ALBERT

Description: Abstract 3510 Poster Board III-447 Introduction Romiplostim is a peptibody protein designed to increase platelet production by binding to and activating the thrombopoietin receptor; it is approved for the treatment of thrombocytopenia in patients with chronic ITP. Home administration of romiplostim may offer a desirable treatment option for some patients. We evaluated the safety and efficacy of romiplostim home administration during a 52-week study in adult ITP patients. Patients and Methods This was a phase 3b, multi-center, randomized, standard of care (SOC) controlled, open-label study comparing the incidence of splenectomy and treatment failure in ITP patients receiving either romiplostim or medical SOC for ITP. Eligible patients were nonsplenectomized adult ITP patients who had received at least 1 prior therapy for ITP, with a baseline platelet count 〈 50 × 109/L. Romiplostim was administered by weekly subcutaneous injections with dose adjustments to target a platelet count of 50 to 200 × 109/L. After study week 8, patients who achieved platelet counts within the target range and a stable dose of romiplostim for at least 3 consecutive weeks were offered the opportunity to receive romiplostim outside the physician's office. Eligible patients were trained to self-inject and were required to return to the study center for platelet count evaluation and to obtain romiplostim for subsequent treatment every 4 weeks. We report data from romiplostim-treated patients, comparing the time 3 weeks before initiating home administration to the time after initiating home administration (either until the end of the treatment or until a 6-week interruption of home administration). Since the observation periods before and after initiation of home administration were not equal, exposure-adjusted data were calculated. Results The 157 patients who were randomized to romiplostim had a median age of 58 (range 18 to 90) years and 85 (54%) were female. Home administration was initiated by 69% (109/157) of the patients who received romiplostim, and home administration was continued for a median of 36 weeks (Interquartile range, 14). Home administration was interrupted for 6 consecutive weeks or more in 24/109 (22%) patients. Of the109 patients who started home administration, 93 (85%) continued to home administer until the end of the study. For each patient, their most frequently used dose of romiplostim was determined. The median of patients' most frequently used dose remained stable after home administration was initiated (Table). There was no difference in the percentage of weeks with a platelet response (defined as a platelet count 〉 50 × 109/L, excluding those within 8 weeks of rescue medication use) during the time before (83%) and the time after (88%) the start of home administration (p=0.147). The rate of adverse events appeared lower after patients began home administration, and did not appear to increase with longer duration of treatment (Table). No deaths occurred either before or after home administration. Conclusions The safety and efficacy profile of romiplostim was not impaired when patients changed from in-office administration to home administration. Home administration of romiplostim appears to be a convenient treatment option for some ITP patients. Disclosures: Lyons: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy; Johnson&Johnson: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau. Boccia:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Macik:Amgen Inc.: Research Funding; Eisai Inc.: Research Funding. Mandanas:Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Wang:Amgen Inc.: Employment, Equity Ownership. Lizambri:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

Description: Abstract 3702 Introduction: Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to endogenous thrombopoietin, and is approved for the treatment of chronic ITP. ITP is characterized by low platelet counts due to increased platelet destruction and suboptimal platelet production. The response rate to ITP therapies is variable and may be associated with substantial adverse effects. Splenectomy is commonly used as a treatment for ITP because it removes the major site of platelet destruction. A recent consensus report (Provan et al., 2010, 168–86) recommends delaying splenectomy for 6–12 months, in keeping with the new definition for chronic ITP (Rodeghiero et al., Blood 2009, 2386–93); therefore, we evaluated patients who had been diagnosed with ITP ≤1 year who participated in a recent study of romiplostim versus standard of care (SOC). Methods: A randomized, open-label study was conducted in nonsplenectomized adult patients with ITP. The co-primary study endpoints were the incidence of treatment failure and the incidence of splenectomy. Treatment failure was defined as: platelet count ≤20 × 109/L for 4 consecutive weeks at the highest recommended dose and schedule of romiplostim or SOC, or major bleeding event, or change in therapy due to intolerable side-effect or bleeding symptoms. The secondary endpoints included platelet counts and safety. Patients who discontinued treatment were considered to have met both primary endpoints. To assess the impact of study discontinuation on the primary endpoints, the actual incidence of treatment failure and splenectomy were also determined (“sensitivity analysis”). An ad hoc analysis of the study endpoints was conducted in those study patients who had been diagnosed with ITP for ≤1 year. Results: Eighty-five of 234 enrolled patients had ITP for ≤1 year; 29 received SOC and 56 received weekly subcutaneous injections of romiplostim. Patient characteristics were similar between treatment groups, as was the distribution of time since ITP diagnosis (romiplostim, 7 – 327 days; SOC 4 – 363 days). The mean (±SD) age was 53 (±20) years and 47% of the patients were male. The mean baseline platelet counts were similar in the romiplostim (26 ± 14 × 109/L) and SOC (23 ± 16 × 109/L) groups. The mean platelet count was higher in the romiplostim arm than the SOC arm at every weekly evaluation until the end of treatment (52 weeks). The incidence of treatment failure was lower in the romiplostim group (9%, 5/56) than in the SOC group (24%, 7/29) [OR, 0.34; 0.10 – 1.14; p= 0.0649]. Similarly, the incidence of splenectomy was significantly lower in the romiplostim group (7%, 4/56) than the SOC group (45%, 13/29) [OR, 0.10; 0.03 – 0.35; p20 × 109/L may have contributed to reduced differences in the rates of treatment failure per the study definition. Romiplostim was well-tolerated in this patient population, and findings were similar to those previously reported for the study population overall (Kuter et al., ASH 2009, #679). Disclosures: Boccia: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acendia: Consultancy; Celgene: Equity Ownership, Honoraria, Research Funding, Speakers Bureau; Merck: Equity Ownership; Johnson & Johnson: Equity Ownership; CTI: Research Funding; Cephalon: Research Funding; Millenium: Research Funding. Kuter:Amgen Inc.: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; ONO: Consultancy; Pfizer: Consultancy, Research Funding; Shionogi: Consultancy, Research Funding. Macik:Amgen Inc.: Research Funding; Pfizer: Research Funding; Eisai: Research Funding; Grifols: Research Funding; FDA: Consultancy; Center for Biologics Evaluation and Research: Consultancy; Hematology Consultant: Consultancy. Pabinger:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Selleslag:Amgen Inc.: Consultancy, Honoraria. Rodeghiero:Amgen Inc.: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Speakers Bureau; Shionogi: Consultancy. Chong:CSL Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Wang:Amgen Inc.: Employment, Equity Ownership. Lizambri:Amgen Inc.: Employment, Equity Ownership.

Description: Abstract 3704 Introduction: Chronic immune thrombocytopenia (ITP) is an autoimmune disorder characterized by both increased platelet destruction and decreased platelet production. Romiplostim increases platelet counts by binding and activating the thrombopoietin receptor. Romiplostim has been approved for the treatment of adult ITP in the United States, Europe, Canada, and Australia. This study evaluated dosing, efficacy, and safety in a Japanese population of adults with ITP. Methods: This phase 3 study was placebo-controlled, double-blind, and randomized 2:1 (romiplostim:placebo). Patients were eligible for the study if they were Japanese patients with ITP diagnosed at least 6 months before the initial screening, were aged ≥ 20 years, and were H pylori negative or had received at least 1 treatment for H pylori eradication. Patients were stratified by splenectomy status (yes or no). After a 3-week evaluation period, patients were treated for 12 weeks with a weekly subcutaneous injection of either romiplostim or placebo. The starting dose was 3 mcg/kg with dose adjustments to a maximum of 10 mcg/kg to achieve a platelet count within the target range of ≥ 50 to ≤ 200 × 109/L. Patients were monitored posttreatment until their platelet count dropped to ≤ 50 × 109/L or for a maximum of 12 weeks. The primary endpoint was number of weeks with platelet response (platelet count ≥ 50 × 109/L). Results: Thirty-four patients enrolled (22 romiplostim, 12 placebo), 24 (71%) were female, the median (range) age was 55 (44 - 64) years, and the median (range) baseline platelet count was 19 (3 – 32) × 109/L. Patients had received a median of 4 (1 – 19) prior ITP therapies, and 15 (44%) had previously undergone a splenectomy; 23 (68%) patients were receiving concurrent ITP therapy at baseline. All patients completed the study. Romiplostim demonstrated superiority to placebo on weekly platelet response, incidence of increase in platelet count ≥ 20 × 109/L from baseline, change from baseline in mean of last 4 platelet counts during week 2 to week 13, and number of weeks with platelet counts within the target range (Table 1), and 16 (73%) romiplostim patients had platelet counts ≥ 200 × 109/L. Twenty-one (95%) patients in the romiplostim group had a platelet response with a median time of 1 week until first response. Results for weekly platelet response were comparable irrespective of splenectomy status and baseline concurrent ITP therapy. Two (17%) patients in the placebo group achieved a platelet response. In romiplostim-treated patients, posttreatment platelet counts remained 〉 50 × 109/L for 8 weeks in one and for 12 weeks in another. The mean weekly dose of romiplostim for the study was 2.6 mcg/kg compared with the dose range of 3–4 mcg/kg in prior phase 3 studies (Kuter et al. Lancet. 2008;371:395–403). There was a low incidence of rescue medication use in the study (Table 1). The adverse events profile was comparable to that seen in non-Japanese studies. Patients in both treatment groups experienced similar proportions of adverse events (91% romiplostim, 92% placebo). Adverse events with 〉 10% higher frequency in the romiplostim group than placebo group) were (romiplostim, placebo) nasopharyngitis (41%, 17%), headache (32%, 17%), peripheral edema (18%, 0%), back pain (14%, 0%), and pain in extremity (14%, 0%). Significant (≥ grade 3) bleeding events occurred in 1 patient in the romiplostim group (subarachnoid hemorrhage) and 1 patient in the placebo group (subarachnoid hemorrhage, cerebral hemorrhage, and gastrointestinal hemorrhage). There were no adverse events of bone marrow reticulin, thrombosis, or detection of neutralizing antibodies. Conclusion: Romiplostim significantly increased and maintained platelet counts and was well-tolerated in a Japanese ITP population. Disclosures: Tomiyama: Kyowa Hakko Kirin Co.: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Kurokawa:Novartis: Consultancy; Shionogi & Co., Ltd.: Consultancy. Wei:Amgen Inc.: Employment, Equity Ownership. Lizambri:Amgen Inc.: Employment, Equity Ownership.

Description: Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were 〉 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

Description: Abstract 3282 Background/Methods: The relative safety and efficacy of romiplostim and rituximab in ITP have not been compared in clinical trials. In an open-label 52-week trial of SOC (N = 77) and romiplostim (N = 157) in ITP patients without prior splenectomy (Kuter et al, NEJM 2010), treatment failure was lower with romiplostim vs SOC (11% vs 30%, P50×109/L, excluding 8 weeks after rescue medication) were higher with romiplostim than with SOC-rituximab or SOC as a whole (Graph). When comparing concomitant ITP medications prior to rituximab and during or after rituximab treatment in the SOC-rituximab patients, there was no change in the proportion of patients receiving ITP medications (9/16 vs 10/16) or the number of medications per patient [median (range) of 1 (0, 3) vs 1 (0, 4)]. The most common prior to rituximab treatment were prednisone (7/16), IVIg (3/16) and anti-D (2/16); during or after rituximab treatment, the most common were prednisone (6/16), IVIg (4/16), anti-D (2/16), and methylprednisone (2/16). Conclusion: This post hoc non-randomized comparison indicates that romiplostim may have greater effects on platelet responses than SOC-rituximab or SOC, with similar safety profiles. However, different treatment goals – ongoing use of romiplostim to maintain platelet response as opposed to one or more courses of rituximab which may result in a long-term response in the absence of other therapies (∼20% response rate at 5 years, Patel, ASH 2010) – makes efficacy comparisons problematic, particularly as the long-term response rate was not measured in this one-year study. Also not analyzed was how the use of concomitant ITP medications changed over the course of the study. As splenectomy and many immunosuppressive ITP medications are associated with significant morbidity and mortality over time, this is an important consideration. Most importantly, patients were selected for rituximab treatment by the investigators in a non-random way, as evidenced by the longer duration of ITP, making any generalizations difficult. Prospective controlled studies of romiplostim and rituximab in patients with ITP would be needed to provide further information. Disclosures: Wasser: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Rituximab is not indicated for ITP. Boccia:Amgen: Equity Ownership, Speakers Bureau. Lyons:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mandanas:Amgen: Membership on an entity's Board of Directors or advisory committees. Pabinger:Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Michel:Roche: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Viallard:Amgen: Consultancy. Wang:Amgen: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.