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M. Mahevas et al.
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with better outcomes,4,5,17,18 which could represent a bias although these factors were not associated with the over- all long-term response in our large French prospective reg- istry study.21
The combination strategy was well tolerated, with no severe adverse events and in particular no severe infection. Despite a significant decrease in IgG and IgM titers, we did not observe severe hypogammaglobulinemia. This finding contrasted with the results of the phase IIa study conducted in severe systemic lupus erythematosus, in which severe hypogammaglobulinemia developed in three of 16 patients, with IgG titers <4.5 g/L.22 However, these patients had previously received immunosuppres- sive therapies, which was not the case for our patients. No significant changes in IgG or IgM titers were observed in patients receiving two infusions of 1,000 mg of RTX or 375 mg/m2 once weekly for 4 weeks.5,23,24,25 Therefore, the slight decrease in IgG/IgM titers may reflect the impact on splenic PC, because anti-tetanus and anti-measles anti- body titers, which are secreted by bone-marrow long- lived PC, remained stable over time. The study was not specifically designed to assess the vaccine response; indeed, the timing of pneumococcal vaccination was het- erogenous, and two patients received T-cell–independent vaccines. Half showed no decrease in serological protec- tion for most serotypes with treatment, and only four patients had lost protection for more than seven serotypes. In the absence of a control cohort, it was not possible to measure the specific impact of combination therapy versus rituximab given alone. Vaccine-induced antibody titers against measles and tetanus toxoid were not reduced at 1 year, suggesting that bone marrow long- lived PC were not affected by the combination therapy. Altogether, these results suggest that belimumab and RTX did not induce significant immunodepression.
From an immunological perspective, achieving a sus- tained CR indicates that pathogenic PC were efficiently
Figure 2. Efficacy of rituximab and belimumab combina- tion in adults with persistent and chronic immune throm- bocytopenia. (A) Outcome at week 4 (W4), W12, W24, W36, and W52 according to international recommenda- tions. Complete response (CR) was defined by a platelet count >100x109/L and response (R) by a platelet count 30-100x109/L with at least a 2-fold increase from base- line. Non-responders (NR) are labeled in red; platelet counts were censured when an ITP-directed therapy was started. (B) Evolution of platelet count for each patient dur- ing the study. ITP: immune thrombocytopenia; NR: no response.
targeted. This
platelet autoantibodies in all but one patient with an initial positive test. Despite the absence of a control cohort to clearly assess the impact of this combination on PC, our results support previous results obtained in mouse models showing that combination of RTX and belimumab inhibits the emergence of pathogenic splenic long-lived PC and anti-platelets antibodies.10 Of note, the addition of belimumab had no significant impact on residual circulat- ing PC/plasmablasts, which were mainly expressing IgA and have been described as originating from resident mucosal B cells.26 The kinetics of B-cell repopulation seemed similar regardless of belimumab exposure. We observed a slight delay in the beginning of B-cell reconsti- tution (i.e., reappearance of naïve and transitional B cells), but at W52, all but one patient had detectable B cells in peripheral blood. As previously reported, the memory B-cell pool was profoundly depleted until W52 in both cohorts.
Elevated BAFF levels may lower the stringency of the B- cell selection and allow for rescuing autoreactive cells.27 This hypothesis is supported by studies showing that neg- ative selection of high-affinity DNA-reactive B cells was impaired by increased levels of BAFF during B-cell deple- tion in an auto-immune mouse model.28 This was the basis for studies conducted in systemic lupus erythemato- sus in which belimumab is maintained for more than 52 weeks after RTX. In the present study, the last belimumab infusion was administered at W12 and resulted in a com- plete blockade of BAFF at least until W24. Therefore, B-cell reconstitution occurred in a milieu with increased BAFF levels. Maintaining belimumab for 6 to 9 months after RTX may allow for dampening BAFF levels during B- cell reconstitution and improve the stringency of B-cell selection, thus limiting the risk of relapse after B-cell reconstitution.
Our results also suggest that RTX followed by belimum-
is exemplified by the disappearance of
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haematologica | 2021; 106(9)