Determinants of outcomes for natalizumab-associated PML

Natalizumab is an effective treatment for patients with active MS, but is associated with an increased risk of progressive multifocal leukoencephalopathy (PML) [1,2]. “We are concerned as clinicians about PML risk and how to manage it”, Prof. Chris McGuigan (University College Dublin, Ireland) stated.

Following a diagnosis of PML, various interventions, such as rapid natalizumab clearance by plasma exchange (PLEX), have been adopted in clinical practice [3,4]. PLEX is associated with increased clearance of natalizumab [5]. “However, the impact of PLEX on clinical outcomes was based on pharmacokinetic data and not on clinical evidence or real-world experience”, Prof. McGuigan added.

In the current analysis, the impact of PLEX and patient characteristics on the outcome of natalizumab-associated PML was investigated. Of the 787 confirmed natalizumab PML cases, 725 had a known PLEX status (PLEX-positive in 85.0%). A higher percentage of PLEX positive patients than PLEX-negative patients were symptomatic at diagnosis (87.8% vs 78.9%) and had a high JC virus viral copy number (33.3% vs 17.4%). The cumulative probability of survival 2 years post-PML diagnosis for PLEX-positive vs PLEX-negative patients was 88.2% vs 89.3% (P=0.857). Death within 2 years was less likely for patients who were asymptomatic (HR 0.38; P=0.012); and more likely for patients aged >50 years (HR 1.56; P=0.014), with widespread MRI lesions (HR 1.61; P=0.007), or higher JC virus load (HR 2.86; P< 0.001) [6].

It should be noted that pharmacovigilance data has some limitations. “This dataset was entirely dependent on physicians providing the data”, Prof. McGuigan mentioned. “We had missing data in terms of EDSS scores at baseline and after the confirmed diagnosis of PML.” Furthermore, there is possible indication bias secondary to lack of baseline EDSS data, whereby patients with more severe functional impairment pre-PML might be more likely to receive PLEX. For PLEX-positive (n=177) and PLEX-negative (n=31) patients who had an EDSS score reported in the 6 months before PML diagnosis, the median EDSS score was 3.5 in both groups. “We also included all-cause mortality in the study”, Prof. McGuigan added. “So, we can not specify whether the cause of death was the PML itself or another cause, such as immune reconstitution inflammatory syndrome (IRIS) or recurrence of the MS itself.” Due to limited data, it is not known whether the severe disability impairment in survivors was transient or long lasting. Finally, the potential impact of DMT use in the post-PML phase in patients with functional data is not accounted for [6].

In conclusion, even though the majority of patients with natalizumab-associated PML received PLEX, this analysis showed no beneficial effects of PLEX on PML outcomes. PLEX treatment did not have a significant effect on 2-year survival rates. The risk of advanced disability or death appeared to be worse in patients who received PLEX, but missing data and selection biases may have contributed to these findings. Consistent with prior analyses [7,8], asymptomatic detection, more localised MRI lesions, and fewer copies of JC virus were associated with better PML outcomes. These data support early, vigilant monitoring for PML as an important component of improving post-PML outcomes.

1. Bloomgren G, et al. N Engl J Med. 2012;366:1870-80.
2. Ho PR, et al. Lancet Neurol. 2017;16:925-933.
3. Kappos L, et al. Lancet Neurol. 2011;10:745-58.
4. Landi D, et al. 2017;88:1144-1152.
5. Khatri BO, et al. 2009;72:402-9.
6. Kappos L, et al. ECTRIMS 2019, abstract 63.
7. Dong-Si T, et al. Ann Clin Transl Neurol. 2014;1:755-64.
8. Dong-Si T, et al. J Neurovirol. 2015;21:637-44.

Posted on 8 November, 201922 March, 2021