Elsevier

Seminars in Hematology

Volume 47, Issue 2, April 2010, Pages 187-198
Seminars in Hematology

Rituximab-Associated Infections

https://doi.org/10.1053/j.seminhematol.2010.01.002Get rights and content

After more than 10 years of use, rituximab has proven to be remarkably safe. However, accumulated evidence now suggests that under some circumstances it may significantly increase the risk of infections. This risk is difficult to quantify because of confounding factors (namely, concomitant use of immunosuppressive or chemotherapeutic agents and underlying conditions), as well as under-reporting. Increased number of infections has been documented in patients treated with maintenance rituximab for low-grade lymphoma and in patients with concomitant severe immunodeficiency, whether caused by human immunodeficiency virus (HIV) infection or immunosuppressive agents like fludarabine. From the practical standpoint, the most important infection is hepatitis B reactivation, which may be delayed and result in fulminant liver failure and death. Special care should be placed on screening for hepatitis B virus (HBV) and preemptive antiviral treatment. Some investigators have reported an increase in Pneumocystis pneumonia. Finally, there is increasing evidence of a possible association with progressive multifocal leukoencephalopathy (PML), a lethal encephalitis caused by the polyomavirus JC. This review enumerates the described infectious complications, summarizes the possible underlying mechanisms of the increased risk, and makes recommendations regarding prevention, diagnosis and management.

Section snippets

Overall Infectious Complications

The pivotal trial of rituximab in low-grade lymphoma administered four doses of 375 mg/m2 at weekly intervals to 166 patients with relapsed low-grade or follicular lymphoma, and showed profound depletion of B cells (usually to undetectable levels) that persisted for 6 to 12 months. Mean serum levels of IgG and IgA remained within the normal range and mean IgM levels decreased slightly below normal. Only 23 of 166 patients had significant reduction of their immunoglobulin levels. There were 68

Rituximab in Autoimmune Diseases: RA, SLE, Cryoglobulinemia, ITP, and Other Autoimmune Diseases

The standard dosing of rituximab in RA is 1,000 mg twice, administered 2 weeks apart. It may be given with weekly methotrexate, but the overall immunosuppression of these patients is generally lower than those receiving chemotherapy for hematologic malignancies. Perhaps for this reason, infections have been even less of an issue in trials for these conditions than in oncology. In the large randomized trials in RA,1, 2, 3, 4 serious infections were described in only 1% to 3% of patients. In the

Infections Associated With Rituximab Use in Solid Organ Transplantation

Rituximab was used originally in solid organ transplantation to prevent acute rejection in cases of HLA-sensitization102 or ABO-incompatible transplants,103, 104 or to treat acute humoral rejection.105 Several case series of rituximab use in highly sensitized patients have been published showing either no infections during relatively short follow-up periods106 or “no more infections than expected.”105, 107 However, a retrospective series of 34 patients documented increased number of infections

Potential Mechanisms of Increased Risk of Infections Associated With Rituximab

Of the multiple associations described in the preceding sections, the one better supported by evidence is the increased risk of infection with maintenance rituximab detected by meta-analyses.11, 12, 58 These seem to be non-opportunistic infections, and they could be explained by hypogammaglobulinemia and neutropenia, which are known to occur more frequently with more frequent administration of rituximab. Hypogammaglobulinemia is uncommon after rituximab therapy, but it was associated with

Summary and Recommendations

Rituximab has proven remarkably safe over years of use in hundreds of thousands of patients. The more important infectious risks seem to be reactivation of hepatitis B and increased infections with repeated administration. In addition, data derived from the experience in oncology and solid organ transplantation support the notion that the administration of rituximab to patients with pre-existing immune defects (advanced HIV infection) or concomitant intense immunosuppression may result in

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