Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study

Abstract

BackgroundParaneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy.MethodsWe included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively.FindingsOf the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45–88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1–2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1.InterpretationOur results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors

“…Current literature covers mainly paraneoplastic neurological syndromes with few published data regarding paraneoplastic rheumatic syndromes. 120 121 However, based on the clinical experience of task force members, the group agreed to include paraneoplastic syndromes in the differential diagnosis of rheumatic irAEs to inform clinicians that they may encounter newly and not pre-existing paraneoplastic syndromes following CPI therapy, notably hypertrophic osteoarthropathy. RS3PE and dermatomyositis were also reported, either as paraneoplastic syndromes or induced by CPI therapy, but one may not be able to make the distinction when appearing under CPI therapy.…”

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors

“… 17 Fourthly, cross reactivity between tumour cell antigens and normal tissue clinically translates as paraneoplastic syndromes in some cases. 18 Pre-existing paraneoplastic syndromes have been shown to worsen in 50% of patients treated with anti-PD-1 or anti-PD-L1 immunotherapy. 18 Finally, regulatory T (Treg) cell depletion has been suggested to play a role in the development of irAEs, as Treg cells are essential for maintaining peripheral tolerance.…”

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

“…We believe it is essential to question patients undergoing evaluation for ICI about immune antecedents, including a previous diagnosis of immune-mediated disorders and current or previous symptoms that may be caused by an undiagnosed inflammatory condition, such as paraneoplastic disorders (67). In patients who underwent brain MRI for another reason, even without symptoms of MS, it is also interesting to evaluate whether lesions suggestive of demyelination already existed before ICI treatment, as these patients may be more at risk of developing more severe nirAEs (21).…”