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Romiplostim – Management of Chronic Immune Thrombocytopenic Purpura in Adults
dependent increases in platelet counts, with peak counts being achieved
Figure 1: Increase and Maintenance of Weekly Platelet
on days 12–16.
18 Counts in Splenectomised and Non-splenectomised
Patients Treated with Romiplostim
Phase I–II Clinical Trials
200
Two phase I–II trials conducted in the US
20
and Europe
21
in
Splenectomised
Romiplostim
150
Placebo
splenectomised patients with ITP found that romiplostim increased
100
platelet counts in a dose-dependent manner. In the US study (n=24),
50
a platelet count
0
≥50x10
9
/l was achieved in seven of 12 patients treated
02345678 9 1011 12131415 16 1718 19 20 21 22 23 24 25
with 3, 6 or 10µg/kg romiplostim. The platelet count was within the Study week
target range in four patients and above the target range (i.e. >450x10
9
/l)
Placebo* 21 21 21 21 21 21 21 21 21 21 11 12 20 20 20 20 20 20 18 19 18 18 19 17 19
Romiplostim* 42 42 42 42 42 42 41 42 41 41 40 39 41 39 40 40 39 40 39 39 40 38 38 39 40
in three patients. In the European study (n=16; romiplostim dose range
30–500µg administered on days one and 15), platelet responses were 200
Non-splenectomised
seen at all dose levels (30, 100 and 300µg). Treatment with the 500µg
150
100
romiplostim dose was discontinued because of an excessively high
50
platelet count measured in the first patient treated. It was calculated that
0
doses equivalent to
02345678 9 1011 12131415 16 1718 19 20 21 22 23 24 25
≥1µg/kg induced platelet responses in eight of 11
Study week
patients. Transient rebound thrombocytopenia after discontinuation of
Placebo* 21 21 21 21 21 21 21 20 18 19 19 19 18 18 18 18 18 18 18 18 18 18 17 16 17
romiplostim, possibly resulting from enhanced clearance of endogenous
Romiplostim* 41 41 41 41 41 41 40 41 41 40 40 37 40 38 40 38 39 39 38 39 38 36 38 39 39
TPO by the increased number of megakaryocytes or from discontinuation
of concurrent ITP medications during treatment with romiplostim, was
*Number available for measurement.
Source: Kuter et al., 2008.
22
reported in approximately 10% (4/41) of patients in a phase I–II study.
20
This suggests that abrupt cessation of romiplostim without tapering or re-
Table 1: Incidence of Durable* and Overall
†
Platelet Response
initiation of other ITP treatments might be inadvisable.
Splenectomised Patients Non-splenectomised Patients
n (%) n (%)
Phase III Trials
Romiplostim Placebo p-value
‡
Romiplostim Placebo p-value
‡
Two similarly designed, multicentre, randomised, placebo-controlled,
(n=42) (n=21) (n=41) (n=21)
double-blind phase III trials were conducted in parallel. These studies
Durable 16 (38) 0 (0) 0.0013 25 (61) 1 (5) <0.0001
included 63 splenectomised and 62 non-splenectomised patients who response
had chronic ITP and a mean of three platelet counts
Overall 33 (79) 0 (0) <0.0001 36 (88) 3 (14) <0.0001
≤30x10
9
/l despite
treatment for ITP.
21
Patient criteria were identical for both studies, with
response
the exception of splenectomy status. The splenectomised patients had a
*Durable response defined as a platelet count ≥50x10
9
/l during at least six of the last eight
weeks of treatment in the absence of rescue medication at any time during the study.
longer duration of ITP (median eight years versus 2.1 years in non-
†
Either durable or transient response where transient response defined as four or more
splenectomised patients) and were more heavily pre-treated, with over
weekly platelet responses without a durable response from weeks two to 25.
‡
Cochran-Mantel-Haenszel test.
90% of splenectomised patients having received more than three
previous treatments for ITP compared with 32% of non-splenectomised Figure 2: Proportion of Patients Receiving Rescue Medication
patients. Patients were randomised 2:1 to receive romiplostim (n=42
(by Study and Integrated)
splenectomised; n=41 non-splenectomised) or placebo (n=21 in each
100
Placebo
study) once weekly for 24 weeks. Patients receiving concurrent ITP
Romiplostim
treatment with corticosteroids, azathioprine and danazol at a constant 80
dose and schedule were permitted to enter the study. The starting dose
60
of romiplostim or placebo was 1µg/kg and was adjusted to maintain
platelet counts within a target range of 50–200x10
9
/l. A rigorous primary
40
end-point was chosen: durable platelet response, defined as a platelet
count
20
≥50x10
9
/l during at least six of the last eight weeks of treatment in
the absence of rescue medication at any time during the study. A
0
transient response was defined as four or more weekly platelet responses
(p=0.0175) (p=0.0004) (p=0.0001)
Splenectomised Non-splenectomised Total
without a durable response from week two to week 25. Patients assessed
as having had a transient response were not allowed to have received
Source: Kuter et al., 2008.
22
rescue medications within eight weeks of the response. rates are shown in Table 1. Across both studies, 23 romiplostim- and 16
placebo-treated patients were receiving concomitant ITP medications at
Efficacy enrolment. Most of the romiplostim patients (20/23 [87%]; 12/12
Romiplostim increased and sustained platelet counts in both splenectomised splenectomised, 8/11 non-splenectomised) were able to discontinue or
and non-splenectomised patients during the study period (see Figure 1). A substantially reduce (by >25%) these medications by the end of the study,
platelet count ≥50x10
9
/l was maintained for a mean (standard deviation compared with only 38% (6/16; 1/6 splenectomised, 5/10 non-splenectomised)
[SD]) of 15.2 (7.5) and 12.3 (7.9) weeks for non-splenectomised and of the placebo patients. Romiplostim also reduced the percentage of patients
splenectomised patients, respectively, over the 24-week course of the study requiring rescue medications (immunoglobulins, corticosteroids, platelet
compared with 1.3 (3.5) or 0.2 (0.5) weeks, respectively, for placebo transfusions) compared with placebo (26.2 versus 57.1% of splenectomised
recipients. Durable and overall (durable plus transient) platelet response and 17.1 versus 61.9% of non-splenectomised patients; see Figure 2).
EUROPEAN HAEMATOLOGY 49
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