How do you handle hypogammaglobulinemia detected in patients prior to maintenance rituximab infusion?
Do you check immunoglobulin levels prior to starting B-cell depleting therapy?
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That is a good question. Adding on to Dr. @Dr. First Last's response, rituximab has been shown to cause hypogammaglobulinemia that can persist or worsen with ongoing therapy. In a study published by Barmettler and colleagues, 133 patients out of a cohort of 8633 patients had serum IgG levels checked prior to initiating rituximab. Amongst these patients, 47.8% had developed or worsened hypogammaglobulinemia. Severe infections were observed in 1261 patients (approximately 28%) and seemed to have worse outcomes in men and older adults. Notably, patients who had hypogammaglobulinemia after rituximab infusion also had a higher rate of severe infections, and patients who received immunoglobulin replacement dose had a reduced risk of serious infections. It is worth noting that the majority of patients in this cohort were receiving rituximab for malignancy, with about 28% receiving rituximab for various autoimmune diseases. In clinical practice, rituximab is often held when patients experience infections regardless of their immunoglobulin status.
Further studies are needed to examine the utility of immunoglobulin replacement therapy. I often will refer patients to my allergy/immunology colleagues when I face persistent hypogammaglobulinemia in patients who require long-term rituximab therapy.
There is a lack of clear evidence or guidance on whether to monitor immunoglobulin levels in patients receiving repeated courses of rituximab or about how to react to findings of hypoimmunoglobulinemia. The absolute risk of infection in patients on rituximab who are hypoimmunoglobulinemic is not known, but appears low. Some would advocate checking levels only if an infection occurs that is possibly related to immunoglobulin deficiency, since only in that case would action be taken. Others feel it is reasonable to follow IgG, IgM, and IgA levels in patients receiving repeated doses of rituximab so trends are noted and consider dose alterations (reduction or longer intervals between doses) if, for example, IgG < 3 g/L (exact cut-off not known). There is currently no good evidence that administering immunoglobulin supplementation is necessary in the absence of infection. Certainly, individual patient circumstances must be taken into consideration.
This interesting issue is challenging to study, given the final outcome of interest is related to infections within a subset of patients given a specific treatment for a rare condition and necessitates repeated measurements. We plan to address these questions in the RITAZAREM dataset to the extent possible since immunoglobulin levels were obtained at each study visit over several years of observation.