ORIGINAL ARTICLE
Progressive Multifocal Leukoencephalopathy after Natalizumab Discontinuation Andrew J. Fine, PharmD, BCPS,1 Alfred Sorbello, DO, MPH,1 Cindy Kortepeter, PharmD,1 and Linda Scarazzini, MD, RPh2 Objective: To identify cases of laboratory- or biopsy-confirmed progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) who previously discontinued natalizumab (NTZ) for reasons unrelated to suspected or proven PML and assess PML risk factors in these cases. Methods: We searched the US Food and Drug Administration Adverse Event Reporting System and MEDLINE for reports submitted from 2006 to 2012 of laboratory-confirmed PML with symptom onset 30 days following NTZ withdrawal. We only analyzed cases where NTZ discontinuation was unrelated to suspected PML. Results: Seventeen patients discontinued NTZ for reasons unrelated to PML but were subsequently diagnosed with the disease. The median NTZ duration was 47 monthly doses (range 5 9–59 doses). All patients presented with compatible clinical symptoms within 6 months following withdrawal, and PML was confirmed by brain biopsy or by identifying JC virus in the cerebrospinal fluid by polymerase chain reaction. Immune reconstitution inflammatory syndrome (IRIS) was reported in 11 patients. Eleven patients (65%) received new MS treatments between NTZ discontinuation and PML confirmation. No deaths were reported. At NTZ withdrawal, 16 patients (94%) had 1 PML risk factor, including NTZ duration 2 years (n 5 13), prior immunosuppressive agents (n 5 8), and reported anti–JC virus seropositivity (n 5 13). Interpretation: NTZ-treated patients presenting clinically with PML within 6 months after NTZ withdrawal frequently have pre-existing PML risk factors. Clinicians need heightened awareness for new onset PML, IRIS, and MS relapse in evaluating neurological decline following NTZ discontinuation. ANN NEUROL 2014;75:108–115
N
atalizumab (NTZ), an a4-integrin antagonist used to treat multiple sclerosis (MS) and Crohn’s disease, hinders leukocyte migration (including T lymphocytes) across the blood–brain barrier. The resulting depletion of CD4 T lymphocytes in the central nervous system (CNS) leads to weakened immune surveillance for opportunistic infections of the brain, such as progressive multifocal leukoencephalopathy (PML) due to the JC human polyomavirus. Through September 2012, 285 confirmed cases of PML have been identified in NTZtreated patients worldwide.1
Observational data indicate that NTZ-induced CD4 T-cell depletion may persist in the CNS up to 6 months beyond product discontinuation, during which time patients remain at risk for PML.2 Treatment duration beyond 2 years, prior immunosuppressive therapy, and anti–JC virus antibody seropositivity have been identified as factors associated with an enhanced risk for PML in NTZ-treated MS patients.3 The purpose of this study was to identify confirmed PML cases among patients who previously discontinued NTZ for unrelated reasons and to assess
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24051 Received Feb 7, 2013, and in revised form Oct 21, 2013. Accepted for publication Nov 8, 2013. Address correspondence to Dr Fine, US Food and Drug Administration, Center for Drug Evaluation and Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993. E-mail:
[email protected] From the 1Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 2 Current address for Dr Scarazzini: Global Pharmacovigilance, AbbVie, Inc, North Chicago, IL, 60064. The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the US Food and Drug Administration or the US government.
C 2013 American Neurological Association 108 V
Fine et al: PML after NTZ Discontinuation
whether existing risk factors at withdrawal may be associated with an increased risk for PML in the posttreatment period.
Patients and Methods We searched the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for reports of laboratory- or biopsy-confirmed PML in patients with clinical onset 30 days following the last NTZ infusion. We limited our search to the time period between June 5, 2006 (date of FDA reapproval of NTZ) and September 30, 2012. We analyzed only the cases in which the documented reason for NTZ discontinuation was unrelated to clinically suspected or laboratoryproven PML. We also searched MEDLINE for case reports published in the English language scientific literature during the same time period. The adverse event reports retrieved from FAERS for the patients included in our case series were reviewed for relevant demographic, clinical, laboratory, and radiologic details. We relied on case descriptions as reported, including dates of symptom onset, PML confirmation, immune reconstitution inflammatory syndrome (IRIS), plasma exchange (PLEX), and followup after PML confirmation. If a date was incompletely reported, but the month and year were described, we used the first day of the month for our analysis. Missing or unknown information was categorized as “not reported.” For cases retrieved from FAERS that were also reported in the medical literature, we evaluated information from both sources. In instances where data from the two sources conflicted, we relied on data from the published reports; however, an exception was related to NTZ dosing, in which US FAERS reports may provide the exact number of infusions administered based on data from the TOUCH (Tysabri Outreach: Unified Commitment to Health) program.3 FAERS is a computerized repository of spontaneous adverse event reports submitted by product manufacturers, consumers, and health care professionals from US and non-US sites. FAERS supports the FDA’s postmarketing safety surveillance program for drug and therapeutic biologic products. Adverse event information in FAERS is classified using the Medical Dictionary for Regulatory Activities.4 In this case series, we provide only a descriptive analysis using line listing tables and measures of central tendency owing to missing data and the lack of a concurrent comparator treatment group.
Results We retrieved 41 reports from FAERS of laboratory- or biopsy-confirmed PML with clinical onset 30 days following the date of the last NTZ infusion. We analyzed only the 17 cases (41%) for which NTZ was discontinued for reasons unrelated to suspect PML. We excluded cases where NTZ was discontinued either due to suspect January 2014
PML (n 5 16) or for undocumented reasons (n 5 8; Fig. 1). Patient Characteristics Between 2009 and 2012, 17 cases of PML were identified in patients who previously stopped NTZ therapy (Table 1). Two PML cases (12%) were reported from within the United States, and 6 (38%) had been published previously in the literature.5–10 The patients received a median of 47 monthly doses of NTZ (range 5 9–59 doses) prior to treatment discontinuation, and all patients presented with compatible clinical symptoms of PML within 6 months following NTZ withdrawal. PML was confirmed in 16 (94%) patients by detection of JC virus in the cerebrospinal fluid by polymerase chain reaction; in the remaining case, PML was confirmed by brain biopsy. Reasons for NTZ Discontinuation Ten (59%) patients discontinued NTZ after testing seropositive for anti–JC virus antibodies, 3 patients discontinued due to lack of efficacy, and 1 patient each discontinued due to biologic product holiday, excessive alcohol intake, breast cancer, and lack of efficacy/PML risk. Risk Factors for PML among NTZ Discontinued Patients Notwithstanding the reported reasons for NTZ discontinuation, many of the 17 patients had pre-existing risk factors that may have enhanced their risk for PML in the post-treatment period. Sixteen (94%) patients had at least 1 risk factor, and 13 (76%) had multiple risk factors, including 5 patients with all 3 risk factors. Regarding individual risk factors, 13 patients (76%) received NTZ for >2 years, 8 (47%) patients received prior immunosuppressive (IS) therapy, and 13 reported positive anti–JC virus serology. Anti–JC virus serology was not reported for 4 cases. Clinical Events and Outcome following NTZ Withdrawal Clinical symptoms (see Table 1) consistent with PML developed approximately 2 months following NTZ withdrawal (median 5 66 days, range 5 35–109 days). Confirmation of the diagnosis followed symptom onset by a median of 22 days (range 5 0–93 days; Table 2). Seven (41%) patients received new disease-modifying MS therapies in the time interval between NTZ discontinuation and PML confirmation, including fingolimod (n 5 5), glatiramer (n 5 1), and interferon beta-1a (n 5 1). Nine patients (53%) received high-dose intravenous methylprednisolone during this same time interval. 109
110
43
59
44/F
8b/10/Australia 57/M
52/M
51/M
50/F
28/F
7b/9/Europe
9/—/US
10/—/Europe
11/—/Europe
12/—/Europe
49
47
32
49
48/F
47
44
9
17
6 /8/Europe
b
5 /7/Europe
24/F
30/F
4/—/Europe
b
45/M
None
None
MTX
None
None
None
AZA
MTX
None
MTX
None
1
1
1
1
1
1
1
1
NR
NR
NR
92
87
76
84
140
62
112
115
197
60
53
Cognitive disorder (fatigue), muscular fatigue with loss of ambulation, cerebellar syndrome, dysarthria
Malaise
Right leg palsy, cognitive impairment, left-sided hemiparesis
RUE weakness, fatigue
Visual disturbances, ataxia, difficulty walking, anxiety
Dysarthria, left-sided visual disturbance, left-sided paresis VI and VII
Aphasia, hemiparesis, mutism, cortical blindness, seizure
Seizure, personality change
Seizure, deteriorating walking
Cognitive impairment, speech difficulties, anomia, decreased strength
Ataxia, bilateral pyramidal syndrome, planning difficulties, aphasia lethargy, hemiplegia
Mild deterioration in cerebellar ataxia
3/—/Europe
43
167
23/M
NR
2b/6/US
Yes, not otherwise specified
49/F
1b/5/Europe
13
Previous Serology for Estimated Time Reported Clinical Age, No. of NTZ Symptoms of PML yr/Sex Monthly Doses Immunosuppressive JC Virus prior from NTZ prior to PML Agents to PML Onset Discontinuation Symptom Onset to Confirmation of PML, Days
Case No./ Origin/ Reference No.
Positive [local]
552 [NR]
396 [local]
Positive [NR]
Positive [NR]
31 [NR]
3,355 [local]
Positive [NR]
37 [NIH]
1,261 [NR]
9,900 [NR]
Negativec [NR]
Quantitative PCR for JC Virus in CSF, Copies/ml,a [Laboratory]
TABLE 1. Select Patient Characteristics and Clinical Features of PML following Discontinuation of NTZ in Multiple Sclerosis Patients, 2009–2012
ANNALS
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January 2014
39/F
NR/F
53/F
15/—/Europe
16/—/Europe
17/—/Europe
50
23
49
53
MTX, AZA
CP
None
None
1
1
1
1
101
136
60
121
Cognitive (subcortical frontal syndrome, slow ideation) and cerebellar (dysarthria, ataxia of 4 limbs) worsening
Ataxia, personality change
Impaired memory, bradypsychism, disturbed behavior, indifference, apraxia, bladder dysfunction
Left facial paresis, speech difficulties
2,499 [Focus Diagnostics]
10 [NIH]
50 [local]
14 [NIH]
18 [NR]
Quantitative PCR for JC Virus in CSF, Copies/ml,a [Laboratory]
b
Qualitative result provided if quantification not reported. Includes case information from published case reports and US Food and Drug Administration Adverse Event Reporting System cases. c PML confirmed based on cerebral tissue biopsy: positive by immunochemistry and hematoxylin and eosin staining. AZA 5 azathioprine; CP 5 cyclophosphamide; CSF 5 cerebrospinal fluid; F 5 female; M 5 male; MTX 5 mitoxantrone; NIH 5 National Institutes of Health; NR 5 not reported; NTZ 5 natalizumab; PCR 5 polymerase chain reaction; PML 5 progressive multifocal leukoencephalopathy; RUE 5 right upper extremity.
a
35/F
Estimated Time Reported Clinical Age, No. of NTZ Previous Serology for Symptoms of PML yr/Sex Monthly Doses Immunosuppressive JC Virus prior from NTZ prior to PML Agents to PML Onset Discontinuation to Confirmation Symptom Onset of PML, Days 42/F 50 AZA 1 85 Seizure, asthenia, motor aphasia
14/—/Europe
13/—/Europe
Case No./ Origin/ Reference No.
TABLE 1: Continued
Fine et al: PML after NTZ Discontinuation
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ANNALS
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TABLE 2. Clinical Syndromes, Adjunctive Treatments, and Disease-Modifying MS Therapies following NTZ Discontinuation
MS Therapies Administered between NTZ Discontinuation and Confirmation of PML Estimated Time from NTZ Discontinuation to PML Onset, Daysa 81
Estimated Time IRIS from PML Onset to following Confirmation, NTZ Daysa Discontinuation 86 Yesb
2
50
3
Yesb
NR
IFN b-1a
None
3
35
25
NR
Yes
None
None
4
104
93
NR
None
None
None
NR
None
None
Case No. 1
b
PLEX to Accelerate NTZ Disease-Modifying Intravenous Clearance Therapies Steroids None None None
5
109
6
Yes
6
61
51
Yes
Yes
None
Yes
7
53
9
Yes
None
Glatiramer
None
8
66
74
NR
NR
Fingolimod
Yes
9
67
17
Yes
NR
None
Yes
10
56
20
Yes
Yes
None
Yes
NR
None
None
b
11
87
0
Yes
12
89
3
Yes
None
Fingolimod
Yes
13
63
22
Yes
NR
Fingolimod
Yes
14
90
31
NR
Yes
Fingolimod
Yes
15
56
4
NR
Yes
None
None
16
104
32
Yes
NR
Fingolimod
Yes
17
61
40
None
Yes
None
Yes
a
NTZ stop is date of last infusion; PML onset is date of first clinical symptom or radiologic suspicion of PML; confirmation is date cerebrospinal fluid sample was drawn. b Suspected simultaneous PML-IRIS: magnetic resonance imaging findings or pathologic evidence consistent with PML and IRIS at presentation. IFN 5 interferon; IRIS 5 immune reconstitution inflammatory syndrome; MS 5 multiple sclerosis; NR 5 not reported; NTZ 5 natalizumab; PLEX 5 plasma exchange; PML 5 progressive multifocal leukoencephalopathy.
Six patients underwent PLEX to accelerate NTZ clearance from the circulation following suspected or confirmed PML. Four patients did not undergo PLEX, and relevant information was missing for the remaining 7 patients. Data relevant to IRIS were incompletely reported. Based on our review, 11 patients were reported to have developed IRIS post-NTZ discontinuation, 1 patient did not develop IRIS, and missing information precluded an assessment for the remaining 5 cases. Simultaneous PML and IRIS upon initial presentation were reported for 4 of the 11 IRIS patients. These 112
cases reported magnetic resonance imaging (MRI) findings or pathologic evidence consistent with PML and IRIS upon presentation; 3 of these were also published in the medical literature.5–7 Functional status following PML confirmation was reported for 11 (65%) patients, ranging from mild to severe disability. Baseline functional status (prior to PML onset) was infrequently described, which further precluded assessment of each patient’s clinical course. No deaths were reported, but the duration of follow-up after PML confirmation was quite short and varied from days to 8 months. Volume 75, No. 1
Fine et al: PML after NTZ Discontinuation
Discussion 1
Of the 285 PML cases through September 2012, we retrieved postmarketing adverse event reports for 17 MS patients with confirmed PML in whom clinical symptoms developed 30 days following the last NTZ infusion, despite discontinuation of the biologic product for reasons unrelated to suspect PML. Overall, in reviewing the FAERS reports, ascertainment of the time sequence of clinical events between NTZ discontinuation and PML confirmation was a substantial challenge. In patients experiencing immune recovery following NTZ withdrawal, we frequently ascertained the occurrence of IRIS based solely on reporter-designated diagnoses. Many reports lacked descriptions of compatible clinical and radiologic findings to permit independent assessment of IRIS. Additionally, as imaging findings were rarely reported, we could not correlate clinical worsening attributed to IRIS by reporters with objective MRI evidence of new paradoxical inflammation involving PML lesions in affected patients. By enhancing NTZ clearance from the serum, desaturation of a4-integrin receptors, and restoration of leukocyte migration, PLEX boosts immune recovery and surveillance in the brain; in general, nearly all NTZtreated patients with PML undergo PLEX to augment immune reconstitution.11,12 In our case series, although 6 patients received PLEX following PML suspicion, its potential benefit in enhancing immune reconstitution is unclear. Considering that the approximate time interval from NTZ withdrawal to PML suspicion/confirmation did not differ among patients who did and did not receive PLEX, the delay of >1 month between NTZ withdrawal and PML suspicion/confirmation may have been sufficient to allow substantial physiologic elimination of NTZ to have occurred independent of the clearance of the biologic product by PLEX. Potential flares of MS activity, which can occur within 3 months13 after NTZ discontinuation, prompted initiation of high-dose steroids and other new MS treatments in most patients. However, of the 11 (65%) cases in which new MS therapies were initiated, it was impossible to assess whether steroids or disease-modifying therapies further diminished CNS immune surveillance or otherwise adversely affected overall PML risk, although such an effect has been postulated.14,15 Several patients in our case series received high-dose intravenous methylprednisolone for suspected MS rebound prior to PML confirmation only to be diagnosed with PML at a later time, underpinned by clinical failure or decline on steroid therapy. Thus, this scenario raises concern that PML was initially misdiagnosed as MS rebound, leading to delayed PML confirmation. It is unknown if this conJanuary 2014
tributed to more unfavorable outcomes, as all patients ultimately survived. A larger study is necessary to further assess the role of intravenous steroids in these patients. Despite diagnostic delays in some patients, all patients survived to latest follow-up, which compares favorably to the larger NTZ-associated PML experience, with a 20% mortality.1 However, interpretation of survival statistics in all NTZ-associated PML patients is limited by variable and sometimes limited follow-up. In terms of pre-existing risk factors for PML, nearly all of the patients had at least 1 risk factor, and JC virus seropositivity was the most frequently reported. Most patients had a prolonged duration of NTZ treatment (>2 years), with many exposed for 4 years. Additionally, 47% of patients reported prior IS therapies, which is consistent with the 35% frequency reported in a large NTZ PML case series.16 Among our cases, those having shorter NTZ treatment durations (