Rituximab postprogressive multifocal leukoencephalopathy: a Feasible therapeutic option in selected cases

Today, a growing armamentarium of potent immunotherapies exists for the treatment of severe relapsing remitting multiple sclerosis (RRMS). Some of these drugs may cause progressive multifocal leukoencephalopathy (PML), a John Cunningham virus (JCV) infection of the central nervous system [Dahlhaus et al. 2013; Hoepner et al. 2014; Schmedt et al. 2012]. In PML survivors, RRMS-disease activity will usually return to high pre-natalizumab (Nat) levels within 1 year [Dahlhaus et al. 2013]. Thus a post-PML immunotherapy is mandatory and still an unsolved problem.

Here, we report our experience concerning follow-up therapy with rituximab in a JCV antibody-positive 32-year-old male RRMS patient, who developed PML after 34 Nat infusions (duration of Nat treatment 34 months, December 2006 to 28 September 2009 [date of last infusion]). He had suffered from bipolar disorder since adolescence. RRMS was diagnosed in 1997. From 1997 to 2006 he was treated with different interferon brands: interferon-β1a intramuscular (im) 1 × 30 µg/week and interferon-β1b subcutaneous (sc) 250 µg every second day). Owing to an annual relapse rate ≥ 2, the patient was switched to Nat in 2006. At this time point he could walk without aid or rest for 400 m (Expanded Disability Status Scale [EDSS] 4.5, Figure 1). Nat, which was infused every 4–6 weeks, completely suppressed clinical and radiological disease activity until September 2009, when he developed a psychiatric deterioration accompanied by a right-sided haemiataxia and gait disturbance. Considering a mixture of seasonal depression and MS relapse the Nat infusion number 34 was given on 28 September 2009. Nevertheless the hemiataxia worsened and aphasia developed leading to an inpatient admission at the end of September. Here, the magnetic resonance imaging (MRI) scan unmasked a left-sided subcortical lesion without gadolinium enhancement or mass effects (Figure 2) suggestive for a PML. Diagnosis was proven by JCV polymerase chain reaction (PCR) analysis in cerebrospinal fluid (CSF) demonstrating 237 JCV DNA copies/ml. Nat was immediately withdrawn and six plasma exchanges combined with a previously described standardized PML therapy were carried out [Hoepner et al. 2014]. During PML and the associated immune reconstitution inflammatory syndrome, the patient was bedridden (EDSS 8.5, Appendix 1) and developed symptomatic focal epilepsy with generalized tonic-clonic seizures.

Figure 1.

Disability progression over time measured by the Expanded Disability Status Scale. IRIS, immune reconstitution inflammatory syndrome; MS, multiple sclerosis; PML, progressive multifocal leukoencephalopathy.

Figure 2.

Magnetic resonance imaging: T2, fluid attenuation inversion recovery and T1 postgadolinium.

In March 2010, MRI was stable, a JCV DNA PCR re-testing in the CSF was negative and the physical disability had improved (walking range 100 m, EDSS 5.5). Subsequently, in May 2010 glatiramer acetate (20 mg sc/day) was initiated as the first post-PML MS therapy. He remained relapse free until spring 2011, 12 months after a proven absence of JCV in the CSF. At this time point the pre-existing gait disturbance and ataxia worsened. An MS relapse was diagnosed and an intravenous (iv) steroid cycle was given. Nevertheless, the physical disability deteriorated (EDSS 6.5, Figure 1). Therefore the patient was switched from glatiramer acetate to fingolimod (FTY) in May 2011. FTY led to a stable MS-disease course but epileptic seizures occurred more frequently. Due to a 46% decrease in lamotrigine serum levels after the initiation of FTY (serum levels of 300 mg/day lamotrigine: prior FTY 3.7 mg/L; during FTY therapy 2.0 mg/L), we assumed an up to now unreported FTY side effect on intrahepatic cytochrome P450 pathways leading to an accelerated degradation of the antiepileptic medication; FTY was discontinued. In April 2013, several weeks after FTY withdrawal, another MS relapse occurred and MRI demonstrated multiple gadolinium-positive brain lesions.

Due to further physical deterioration the patient was readmitted to our hospital in October 2013. A lumbar puncture showed negative JCV DNA in the CSF and rituximab (500 mg iv) was initiated because of the aggressive MS-disease course with documented increase in physical disability (EDSS on admission 7.5, Figure 1). Treatment with rituximab was on the basis of an individualized clinical trial (according to §4 Arzneimittelgesetz – German medicinal drug legislation), and the observation of PML patients was approved by the local ethics committee of Ruhr University Bochum (no. 4566-13). Within the documented follow-up period of 9 months the patient was free of clinical and radiological disease activity, the physical disability improved (EDSS 6.5) and no JCV reinfection occurred. Thus a second rituximab infusion was given in summer 2014.

We report the first post-Nat PML RRMS patient with the need for a highly active MS treatment, here rituximab. As previously demonstrated by our research group, MS-disease activity returns within the first year after JCV negativity in the CSF (JCV negative [median] 4.5 months and MS re-occurrence [median] 11 months after PML diagnosis) [Dahlhaus et al. 2013]. As a consequence we suggest starting a subsequent MS therapy 3 months after proven JCV elimination in the CSF. Glatiramer acetate, interferons and teriflunomide are assumed to suppress relapse activity with similar power. In addition, long-term experience of MS therapy exists only for glatiramer acetate and interferon-b. Therefore we did not consider teriflunomide treatment in this specific condition. An early subsequent MS therapy might delay RRMS re-manifestation, as observed in the presented case. If MS-disease activity returns to pre-Nat levels [Dahlhaus et al. 2013], glatiramer acetate or interferon therapy might be less effective. In these cases our group recommends switching to FTY [Dahlhaus et al. 2013; Maillart et al. 2014]. To the best of our knowledge up to now FTY has not been associated with a PML risk compared with others such as fumarates and monoclonal antibodies [van Oosten et al. 2013; Schmedt et al. 2012]. Also no data exist for a post-PML MS therapy with alemtuzumab, a novel monoclonal antibody, which leads to a remodelling of the immunosystem and might cause other severe immunological disease such as Goodpasture’s syndrome. Thus alemtuzumab with its profound effects on the immunological homeostasis was not our first choice. Nevertheless subsequent PML monitoring should be performed, including MRI and lumbar punctures, if any clinical deterioration occurs. In some RRMS patients FTY might not lead to a stable disease course or has to be stopped due to side effects. Thus another treatment option is warranted in order to prevent MS-associated disability progression. Here rituximab might be a valid alternative. Within 9 months of rituximab therapy, our patient was free of clinical and radiological disease activity, JCV was not reactivated and the physical disability improved (Figure 1). Nevertheless, as rituximab is known to seldom cause PML [Schmedt et al. 2012], the indication of rituximab therapy should be carefully evaluated, it should be started with a low dosage (single infusion with 250–500 mg) and patients should be monitored closely (authors recommendations: stable disease: clinical visits every 3–4 months, MRI and lumbar puncture every 6 to 12 months; new neurological deficit: immediate clinical visit, MRI and lumbar puncture). To better understand the fragile immunological situation in post-PML RRMS patients, further studies in larger patient populations are warranted.