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Rituximab combined with belimumab for adult ITP
Table 2. Adverse events reported in the study. Patients Infusion related reactions
1 Throat itching, grade I, (RTX W0)
2 Sore throat, grade I, (RTX W0)
3 No
4 No
5 Throat itching, grade I, (RTX W0)
6 No
7 Headache, grade I, (RTX W0)
8 No
9 No
10 No
11 No
12 Abdominal discomfort grade I, (RTX W0)
13 No
14 No
15 No
Adverse events, CTCAE grade, imputability
Arthralgia (W2- W8) grade I, possible No
Transient hypereosinophilia < 1000 /mm3 (W40) treated with zentel/stromectol, grade 1, not related
Gluteus medius tendinitis (W8-W12), grade I, not related Nasopharyngitis (W10), grade I possible
Supraspinatus tendinitis (W24), grade I, not related
Serum thickness (W2), grade I, related
Candida vulvovaginitis (W8), grade I, not related
Rhinorrhea (W2) and (W12), grade I, not related Bronchitis (W5), possible
Pain extensor muscles of the forearm, (W24), grade I, not related Acute cystitis (W4), grade I, possible
Arthralgia (W3), thoracic pain (W3), grade I, not related Viral conjunctivitis (W4), grade I, not related
Arthralgia (W52), grade I, not related
Rhinorrhea (W8), grade I, not related Pharyngitis (W4), grade I, possible Bronchitis (W50), grade I, possible
Gout arthritis (W44), grade I, not related
Increased number of monocytes after TPO-RA, grade I, not related
Nasopharyngitis (W20), myalgia (W20), grade I, possible Knee pain (W52), grade I, not related
Bronchitis (W9), grade I, possible
Memory problems W14, grade I, not related Erectile dysfunction W36, grade I, not related
Low back pain (W12), grade I, not related
Bronchitis (W0-W2), grade I, possible
CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; RTX: rituximab; W: week.
the Ki67 marker) was increased at baseline in ITP patients as compared with healthy donor controls (n=11, P<0.05, Online Supplementary Figure S4). A marked reduction of plasmablasts/PC was observed from W4 and lasted until W52, when the number of circulating plasmablasts was low and comparable to that in healthy donors (Figure 3H; Online Supplementary Figure S5).
Because changes in T-cell homeostasis have been described with RTX, we investigated peripheral T-cell compartments before and after treatment. We observed no significant changes in the distribution of CCR7+CD45RA+ naive (TN), CCR7− CD45RA− memory (TEM), and CCR7+CD45RA− central memory (TCM) in CD4+ and CD8+ cells. The expression of CD38 and HLA- DR activation markers on CD4+ or CD8+ T cells was not modified with treatment. Finally, we observed no signifi- cant change in CD4 T-cell polarization (TH1/TH2/TH17) based on the expression of CXCR3, CXCR5, CCR6 (Online Supplementary Figure S6). By contrast, the activated subset of circulating follicular helper T cells (activated cTfh) identified as CD4+CD45RA−CXCR5+ inducible T-cell costimulator (ICOS)+ programmed death1 (PD1)+ cells16 (Figure 4A) was increased at baseline in ITP patients as compared with healthy controls (Online Supplementary Figure S4). While circulating Tfh percentage remained sta- ble throughout the study, the percentage of activated cTfh cells was significantly decreased in patients receiving RTX plus belimumab but not RTX alone despite a trend at W4, and remained significantly decreased at W24 and W36 in patients receiving RTX plus belimumab versus RTX alone
(Figure 4B and C). There was no correlation between the response (initial response or at W52) and BAFF or cTfh (not shown).
Discussion
The rationale of this study was based on three observa- tions: i) the presence of anti-platelet long-lived PC in the spleen of patients who did not respond to RTX; ii) the increased BAFF level in the spleen and serum of these patients, and iii) the observation that combining an anti- BAFF antibody with anti-CD20 treatment induced a major depletion of long-lived PC in a mouse model.6,9,10 The results of this prospective phase IIb pilot trial of ITP showed that combining RTX with five infusions of beli- mumab led to an overall response rate of 80% with a 66.7% CR rate at 1 year. Although the sample size was limited, these response rates were higher than expected with RTX alone (overall response rates of 40% to 50% at 1 year, with 30% of CR, according to most previous stud- ies conducted in ITP).4,5,17,18 These response rates were also higher but closer to those obtained with RTX and dexam- ethasone19 or RTX associated with high-dose dexametha- sone and ciclosporin.20 Hence, these results are promising and provide a real proof of concept for this new combina- tion.
Most consecutive patients included in this study were women with persistent ITP. Disease duration <12 months, young age and female sex have been found associated
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