Absent Influenza Vaccine Response in Rituximab-treated Lymphoma Patients

Abstract & Commentary

By William B. Ershler, MD, Editor

Synopsis: Influenza remains a major source of morbidity and increased mortality among patients with cancer, and prior studies had indicated impaired response to vaccination. In the current report, lymphoma patients treated with rituximab, either in combination with chemotherapy or as a single agent, were found to have markedly deficient influenza vaccine response, with not 1 of 67 achieving a protective titer, compared with 42 of 51 controls. Thus, rituximab-treated lymphoma patients are particularly susceptible to vaccine failure and influenza infection should be highly considered in symptomatic patients, even in those who had been appropriately vaccinated.

Source: Yri OE, et al. Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment. Blood 2011;118:6769-6771.

The concern regarding influenza is high among cancer patients as the rate of infection is considerably higher and mortality is four times greater than in the general population.1 Cancer itself is immunosuppressive, but additional impairment from therapy is also of importance. Patients with lymphoma receiving rituximab may be particularly susceptible as this agent produces a prolonged depletion of B cells and impaired humoral responses.2 It is known that in patients with rheumatoid arthritis receiving rituximab, antibody responses to both carbohydrate and protein vaccines are impaired.2,3 Similarly, it is likely that rituximab-treated lymphoma patients also are likely to have diminished vaccine response, although this has not been definitively established.

Yri and colleagues throughout Norway have addressed this in the current report. Their aim was to investigate whether lymphoma patients undergoing rituximab-containing treatment regimens or having received such regimens within the past 6 months were able to mount protective antibody responses to the influenza A (H1N1) 2009 virus vaccine during the 2009 "swine flu" pandemic. A total of 67 lymphoma patients and 51 controls, all of whom had low prevaccination titers, received the monovalent influenza A (H1N1) vaccine (Pandemrix; Glaxo SmithKline) and antibody levels were determined before and 3 weeks or more after vaccination by standard hemagglutination-inhibition assay. An antibody titer of > 40 was considered protective. The patients were somewhat older than controls (mean age 63 years vs 47 years, respectively) and most patients had received combined chemotherapy plus rituximab, although seven had received rituximab alone.

Among the vaccinated lymphoma patients, five persons had a post-vaccine titer of 20 and the remaining 62 patients had no detectable titers at all. In contrast, 42 of the 51 controls (82.4%) had a post-vaccination titer > 40, eight had a titer of 20, and only one showed no response. Thus, the sero-protection rate for this vaccine was 0% in treated lymphoma patients and 82% in controls.

Commentary

These are striking findings with serious clinical implications. Of course, patients on chemotherapy would be expected to have a reduced response to vaccine, especially to one that is only moderately immunogenic, such as influenza vaccine. However, the use of rituximab might be of critical importance in explaining the nearly absent response. In a prior study of vaccination from the same group of investigators, 72% of non-rituximab treated cancer patients, including those with both solid tumor and lymphoma, achieved protective antibody levels after receiving the trivalent influenza vaccine. However, the lymphoma subgroup fared less well than those with solid tumor, only 38% responding, compared to 82% of those with solid tumor.4 Thus, vaccine response is less among lymphoma patients, but the current data would suggest that the inclusion of rituximab is of incremental importance in this regard. Physicians should be aware that such patients are particularly susceptible to influenza, despite having received vaccine, and if infection is suspected, the threshold for starting antiviral treatment should be lowered.

Under optimal circumstances, response to the commercially available influenza vaccines is far from ideal, and those with compromised immunity remain susceptible to infection despite infection. Improved vaccines are needed, including those that employ various adjuvants or that target influenza antigens other than hemagglutin, yet much research needs to be completed before these become available. In the meantime, other strategies, including vaccines with larger doses of antigen, or double administration (e.g., vaccination twice during influenza season) remain viable options worthy of clinical investigation.

References

1. Cooksley CD, et al. Epidemiology and outcomes of serious influenza-related infections in the cancer population. Cancer 2005;104:618-628.

2. Cohen Y, et al. Rituximab therapy for follicular lymphoma: A comprehensive review of its efficacy as primary treatment, treatment for relapsed disease, re-treatment and maintenance. Haematologica 2003;88:811-823.

3. Rehnberg M, et al. Vaccination response to protein and carbohydrate antigens in patients with rheumatoid arthritis after rituximab treatment. Arthritis Res Ther 2010;12:R111.

4. Nordoy T, et al. Cancer patients undergoing chemotherapy show adequate serological response to vaccinations against influenza virus and Streptococcus pneumoniae. Med Oncol 2002;19: 71-78.