Author Of 2 Presentations
P0362 - Novel treatment approach for fingolimod-associated progressive multifocal leukoencephalopathy in a patient with relapsing remitting multiple sclerosis (ID 967)
Progressive multifocal leukencephalopathy (PML) due to the polyoma JC virus (JCV), remains an untreatable viral infection. Aside from addressing the underlying cause of immunodeficiency, there remains no evidenced-based treatment for PML. PML is rarely seen in fingolimod-treated relapsing remitting multiple sclerosis (RRMS) patients.
We present a 62 year-old man with RRMS of 20-years duration treated with fingolimod for 6 years who developed PML and discuss the response to a PD-1 inhibitor, pembrolizumab.
Onset of illness was insidious with progressive left leg weakness, gait unsteadiness, slurred speech, double vision, asymmetric cerebellar ataxia, bilateral internuclear ophthalmoplegia and spastic paraparesis. Expanded disability status scale (EDSS) increased from 6.0 to 6.5. Fingolimod was immediately withheld.
Magnetic resonance imaging (MRI) scan demonstrated new, patchy, non-enhancing hyperintense lesions within the white matter of frontal lobes, right thalamus and brainstem. 160 copies/ml of JCV-DNA were detected in the cerebrospinal fluid (CSF). Mirtazepine dose was increased to 45mg daily. Despite a few weeks’ clinical stability, MRI appearances and JCV-DNA copies worsened over the next 3 weeks followed by gait deterioration. Maraviroc 300mg twice daily was then introduced. Subtle punctate contrast enhancement, suggestive of a mild immune reconstitution inflammatory syndrome (IRIS), was transiently seen within the midbrain and right frontal areas of signal change 6 weeks after fingolimod cessation, followed by a single focal-to-generalised tonic clonic seizure. EDSS increased to 8.0. Mefloquine 250mg weekly and 3 monthly doses of 200mg pembrolizumab, were administered. Serial CSF examinations and several imaging modalities including spectroscopy and fused FDG-PET-MRI were used to distinguish between PML, PML-IRIS and MS activity. The patient’s symptoms and “PML lesions” on brain MRI scans remained stable, although a handful of small, enhancing ovoid lesions developed between the first two doses of pembrolizumab. Following the second dose of pembrolizumab, a sustained but gradual improvement in imaging and examination parameters was observed with JCV-DNA becoming undetectable 16 weeks following fingolimod withdrawal. EDSS improved from 8.0 to 6.5.
This case highlights several challenges of managing PML, a highly life threatening condition. To our knowledge this is the first case of combined therapy and use of pembrolizumab in a fingolimod-associated PML.
P0415 - Updated post-approval safety of cladribine tablets in the treatment of multiple sclerosis, with particular reference to respiratory viral infections (ID 965)
Several integrated analyses have reported on the safety of cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years [CT3.5]) during clinical development for the treatment of patients with relapsing multiple sclerosis (RMS). Additional real-life safety data have accrued since the approval of CT3.5 in many countries worldwide. In recent months the COVID-19 pandemic has become a concern for MS patients and their healthcare providers in terms of the associated safety of their disease-modifying therapy.
To update on the post-approval safety profile of CT3.5 in patients with RMS, including COVID-19 and other respiratory viral infections.
Serious and non-serious adverse events (AEs) from post-approval sources (including spontaneous individual case safety reports, non-interventional post-marketing studies, and reports from other solicited sources) are presented to Jan 2020. AE rates are shown as crude incidences (events/number of patients). Up-to-date COVID-19 findings are summarized.
A total of 2570 AEs were reported for the first 14,813 patients who received CT3.5 post-approval; 303 (12%) events were classified as serious and none represented a new safety signal. Crude incidences for AEs of special interest were as follows: severe lymphopenia, 0.002; herpes zoster, 0.008; tuberculosis, 0.0004; severe infections, 0.009; progressive multifocal leukoencephalopathy, 0; opportunistic infections, 0.001; malignancies, 0.0015; and teratogenicity, 0. The majority of opportunistic infections were superficial dermal and mucosal fungal infections that resolved on standard treatments.
The pattern of respiratory viral infections (typically non-serious) with post-approval use of CT3.5 was also consistent with that from the clinical development program; crude incidences were as follows: influenza, 0.005; viral infection, 0.002; and viral upper respiratory tract infection, 0.0004. As of 29 Jun 2020, the Merck safety database included 18 cases of confirmed COVID-19 in CT3.5-treated patients. An update on latest findings on COVID-19 infections will be presented, including analysis of time of infection since treatment where available.
No new safety signals were identified in the real-world post-approval data of CT3.5, cumulative to Jan 2020. The safety profile of CT3.5, including respiratory viral infections, is consistent with previously published integrated safety analyses of the clinical development data.