Evaluation of Bleeding and Thrombotic Events during Long-Term Use of Romiplostim in Patients with Chronic Immune Thrombocytopenic Purpura.

Immune thrombocytopenic purpura (ITP) is an autoimmune hematologic disorder of increased platelet destruction and sub-optimal platelet production. Patients (pts) often have low platelet counts (<50 x 109/L) and present with bleeding, purpura, and petechiae; at very low counts, there is a risk of spontaneous intracranial or other life-threatening bleeding. Romiplostim is an investigational thrombopoiesis-stimulating Fc-peptide fusion protein (peptibody) that increases platelet production via binding to and activating the megakaryocyte thrombopoietin receptor. Objective: This study evaluated bleeding and thrombotic events (TEs) occurring in adults with ITP treated with romiplostim during two phase III, randomized, placebo-controlled, 24-week studies, and an open-label extension study. Patients with platelet counts <50 x 109/L were eligible to enter the extension study in which all pts received romiplostim; rates of bleeding events (up to 48 weeks of treatment) and TEs (up to 84 weeks) for these pts were analyzed. Results: In the phase III trials, 84 pts received weekly subcutaneous injections of romiplostim (initial dose 1μg/kg, dose adjusted to maintain platelet counts of 50–200x109/L) and 41 pts received placebo. 115 pts completed the phase III trials, and 101 pts (romiplostim N=68; placebo N=33) entered the extension study. Bleeding events were captured as adverse events (AEs) and graded according to severity. Clinically significant bleeding AEs (i.e. severity grade ≥2 or higher, where 2= moderate, 3=severe, 4=life-threatening, or 5=fatal) were noted in 16% of romiplostim- and 34% of placebo-treated patients (P=0.018). The percentage of pts experiencing bleeding AEs ≥ grade 3 severity was 7% and 12% in the romiplostim and placebo groups, respectively (P=0.36) None of the pts with bleeding events ≥ grade 3 had achieved a durable platelet response (defined by platelet count of ≥50x 109/L during at least 6 of the last 8 weeks of treatment). No bleeding AEs ≥ grade 3 occurred in pts with platelet counts >20 x 109/L while no bleeding AEs of grade ≥2 occurred at counts >50 x 109/L. During the extension study, the percentage of pts with a bleeding AE of any severity decreased from 36% (Weeks 1–12) to 12% (Weeks 36–48). The percentage of pts with bleeding AEs of grade 2 or higher severity decreased steadily from 16% (Weeks 1–12) to 5% (Weeks 37–48). In the phase III studies, the incidence of TEs was 2.4% in both the romiplostim and placebo groups. In the romiplostim group, one patient had a cerebrovascular accident while another had a right popliteal arterial embolism; one placebo-treated patient had a fatal pulmonary embolism. During the extension study, 7 additional TEs occurred in four more pts (patient incidence: 4%): one patient with coronary artery occlusion; one with a calf vein thrombosis; two pts with multiple events. Platelet counts at the time of TEs in all studies ranged from 3 x 109/L to 948 x 109/L. Seven of the 10 TEs occurred at counts below the median peak platelet count for all pts treated with romiplostim in both the phase III and extension studies (167 x 109/L). Furthermore all pts who experienced thrombotic AEs had multiple risk factors for thrombosis including congestive heart failure, antiphospholipid antibodies, coronary artery disease, hypertension, cancer, and/or a history of thrombotic events. Conclusion: Romiplostim appears to be an efficacious and well-tolerated treatment for adults with chronic ITP. The severity of bleeding events decreased during short-term (24-weeks) treatment, and long-term (up to 48 weeks) treatment resulted in further decreases in severe bleeding AEs and overall bleeding frequency. Thrombosis occurred in pts with risk factors, but did not appear to be related to higher than normal platelet counts.