Occasional neurological complications of anti-PD-1 antibody treatment

Last Updated: 2017-09-07

By Will Boggs MD

NEW YORK (Reuters Health) - Diverse neurological adverse events occur in about 3% of patients with solid-organ tumors treated with anti-programmed death 1 (PD-1) antibodies, according to a retrospective study.

"Clinicians need to consider a PD-1 therapy-related complication in patients developing new neurologic symptoms while on treatment, as the presentations are diverse, have variable time of onset, and can rapidly progress," Dr. Michelle L. Mauermann from Mayo Clinic, Rochester, Minnesota, told Reuters Health by email.

Neurological adverse events have been reported after the use of anti-PD-1 antibodies, such as nivolumab and pembrolizumab, in the treatment of solid-organ tumors, with estimated frequency of 4.2%.

Dr. Mauermann's team investigated the frequency, phenotypes, and severity of neurological complications among 347 patients treated with anti-PD-1 antibodies at Mayo Clinic.

Ten patients (2.9%), eight men and two women (median age, 71) experienced treatment-related neurological complications: seven were treated with pembrizolumab and three with nivolumab, according to the September 5 JAMA Neurology online report.

Neuromuscular disorders were most common, including two cases of myopathy and four cases of neuropathy.

Cerebellar ataxia, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache each affected one patient.

Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 therapy, although the time of onset to maximum symptom severity varied considerably, from 1 day to more than 3 months.

Five patients also experienced other PD-1-related immune-mediated complications, including hypothyroidism in three, colitis in two, and hepatitis in one. These complications were associated with mild-to-moderate disability.

Nine patients improved, one spontaneously and eight after immune rescue treatment ranging from corticosteroids to intravenous immunoglobulin to plasma exchange. One patient died despite high-dose prednisone and plasma exchange after withdrawal of ventilatory support 1 month after symptom onset.

Three out of four patients who received subsequent anti-PD-1 therapy were able to tolerate further treatment, although two of them required maintenance intravenous immunoglobulin or dexamethasone for immunomodulation.

"These patients should be evaluated by a neurologist in conjunction with their oncologist," Dr. Mauermann said by email. "Some of these patients will require inpatient treatment, given the severity of the neurological dysfunction and risk of rapid progression of symptoms."

"In most cases the PD-1 therapy should be discontinued when symptoms appear, and some patients may require immune rescue treatment," she said.

Dr. Roy E. Strowd III from Wake Forest School of Medicine, Winston-Salem, North Carolina, who wrote an accompanying editorial, told Reuters Health by email, "These drugs, which are some of the newest on the market for treating patients with cancer, activate the immune system to fight cancer. The risk of neurologic complications with these agents has been well described in randomized trials, but these trials do not necessarily include all of the patients that might be treated with these agents in the clinic."

"This study suggests that neurologic complications are uncommon in general practice but do occur and can be severe," he said. "The description of mostly neuropathy and myopathy complications is important and needs to be fleshed out in ongoing (studies)."

"Neurologists should be aware of these new agents, the frequency and type of neurologic complications, and the current guidelines for management," Dr. Strowd said. "Close communication between oncologist and neurologist is important, as the treatments to improve the neurologic complications (i.e., corticosteroids) can worsen the underlying anticancer response to these drugs."

"A multidisciplinary team, including oncologists, neurologists, and likely physical therapy, occupational therapy, and others, is often important for the management of these patients," he said.

"Additional research is needed to determine potential risk factors for neurologic complications from immune checkpoint inhibitors like nivolumab and pembrolizumab," Dr. Strowd said. "Whether the rates of these complications are higher in patients with underlying autoimmune disease is not known and is an area that is being studied."

Dr. Lavinia Spain from Royal Marsden NHS Foundation Trust, in London, who recently reviewed neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma, told Reuters Health by email, "In our Royal Marsden series, although our numbers were small (N=10), median overall survival was excellent for the group of patients experiencing (and surviving) neurotoxicity (46 months vs. 11 months in those who did not develop neurotoxicity), and 70% had a RECIST response (2 complete responses, 5 partial responses)."

"As patients may require a long period of intensive care support and rehabilitation following severe cases, understanding that durable responses can still occur in this group is helpful when making critical decisions in their management," she said.

Dr. Spain added, "Patients with suspected neurological toxicity should ideally be treated in a center with experience in the management of complex immune-related adverse events where admission to intensive care is available if required (e.g., for ventilatory support)."

SOURCES: http://bit.ly/2xdCnNk and http://bit.ly/2wccxoa

JAMA Neurol 2017.