Ever since their initial approval by the Federal Drug Administration (FDA) for the treatment of unresectable metastatic melanoma in 2015, the use of ICIs has rapidly expanded to include many other cancers.14 There are a number of irAEs that have been associated with ICI use, including those that produce rare and difficult to diagnose and treat neurological conditions.2-10 For example, multiple cases of MG associated with ICIs have been reported in the literature.2, 5, 6
Guidelines for the treatment of ICI associated MG, include the use of pyridostigmine, corticosteroids, IVIG, and plasmapheresis.1, 11, 15 However, some patients are refractory to these treatments. Rituximab has been previously reported as a potential third-line therapy for non-ICI related MG which is refractory to standard immunosuppressive approaches.13 To our knowledge, our patient is the second case reported with ICI-induced MG successfully treated with rituximab.13
Our patient showed a dramatic improvement in her pulmonary function tests and other MG-related symptoms (dyspnea, diplopia, and ptosis) immediately after the initial therapy with rituximab IV 375 mg/m2, as well as following every rituximab infusion thereafter. In this case, rituximab therapy had lasting therapeutic effects overall for three to four weeks. The optimal schedule of rituximab is unclear and published experience suggests a 375 mg/m2 weekly x 4 doses.16 Nonetheless, our patient showed a marked clinical and objective improvement on a single dose given monthly. Her clinical and objective response to rituximab was consistent to the response typically seen in patients with non-ICI related MG.16
It is also possible that her clinical improvement was due to her other MG treatments, which are pyridostigmine, prednisone, and IVIG therapy, which were administered two days prior to rituximab. Certainly her favorable clinical response to rituximab could have been secondary to a delayed effect of these standard MG therapies. However, the close temporal association between clinical improvement and each rituximab infusion as well as the dramatic objective response within 48 hours of rituximab administration suggests—but don’t prove—that rituximab treatment produced her dramatic recovery.
Although rituximab traditionally acts to deplete the plasma cells, recent evidence has shown that it has direct influence in the T-cell responses.17 Given this common substrate with ICIs, perhaps rituximab should be considered as a more effective therapy in ICI-induced MG compared to the traditional and standard immunosuppressive therapies.1, 11, 15 It is important to report similar successful cases in the literature to increase awareness about these rare neurological irAEs, and make others acquainted with the use of non-standard therapies in cases that are refractory to standard therapy. It is also important to obtain a prompt neurological consultation as soon as these types of irAEs are suspected, as these syndromes are difficult to detect and could be misdiagnosed. We suggest considering a low-dose of rituximab (375 mg/m2) as an initial therapeutic option for ICI-induced MG that is refractory to standard immunotherapies. This might help to achieve a quicker positive clinical response, avoid unnecessary hospitalizations and the serious side effects of chronic corticosteroid use.
As with any case report there are limitations to consider. We have interpreted this patient’s MG to be de novo, and directly related to ICI administration. An alternative explanation is that the patient had preexisting asymptomatic MG (i.e., with positive AChR antibodies) and treatment with Nivo + Ipi unmasked her condition. Also, while we observed an excellent and reproducible response to rituximab, prospective studies will be needed to definitively evaluate the efficacy of rituximab in ICI-induced MG. Establishing an animal model of ICI-associated MG may also suggest mechanistic and therapeutic interventions. However, given the rarity of this condition, including in both non-immunotherapy and immunotherapy induced cohorts, it may be challenging to complete prospective clinical studies needed to prove efficacy of this approach. Further evaluation with prospective studies looking at AChR antibodies pre and post ICI treatment may be useful to help establish the biological basis for ICI-induced MG.