Treatment of natalizumab-associated PML with filgrastim

Abstract

Objective: There is no consensus on the treatment of progressive multifocal leukoencephalopathy (PML) occurring in multiple sclerosis (MS) patients treated with natalizumab (Nz). We report novel immune activating treatment with filgrastim of Nz-associated PML in MS patients treated at Rush University Medical Center.

Methods: We retrospectively analyzed 17 Nz-PML patients treated at this single tertiary referral center between 2010 and 2017. We reviewed the clinical symptoms, diagnostic methods, survival, outcome and MS modifying therapy (MSMT) after Nz-PML.

Results: PML occurred after an average of 49 Nz infusions. To facilitate JCV elimination by accelerating immune reconstitution inflammatory syndrome (IRIS), all patients received subcutaneous filgrastim upon PML diagnosis and discontinuation of Nz; eight received plasma exchange (PLEX). Earlier than previously published, PML-IRIS occurred in 15 of 17 (88.2%) patients within a mean of 57.4 days (SD 21.20) after the last Nz infusion. Seven patients recovered to or near baseline. There were no PML/IRIS-related fatalities but one patient committed suicide 2.5 years later. PLEX had no impact on PML outcome. Of 17 patients, 3 (18%) had MS relapses within 1 year after PML, and 5 (29%) beyond 1 year of PML onset, which is lower than expected in highly active MS patients. Eight patients started MSMTs after Nz-PML on an average of 26 months after Nz withdrawal.

Interpretation: Our findings indicate that immunoactivation with filgrastim during PML and careful management of subsequent IRIS is likely beneficial in patients with Nz-PML, without worsening MS. The clinical course of MS may be ameliorated by PML.

Figure 1

Evolution of PML lesions on MRI after filgrastim treatment in two patients. MRI findings of patient #1 (A–C) and #2 (D–F) demonstrate a PML lesion at symptom onset, during IRIS after filgrastim treatment and 2–3 years later: (A) Axial fluid‐attenuated inversion recovery (FLAIR) image shows a PML lesion in the right occipital lobe (arrow). (B) Axial postcontrast T1‐weighted image demonstrates peripheral enhancement in the lesion (arrow) 14 days after peak ALC on filgrastim treatment and 49 days after Nz withdrawal. (C) Axial FLAIR image shows atrophy at the site of the PML lesion 3 years after symptoms onset. There were no new MS lesions off MSMT (not shown here). (D) Axial FLAIR image shows a PML lesion in the left temporal lobe (arrow). (E) Axial postcontrast T1‐weighted image demonstrates peripheral enhancement in the lesion (arrow) within 1 week of peak ALC on filgrastim treatment and 37 days after Nz withdrawal. (F) Axial FLAIR image shows atrophy at the site of the PML lesion 2 years after onset. There were no new MS lesions off MSMT (not shown here).

Figure 2

Progression of PML lesions after premature corticosteroid treatment. Axial FLAIR (A, C, E, G, I) and postcontrast T1‐weighted images (B, D, F, H, J) demonstrate PML lesion in the right frontoparietal area (arrows) of one representative MS patient. A, B) The PML lesion is devoid of contrast enhancement at the time of PML diagnosis. (C, D) Contrast enhancement on MRI and clinical worsening indicative of IRIS occurred 9 days after peak ALC on filgrastim treatment and 63 days after Nz withdrawal. The patient received intravenous methylprednisolone followed by oral prednisone taper. Three to 4 weeks later, while on prednisone taper, the patient began to worsen clinically. Repeat brain MRI exams revealed increased size PML lesions without contrast enhancement (E, F, G, and H). Prednisone was discontinued and filgrastim reinstituted. There was evidence of a more robust IRIS by contrast enhancement on MRI 1 week after the second filgrastim treatment (I, J).