Persistent Impairments in Humoral and Cellular Immunity in Patients with Immune Thrombocytopenia Treated with Rituximab: A Sub-Study of a Randomized Controlled Trial
Bibliographic record
Abstract
Abstract Abstract 492 Background: The anti-CD20 antibody, rituximab, is increasingly being used as a treatment for immune thrombocytopenia (ITP). The concern about rare occurrences of progressive multifocal leukoencephalopathy in this population and the reliance on vaccine responses in patients who ultimately require splenectomy calls for additional studies into the integrity of the immune system after rituximab treatment. The objective of this study was to evaluate both the antibody and cellular responses to the Streptococcus pneumoniae polysaccharide vaccine and to the Haemophilus influenza type b (Hib) conjugate vaccine in rituximab-treated patients with ITP. Methods: Adults with primary ITP and a platelet count below 30 x109/L who had participated in a randomized trial of rituximab or placebo were eligible for this prospective sub-study. Six months after the study intervention, patients were given the S. pneumoniae polysaccharide vaccine (Pneumovax-23®, Merck) and the Hib conjugate vaccine (ActHIB®, Aventis). Antibodies against the pneumococcal capsular polysaccharide (anti-PCP) and Hib polyribosyl-ribitol phosphate (anti-PRP) were measured by EIA. A bactericidal assay was used to measure the ability to eradicate Hib in culture. An adequate antibody response was defined as a 4-fold increase in antibody concentration from baseline in the first month post vaccination. IgG anti-PRP ≥ 1 μg/mL was considered protective. For the bactericidal assay, a 4-fold increase from baseline was considered positive. CD3+ T-cells and total (CD19+), naïve (CD19+, CD27−), memory (CD19+, CD27+, CD38−) and pre-plasma (CD19low, CD27hi, CD38hi) B-cells were determined by flow cytometry before and after vaccinations. Interferon-γ (IFN-γ) secreting T-cells were measured by elispot. Results: Patients who had been randomized to receive rituximab (n=14) or placebo (n=6) participated in this prospective study. Compared with placebo, fewer patients in the rituximab group achieved an adequate antibody response to S. pneumonia vaccine (21.4% versus 66.7%) or the Hib vaccine (28.6% versus 83.3%). These results correlated with a reduced bactericidal effect of anti-PRP antibodies observed in patients treated with rituximab compared with placebo (14.2% versus 83.3%). Two patients in the rituximab group demonstrated an adequate rise in antibody titer but with no functional bactericidal activity. In addition, 3 patients who did not mount an adequate antibody response, had IgG anti-PRP titers below protective levels and did not demonstrate bactericidal activity in vitro were considered Hib vaccine failures. There were no Hib vaccine failures in the placebo group. In the rituximab group, total number of B-cells declined rapidly after treatment (1.895 × 104/mL) relative to the placebo group (5.65 × 104/mL) and never fully recovered even 1 year post-treatment. Resting memory B-cells were significantly reduced after rituximab and remained at low levels even up to 1 year. Conversely, naïve B-cells recovered to near normal levels within 6 months of treatment. Activated pre-plasma B-cells increased following vaccination in the placebo group; yet, this response was variable in patients who had received rituximab. CD3+ T-cell numbers were unaffected by rituximab and vaccination; however, the number of IFN-γ- secreting T-cells were lower in the rituximab group. Conclusions: Rituximab treatment was associated with an impaired antibody response to vaccination, which in some patients was only demonstrated by impaired bactericidal activity. The expected increase in B-cell subsets was not observed following vaccination in the rituximab group, and T-cells, while normal in number, demonstrated functional impairments. Our findings characterize subtle defects in immunity which may persist after rituximab treatment. Disclosures: Off Label Use: Rituximab is not licensed for use with ITP patient. Kelton:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman-LaRoche: Research Funding. Arnold:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman-LaRoche: Research Funding.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.007 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.006 | 0.006 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.004 | 0.003 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".