Is Rituximab Safe to Use in Kidney Transplant Patients? (2009)

Rituximab is a chimeric monoclonal anti‐CD20 antibody that selectively depletes B‐cells and can reduce antibody production. The drug was originally developed and licensed for use in B‐cell lymphomas, but is now widely used in solid organ transplantation for desensitization, prophylaxis of rejection as well as treatment of antibody‐mediated rejection and recurrent glomerular diseases. Unfortunately, no controlled study, allowing a precise measurement of efficacy and side effects, most notably infections, has been reported. This is a critical point because rituximab does not deplete all B‐cells and its effect on alloantibody is not established. The development of progressive multifocal leukoenchephalopathy (PML) in patients treated with rituximab is the first concern. Safety alerts were issued by the United States Food and Drug Administration (FDA), the European Medicines Agency, and the World Health organization in 2006 and 2007 describing two cases of PML in patients with systemic lupus erythematosis treated with rituximab and other immunosuppressive agents. PML is caused by the reactivation of latent JC polyoma virus (JCV) as a result of defects in cellular immunity. There were no cases reported in renal transplant recipients (1Carson KR Evens AM Richey EA et al.Progressive multifocal leukoencephalopathy following rituximab therapy in HIV negative patients: A report of 57 cases from the Research on Adverse Drug Event and Reports (RADAR) project.Blood. 2009; 113: 4834-4840Crossref PubMed Scopus (781) Google Scholar). Kamar et al. screened 73 solid organ transplant recipients who received rituximab, 37 of whom received a kidney transplant, for JCV reactivation (2Kamar N Mengelle C Rostaing L Incidence of JC‐virus replication after rituximab therapy in solid‐organ transplant patients.Am J Transplant. 2009; 9: 244-245Crossref PubMed Scopus (23) Google Scholar). They assessed JCV DNA in whole blood by qualitative real time polymerase chain reaction (PCR). Monitoring was done every 3 to 4 months after rituximab administration with an average follow‐up of 13 months. Polyoma BK virus (BKV) was also assessed. JCV was detected in 5.5% of patients. They were all in renal transplant patients who had also received T‐cell‐depleting agents. No cases of PML developed and all patients responded to a reduction in immunosuppression. The second concern is the risk of severe bacterial and fungal infections. Controlled clinical trials in rheumatoid arthritis and lymphoma treatment have not demonstrated a significant increase in infectious episodes (3Mclaughlin P Grillo‐Lopez AJ Link BK et al.Rituximab chimeric anti‐CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four‐course treatment program.J Clin Oncology. 1998; 16: 2825-2833Crossref PubMed Scopus (2585) Google Scholar,4Van Vollenhoven RF Emery P Bingham III, CO et al.Long‐term safety of rituximab: follow‐up of the RA clinical trials and re‐treatment population [EULAR Abstract #OP‐0026].Ann Rheum Dis. 2009; 68Google Scholar). However, a trend toward an increased rate of infections was reported in a small group of patients (n = 21) that received rituximab for ABOi transplantation or a positive CMX (5Usui M Isaji S Mizuno S Sakurai H Uemoto S Experiences and problems pre‐operative anti‐CD20 monoclonal antibody infusion therapy with splenectomy and plasma exchange for ABO‐incompatible living‐donor liver transplantation.Clin Transplant. 2007; 21: 24-31Crossref PubMed Scopus (33) Google Scholar). There was no difference in patient or graft survival. Patients treated with rituximab in this series also received ATG. Types of infections included blood stream infection, pneumonia, esophagitis, peritonitis, colitis, skin and soft tissue infection. In this issue of the American Journal of Transplantation, Kamar et al. (6Kamar N Milioto O Benedicte P‐L et al.Incidence and predictive factors for infectious diseases after rituximab therapy in kidney transplant patients.Am J Transplant. 2010; 10: 89-98Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar) report on a disturbing association between rituximab use and a significant risk of infection‐related deaths posttransplant. The paper compares 77 rituximab treated patients that received 2–8 courses of rituximab therapy for treatment of AMR or recurrent glomerular diseases posttransplant to 902 patients retrospectively reviewed. The rational for the rituximab dosing regimens was not given. These investigators found that both groups had very high infection rates (53.9% retrospective controls vs. 45.5% rituximab treated), but the death rates from infection were significantly higher in the rituximab treatment group (9.1% vs. 1.6%). These findings are of great concern since this is, to date, the largest reported cohort of transplant patients treated with rituximab. Despite the above findings, there are many reports that have demonstrated the safety of rituximab with infection rates similar to those seen in renal transplant recipients who did not receive rituximab (4Van Vollenhoven RF Emery P Bingham III, CO et al.Long‐term safety of rituximab: follow‐up of the RA clinical trials and re‐treatment population [EULAR Abstract #OP‐0026].Ann Rheum Dis. 2009; 68Google Scholar,7Vo AA Lukovsky M Toyoda M et al.Rituximab and intravenous immune globulin for desensitization during renal transplantation.N Engl J Med. 2008; 359: 242-251Crossref PubMed Scopus (566) Google Scholar). The largest analysis of safety of rituximab comes from rheumatoid arthritis (RA). A pooled analysis was conducted to evaluate the long‐term safety of single and multiple courses of rituximab treatment in patients with active RA during 5 years of follow‐up. At the time of the report, 2579 patients had been treated with rituximab in the clinical trial program. The total exposure duration was 5964 patient‐years. Infusion reactions were the most frequent adverse events, occurring in 25% of patients for the first infusion of the first course, and decreased in subsequent infusions. The most commonly observed serious infections included pneumonia (n = 36; 1%), cellulitis (n = 19; <1%), and urinary tract infections (n = 14; <1%). There were no other cases of serious opportunistic infections or tuberculosis and no increase in death rate compared to control RA patients (4Van Vollenhoven RF Emery P Bingham III, CO et al.Long‐term safety of rituximab: follow‐up of the RA clinical trials and re‐treatment population [EULAR Abstract #OP‐0026].Ann Rheum Dis. 2009; 68Google Scholar). The compelling question raised by Kamar et al. (6Kamar N Milioto O Benedicte P‐L et al.Incidence and predictive factors for infectious diseases after rituximab therapy in kidney transplant patients.Am J Transplant. 2010; 10: 89-98Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar) is rituximab safe to use in transplant patients? This is a critical question because the indications for rituximab use in kidney transplant patients are not well established. We feel that this paper raises a red flag regarding rituximab use in transplant patients, but it is by no means clear that this is the final answer. Both groups analyzed had very high infection rates that may point to an overly immunosuppressed state. More importantly, data from clinical trials that were randomized and prospectively conducted did not report an increased risk for infections or deaths in rheumatoid arthritis and lymphoma patients treated with rituximab. In summary, serious infectious complications have been noted after rituximab administration. However, with appropriate surveillance, the risk can be minimized. Consideration should be given to viral PCR monitoring, especially in those patients who receive agents that alter T‐cell function in addition to rituximab. The neurological status of patients who receive rituximab should also be monitored. Finally, the avoidance of excessive immunosuppression may reduce the risk of infectious complications. As with other immunosuppressive agents, finding the most effective and safe dosing regiments is paramount.