Original study
Incidence of Hypogammaglobulinemia in Patients Receiving Rituximab and the Use of Intravenous Immunoglobulin for Recurrent Infections

https://doi.org/10.1016/j.clml.2012.11.011Get rights and content

Abstract

Background

Rituximab has altered the treatment approach to B-cell malignancies and other diseases. Reports consider that rituximab had limited impact on serum immunoglobulins. However, anecdotes suggest that rituximab can cause symptomatic hypogammaglobulinemia. This retrospective study examined the relationship among rituximab, hypogammaglobulinemia, and treatment of symptomatic hypogammaglobulinemia with intravenous immune globulin (IVIG).

Methods

Patients with serial quantitative serum immunoglobulin (SIgG) concentrations before and subsequent to rituximab administration at Memorial Sloan-Kettering Cancer Center were identified. Information regarding rituximab administration, SIgG concentrations, frequency of infection, and administration of IVIG were recorded.

Results

Between December 1998 and April 2009, 211 patients with B-cell lymphoma treated with rituximab and with serial SIgG concentrations were identified. One hundred seventy-nine (85%) patients had normal SIgG before rituximab, 32 (15%) had low SIgG. After rituximab use, hypogammaglobulinemia was identified in 38.54% of patients with initially normal SIgG. The risk was greater in patients who received maintenance rituximab. Symptomatic hypogammaglobulinemia that prompted IVIG administration developed in 6.6% of patients.

Conclusions

In this data set, rituximab administration was associated with a high frequency of hypogammaglobulinemia, particularly symptomatic hypogammaglobulinemia, among patients who received multiple courses of rituximab. Baseline and periodic monitoring of SIgGs is appropriate in patients who receive rituximab.

Introduction

Rituximab is a chimeric monoclonal antibody that binds to the CD20 antigen present on all peripheral B cells. In 1997, it became the first antibody approved for treatment of relapsed or refractory low-grade or follicular CD20+ B-cell non-Hodgkin lymphoma (NHL), based on clinical trials that evaluated its safety and efficacy in the early 1990s.1, 2, 3 Its use has subsequently widened to include treatment of all B-cell malignancies, including aggressive NHL and chronic lymphocytic leukemia.4, 5, 6, 7, 8, 9 The use of rituximab has also extended to nonmalignant indications, including rheumatoid arthritis.9

The efficacy of rituximab in these conditions as well as rituximab's favorable toxicity profile have led to several studies that evaluated rituximab as maintenance therapy after treatment for newly diagnosed or relapsed NHL. In addition, maintenance rituximab has been evaluated after high-dose therapy and autologous stem cell rescue in both indolent and aggressive lymphoma.10, 11, 12, 13, 14, 15, 16, 17

To date, 6 randomized trials have published results on the role of maintenance rituximab in indolent NHL and have noted improvements in progression-free survival. Maintenance therapy should ideally sustain prolonged remission, be well tolerated, and have minimal toxicities. Although rituximab meets these criteria and has contributed to extending periods of remission duration, the long-term impact of rituximab on B-cell depletion is not well understood. Long-term use may be associated with an increased incidence of grade 3 and 4 infections, neutropenia, hepatitis B reactivation, squamous cell skin carcinoma, and progressive multifocal leukoencephalopathy.18, 19, 20, 21 Furthermore, hypogammaglobulinemia associated with rituximab use has been documented in several settings: rituximab after high-dose therapy and autologous stem cell rescue, rituximab for autoimmune disorders in children with immunosuppression, and rituximab in patients with T-cell abnormalities.22, 23, 24, 25, 26, 27

To understand the relationship between the use of rituximab and the development of hypogammaglobulinemia, we undertook a retrospective study to evaluate serum immunoglobulins (SIgG) and rituximab. In addition, we examined if patients receiving rituximab developed symptomatic hypogammaglobulinemia that required treatment with intravenous immunoglobulin (IVIG).

Section snippets

Patients and Methods

This study was performed under a waiver of authorization from the institutional review board at Memorial Sloan-Kettering Cancer Center (MSKCC). We used DAVInCI (Data Analysis and Visualization for Integrated Cancer Information), a Web-based data mining tool, to identify patients with B-cell lymphoma who had been treated with rituximab either as a single agent for primary or maintenance therapy or in combination with chemotherapy as part of induction or salvage treatment at MSKCC between

Patient Characteristics

Two hundred eleven patients with NHL had serial quantitative immunoglobulin studies before and subsequent to therapy with rituximab, and were included in the analysis (Table 1). Eighty-two percent of patients (173/211) received rituximab as immunotherapy or chemoimmunotherapy for first-line treatment. Eighteen percent of patients (38/211) received rituximab for relapsed or refractory disease. The median age of patients was 58 years old (range, 9-90 years). The histologies included diffuse large

Discussion

In this data set, we observed that rituximab administration was associated with a high frequency of hypogammaglobulinemia. This occurred in concert with a moderate risk of symptomatic hypogammaglobulinemia that required use of IVIG, particularly among patients who received multiple courses of rituximab. In addition, we found that the number of doses of rituximab significantly correlated to the development of symptomatic hypogammaglobulinemia.

In this study, we examined the impact of rituximab on

Disclosure

A. Zelenetz has received research support from Genentech, Roche, and Biogen/IDEC; he has also performed consulting for Genentech and Roche. Genentech/Roche and Biogen/IDEC were not involved in this study. The remaining authors have stated that they have no conflicts of interest.

Acknowledgment

The authors thank Carol Pearce, MSKCC Department of Medicine writer/editor, for her editorial assistance.

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