Response to pneumococcal en Hib vaccination in lymphoma patients treated with chemotherapy and rituximab.

Rituximab is a chimeric anti-CD20 monoclonal antibody used in combination with
chemotherapy for the treatment of non-Hodgkin*s lymphoma (NHL). Following
infusion with rituximab, B-cell depletion in the peripheral blood occurs within
days. Levels of normal peripheral B cells remain low for 2-6 months. Because of
the immune suppressive (chemo) therapy, patients are prone to develop
infectious complications with Hemophilus infleunza type B (Hib) or S.
pneumoniae. There is no data on the infectionrates of S.pneumoniae and Hib in
patients with NHL who were treated with chemotherapy and rituximab. However
vaccination seems indicated for this patientgroup. Little is known about the
effect of rituximab and chemotherapy on the response to pneumoccocal and Hib
vaccination.

To compare the number of responders to vaccination with pneumococcal and
conjugated Hib vaccine at different time points after last dose of rituximab,
to investigate what the ideal moment of vaccination would be.
Secondly to study the immune-response to vaccination with conjugated Hib and
pneumococcal vaccine after treatment with rituximab in relation to the
reconstitution of immune-function (in terms of number and subsets of B-cells,
lymphocyte subsets, immunoglobulin levels and IgG subclasses, CD4+ IFN-gamma
production, BAFF, CXCl13 and IL-10).

The design is a randomised trial. A total of hundred-fifty-two (152) patients
with non-Hodgkin*s lymphoma, who were treated with rituximab in the last five
months before start of the study and are in remission, will be included.
Patients will be randomised for early vaccination (six months after rituximab)
or late vaccination (twelve months after rituximab). Two and six months after
the first vaccination with synflorix (conjugated pneumococcal vaccine) and
act-Hib (conjugated Hib vaccine), the second and third vaccination will be
given with synflorix and act-Hib and pneumovax (pneumococcal polysaccharide
vaccine) and act-Hib respectatively.

- At the first visit when patients are randomized, blood will be drawn and the
first vaccination with Prevnar 13 and Act-Hib will be given.
- 3 weeks later, blood will be drawn.
- 2 months later, the second vaccination with Prevnar 13 and Act-Hib will be
given.
- 3 weeks after de second vaccination, blood will be drawn.
- 8 months later, the third vaccination with Pneumovax and Act-Hib will be
given.
- 3 weeks after the 3rd vaccination, blood will be drawn.
-14 months later, blood will be drawn.

Patients will be vaccinated at three separate moments with pneumococcal and
conjugated Hib vaccines that are indicated for this patient group according to
existing vaccination protocols. Blood samples will be drawn before the first
vaccination and three weeks after each vaccination and six months after last
vaccination, so five blood samples will be drawn. The vaccine will be used in
the authorised form and for the authorised purpose, therefore no additional
risks are to be expected. Patient discomfort might consist of a painful arm/leg
after vaccination. Adverse events which are common (0.1-1%) include headache,
fever, myalgia, artralgia, nausea, vomiting, and pain and redness at the
vaccination spot. Rare events are allergic reactions (very rare leading to
shock), angio edema, neurologic disorders and urticaria. Benefit is protection
against infection with Hib and S. pneumoniae.