H e m a t o lo g y E d u c a t io n - European Hematology Association

platelet counts and/or bleeding. The primary study endpoint
was a durable response, defined by a platelet
count of more than 50x10 9 /L and twice baseline for 6
out of the last 8 weeks. Both splenectomized and nonsplenectomized
patients had overall responses to
Romiplostim (4 weeks of 24 with platelets > 50x10 9 /L)
with 79% and 88% response rates, respectively. Less
rescue medications were used on the active treatment
arm, and there were increased rates of discontinuation
or reduction of concomitant medications. As before, the
most common adverse event was headache. There were
three deaths during the study in the placebo arm. One
subject from the treatment arm died of intracranial
hemorrhage soon after completion of the study. One
splenectomized patient developed increased bone marrow
reticulin while receiving Romiplostim, which
resolved after cessation of the drug. One elderly subject
with extensive thrombotic history developed a popliteal
thrombosis on the treatment arm: the platelet count
was 11x10 9 /L at the time. The clot was treated and the
patient remained on the study.
Results from a long term, open label study continued
to support the efficacy and safety of Romiplostim. 16
From 2004 to 2010, 292 patients had been followed for
up to 5 years. Romiplostim increased the platelet counts
to over 50x10 9 /L in 95% of patients. Of these responders,
their platelet counts were in the target range on
67% of visits. More than half of the patients maintained
platelet counts greater than 50x10 9 /L for 90% of visits.
Study subjects had the option to self-administer at
home, and two-thirds of patients did so successfully.
Most patients were maintained on a constant dose.
Headache was the most common adverse event. There
were serious adverse events related to Romiplostim in
13 patients: bone marrow reticulin was elevated in 8
patients, 12 patients had severe bleeding, and 7 patients
had thrombotic events. Three patients died during the
study, but none of the deaths was deemed related to
Romiplostim therapy. Two patients developed neutralizing
antibodies against Romiplostim that disappeared
after cessation of the drug; these antibodies did not
cross react with native TPO.
Finally, a phase 3 comparison study of Romiplostim
involved head-to-head comparison with standard of care
in a multi-center, randomized, open label, 52-week efficacy
study. 17 Non-splenectomized adults were treated
with weekly subcutaneous Romiplostim (157 patients)
or the institutional standard of care (77 patients).
Subjects receiving Romiplostim had fewer treatment
failures than those receiving standard of care (11% vs.
30%, respectively) as well as fewer splenectomies (9%
vs. 36%, respectively. Patients receiving Romiplostim
also had lower rates of bleeding and fewer blood transfusions.
Using the SF36 assessment scales, the
Romiplostim arm had improved quality of life compared
with standard of care. Adverse events were similar to
previous studies, with headache as the most common
adverse event. No patients had to cease Romiplostim use
due to an adverse event. There were two deaths in the
standard of care arm and one death in the Romiplostim
arm: none were felt to be related to therapy. This study
suggested that Romiplostim therapy in adults with
chronic ITP prior to splenectomy could delay splenectomy
as compared with standard of care. Long term follow
London, United Kingdom, June 9-12, 2011
up of these patients has not been reported.
A 12-week randomized, placebo-controlled pediatric
phase 2/3 trial was performed to determine the safety,
dosing, and efficacy of Romiplostim in children with
chronic ITP. 18 Fifteen of 17 subjects responded to
Romiplostim by achieving a platelet count greater than
50x10 9 /L for 2 weeks in a row; none of the five placebo
patients did this. Only one patient had an (unrelated)
serious adverse event, a flu-like illness followed by sepsis.
Eltrombopag clinical trials
The first phase II clinical trial of Eltrombopag in
chronic (then duration of ITP of 6 months) ITP with
platelet counts less than 30x10 9 /L was a randomized,
double blind, placebo-controlled study comparing
placebo with 30 mg, 50 mg, or 75 mg of Eltrombopag
daily for 6 weeks. 19 Randomization was stratified by
splenectomy status, concomitant ITP medication use,
and baseline platelet count below 15x10 9 /L. Primary
endpoint was platelet count greater than 50x10 9 /L at
day 43. This endpoint was achieved by 81% of patients
in the 75 mg arm and by 70%, 28%, and 11% of those
in the 50 mg, 30 mg, and placebo arms, respectively.
Median platelet counts by the end of six weeks were 16,
26, 128, and 183x10 9 /L in the placebo, 30 mg, 50 mg,
and 75 mg arms, respectively. Adverse events were similar
in all groups. However, one patient developed serious
liver abnormalities, and a black box warning was
added to the package insert when eltrombopag was
licensed. Interim data analysis after 117 subjects were
enrolled met the stopping criteria for effectiveness; the
study was closed due to eltrombopag showing clear
efficacy at the 50 and 75 mg doses.
A phase III confirmation study included 114 patients
randomized to either 50 mg or placebo. 20 Patients
assigned to the 50 mg dose could increase their dose to
75 mg if they had not achieved 50x10 9 /L by 22 days of
the 43 day trial. The design was otherwise parallel to
the phase II trial above. Response was achieved by 59%
on active drug compared with 19% on placebo, a highly
significant difference. In addition, a small number of
patients increased their platelet count into the 30–
50x10 9 /L range, a clinically significant improvement.
There was no increased incidence of serious or severe
AEs on the active drug arm.
A phase III, randomized, double-blind, placebo-controlled
study compared the efficacy of standard of care
therapy with standard of care plus eltrombopag (RAISE)
over 6 months of therapy, 21 paralleling the Romiplostim
pivotal trials. Subjects were started at a dose of 50
mg/day and then the dose was adjusted to keep the
platelet count above 50x10 9 /L, up to a maximum of 75
mg/kg/day or down to 25 mg/day or even less. Subjects
were also stratified according to baseline platelet count
less than 15x10 9 /L, concurrent ITP therapy, and splenectomy
status. The primary endpoint was the odds of
response to eltrombopag versus placebo.
Of the 135 subjects receiving eltrombopag, 79%
responded, compared with 28% response to placebo, a
more than eight-fold odds increase. Most patients were
taking 75 mg at the end of the 6 month study. In addition,
59% of patients receiving eltrombopag reduced
their concomitant therapies, compared with 32% of
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 181 |