Advances in the management of PML: Focus on natalizumab
ABSTRACTProgressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the central nervous system, occurs mainly in the setting of broad-based and selective immunosuppression. The immunomodulatory agent most often implicated in the development of PML is the monoclonal antibody natalizumab. Management of PML begins with risk stratification. Factors that predict the risk of PML are JC virus (JCV) antibody status, history of chemotherapy use, and cumulative exposure to natalizumab. The risk of natalizumab-related PML increases up to a duration of 36 months of therapy, after which the risk appears to level off. If suspicious for PML, the use of a sensitive JCV polymerase chain reaction assay permits early diagnosis. Immune reconstitution represents the mainstay of treatment for PML. With rapid reversal of immunosuppression followed by immunologic recovery, almost all patients suffer clinical deterioration termed immune reconstitution inflammatory syndrome (IRIS). High-dose corticosteroids are often recommended if a clinical and imaging syndrome resembling IRIS develops after immune restoration.
Natalizumab holidays and PML risk
The possibility of reducing the risk of PML in natalizumab-treated patients through natalizumab holidays is attractive. When exploring this option, one must consider whether the risk of recurrent disease activity with treatment interruption outweighs the potentially decreased risk of PML.8 A randomized controlled multicenter clinical trial of natalizumab interruption is ongoing, with the recruitment phase complete after enrollment of 175 patients. Patients taking natalizumab at study entry have been randomized to one of three arms: continuation of monthly natalizumab for 6 months, placebo for 6 months, or an alternate treatment (interferon beta-1a, glatiramer acetate, or monthly intravenous steroids) for 6 months administered open-label by clinician and patient choice.
The primary outcome measures are markers of immune function and overall disease activity during treatment interruption and after resumption. Patients are monitored monthly using MRI to measure disease activity. Those who experience relapse will have the option of returning to natalizumab therapy or switching to an alternate treatment. The results of this prospective, randomized, controlled trial will provide a greater understanding of the safety issues surrounding natalizumab holidays.
Management of natalizumab-related PML
Management of patients taking natalizumab starts with risk stratification in an attempt to prevent the development of PML. If suspicion for PML is raised based on symptoms, early diagnosis can be accomplished through the use of a sensitive JCV PCR assay, with a repeat PCR if negative. Natalizumab treatment should be withheld during the workup for PML.
When immunosuppression is rapidly reversed in cases of natalizumab-associated PML, an overly exuberant immune response targeting JCV in the CNS is observed 2 to 6 weeks later. The response, termed immune reconstitution inflammatory syndrome (IRIS), is not always easy to differentiate from progression of PML. Nonetheless, most clinicians recommend high-dose corticosteroids if a clinical and imaging syndrome resembling IRIS develops several weeks after immune restoration.10 The objective is to achieve the immune reconstitution needed to control JCV infection while limiting the collateral damage of inflammation on the remaining brain tissue.
SUMMARY
Risk factors for natalizumab-associated PML include duration of treatment with natalizumab, previous chemotherapy, and JCV antibody serology. Early diagnosis requires the use of an ultrasensitive JCV PCR assay. Treatment is focused on early diagnosis, immediate cessation of pharmacologic causes of immunosuppression, and active efforts to accelerate immune restoration.
DISCUSSION
Dr. Calabrese: What are your thoughts about plasmapheresis for rituximab-related cases of PML?
Dr. Fox: It’s probably not going to be as helpful as with natalizumab. Rituximab has pharmacokinetics that are similar to those of other monoclonal antibodies, with a half-life in the range of 14 to 20 days. So it’s pretty much absent from the body within 1 to 2 months of infusion. The enduring benefit from rituximab comes not from the persistent presence of the monoclonal antibody, but the persistent absence of CD19 B cells. Plasmapheresis is unlikely to be effective because it won’t accelerate return of CD19 B cells to the peripheral circulation. In rituximab-related PML, stimulating the bone marrow to produce more B cells in order to restore the immune system is more likely to be effective. In contrast, I did recommend plasma pheresis in a case of efalizumab-related PML. Because efalizumab is a binding antibody to the CD11a receptor, we wanted to accelerate its removal.
Dr. Molloy: In an MS patient who responds well to natalizumab, do you ever explore a strategy of dose reduction or extending the dosing interval of natalizumab?
Dr. Fox: Let me put that into a clinical context. A 35-year old man has had relapsing-remitting MS for 3 years. Two years ago, after disease activity occurred while he was using an injectable therapy, he started natalizumab and has been clinically and radiologically stable on natalizumab. Then, he gets the JCV assay, it’s positive, and he asks if it’s time to get off natalizumab “because of the risk of that brain virus.”
What do I tell him? Should I change the dosing interval? At this point, we are not doing either. One reason is the unpredictable pharmacokinetics of the drug. The dose and dosing regimen were chosen to have 85% or greater receptor saturation in 95% or more of patients over the course of the recommended 4-week dosing interval. If you increase the interval to 6 weeks or 8 weeks, you can’t predict in individual patients whether or not meaningful desaturation occurs and thus allows some immune cells to enter the brain to protect against PML (but not too many, or MS disease activity will return).
Dr. Simpson: Do you have an algorithm for working up patients?
Dr. Fox: It depends on the level of suspicion given the patient’s symptoms. It’s difficult to find a single MS patient who does not have some fluctuation of symptoms over time and some worsening of symptoms such as stiffness, fatigue, and cognitive difficulties. They all have changes in mood, so if one took any symptom change—any change in their report of mood and cognition— as the cutoff for a workup, we wouldn’t be giving natalizumab at all. But if a patient or family says, “I am worried,” then we need to work it up. Also, if there are clearcut new or worsening neurologic symptoms, we pursue a workup. Often, the change in symptoms is revealed when the patient comes in for his or her monthly infusion and the nurse asks the four questions from the preinfusion checklist (as part of the mandatory Tysabri Outreach: Unified Commitment to Health [TOUCH] prescribing program for natalizumab).11
If there are new symptoms, we hold infusions and do a two-stage evaluation. The first stage is a brain MRI to evaluate for change from baseline (the US Food and Drug Administration requires a brain MRI at baseline before starting natalizumab therapy). Most patients undergo a brain MRI every 6 to 12 months while on natalizumab therapy, with instructions to the neuroradiologist to evaluate carefully for new lesions. In our institution, the PML MRI evaluation is a fine-toothcomb assessment of lesions from the most recent MRI compared with the current MRI. Depending on the results of the current MRI and on our level of suspicion, we may proceed to a spinal tap, even if the MRI findings are stable. We have done 8 to 10 spinal taps in patients taking natalizumab when we were suspicious enough to evaluate for PML. Occasional patients continue to have active disease, relapses, and new lesions even without developing antibodies while taking natalizumab.
Dr. Rudick: We need a quick, quantitative analysis method to compare one MRI with another. It is easy to say, “Consider PML if there are new lesions.” It’s not so easy to know if the lesions are new. We are participating in a National Institutes of Health study regarding identification of biomarkers of interferon’s effects, and the study requires obtaining MRI scans at baseline and 6 months. We have state-of-the-art subtraction MRI to quantify new lesions on the followup MRI. However, there is significant disagreement on the number of new lesions determined by clinical raters, and disagreement between the clinical raters and the numbers generated by the computer program.
Dr. Major: Is the incidence of natalizumab-related PML based on the number of months or on the number of infusions?
Dr. Fox: It is based on the number of infusions. You bring up a good point because these patients may interrupt treatment when they go on vacation, for example, or have a lapse in insurance coverage. Most patients follow the every-4-weeks protocol and receive 13 infusions in a year. Perhaps 10% to 15% do not follow it precisely.
Dr. Molloy: Is everyone who takes natalizumab being followed for PML even if they discontinue natalizumab? Have any differences emerged in the factors that predispose to PML among those who continue therapy compared with those who discontinue? I ask because I’m wondering why the incidence appears to stabilize, or even go down, after 36 infusions.
Dr. Fox: PML has not been reported beyond several months after stopping natalizumab; concern about PML can decrease fairly quickly after stopping the drug. Many of us expected the risk of PML to continue rising with cumulative treatment, so were pleasantly surprised to see a plateau in the risk of PML after about 36 months. We don’t understand what leads to this plateau.
