Filgrastim for natalizumab-induced PML

F
PML, JCV infection

Natalizumab (aka Tysabri), is one of the hard hitters in the DMT world and owing to its mechanism of blocking the ingress of immune cells into the brain, works quickly – achieving control in as little as 4 weeks. In the AFFIRM study, natalizumab reduced the rate of clinical relapse by 68% in the first year!

But, one of the drawbacks of stopping the immune surveillance of the brain has been the development of PML. This has hit the use of natalizumab by the MS community hard, and as yet there is no cure for the condition.

The product safety information from Biogen reads as follows:

TYSABRI increases your risk of getting a rare brain infection—called progressive multifocal leukoencephalopathy (PML)—that usually leads to death or severe disability.

  • There is no known treatment, prevention, or cure for PML.
  • You should not take certain medicines that weaken your immune system at the same time you are taking TYSABRI. Even if you use TYSABRI alone to treat your MS, you can still get PML.
  • Your risk of getting PML is higher if you:
    • have received TYSABRI for a long time, especially for longer than 2 years
    • have received certain medicines that can weaken your immune system before you start receiving TYSABRI
    • have been infected by the John Cunningham Virus (JCV). Before or while you receive TYSABRI, your doctor may do a blood test to check if you have been infected by JCV. JCV is a common virus that can cause PML in people who have weakened immune systems, such as people taking TYSABRI.
  • Your risk of getting PML is greatest if you have all 3 risk factors listed above. There may be other risk factors that have not yet been identified.
  • Patients who are anti-JCV antibody negative are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. Therefore, patients with a negative test result should be retested periodically.

Strategies are therefore focused more on prevention rather than treatment. These include, STRATIFY (determining JCV titre and evidence of previous exposure), de-escalating to another treatment after two years, and more recently, extended-interval dosing of using natalizumab every 5-8 weeks rather than previous every 4 weeks.

This is not to say that there haven’t been those that have been working on a treatment for PML. Filgrastim is an example of such. Originally developed in oncology for use after chemotherapy in order to stimulate the production of neutrophils and reduce the risk of infections. It belongs to a class of drugs called granulocyte-colony stimulating factor (G-CSF) and is commenced 24h after cytotoxic-chemotherapy and continued up to 14-38 days until the neutrophil count comes into range. Despite it being predominantly granulocyte stimulating, it has also been noted to promote the production of lymphocytes and antigen-presenting cells, while also increasing the adhesion of T lymphocytes to the blood vessel wall via other extracellular matrix components independent of VLA-4, that is blocked by natalizumab.

Here, Stefoski et al (see abstract below), report on the outcomes of 17 natalizumab-PML cases using filgrastim.

Firstly, natalizumab was discontinued in all 17 cases and 8 underwent PLEX (plasma exchange for drug elimination). All were treated using filgrastim 5mcg/kg subcutaneously until approximate doubling of the baseline absolute lymphocyte counts. The mean duration of treatment was just under 10 days.

There was no worsening of the MS with filgrastim. The only side effect was bone pain, but this didn’t prevent continuation of the treatment. PML-IRIS (immune reconstitution syndrome) invariably occurred in 15 of the cases (mean time to PML-IRIS was 8 weeks). Those who developed IRIS were given IV methylprednisolone. Paradoxically, the conditions of two cases worsened after steroid use with enlargement of the PML lesions, suggesting that the immunosuppression enhanced PML expansion (see Figure 1 below).

Figure 1: 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).

Over the long-term there were no PML-related fatalities, but sadly one person committed suicide a few years later. 4 recovered to baseline, and three near baseline, while 7 had poor outcomes requiring full care.

Inadequate recovery was related to large PML lesions in the context of delayed diagnosis, ineffective IRIS and premature use of steroids for underdeveloped IRIS. No significant changes in the EDSS (disability) scores were noted in the PML-IRIS cases after two years. However, 8 required further MS treatments on average 26 months after natalizumab discontinuation. Not surprisingly, the therapies utilized were first-line drugs in such instances.

In my MS work I have been fortunate enough not to have a case of single PML to manage, but I have looked after post-bone marrow transplant PML cases that are more difficult to treat simply because the bone marrow is depleted. I have utilized G-CSF in these instances and found it to be ineffective, but the difference here is that in natalizumab-PML you’re not dealing with a failed marrow as an additional complication. Therefore, definitely a treatment strategy to take forward in natalizumab-PML cases.

ABSTRACT
Ann Clin Transl Neurol. 2019 Apr 8;6(5):923-931. doi: 10.1002/acn3.776. eCollection 2019 May.

Treatment of natalizumab-associated PML with filgrastim.
Stefoski D, Balabanov R, Waheed R, Ko M, Koralnik IJ, Sierra Morales F.

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.

About the author

Neuro Doc Gnanapavan

7 comments

Leave a Reply to Neuro Doc Gnanapavan Cancel reply

    • There have been small reports on this, but nothing that’s stuck. I’ve used risperidone on a case and found no effect.

  • Filgrastim is also use to stimulate the bonne marow to produce cd34+ stem cells and release them in circulation to BE colected before bonne marrow transplat

    I had filgrastim

    • Not a common side effect, although there was a case of increased suicidal ideation. Depression in MS on the other hand does occur and is dependent on many factors -the biology of the disease and brain areas affected, fatigue, congnitive problems and disability level.

  • My question is regarding the wording about risk on the data sheet.

    Biogen appear to have managed to avoid putting any context around the risk warnings.

    Wouldn’t it help patients, potential patients and possibly some prescribers if there were some clearer and more easily understood statements?

    For example: the risk of a healthy person (no MS, no JCV) developing PML is X. The risk when having MS and being treated with natalizumab is Y. Therefore the risk is X-fold over normal?

    It is more easily understood. Presently, it seems as if they are trying to mitigate a risk that may sound worse if put into a context that was more easily understood.

    Thank you.

    • So they do update regularly on PML cases and future risk of PML based on titres. Unfortunately, this isn’t included in the generic info and for obvious reasons is kept vague.

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