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E. Lucchini et al.
Potential advantages of the lower dose include avoidance of severe side effects, steroid-sparing effects, the greater possibility of administering repeated courses, and decreased cost. Zaja et al. investigated the efficacy of ritux- imab given at a dose of 100 mg (“low dose”) weekly for 4 weeks in 48 ITP patients.50 In an indirect, non-randomized comparison, both the initial response (ORR 60.5% and CR 39.5%) and the duration of response (12- and 24-month cumulative relapse-free survival rates of 61% and 45%, respectively) were moderately lower in this group than in patients treated with “standard dose”. The time to response was also longer than that observed with the “standard dose”. This may be due to the fact that the depth of B-cell depletion reached in peripheral blood might not correlate with the depletion in other organs, and the 100 mg dose is probably not enough.
A recent UK study retrospectively compared 113 patients who received “standard dose” rituximab to 169 who received the “low dose”. They found that the low dose was not significantly different from the standard dose with regards to ORR (at 2 months, 56% vs. 59%; at 6 months, 62% vs. 64%), time to maximum platelet count (77 vs. 74 days), time to next treatment (4.6 vs. 4.3 months) and duration of response.51
Some groups explored a fixed dose of rituximab, 1000 mg given twice on days 1 and 15, which is the dose sched- ule licensed for rheumatoid arthritis. Khellaf et al., in a prospective registry including 248 patients, compared the “standard dose” to the “rheumatoid arthritis-like” regi- men. They did not find any difference in terms of initial or long-term response between the two groups.41 In a multi- center, single-arm study (R-ITP1000 study), Tran et al.
found that the “rheumatoid arthritis-like” fixed dose led to an ORR of 44% at week 8 in patients with relapsed/refrac- toryITP.52
A multicenter, randomized, phase II Dutch trial com- pared three rituximab dosing schemes in 156 patients with relapsed or refractory ITP: “standard dose” ritux- imab, two weekly 375 mg/m2 doses and two weekly 750 mg/m2 doses. Response rates were similar within the three arms (63%, 59% and 61%, respectively), with a relapse- free survival of 72% at 1 year and 58% at 2 years.53
The results of the most relevant studies with different dosing schedules of rituximab are summarized in Table 2.
Factors predictive of response
Over the years, multiple factors have been investigated with the aim of predicting response to treatment. Several studies highlighted the correlation of age and gender with outcome. In the very first study, Stasi had already pointed out that women and young patients had better responses.38 This finding was subsequently extended by Bussel et al.,54 who showed that women of child-bearing age whose duration of ITP was less than 24 months had a long-term response comparable with that obtained after splenectomy (60% long-term treatment-free responses). Another study with the same treatment schedule pointed out that adoles- cent females with an ITP duration of less than 12 months had the longest duration of response.55 Similar results were also reported with rituximab alone: young (<40 years) women had a significantly higher probability of achieving a response (73%), a complete response (56%), and as well as a better long-term response (47% after 72 months) com- pared with the other groups.56 It must be noted, however,
Table 1. Most relevant studies with rituximab administered at a standard dose of 375 mg/m2 weekly for 4 weeks in patients with immune thrombocytopenia.
Author Number of Median age, F:M ITP phase
ORR 6 months 12 months 24 months 36 months Last follow-up
patients
Stasi 200138 25
Cooper 2004£, 46 57
Zaja 2006£, 58 37
Medeot 2008£, 68 26
Godeau 2008£, 39 60
Cervinek 2012£, 43 114
Patel 2012£, 40 72 Arnold 2012£, 47 33 Mahevas 2013£, 45 61
Khellaf 2014$, 41 173 Ghanima 2015$, 48 55
Marangon 2017£, 56 103
years (range)
46 (22-74)
46 (21-79)
NA
55 (18-76)
48 (18-84)
55 (21-89)
39 (18-78) 40 (30-59) 52 (34-70)
51 (21-71) 46 (27-61)
46 (15-82)
64%:36% Chronic
68%:32% Chronic
NA Median ITP duration: 34.5
(1-264) months
81%:19% Median ITP duration 34.5
(4 - 264) months 67%:33% Chronic
53%:47% 16% ND; 84% chronic
or persistent phase 65%:35% Most chronic phase
58%:42% 50% ND
64%:36% 18% ND; 26% persistent phase;
56% chronic phase 64%:36% 56% chronic
73%:27% 33% ND; 24% persistent phase;
44% chronic phase
59%:41% Median ITP duration
20 (1 - 403) months
52% (20% CR)° NA
NA NA
NA NA
NA NA
55% 45%
40% (30% CR)° 33%
NA
NA
NA
41%
NA
NA
NA
NA
31% (26% CR) median FU of 36 months
38% NA
40%
NA
32% at a median FU of
72 weeks (18 months)
40.5% at a median FU of 25 months (3-55)
35% at a median FU of 57 months
NA
NA
21% at 5 years FU NA
NA
NA
24% at 78 weeks FU
21% at 96 months
54%
(32% CR)°
73% (54% CR)°
69% (54% CR)°
NA
NA
57%° NA
NA
NA
NA
NA
54% NA (32% CR)
at 3 months*
62%* 80%
73% 60% (51% CR)*
55% NA
(36%CR)*
36% (28% CR) NA
62% 50% 45% NA
NA 42%
72% (48% CR)* ORR 69% NA
(45% CR)
NA 38% 31%
62.5% (53% CR)* NA NA
F:M: female to male ratio; ITP: immune thrombocytopenia; ORR: overall response rate; CR: complete response; NA: not available; FU: follow-up; ND: newly diagnosed. £Considering as denominator all the patients.$Considering as denominator only patients who responded to rituximab. *response = platelet count ≥30x109/L. °response = platelet count ≥50 x 109/L
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haematologica | 2019; 104(6)