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The role of rituximab in ITP
lular immunity. In a mouse model of T-cell-mediated ITP, B-cell depletion resulted in a significantly decreased prolif- eration of splenic CD8+ T cells in vitro, which correlated with an in vivo normalization of platelet counts.86
However, T-cell remodulation in responders seems not to be a specific effect of rituximab since similar changes have also been observed in patients who respond to dex- amethasone or thrombopoietin receptor agonists.87–89 It is possible that other biological factors concur to this effect. In particular, it has been proposed that the platelet count increase itself, either directly or via release of transforming growth factor-b, may cause a positive immune-modulat- ing effect.90
Why a proportion of patients do not respond to ritux- imab is unknown. This could be caused by either the per- sistence of long-lived, antibody-secreting plasma cells in the spleen81,91 and/or in the bone marrow or by the abnor-
mal activation of T cells, whose activity is not switched off by B-cell depletion. Finally, if the patient does not actu- ally have ITP this would likely explain non-response as well.
Adverse events
Rituximab is generally a well-tolerated therapy, and adverse events are usually mild and easily manageable. The major concerns derive from the possible induction of hypogammaglobulinemia, and the increased risk of cer- tain infections.
Infusion reactions after the first administration of ritux- imab are experienced by a variable proportion of patients, ranging from nearly 60% in the first trials46 to 15% in the more recent reports,41 and are related to immediate cytokine release. They are usually easily manageable, and
Table 3a. Studies with rituximab plus dexamethasone.
Author
Zaja 201069
Gudbrandsdottir 201370
Bussel 201454
Chapin 201655
Treatment
375 mg/m2 x 4 weekly + 1 cycle dexa (40 mg/day for 4 days)
375 mg/m2
x 4 weekly +
up to 6 cycles dexa (40 mg/day for 4 days every 1
to 4 weeks)
375 mg/m2 x
4 weekly + 3 cycles dexa (28 mg/m2/day for 4 days)
375 mg/m2 x
4 weekly + 3 cycles dexa (28 mg/m2/day for 4 days)
Number of patients
Median age, years (range)
49 (33-65)
ITP phase
Previously untreated
ND
Median ITP
duration: 16 (1-286) months
Early response
37%° at week 4
NA
88% at week 8°
NA
6 months
12 months 24 months
36 months
43%
NA
50%
NA
Last follow-up
43% 30-months estimated probability of duration of response
NA
47% estimated sustained response at 64 months FU
33.3% sustained response at 72 months FU°
49
62
41
49
F:M
55%:45%
63% 50%
57%° 53%
82% 65%
NA NA
47%
NA
58%
NA
51 (36-63) 58%:42%
36 (18-64)
37
53%:46%
55%:45% Duration of ITP: range
0 – 258 months
F:M: female to male ratio; ITP: immune thrombocytopenia; dexa: dexamethasone; ND: newly diagnosed; NA: not available; FU: follow-up; yrs: years. Response rates are calculated using as denom- inator all the patients treated with rituximab.°response = platelet count ≥50x109/L
Table 3b. Studies with rituximab in combination with drugs other than dexamethasone.
Author
Zhou 2015£,73
Choi 2015$,71
2017£,74 + dexa 40 mg days 1-4 + rituximab
100 mg weekly for 4 weeks
Treatment
Rituximab 100 mg weekly for
4 weeks + rhTPO 300 μg/kg/day for 14 days
Rituximab 100 mg weekly
for 4 weeks
Number Median age, of patients years (range)
F:M
65%:35% 66%:34%
55%:45%
93%:7%
62%:38%
ITP phase
Median ITP duration
12.5 months (3-72) Median ITP
duration
11 months (3-65)
ND or Persistent ITP: 7; Chronic ITP: 13
Unknown
ND
ORR
93% (50% CR)* 93% (50% CR)*
NA
6 months
67.2% 55.6%
60%*
12 months
24.6% 18.5%
92%
NA
80%
24 months
NA NA
76%
NA
70%
77 38
42 (13-82) 42.5 (12-68)
NA
52 (18-76)
40 (16-61)
Rituximab 100 mg weekly for 4 weeks 20 + dexa 40 mg days 1-4 + cyclosporine 2.5-3 mg/kg/day (days 1-28)
Li 2015£,72
Rituximab 100 mg weekly for 4 weeks 14
93% (50% CR)* 71% (40% CR)
100% (92% CR)* NA
+ rhTPO 300 μg/kg/day for 14 days Gomez-Almaguer Eltrombopag 50 mg/day, days 1-28 13
F:M: female to male ratio; ITP: immune thrombocytopenia; ORR: overall response rate; rhTPO: recombinant human thrombopoietin; CR: complete response; NA: not available; dexa: dexamethasone; ND: newly diagnosed. $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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