Influenza Vaccination In Non-Hodgkin Lymphoma Patients Treated With Rituximab-Based Chemotherapy: 3 Sequential Studies.

Hematological Malignancies (e.g., leukemia and lymphoma) are among the top 5 causes of cancer death in the Middle Eastern Countries, including Qatar, Kuwait and Saudi Arabia. The monoclonal antibody rituximab, directed at the CD20 antigen, has become an essential drug for the treatment of Non Hodgkin Lymphoma (NHL). Although transient B cells depletion frequently occurs after rituximab treatment, it usually resolves after 6-9 months. Nevertheless, high frequency of non-neutropenic infections and persistent hypogammaglobulinaemia during follow-up period have been recently reported. However, impaired humoral response to the recall and primary antigens was found in NHL patients during (or few months after), rituximab treatment. Influenza vaccination is generally recommended in lymphoma patients, but few data are available about the activity of this vaccine after rituximab-containing regimens (RCR). It is presently unclear whether patients treated with RCR regain normal immunocompetence after achievement of complete remission. We presently combined data of 3 sequential studies conduced at our Institutions assessing the humoral response to seasonal influenza vaccination (2008/2009, 2009/2010 and 2011/2012 seasons; RIT-01, RIT-02, and RIT-03 studies, respectively) in NHL patients in complete remission (CR) for at least 6 months after treatment with rituximab-containing regimens (RCR). Response was evaluated by hemagglutinin inhibition assay 3 or 4 weeks after vaccination. The following (inactivated) vaccine formulations were used: virosomal vaccine (RIT-01; N=31), MF-59 adjuvanted vaccine (RIT-02; N=14), and intradermal vaccine (RIT-03; N=22). Data were compared with those from age-matched cohorts of healthy volunteers (HV). In the RIT-03 study, cancer patients who received chemotherapy without rituximab (CWR) more than 6 months before study entry were also evaluated. In the RIT-02 study, patients also received two doses of pandemic H1N1 vaccine. To determine early transcriptional changes predictive of immunoresponsiveness and to determine differences in innate immunity activation among patients treated with RCR, HV, and patients treated with CWR, PBMC were collected just before and 1 day after vaccination (RIT-03 study). Whole-genome gene expression analysis of these samples using microarray analysis is currently ongoing. We found that the intradermal vaccination is associated with dramatic transcriptomic changes in PBMC, already detectable 24 hours after vaccination. These changes underlie modulation of innate response (eg, interferon stimulated genes). Changes after influenza vaccination differ among CWR, CRC, and healthy volunteers. Overall, we found that patients treated with RCR have a significant lack of humoral response to both recall and naive influenza antigens as compared with HV and with cancer patients treated with CWR. This impairment persisted even long time (g 6 years) after last rituximab administration and was associated with depletion of CD27+ memory B cells and hypogammaglobulinemia. Therefore, patients previously treated with RCR should be strictly monitored during influenza epidemic season. Intradermal vaccination seems to induce a stronger response as compared with the other two formulations.