Evaluation of Prime-boost Anti-pneumococcal Vaccination in Patients With Diffuse Large B Cell Lymphoma Treated With Rituximab

Study Overview
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Brief Summary
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Pneumococcal infections remain frequent and potentially fatal. To prevent them, two anti-pneumococcal vaccines exist: a 13-valent conjugate vaccine (Prevenar®) and a 23-valent polysaccharide vaccine (Pneumovax®). For their utilization, several studies approved a prime-boost strategy. It consist two administer Pneumovax® at least two months later than Prevenar®. Patients with diffuse large B-cell Lymphoma (DLBCL) have a higher-risk to develop a pneumococcal infection. The main reason is immunosuppression, induced by rituximab (B cell depletion), chemotherapy and lymphoma. Patients are treated by immunochemotherapy, combining rituximab (anti-CD20 monoclonal antibody) and conventional chemotherapy (CHOP). However, those patients have a low rate of vaccination (about 15%).

Detailed Description
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Pneumococcal infections remain frequent and potentially fatal. To prevent them, two anti-pneumococcal vaccines exist: a 13-valent conjugate vaccine (Prevenar®) and a 23-valent polysaccharide vaccine (Pneumovax®). For their utilization, several studies approved a prime-boost strategy. It consist two administer Pneumovax® at least two months later than Prevenar®. Patients with diffuse large B-cell Lymphoma (DLBCL) have a higher-risk to develop a pneumococcal infection. The main reason is immunosuppression, induced by rituximab (B cell depletion), chemotherapy and lymphoma. Patients are treated by immunochemotherapy, combining rituximab (anti-CD20 monoclonal antibody) and conventional chemotherapy (CHOP). However, those patients have a low rate of vaccination (about 15%). Also, in the current literature, rare studies investigated prime-boost immunogenicity in this relevant population. The investigators will evaluate vaccinal response of 10 serotype-specific immunoglobulin G (1, 3, 4, 6B, 7F, 9V, 14, 18C, 19F, 23F) at different time of treatment. The investigators search to compare efficiency of prime-boost anti-pneumococcal vaccination according to the time of prevenar administration (before or after immunochemotherapy) and to the dose of Prevenar® (single or double-dose).

Official Title
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Evaluation of Prime-boost Anti-pneumococcal Vaccination in Patients With Diffuse Large B Cell Lymphoma Treated With Rituximab (EVAPOR Study)

Conditions
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Pneumococcal Infections, Lymphoma, Large B-Cell, Diffuse

Intervention / Treatment
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* Biological: Anti-pneumococcal vaccination with prime-boost strategy in patients with diffuse large B cell lymphoma


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: De novo Diffuse Large B-Cell Lymphoma diagnostic (according 2016 World Health Organization (WHO) classification) Treatment decision by immunochemotherapy (R-CHOP) Age over 18 years old Negative pregnancy test at inclusion Active contraception at inclusion Free and informed consent procedure at inclusion Affiliation of the social security system Exclusion Criteria: Patient with prior treatment by immunotherapy or chemotherapy Patient with prior treatment by debulking chemotherapy (COP) Patient with prior treatment by high-dose of corticosteroids Patients with an autoimmune disease Patients with a diffuse large B-cell lymphoma from transformation (follicular lymphoma, chronic lymphoid leukemia) Immunosuppressed patient with : asplenia, hereditary immunodeficiency disorder, infection by HIV, hepatitis B or C viruses, transplanted patient, hematopoietic stem cell transplantation, nephrotic syndrome, meningeal breach, cochlear implants. Patients vaccinated in the last month before inclusion Patients with prior transfusion of blood-products or immunoglobulins in the last three months before inclusion Patient with bleeding disorders or thrombopenia contraindicating intramuscular injection Patient with prior pneumococcal documented infection Patient with current pregnancy and/or breastfeeding Patient under curatorship or guardianship

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Single-dose before treatment<br>12 patients will receive a single-dose of prevenar before immunochemotherapy (R-CHOP) following two months later by pneumovax injection | Biological: Anti-pneumococcal vaccination with prime-boost strategy in patients with diffuse large B cell lymphoma<br>* The investigators aim to describe efficiency and tolerability of prime-boost vaccination against pneumococcus in patients with Diffuse large B-cell Lymphoma. The investigators search to evaluate immunogenicity of prime-boost depending on the time of prevenar administration (before or after immunochemotherapy) and on the dose (single or double dose).<br>|
| Active Comparator: Single-dose after treatment<br>12 patients will receive a singe-dose of prevenar three weeks after the beginning of the immunochemotherapy (R-CHOP) following two months later by pneumovax injection | Biological: Anti-pneumococcal vaccination with prime-boost strategy in patients with diffuse large B cell lymphoma<br>* The investigators aim to describe efficiency and tolerability of prime-boost vaccination against pneumococcus in patients with Diffuse large B-cell Lymphoma. The investigators search to evaluate immunogenicity of prime-boost depending on the time of prevenar administration (before or after immunochemotherapy) and on the dose (single or double dose).<br>|
| Experimental: Double-dose before treatment<br>12 patients will receive a double-dose of prevenar before immunochemotherapy (R-CHOP) following two months later by pneumovax injection. | Biological: Anti-pneumococcal vaccination with prime-boost strategy in patients with diffuse large B cell lymphoma<br>* The investigators aim to describe efficiency and tolerability of prime-boost vaccination against pneumococcus in patients with Diffuse large B-cell Lymphoma. The investigators search to evaluate immunogenicity of prime-boost depending on the time of prevenar administration (before or after immunochemotherapy) and on the dose (single or double dose).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of responder patients at the end of treatment. | The response to a specific serotype was defined as both a 2-fold increase of pneumococcal IgG antibody level (ELISA) between baseline and end of treatment (one month after last RCHOP cycle) and an antibody level >= 1µg/mL. at end of treatment. | - day of Prevenar® administration, - day of Pneumovax® injection (2 months after Prevenar® injection) - six weeks after Pneumovax® injection - 1 month after last R-CHOP cycle, - at six months after end of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of responders patients to each serotype as assessed by opsonophagocytosis | response to a specific serotype was defined by both at least a fourfold increase of the opsonization index (OI, defined by the serum dilution killing 50% of the bacterial inoculum) between baseline and end of treatment. | - day of Prevenar® administration, - day of Pneumovax® injection (2 months after Prevenar® injection) - six weeks after Pneumovax® injection - 1 month after last R-CHOP cycle, - at six months after end of treatment. | 
| Tolerance of the double-dose compared to single dose of Prevenar® | Presence of local and/or systemic reaction detailed on a questionary (fever, headache, fatigue, chills, rash, muscle pain, joint pain) | During the two weeks after both vaccines injection | 
| Clinical efficiency | Pneumococcal documented infection during treatment (pneumonia, meningitis, acute media otitis, bacteremia) with proof of pneumococcal presence (on blood cultures, chest radiography, other samples) | During all the study (one year for each patient) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, pneumococcal vaccination, prime-boost, rituximab