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The role of rituximab in ITP
that in several other studies the predictive role of age and gender could not be confirmed.40,41,43,46,57 A disease duration of less than 12 months has also been frequently related to better outcomes,41,43,54,58 as well as the achievement of com- plete remission,39,40,46,54,56 while the influence of a previous splenectomy is not completely clear.40,46
The role of antiplatelet autoantibodies (APA) as factors predictive of response is controversial. Differently from other autoimmune diseases, APA in ITP are neither very specific nor sensitive, and for this reason APA are not cur- rently recommended as a diagnostic test for ITP.59,60 A reduc- tion of APA levels has been associated with an increase in platelet count,61 and the presence of platelet-bound antibod- ies has been associated with a better response to ritux- imab.62 The persistence of autoantibodies in non-respon- ders may suggest that rituximab had not removed the long- lived, antibody-producing plasma cells. There is also a small cohort of patients who respond despite undetectable anti- bodies: in those cases, either laboratory assays are not able to identify the antibody, or the response comes from the elimination of B-cell-mediated activation of T cells.61
A more recent study did not show any correlation between the presence of APA and the response to ritux-
Table 2. Most relevant studies with different dose schedules of rituximab.
imab, but found that rituximab resulted in a significant reduction of anti-GPIIb/IIIa but not anti-GPIb/IX levels.63 In an unconfirmed study, patients with anti-GPIb/IX were shown to have a lesser response to intravenous immunoglobulins and steroids.64,65 In patients treated with rituximab, the presence of antibodies against GPIIb/IIIa led to a higher response rate than that in patients without anti-GPIIb/IIIa, while the presence of anti-GPIb/IX did not significantly influence the outcome.66 This is potentially due to the different modes of action of the autoantibodies: anti-GPIIb/IIIa antibodies induce platelet destruction by Fc-dependent phagocytosis, while the action of anti- GPIb/IX may be FcR-independent67 and instead increase the hepatic clearance of desialylated platelets.
In summary, the role of APA in response to rituximab remains unclear and may depend on the laboratory doing the testing, the phase of the disease, and which tests are performed.
Long-term outcome of rituximab treatment of immune thrombocytopenia
Only a small proportion of patients maintain a long- term remission after rituximab: in a prospective French
Author
Mahevas 2013£,45
Khellaf 2014$,41
Tran 201452
Zaja 2010$,50
Zaja 2012£,44
Gracie 2018$,51
Rituximab dose
375 mg/m2 weekly x 4
Number Median age, ofpatients years(range)
F:M
64%:36% 67%:33%
64%:36% 65%:35%
57%:43%
62%:38%
NA
NA
57%:43%
42%:58%
ITP phase
ND 18%;
P 26%; C 56%
ND 17%; P 26%; C 57%
56% chronic 66% chronic
Median ITP duration 24.8 months (1.2 - 470)
Median ITP duration 16 months (2 - 451)
Median ITP duration 24 months (2-324) Median ITP duration 31 months (3-264)
Median ITP duration 12.9 months (3.1-62) median ITP duration 12 months (2.9-43.5)
Early response
54% (32% CR) at 3 months*
54% (32% CR) at 3 months*
62%* 61%*
43.5% (CR 9.3%) at week 8°
6 months
NA NA
80% 90%
NA
NA
NA
NA
61.7% (35% CR)*
64.1% (42% CR)*
12 months
36% (28% CR)
50% (41% CR)
62% 70%
29%£ 66%$
61%
32%
50%
60%
60%
24 months 36 months Last follow-up
1000 mg on days 1 46 and 15
375 mg/m2 173 weekly x 4
1000 mg 72
2 weeks apart
1000 mg on days 1 108 and 15
100 mg weekly x 4 48
100 mg weekly x 4 25
375 mg/m2 weekly x 4 32
100 mg weekly x 4 169
375 mg/m2 weekly x 4 113
60.5% (CR 39.5%)°
61
52 (34-70) 55 (34-76)
51 (21-71) 53 (33-73)
49 (19-85)
41 (16-74)
43 (14-74)
51 (16-80)
57 (30-70)
59 (35-72)
NA NA
50% 43%
NA
45%
28%
45%
53%
51%
NA 31% (26% CR) Median FU 36 months
NA 48% (41% CR) Median FU
20.5 months
38% NA / NA
NA NA
40% NA
23% 23% at 48 months
40% 35% at 48 months
50% NA
40% NA
52% (28% CR)*
66% (50% CR)*
NA
NA
F:M: female to male ratio; ITP: immune thrombocytopenia; ND: newly diagnosed; P: persistent phase ITP; C: chronic phase ITP; NA: not available; CR: complete response; FU: follow-up. $Response rates calculated considering as denominator only patients who responded to rituximab. £Response rates calculated considering as denominator all treated patients. *response = platelet count ≥30x109/L ° response = platelet count ≥50x109/L
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