Page 49 - 2019_06-Haematologica-web

The role of rituximab in ITP
Table 4. Rituximab in children.
Author
Wang 2005117
Taube 2005121
Bennett 2006118 & Mueller 2009119
Parodi 2009123
Grace 2012124
Patel 201240
Matsubara 2014125
Oved 2017122
Rituximab dose (mg/m2)
375 mg/m2 x 4 weekly
375 mg/m2
375 mg/m2 x 4 weekly
375 mg/m2
x 4 weekly
NA
375 mg/m2 x 4 weekly
375 mg/m2 x 4 weekly
Rituximab
375 mg/m2
x 4 weekly + dexamethasone 28 mg/m2 days 1-4; 15-18; 29-32
Number of patients
24
22
36
49 80 66
22
33
Median age years (range)
12 (2-19)
5.8 (2.5-15.2)
11.2 (2.6-18.3)
7.4 (0.7-17.6) 7.5 (4.9-12) 12 (2-17)
F:M
58%:42%
64%:36%
42%:58%
67%: 33% 56%:44% 61%:39%
ITP phase
Chronic
Chronic
Chronic
77% chronic
Chronic
Median duration of
ITP 20 months (1 month – 9 years)
Median duration of ITP 18.5 months (2 – 120 months)
Persistent/ chronic ITP
ORR (CR)
78%* (63%)
59%*
(32%) 31%°
69%° (53%) 64%° 57%°
50%* (41%)
48%°
12 months
NA
NA
31%
NA NA 33%
27%
NA
24 months
NA
NA
NA
NA NA NA
18%
NA
36 months
NA
NA
NA
60% NA NA
NA
NA
Last follow-up
NA
NA
NA
NA
NA
26% at 5 years
14% at 5 years
27% at a median
FU of 35 months (range 10-58)
4.2 (0.25-11.6) 50%:50%
11 (1-17)
58%:42%
F:M: female to male ratio; ITP: immune thrombocytopenia; ORR: overall response rate; CR: complete response; NA: not available; FU: follow-up; Response rates are calculated using as denomina- tor all the patients treated with rituximab. *response = platelet count ≥30x109/L; °response = platelet count ≥50 x 109/L; §sustained platelet count over 50x109/L in 4 consecutive weeks.
patients with severe refractory ITP or Evans syndrome treated with “standard-dose” rituximab. After a follow up of 1 year, 31% of them maintained a platelet count >50x109/L.118,119
A systematic review including 14 studies with a total of 323 pediatric ITP patients reported a pooled response rate of 68%, and a pooled CR rate of 39%, with a median duration of response of 12.8 months.120
“Low-dose” rituximab has also been tested in children with ITP: Taube et al. explored the efficacy of a single dose of rituximab (375 mg/m2) in 22 patients with chronic ITP; the ORR was 59%, with a 27% CR rate, and 36% of patients maintained a long-term remission (median dura- tion of remission 13.5 months; range 2-16 months).121
Oved et al. explored the addition of three 4-day cycles of dexamethasone (28 mg/m2) to “standard-dose” rituximab in 33 children with persistent/chronic ITP. The ORR was close to 50%, and 62% of the responders maintained the remission for a median of 35.5 months.122
Factors predictive of response were also sought in chil- dren. Bennett et al.118 found a weak association between response and Evans syndrome, female sex and black race. Parodi and colleagues performed a retrospective study including 49 children (77% with chronic ITP) treated with “standard-dose” rituximab (ORR 69%, 60% relapse-free survival at 36 months), and found a significantly higher probability of relapse-free survival in males aged >14 years and females aged >12 years (88.9% vs. 56.7%), in patients who achieved a CR (70.2% vs. 25%) and in patients who achieved the response within 20 days of treatment (73.7% vs. 22%).123
Among 80 pediatric patients with chronic ITP treated with rituximab (ORR 64%), Grace et al. found a higher
response rate in patients who had previously responded to steroids (87.5% vs. 47.9%) and in those with secondary ITP (89.5% vs. 55.7%).124
In a study by Oved et al.,122 female adolescents with ITP lasting less than 24 months had a higher sustained remis- sion rate (47%) than that of either the entire group (27%) or the male patients (7%).
The drug is usually well tolerated also in children, with a toxicity profile superimposable to that of adult patients in terms of immediate and long-term toxicity.117,118,125,40,123 Significant hypogammaglobulinemia was observed in 15% of patients treated with the combination of ritux- imab and dexamethasone,122 although this adverse event was transient.
The reported rate of serum sickness was higher in pedi- atric patients than in adults, particularly in the first series, occurring in up to 10% of the former.117,118 Clinical mani- festations ranged from severe to mild. Laboratory confir- mation can be sought by checking levels of C3 and C4; of note, certain pediatric patients may have a congenitally low C4 level (which may predispose to ITP) and C4 levels should, therefore, be checked prior to rituximab treat- ment.
Discussion
Twenty years after the first use of rituximab in ITP, pub- lished studies show an ORR of nearly 60% and a CR rate of 50%. Long-term remissions occur in 20-30% of patients, with slightly different outcomes possibly related to different selection of populations of patients.
In the interpretation of the results it is worth noting that
haematologica | 2019; 104(6)
1131