Rituximab-Fludarabine Combinations and the Risk of Non-Neutropenic Infection
Rituximab-Fludarabine Combinations and the Risk of Non-Neutropenic Infection
Abstract & Commentary
By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: Rituximab has proven an effective adjunct to various chemotherapy regimens in the treatment of lymphoma. When used alone or with combinations such as CHOP, hypogammaglobulinemia occurs relatively infrequently and no increased risk of infection has been reported. However, in this series, rituximab, when used with fludarabine, was associated with a dramatic increase in non-neutropenic infections, such as bronchitis, sinusitis and pneumonia, and these were most likely to occur in those who developed hypogammaglobulinemia during treatment. Patients with non-neutropenic infections were effectively treated with intravenous immunoglobulin.
Source: Cabanillas F, et al. High incidence of non-neutropenic infections induced by rituximab plus fludarabine and associated hypogammaglobulinemia: a frequently unrecognized and easily treatable complication. Ann Oncol. 2006;17:1424-1427.
Rituximab, a monoclonal antibody which targets CD20+ B lymphocytes would be expected to reduce circulating antibody levels and increase risk for infection. Yet, when used as a single agent, hypogammaglobulinemia occurred in only 14% of patients and was considered not to increase risk of morbidity, including infection.1 This impression varied from the clinical experience at the Auxillo Mutuo Cancer Center in San Juan Puerto Rico and led to an evaluation of their patients treated with rituximab and chemotherapy.
Cabanillas and colleagues report on 97 lymphoma-treated patients with combinations of rituximab and chemotherapy. There were 40 episodes of non-neutropenic infection (NNI) occurring in 19 of the 97 patients. A Kaplan-Meier cumulative estimate revealed that by three years 43% of patients treated with rituximab + chemotherapy were projected to have developed at least one NNI. In univariate analysis, several clinical factors seemed to be associated with increased risk including indolent histology, female sex and the use of fludarabine with rituximab. However, by multivariate analysis, the use of fludarabine (P = 0.0007) and female sex (P = 0.026) were the only two independent variables indicating increased risk. Females who received fludarabine + rituximab had a 63% frequency of NNI.
Of the 19 patients with NNI, serum quantitative immunoglobulin levels were determined in 15, and all 15 had developed abnormally low gamma globulin levels in at least one of the 3 classes (IgM, 93.3%, IgG 92.8%, and IgA 42.8%). Of these, it appeared that the decrement in IgM was most associated with NNI. Of the ten patients whose IgM level was less than 50% below the lower limit of normal, 7 had to be hospitalized for management of infection, compared to only 1 of the 5 with IgM levels 0.5 to 0.99 of the lower limit of normal. Of the 24 patients with low IgG levels, NNI occurred in 10 (42%). However, in contrast to those with low IgM levels, there was no correlation between the degree of IgG decrement and incident NNI.
The NNIs observed included 18 patients with bronchitis, 16 with sinusitis, four pneumonias, 3 with otitis media, 2 with fevers of undetermined origin, and 3 with herpes zoster. Some patients had combined episodes of different types of infection (eg, sinusitis and bronchitis) and seven of 19 required hospitalization. Intravenous gamma globulin (30 g) was used in 12 patients and in each of these there was complete resolution of the NNI.
Commentary
In previous reports, rituximab administered alone,1 or with CHOP chemotherapy,2 hypogammaglobulinemia occurred infrequently and was not associated with infection. However, the current series would suggest that when rituximab is used in combination with fludarabine, the outcomes with regard to hypogammaglobulinemia and infection are different. Although retrospective and relatively small, the incidence of NNI in rituximab-fludarabine patients was remarkably high. Furthermore, the infections tended to occur in those with associated hypogammaglobulinemia and have the clinical distribution of infections typical of those seen in patients with congenital or acquired hypogammaglobulinemia syndromes. These are intriguing observations and warrant prospective analysis.
In the meantime, physicians should be aware of this risk in rituximab-fludarabine treated patients and consider monitoring gammaglobulin levels and treating infected patients with intravenous gammaglobulin (IVIg). Additional clinical investigation might also address the question of whether the preemptive use of IVIg in such patients (either for all rituximab-fludarabine treated patients, or just those who develop hypogammaglobulinemia) would be sufficient to prevent NNI. It would seem the risk is sufficiently high to warrant such a trial.
References
1. McLaughlin P, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825-2833.
2. Coiffier B, et al. Immunochemotherapy is the standard of care in elderly patients with diffuse large B-cell lymphoma. Blood. 2004;104:1584-1585.
Rituximab has proven an effective adjunct to various chemotherapy regimens in the treatment of lymphoma. When used alone or with combinations such as CHOP, hypogammaglobulinemia occurs relatively infrequently and no increased risk of infection has been reported.Subscribe Now for Access
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