Mark Gudesblatt, MD

Natalizumab, the first monoclonal antibodyapproved for the treatment of relapsingforms of MS, was voluntarily withdrawn fromthe US and European markets in February 2005after three patients undergoing therapy withthe drug in combination with other immunoregulatoryand immunosuppressive agentswere diagnosed with PML. 5,8 However, it wasreintroduced again as a monotherapy for MSin June 2006, and since its reintroduction 130additional cases developed PML among 83,300exposed patients through June 1, 2011.Of the three natalizumab-associated PMLcases reported in 2005, two were fatal. In one,the diagnosis of a 60-year-old man who hadreceived natalizumab for Crohn’s disease waschanged from fatal astrocytoma to PML afteranalysis of frozen serum samples revealedthat JC virus DNA was detectable in the serumthree months after the start of monotherapywith the monoclonal antibody and two monthsbefore the appearance of symptomatic PML. 42In a second case, a 46-year-old woman withrelapsing-remitting MS participating in a clinicaltrial of combined therapy with natalizumaband interferon beta-1a, in which she received37 doses of the monoclonal antibody (300 mg)every four weeks, died from PML, which wasdiagnosed by PCR assay (JCV DNA in the CSF)and confirmed at autopsy. 43 The third case,which also involved combination therapywith interferon beta-1a in a patient with MS,highlights the importance of early detection,differential diagnosis, and swift treatment response.44 Although the first PML lesion seen onMRI was indistinguishable from an MS lesion,PML was diagnosed and progressed rapidly,even though natalizumab was discontinuedand treatment with corticosteroids, cidofovir,and IV immunoglobulin was initiated. The patientbecame quadriparetic, globally aphasic,and minimally responsive; but within threemonths following natalizumab discontinuation,changes consistent with PML-IRIS weredetected and systemic cytarabine was initiated,leading to improvement in the patient’scondition in two months.The risk of PML development increaseswith duration of exposure to natalizumab.Once natalizumab was approved again for usein June 2006, no new cases of PML were reportedduring the first two years of the drug’sremarketing. The first reported case was diagnosedin July 2008 following the appearance ofsymptoms. In subsequent months, one to twocases per month were reported, for a total of31 by the end of January 2010. Of the 28 PMLcases confirmed by the end of November 2009,eight were fatal and, of the 20 who survived,many had serious morbidity and substantialand permanent disability. The median treatmentduration to onset of symptoms for all 28cases was 25 months. None of the 28 patientswere on concurrent therapy with interferonbeta and, while three patients had never receivedany disease-modifying therapy otherthan natalizumab, previous treatment withother immunosuppressants (including interferon)may have increased the risk of PML, accordingto the investigators.Treatment response in this series illustratesthe complexities of the improved prognosisin patients with natalizumab-associatedPML. In 27 cases, either plasma exchange orimmunoabsorption was used to achieve rapidclearance of natalizumab and restorationof CNS immune surveillance. In almost all ofthese cases, the subacute progression and exacerbationof earlier symptoms of PML thatare typical of IRIS occurred within days to afew weeks of plasma exchange. High-dose corticosteroidtherapy has been used to treat IRISwith some success, and in many cases in thisseries repeated courses of IV steroid were given.Death was more common among patientswho were either untreated or inadequatelytreated with corticosteroids. Prognosis wasalso related to the location of lesions and isprobably a more important prognostic factorthan is the size of the lesions. Cases in whichlesions affected such critical regions as thebrainstem had the most serious consequencesand, while higher JCV titers in the CSF are generallyassociated with larger lesions size, patientswho presented with low viral loads wereamong the fatal cases in the series. In one casein which JCV was not detected in CSF and neitherplasma exchange nor immunoabsorptionClinical Reviews of JCV and PML • July 2011 S25