Newland_subbed 12/2/09 15:39 Page 50
Coagulation Disorders Platelet Disorders
Table 2: Most Common Adverse Events* Reported During the
related adverse event was an 82-year-old man who experienced a right
Phase III Studies
popliteal arterial embolism. This patient, who had a history of extensive
peripheral vascular disease and atrial fibrillation, underwent successful
Romiplostim (n=84) Placebo (n=41)
embolectomy and anticoagulation treatment, and continued the study.
n (%) n (%)
Patients with any adverse event 84 (100) 39 (95)
Headache 29 (35) 13 (32)
Other than abnormal platelet counts, no clinically significant treatment-
Fatigue 28 (33) 12 (29)
related changes in vital signs or haematological or serum chemistry values
Epistaxis 27 (32) 10 (24) were seen in any of the patients participating in the phase III studies. No
Arthralgia 22 (26) 8 (20)
antibodies against romiplostim or thrombopoietin were detected.
Contusion 21 (25) 10 (24)
Petechiae 14 (17) 9 (22)
Long-term Extension Study
Diarrhoea 14 (17) 6 (15)
Patients from the phase III studies could enter a long-term open-label
Upper respiratory tract infection 14 (17) 5 (12)
Dizziness 14 (17) 0 (0)
extension study.
24
As of July 2007, 143 patients (60% splenectomised;
Insomnia 13 (16) 3 (7)
median baseline platelet count 17x10
9
/l, range 1–50x10
9
/l) have been
Myalgia 12 (14) 1 (2) enrolled and 142 have been treated with romiplostim for up to three
Back pain 11 (13) 4 (10) years (median 65 weeks).
Nausea 11 (13) 4 (10)
Pain in extremity 11 (13) 2 (5)
Efficacy
Cough 10 (12) 7 (17)
A platelet response (>50x10
9
/l and double the baseline value) was
Anxiety 9 (11) 5 (12)
Gingival bleeding 9 (11) 5 (12)
observed in 87% (124/142) of the patients overall: 30% (42/138) of
Abdominal pain 9 (11) 0 (0)
patients responded after the first dose, and 51% (71/138) after the third
Nasopharyngitis 7 (8) 7 (17)
dose of romiplostim. Ad hoc analysis revealed that platelet counts above
Ecchymosis 6 (7) 6 (15) 50x10
9
/l were maintained for ≥10, ≥25 and ≥52 consecutive weeks by
*At least 10% of patients in either treatment group. 78% (102/131), 54% (66/122) and 35% (29/84) of patients, respectively.
Source: Kuter et al., 2008.
22
Altogether, 84% (27/32) of patients receiving concurrent ITP medications
Tolerability at baseline either discontinued these or reduced their dosage by >25%,
Romiplostim was well tolerated during the two 24-week phase III clinical and the use of rescue medications decreased from 23% (33/142) of
trials.
22
Although adverse events were reported in almost all patients patients during weeks one to 12 to 15% (18/124) during weeks 24–36.
treated with either romiplostim (84/84 [100%]) or placebo (39/41 [95%]),
most events were mild to moderate and may have been related to the Tolerability
underlying thrombocytopenia (see Table 2). Very few patients (3 [4%]) In the long-term extension study, romiplostim was generally well tolerated
discontinued romiplostim because of adverse events. An increase in by the patients, several of whom were treated for up to three years. Eight
dizziness, insomnia, myalgia and pain in the extremities and abdomen were patients were found to have bone marrow reticulin present or increased.
24
noted in the romiplostim-treated patients, the clinical significance of which Six patients had mild to moderate reticulin reported (grade 2 or lower or
could not be determined due to the small study size. Thromboembolic within the normal range). Follow-up bone marrow biopsies in two patients
events are a concern in patients with ITP, but there was no evidence in the revealed that one patient showed improvement in the amount of reticulin,
phase III studies that romiplostim treatment increased the risk of such while the other patient had no change. All of the affected patients
events: the overall incidence of thromboembolic events was 2.4% in both continue to be monitored for clinical signs of any progressive bone
the romiplostim (2/84) and placebo (1/42) patient groups. marrow abnormalities, and to date there has been no evidence of
progression to collagen fibrosis, myelofibrosis or clonal myeloproliferative
Clinically significant bleeding adverse events (i.e. severity grade ≥2, where disorder. The incidence and clinical significance of bone marrow reticulin,
2 = moderate, 3 = severe, 4 = life-threatening and 5 = fatal) were observed as well as the extent of regression that occurs following discontinuation of
in 15% of romiplostim- and 34% of placebo-treated patients (p=0.018). romiplostim treatment, will have to be followed closely in future studies of
The percentage of patients who had bleeding events of grade 3 severity or patients with ITP treated with romiplostim.
above was 7 and 12% in the romiplostim and placebo groups, respectively
(p=0.36). None of the patients with bleeding events of grade 3 or above Thromboembolic events were reported in seven patients (5%), six of
had achieved a durable platelet response during the study period. whom had pre-existing risk factors for thrombosis including congestive
heart failure, antiphospholipid antibodies, coronary artery disease,
Serious treatment-related adverse events occurred in two romiplostim- hypertension, cancer and/or a history of thrombotic events. Five
treated patients. After seven weeks of treatment, increased bone marrow thromboembolic events were assessed as being serious treatment-related
reticulin (thought to result from increased transforming growth factor-β events: one patient with myocardial infarction, one patient with portal
released from megakaryocytes within the bone marrow) was noted in one vein thrombosis and deep vein thrombosis, one patient with transverse
patient. This particular patient had bone marrow reticulin present at sinus thrombosis and one patient with thrombosis. Thromboembolic
baseline and was unresponsive to romiplostim treatment. Reticulin events did not appear to be related to higher than normal platelet
returned to baseline 14 weeks after discontinuation of romiplostim. Similar counts, with most events occurring at counts below the median peak
reversible increases in bone marrow reticulin have been noted previously in platelet count (167x10
9
/l). All of the events resolved. One patient
animals and humans exposed to other thrombopoetic agents (rhTPO, developed transient neutralising antibodies to romiplostim, but these did
interleukin [IL]-3 and IL-11).
23
The second patient with a serious treatment- not cross-react to endogenous TPO or affect the platelet response.
50 EUROPEAN HAEMATOLOGY
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100