Plasma exchange for severe immune-related adverse events from checkpoint inhibitors: an early window of opportunity?

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several advanced malignancies leading to durable remission in a subset of patients. Their rapidly expanding use has led to an increased frequency of immune-related adverse events (irAEs). The pathogenesis of irAEs is poorly understood but may involve aberrant activation of T cells leading to inflammatory cytokine release or production of pathogenic antibodies leading to organ damage. Severe irAEs can be extremely debilitating and, in some cases, life threatening. IrAEs may not always be corticosteroid responsive or may require excessively high, often toxic, corticosteroid doses. Therapeutic plasma exchange (PLEX) is a treatment modality that has shown promising results for the management of certain severe irAEs, including irAEs that are not mentioned in current treatment guidelines. PLEX may attenuate ongoing irAEs and prevent delayed irAEs by accelerating clearance of the ICI, or by acutely removing pathogenic antibodies, cytokines, and chemokines. Here, we summarize examples from the literature in which PLEX was successfully used for the treatment of irAEs. We posit that timing may be a critical factor and that earlier utilization of PLEX for life-threatening irAEs may result in more favorable outcomes. In individuals at high risk for irAEs, the availability of PLEX as a potential therapeutic mitigation strategy may encourage life-saving ICI use or rechallenge. Future research will be critical to better define which indications are most amenable to PLEX, particularly to establish the optimal place in the sequence of irAE therapies and to assess the ramifications of ICI removal on cancer outcomes.

Anti-Hu Antibodies in Patients With Neurologic Side Effects of Immune Checkpoint Inhibitors

“…At the moment, prompt ICI discontinuation is essential to prevent further deterioration before neuronal damage is too advanced, and some authors suggest accelerating ICI clearance by the use of plasma exchange, although its schedule still needs to be defined. 41 In addition, even in case of neurologic stabilization, reintroducing ICI is not recommendable, as the risk of neurologic worsening may overcome the modest survival benefit gained by adding ICI to chemotherapy in extensive-stage SCLC. 32 Likewise, extreme caution and reconsideration of oncologic treatment alternatives are advisable when facing a patient with PNS and Hu-Ab before initiation of ICI.…”

Central nervous system adverse events of immune checkpoint inhibitors

“…According to international oncology guidelines [51,52], ICI should be immediately suspended, and high-dose steroid treatment initiated, as soon as a CNS-irAE is suspected. IVIG may be considered, while some authors also suggest that plasma exchanges should be used to accelerate ICI clearance [53]. Immunosuppressants, such as rituximab and cyclophosphamide, should be considered in case of severe presentations (such as loss of consciousness, severe motor weakness, refractory seizures, or massive memory deficits), in patients positive for high-risk antibodies, and/or in the lack of response within 10–15 days of corticosteroid therapy.…”

Evaluation and management of acute high-grade immunotherapy-related neurotoxicity

“…Refractory cases are often treated with intravenous immune globulin or plasmapheresis. The latter modality's efficacy may be due to accelerated clearance of ICI or removal of offending antibodies or cytokines [ 49 ]. Some serious conditions are also treated with immunosuppressants as specified in the disease specific sections below.…”