*Rituximab was given as the induction therapy at transplantation, and then once weekly for 3 weeks because of positive historical cross-match in a highly sensitized patient.
Incidence of JC-Virus Replication After Rituximab Therapy in Solid-Organ Transplant Patients
Article first published online: 19 DEC 2008
© 2009 The Authors Journal compilation © 2009 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 9, Issue 1, pages 244–245, January 2009
How to Cite
Kamar, N., Mengelle, C. and Rostaing, L. (2009), Incidence of JC-Virus Replication After Rituximab Therapy in Solid-Organ Transplant Patients. American Journal of Transplantation, 9: 244–245. doi: 10.1111/j.1600-6143.2008.02499.x
- Issue published online: 19 DEC 2008
- Article first published online: 19 DEC 2008
To the Editor
Several cases of progressive multifocal leukoencephalopathy (PML), a demyelinating infection of the central nervous system caused by reactivation of latent JC virus (JCV), have been recently reported in hematological (1) and bone marrow transplant patients (2) treated with rituximab. Subsequently, the US Food and Drug Administration has warned on the use of rituximab (3). Very recently, the first PML-associated death of a patient treated by rituximab for rheumatoid arthritis has been reported (4). The aim of our study was to assess the incidence of JCV replication in solid-organ transplants who received rituximab therapy.
Between March 2003 and May 2005, 89 solid-organ transplant patients received rituximab therapy at our department. Of these, 73 patients were monitored for JCV. There were 67 kidney-, two liver- and four heart-transplant patients, ranging in age from 22 to 58 years. Rituximab was given at the dose of 375 mg/m2/week for either 4 (n = 68) or 2 weeks (n = 5). Whole-blood JC DNAemia was determined using qualitative real-time PCR at the following time points: before rituximab infusion, every 3 to 4 months thereafter and each time the patient was admitted to hospital. BK virus (BKV) replication was assessed at the same time. The mean follow-up after rituximab administration was 13 ± 12.5 months. The mean number of BKV and JCV detection assays performed was 6.3 ± 5.4 per patient. BK DNAemia was detected in the blood of nine patients (12%). JCV was detected in the whole blood of only four patients (out of 73: i.e. 5.5%). It was detected only once in three patients, and five times in the fourth patient. These four patients had all received a kidney transplant and had received, in addition to rituximab therapy, either T-cell depleting agents (n = 3) or chemotherapy + rabbit antithymoglobulin (n = 1) (Table 1). At the time of first JCV detection, their total lymphocyte counts were 196, 416, 186 and 1448/mm3. CD4-positive cell counts were 78, 124, 6 and 188/mm3. CD19-positive cell counts were 0, 2, 4 and 0/mm3. None of the patients presented with any neurological symptoms and no cases of PML were diagnosed. In contrast, all patients had concomitantly developed BKV replication and biopsy-proven polyoma-virus-associated nephropathy (PVAN), with positive SV40 staining. Because of PVAN, calcineurin inhibitor doses were reduced and mycophenolate mofetil was replaced with lefluomide. JC viremia became negative 2 months later in one patient, and was still negative 8 months later. In the other three patients, in whom JCV was only detected once, it was still negative at 8, 24 and 26 months after JCV detection.
|Cause of rituximab use||Concomitant IS therapy||Other immuno-suppressants received since KT||Time between KT and first rituximab infusion (months)||Number of rituximab infusions||Number of JCV detection assays performed||Number of positive JC viremias||Time between rituximab and first positive JC viremia (months)||BK viremia at JCV detection (Log copies/mL)|
|Patient 1||AHR||Tac/MMF/S||RATG + OKT3||0*||4||19||5||4||4.28|
|Patient 3||FSGS relapse||CsA/MMS/S||RATG||0**||2||39||1||5||3.06|
|Patient 4||PTLD||SRL/S||RATG, CHOP||180||4||19||1||16||5.57|
The role of rituximab in the development of PML, and in reactivating JCV, is still unknown. Cell-mediated immunity, particularly CD4-positive T cells and JCV-specific CD8-positive T cells, are required to avoid JCV replication. It has been suggested that the loss of B-cell antigen-presenting cell function may be responsible for JCV reactivation (5).
Our results have shown that the incidence of JC viremia in rituximab-treated solid-organ transplant patients is at 5.5%. Rituximab decreases the number of B cells, which are a reservoir of JCV (6). JC viremia only occurred in patients in whom both T and B cells were very heavily decreased. Monitoring for JCV replication allows detecting over-immunosuppressed patients. The presence of positive JC viremia should prompt clinicians to reduce immunosuppression in order to prevent PML.
- 3US Food and Drug Administration. FDA Alert: rituximab (marketed as rituxan), (http://www.fda.gov/cder/drug/Infopage/rituximab/default.htm) 18 Dec 2006.
- 4US Food and Drug Administration. FDA Alert: rituximab (marketed as rituxan), (http://www.fda.gov/medwAtch/safety/2008/safety08.htm#Rituxan) 11 September 2008.