1. Utility of Influenza Vaccination for Oncology Patients Daniel A. Pollyea, Janice M.Y. Brown, and Sandra J. Horning Journal of Clinical Oncolgy; Vol 28 May 10, 2010 R2. 석화영 / Prof. 이재진

2. Introduction The Centers for Disease Control and Prevention (CDC) recommends annual vaccination for high-risk populations. The CDC endorses the practice of influenza vaccination for patients with malignancies. Question whether patients receiving chemotherapy are able to mount a sufficient immunological response. The purpose of this article is to review evidence related to the ability of patients with cancer to mount protective immunological responses to influenza vaccination.

3. Influenza and Vaccination Influenza A and B are the subtypes responsible for the majority of cases of severe disease in humans. Influenza A is further classified based on the presence of two surface antigens, hemagglutinin(HA) and neuraminidase (NA). Influenza B is separated into two genetic lineages, Yamagata and Victoria. Minor changes in the amino acid sequences of HA and/or NA result in seasonal epidemics. For this reason, the WHO, US Food and Drug Administration, and CDC annually produce a new vaccine.

4. Influenza and Vaccination Trivalent inactivated influenza vaccine is the most common vaccine formulation administered. Vaccination results in memory B and T-cell formation which allows the adaptive immune system to respond when challenged with exposure to the pathogen. In the general adult population, influenza vaccination results in prevention of infection in 70% to 90% of patients prevention of influenza-related hospitalization in 90%

5. Measuring Immunogenecity to Vaccination and its Limitations A variety of factors substantially limit meaningful comparisons of studies of responses to influenza vaccination. One limitation is that there are several statistical methods used to interpret humoral responses to vaccination, with no accepted standard for reporting. Another limitation to comparing studies is that the definition of seroprotection has changed with time Lastly, published studies are heterogeneous Most studies include an assay of HA inhibition (HI) antibody levels by the HI test NA inhibition (NI) titers are less commonly reported Four main reported assays -geometric mean titers of HI after vaccination: greater than or equal to a 2.5-fold increase in a population -mean fold increases in HI after vaccination -postvaccination seroresponse rate: the percentage of patients with a four-fold increase in titers -seroprotection rate: the percentage of patients with a titer of least 1:40 Before 1985 an increase in the reciprocal serum HI titer from 20 to 40 was considered protective since 1985, a reciprocal serum titer of at least 40, and/or a four-fold increase in titers from the prevaccination baseline, have become the standard for determining successful immunization.

6. Influenza Vaccination in patients with cancer Pediatric Oncology Patients Higher incidence of influenza Greater morbidity and mortality from infection Interrupt and delay chemotherapy as often as 80% higher incidence of influenza

8. Influenza Vaccination in patients with cancer Pediatric Oncology Patients Although vaccination was frequently associated with suboptimal immunogenicity in this population, particularly in patients receiving active treatment, all studies showed at least some immunological response to influenza vaccination. Routine administration was recommended.

9. Influenza Vaccination in patients with cancer Adult Patients With Solid Tumors

10. Influenza Vaccination in patients with cancer Adult Patients With Hematologic Malignancies Patients with hematologic malignancies do not respond to vaccination as well as healthy controls or patients with solid tumors.

14. Influenza Vaccination in patients with cancer Adult Patients With Hematologic Malignancies Timing of vaccination in this population appears to be crucial There was no benefit from immunization in the first 6 months after HSCT, and a longer interval between HSCT and immunization correlated with improved responses. However, when a high risk for influenza infection exists, some centers advocate administering vaccination 3 to 4months after HSCT Overall, influenza vaccination in this population is recommended

15. Influenza Vaccination in Modern Era Immunotherapy and biologic agents represent an important modern advancement in cancer therapy. Rituximab, a chimeric monoclonal antibody, targets pre-B and mature CD20 B lymphocytes The mechanism of action of rituximab suggests it may interfere with immunogenic responses to vaccination. The effect of rituximab on the immunogenicity of influenza vaccination is unclear.

17. Influenza Vaccination in Modern Era These limited data support observations in the oncology literature that rituximab may limit the immune response to influenza vaccination, but more definitive studies are needed.

18. Timing of Influenza Vaccination for Oncology Patients receiving Chemotherapy There is evidence to suggest that the timing of vaccination relative to a chemotherapy treatment cycle is crucial Ortbals et al concurrently with the administration of chemotherapy between cycles of chemotherapy, at the nadir blood count Patients in the first group developed a protective immunologic response 50% of the time, compared with 93% for those in the second group.

19. Timing of Influenza Vaccination for Oncology Patients receiving Chemotherapy Due to a paucity of data in heterogeneous clinical scenarios, a variety of opinions regarding the ideal timing of vaccination have emerged vaccinate 2 weeks before initiation of chemotherapy 1 month after completion of chemotherapy after the peripheral WBC count recovers to greater than 1,000 cells/mm 2 months after completion of chemotherapy simply before the influenza season For actively treated patients, we recommend vaccination at the furthest possible time point away from treatment during a given cycle.

20. Proposed Strategies to Increase the Efficacy of Influenza Vaccination in Oncology patient Two-Shot Series For healthy adults, the CDC recommends a one-shot influenza vaccination Some reports suggest a two-shot influenza vaccination series may be beneficial for oncology patients In a study of 27 children with predominantly hematologic malignancies, most of whom were receiving chemotherapy, 70% of those administered two vaccinations had an adequate response by HI titer, compared with 18% who responded to a one-shot series. In a study of adult patients with NHL receiving treatment, 42% developed protective HI titers to one shot compared with 50% after two shot Larger studies are required to study this issue before definitive recommendations are possible.

21. Proposed Strategies to Increase the Efficacy of Influenza Vaccination in Oncology patient Increased Dose of Antigen In non cancer populations, administration of an increased dose of HA antigen has been shown to increase antibody responses. Safdar el al. In patients with B-cell NHL not receiving treatment → increased antibody response in those who received a higher dose of a recombinant DNA-produced vaccine This approach warrants further study, particularly in patients receiving chemotherapy.

22. Proposed Strategies to Increase the Efficacy of Influenza Vaccination in Oncology patient Use of Adjuvant Therapies Hypothesis : adjuvant therapies to increase responsiveness of immune reactions to influenza vaccination in immunosuppressed patients may be beneficial Granulocyte-macrophage colony-stimulating factor (GM-CSF) Randomized, single-blinded, placebo controlled study of adult with cancer failed to show any improvement in responsiveness with the use of GM-CSF versus placebo as an adjuvant. Despite these disappointing results, use of an adjuvant in patients with malignancies to improve responsiveness to influenza vaccination is logical, and may be successful in the future.

23. H1N1 CDC recommends immunization with inactivated H1N1 vaccine for patients with cancer receiving chemotherapy, followed by a revaccination 3 months after completion of treatment if it is still influenza season (A. Kroger, personal communication, October 2009)

24. Conclusions The majority of patients with malignancies who have not received treatment for greater than 30 days can mount immunologically favorable reactions to influenza vaccination. Patients actively receiving treatment typically have suboptimal responses, but few studies show an absence of responsiveness. Although the ideal time to administer the vaccination during a treatment cycle is unclear, the furthest time point from chemotherapy appears to be preferable. Those with hematologic malignancies tend to have inferior responses to those with solid tumors. Immunotherapy like rituximab may negatively impact the immune response to influenza vaccination, and given the widespread use of rituximab, well-designed immunogenicity studies in this patient population are needed.