


1 Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
2 Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City; Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taiwan
3 Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City; Department of Neurology, School of Medicine, College of Medicine, Taiwan
4 Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City; Department of Neurology, School of Medicine, College of Medicine; Graduate Institute of Biomedical Informatics, Taipei Medical University, Taiwan

Date of Web Publication15-Mar-2018

Correspondence Address:
Dr. Chen-Chih Chung
No. 291, Zhongzheng Rd., Zhonghe District, New Taipei City, 23561
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.227311

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How to cite this article:
Cho HS, Lee KY, Hu CJ, Chung CC. Severe polyradiculoneuritis associated with the combination of ipilimumab and pembrolizumab in a lung cancer patient. Neurol India 2018;66:509-11

How to cite this URL:
Cho HS, Lee KY, Hu CJ, Chung CC. Severe polyradiculoneuritis associated with the combination of ipilimumab and pembrolizumab in a lung cancer patient. Neurol India [serial online] 2018 [cited 2019 Oct 23];66:509-11. Available from: http://www.neurologyindia.com/text.asp?2018/66/2/509/227311




Sir,

In recent years, immunotherapy has emerged as a promising therapeutic approach for lung cancer. Inhibitors of the programmed cell death protein 1 (PD-1) and the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathways are under investigation for non-small cell lung cancer (NSCLC). Inhibition of these pathways is thought to activate T cell immune function and is considered a new treatment for advanced cancer, but this also induces immune-related adverse events (irAEs).[1] Here, we report a case with polyradiculoneuritis induced by ipilimumab and pembrolizumab, which were given for the treatment of NSCLC. To the best of our knowledge, this is the first fatal case due to severe neurological complications induced by combined PD-1 and CTLA-4 immunotherapy for lung cancer.

A 56-year old man was diagnosed as having lung adenocarcinoma (cT2N3M1b), harboring an epidermal growth factor receptor (EGFR)mutation (exon 21, L858R) with lung-to-lung, multiple bone, and brain metastases. He was started on tyrosine kinase inhibitor (erlotinib, 150 mg QID) after the diagnosis. Two months later, to increase progression-free survival, he received the vascular endothelial growth factor receptor inhibitor bevacizumab (1000 mg; 15 mg/kg) every 3 weeks as a combination therapy. To improve the chance of long-term survival, after one course of bevacizumab, an anti-PD-1 receptor antibody (pembrolizumab, 150 mg; 2 mg/kg) was added. Due to no reduction of the tumor size following the administration of chemotherapy, after 7 cycles of the combination therapy, an anti- cytotoxic T lymphocyte-associated antigen (CTLA)-4 antibody (ipilimumab, 100 mg; 2 mg/kg), was prescribed in combination with pembrolizumab every 3 weeks while bevacizumab was discontinued. After 3 cycles of combination therapy with ipilimumab and pembrolizumab, he developed progressive symmetric lower limb weakness, dominant in the proximal parts, and atrophy of the calf muscles. The tendon reflexes were diminished. Vibration and proprioceptive sensations were absent at the toes and reduced at the ankles. Pain sensation was reduced in the lower limbs distally. Nerve conduction studies (NCSs) [Table 1] suggested polyradiculoneuropathy. The cerebrospinal fluid (CSF) study exhibited an increased protein level (262 mg/dL) and cellularity (22 nucleated cells; 98% lymphocytes); the glucose level was normal; the bacterial, fungal, and CSF cytology were negative. Sural nerve biopsy revealed no increased lymphohistiocytic infiltrates. Lumbar magnetic resonance imaging (MRI) showed a mild herniated intervertebral disc prolapse without leptomeningeal enhancement. Intravenous methylprednisolone (80 mg/d) was given for 3 days, with sequential oral prednisolone (30 mg/d). His muscle strength and gait improved markedly. The patient was maintained on oral prednisolone (20 mg QID).
Table 1: Nerve conduction studies: 4 time-points after symptom onset

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One month later, his weakness deteriorated and he became wheel-chair dependent. Repeated NCSs [Table 1] revealed more severe polyradiculoneuropathy. He was readmitted and receive intravenous immunoglobulin therapy (IVIG; 2 g/kg) but the response to IVIG was ineffective. The weakness progressed in one month, and he became bedridden. A repeat CSF study revealed an elevated protein level (600 mg/dL). We prescribed methylprednisolone (1000 mg/d), followed by plasma exchange treatment for 5 sessions and an additional 2 sessions. The weakness improved after plasma exchange; the CSF protein level decreased to 215 mg/dL. However, two months later, the patient developed lung abscesses and died of sepsis.

Limited number cases have reported the association of polyneuropathy with treatments with CTLA-4 or PD-1 inhibitor in combination with other medications [Table 2] ].[2],[3],[4],[5],[6],[7] In these studies, the age of the patients ranged from 31 to 85 years, all of them had a melanoma, the time-to-onset of symptoms ranged from 1 to 16 weeks, and most patients developed neuropathy at approximately 9 weeks after immunotherapy The clinical course of adverse events could be acute or intermittently progressive. Numbness and pain with or without motor impairment are the most common initial symptoms, and the disease severity varies among patients. CSF shows elevated protein levels in all the reported cases. When NCSs are performed at the time of onset of the disease, the results vary, but most patients present with conduction blockage and demyelinating features. Most cases are managed with corticosteroids and the outcomes of those studies were favorable.
Table 2: Reviewed cases of neuropathy that develops when a combination of CTLA 4 and PD 1 inhibitor is administered

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Many studies have described the sequential use or combination therapy of immunoantibodies. Vascular endothelial growth factors (VEGF) inhibitors can interfere with the neuroprotective effects of endogenous VEGF, potentially triggering the exacerbation of chemotherapy induced neuropathy. But the combination of ipilimumab and bevacizumab in metastatic melanoma was considered safe in a phase I trial.[8] Compared with the sequence of anti-CTLA4 followed by anti-PD-1, more frequent toxicities were reported in the sequence of anti-PD-1 followed by anti-CTLA4 among patients harbouring a melanoma.[9] A combination therapy of ipilimumab and nivolumab for NSCLC is being evaluated in the ongoing trials. The combination of these two agents results in elevated toxicity compared to with that of each agent alone.[10]

No reliable predictors for the immune related adverse effects (irAEs) related to the neuropathy are currently known. In one case report,[3] elevated tumor necrosis factor-alpha and interleukin (IL)-17 were detected in the CSF when the patient developed severe polyneuropathy. One study [11] suggested that the baseline pretreatment IL-17 correlated significantly with the risk of subsequent grade 3 immune-mediated diarrhea among patients receiving neoadjuvant therapy for regionally advanced melanoma.

Our patient experienced neuropathy with the combination therapy of ipilimumab and pembrolizumab. The irAEs were partially resolved after stopping the checkpoint blockage and corticosteroid use. However, the disease progressed soon after the steroids were tapered. The sequence and combination of pembrolizumab and ipilimumab may have predisposed the patient to severe neuropathy. This case report emphasizes that neurological irAEs should be detected early in patients receiving ipilimumab, especially when it is administered in combination with other immunotherapy. This association should especially be investigated in patients who develop new onset sensory or motor symptoms.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgement

We acknowledge Wallace Academic Editing for editing this manuscript.

We acknowledge Doctor Yung-Ting Kuo, Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, for conducting the nerve biopsy procedure.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Garon EB. Current perspectives in immunotherapy for non-small cell lung cancer. Semin Oncol 2015;42 Suppl 2:S11-8.  Back to cited text no. 1
    
2.
Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro Oncol 2014;16:589-93.  Back to cited text no. 2
    
3.
Thaipisuttikul I, Chapman P, Avila EK. Peripheral neuropathy associated with ipilimumab: A report of 2 cases. J Immunother 2015;38:77-9.  Back to cited text no. 3
    
4.
Gaudy-Marqueste C, Monestier S, Franques J, Cantais E, Richard MA, Grob JJ. A Severe case of ipilimumab-induced Guillain-Barre's syndrome revealed by an occlusive enteric neuropathy: A differential diagnosis for ipilimumab-induced colitis. J Immunother 2013;36:77-8.  Back to cited text no. 4
    
5.
Manousakis G, Koch J, Sommerville RB, El-Dokla A. Multifocal radiculoneuropathy during ipilimumab treatment of melanoma. Muscle Nerve 2013;48:440-4.  Back to cited text no. 5
    
6.
Bompaire F, Mateus C, Taillia H, De Greslan T, Lahutte M, Sallansonnet-Froment M, et al. Severe meningo-radiculo-neuritis associated with ipilimumab. Invest New Drugs 2012;30:2407-10.  Back to cited text no. 6
    
7.
de Maleissye MF, Nicolas G, Saiag P. Pembrolizumab induced demyelinating polyradiculoneuropathy. N Engl J Med 2016;375:296-7.  Back to cited text no. 7
    
8.
Kourie HR, Klastersky JA. Side-effects of checkpoint inhibitor-based combination therapy. Curr Opin Oncol 2016;28:306-13.  Back to cited text no. 8
    
9.
Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, et al. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): An open-label, randomised, phase 2 trial. Lancet Oncol 2016;17:943-55.  Back to cited text no. 9
    
10.
Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small- cell lung cancer (CheckMate 012): Results of an open-label, phase 1, multicohort study. Lancet Oncol 2017;18:31-41.  Back to cited text no. 10
    
11.
Tarhini AA, Zahoor H, Lin Y, Malhotra U, Sander C, Butterfield LH, et al. Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J Immunother Cancer 2015;3:39.  Back to cited text no. 11
    



 
 
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