Letter to the Editor
To the Editors:
Progressive multifocal leukencephalopathy (PML) is a severe demyelinating disease of the central nervous system. Its causative agent, JC virus (JCV), is a double-stranded DNA virus found worldwide. As JCV seroprevalence is up to 80%, latent persistent infection is assumed. Only impaired cellular immunity leads to reactivation of JCV and manifestation of disease.1 HIV infection is by far the most underlying disease, but PML can also occur in HIV-negative patients with hematological diseases. During recent years, an increased risk has been reported for HIV-negative patients exposed to immune modulatory monoclonal antibodies such as natalizumab, efalizumab, or rituximab.2–4 As the latter is frequently used in the treatment of various CD20-positive lymphoproliferative diseases in HIV-infected patients, these reports have raised concerns about an additive or even exponential risk for PML in HIV-infected patients exposed to rituximab.
In an attempt to evaluate the incidence of PML in a real life-scenario, we conducted a multicentric bi-national retrospective study. The German cohort of HIV-associated lymphoproliferative diseases includes adult HIV-1–infected patients with biopsy proven AIDS-related lymphoma diagnosed in 25 participating German centers. The French cohort is a single institution cohort of patients treated at Saint-Louis Hospital, Paris, France. Entry criteria, enrollment, and follow-up procedures for both cohorts have been described elsewhere.5–8 All HIV-infected patients who participated in these 2 prospective cohorts and were treated with rituximab were analyzed. Death cases due to lymphoma or non-PML causes were censored.
We identified a total of 307 HIV-infected patients treated with rituximab, among them 217 patients with non-Hodgkin Lymphoma (NHL), 6 patients with Hodgkin disease, and 84 patients with multicentric Castleman's disease. The characteristics of the patients treated in both countries are depicted in the Table 1. During a total observation period of 707 patient-years after the first use of rituximab, only 1 case of PML was observed, leading to an incidence of 1.4 cases/1000 patient-years [95% confidence interval (CI): 0.04 to 7.9]. This case occurred in a 51-year-old-male patient diagnosed with HIV (initial CD4 T cells were 60/μL) and NHL at the same time in 2007. After the third and during the fourth cycle of R-CHOP leading to a clinical remission of his NHL, he developed progressive neurological symptoms due to PML, which was confirmed by stereotactic biopsy. The patient died only 5 months after the diagnosis of HIV infection and diffuse large B-cell lymphoma.
In HIV-negative patients, inclusion of rituximab into standard chemotherapy regimens for NHL causes a higher incidence of PML cases.2,3 In a large retrospective monocentric cohort study on 976 NHL patients diagnosed in 1994–2008, the incidence rate of PML was 0.0/1000 patient-years (95% CI: 0.0 to 1.8) in unexposed patients, compared with 2.4/1000 patient-years (95% CI: 1.0 to 5.6) patients exposed to rituximab, leading to an adjusted rate difference of 2.2/1000 patient-years (95% CI: 0.1 to 4.3).9 Data on HIV-infected patients is much more limited. To our knowledge, the present analysis represents the largest group of HIV-infected patients exposed to rituximab world wide. Although selection bias and potential misdiagnosis could not be ruled out in this retrospective analysis, the PML incidence of 1.4/1000 patient-years did not indicate an excess incidence for PML. In large nation-wide cohorts of unselected patients infected with HIV from the United Kingdom, Denmark, and Switzerland, the incidence of PML has been described to be decreased from 2.4–3.3/1000 patient-years in the pre–highly active antiretroviral therapy era down to 0.5–1.3/1000 patient-years during recent years.10–12 Although the PML incidences were markedly lower after introduction of highly active antiretroviral therapy, in all of these studies, low CD4 T cells remained independently associated with an increased risk for the development of PML.
Because a considerable number of patients in our study was severely immunosuppressed at the time of exposure to rituximab, we believe that our observation argue against an excess incidence of PML in HIV-infected patients treated with this immunomodulatory drug. However, give the large CI, there is no doubt that a longer follow-up is needed. This is underlined by the hitherto largest study of 57 PML cases occurring in HIV-negative patients treated with rituximab, in which the median time period between first rituximab dose to PML diagnosis was 16.0 months, showing a broad range of 1.0–90.0 months.2 As the use of rituximab will further increase in the HIV population, clinicians and patients should be aware of the potential for PML after rituximab therapy.
1. White MK, Khalili K. Pathogenesis of progressive multifocal leukoencephalopathy–revisited. J Infect Dis. 2011;203:578–586.
2. Carson KR, Evens AM, Richey EA, et al.. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113:4834–4840.
3. Carson KR, Focosi D, Major EO, et al.. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol. 2009;10:816–824.
4. Yousry TA, Major EO, Ryschkewitsch C, et al.. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354:924–933.
5. Wyen C, Jensen B, Hentrich M, et al.. Treatment of AIDS-related lymphomas (ARL): rituximab is beneficial even in severely immunosuppressed patients. AIDS. 2012;26:457–464.
6. Hoffmann C, Schmid H, Muller M, et al.. Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease. Blood 2011;118:3499–3503.
7. Gerard L, Meignin V, Galicier L, et al.. Characteristics of non-Hodgkin lymphoma arising in HIV-infected patients with suppressed HIV replication. AIDS. 2009;23:2301–2308.
8. Gerard L, Michot JM, Burcheri S, et al.. Rituximab decreases the risk of lymphoma in patients with HIV-associated multicentric Castleman disease. Blood. 2012;119:2228–2233.
9. Tuccori M, Focosi D, Blandizzi C, et al.. Inclusion of rituximab in treatment protocols for non-Hodgkin's lymphomas and risk for progressive multifocal leukoencephalopathy. Oncologist 2010;15:1214–1219.
10. Garvey L, Winston A, Walsh J, et al.. HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era. Eur J Neurol. 2011;18:527–534.
11. Khanna N, Elzi L, Mueller NJ, et al.. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin Infect Dis. 2009;48:1459–1466.
12. Engsig FN, Hansen AB, Omland LH, et al.. Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. J Infect Dis. 2009;199:77–83.