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Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder with the expansion of PIGA mutant clone(s), which is deficient in GPI-anchored proteins including CD55 and CD59. The lack of CD55 and CD59 renders PNH-type red blood cells (RBC) susceptible to complement attacks, resulting in intravascular hemolysis. Classic PNH manifests 3 major symptoms: anemia, bone marrow failure, and thrombosis. Small populations of PNH-type cells ( Methods: Patients diagnosed with PNH, AA, MDS or indistinguishable BMF were prospectively recruited to the study since 2011 in Japan. A high-resolution FCM assay was established to precisely detect a small population of PNH-type granulocytes (with FLAER) and RBCs (with anti-CD55 and CD59 antibodies) ≤ 0.01% of the total granulocyte or RBC population based on the Kanazawa method (Blood 2006 107:1308-1314). Six university laboratories across Japan were designated as regional analyzing centers and measured the percentages of PNH-type cells in the study population, as well as collected clinical and laboratory data. Periodic blind cross validation tests using a positive control sample containing 0.01% PNH-type cells and a negative control sample were performed to minimize inter-laboratory variations. Results: As of July 2016, 2,849 patients were enrolled in the study and 2,734 patients were analyzed. Nine hundred twelve patients (33.4%) were positive for PNH-type cells (≥ 0.005% PNH-type erythrocytes and/or ≥ 0.003% PNH-type granulocytes) and 238 (8.7%) patients had more than 1% of PNH-type cells. PNH-type cells were positive in 90/90 PNH (100%), 512/982 AA (52.1%), 132/822 MDS (16.1%), and 141/512 indistinguishable BMF (27.5%) patients. Among the MDS patients, PNH-type cells were positive in approximately 20% of patients with RCUD, RCMD, MDS-U, or 5q- syndrome, but not in any patients with RARS, RAEB-1, and RAEB-2 (Fig. 1). The serum LDH level increased in proportion to the PNH clone size of RBCs, and 63.3% of the patients possessing ≥1.0% RBCs showed LDH levels more than 1.5 times the upper limit of normal. Of 171 patients who completed submission of 3-year follow-up data, BMF patients with PNH-type cells showed a better response rate [CR+PR, 99/107 (92.5%)] to IST compared to those without PNH-type cells [44/64 (68.8%)] (P Conclusions: These interim analyses of the OPTIMA study demonstrate that our high-resolution FCM is reliable in detecting small populations of PNH-type cells and produces consistent results among different laboratories. The presence of PNH-type cells exclusively in patients with AA and low-risk MDS suggests a link between benign pathophysiology of BMF and an increase in the number of PNH-type cells. The better response of PNH-type cell-positive BMF to IST compared to BMF without PNH-type cells was consistent with previous reports. Our data, for the first time, prospectively confirms the significance of small populations of PNH cells in BMF patients in Japan and warrants further worldwide, prospective studies on non-Japanese patients with BMF. Disclosures Ueda: Alexion Pharmaceuticals: Honoraria, Research Funding. Nishimura:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hosokawa:Aplastic Anemia and MDS International Foundation: Research Funding. Yonemura:Alexion Pharmaceuticals: Research Funding. Obara:Alexion Pharmaceuticals: Honoraria, Research Funding. Shichishima:Alexion Pharmaceuticals, Inc. Japan: Honoraria. Ninomiya:Alexion Pharmaceuticals: Honoraria. Kawaguchi:Alexion Pharmaceuticals: Honoraria. Kanakura:Fujimotoseiyaku: Research Funding; Toyama Chemical: Research Funding; Bristol - Myers: Research Funding; Nippon Shinyaku: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Chugai Pharmaceutical: Research Funding; Shionogi: Research Funding; Kyowa Hakko Kirin: Research Funding; Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Nakao:Alexion Pharmaceuticals: Honoraria, Research Funding.

Dasatinib (DA) is a tyrosine kinase inhibitor (TKI), and is approved for the treatment of naïve and relapsed/refractory Philadelphia chromosome positive leukemia. DA is a potent and multi-target TKI, and a part of patients treated with DA are reported to exhibit lymphocytosis and that is caused by a proliferation of NK cells or CD8 T cells. Nowadays, a lot of reports about the stop TKI trials suggested that treatment free remission of the CML after TKI discontinuation was significantly associated with NK cell proliferation in peripheral blood of the patients. So far, little is known about the individual differences in NK cell response among patients treated with Dasatinib. NKG2D is an activating receptor expressed on NK cells. Recently, functional SNP were identified between LNK1 and HNK1 haplotypes of the NKG2D gene. We analyzed the association between patient's NKG2D polymorphism and achievement of the deep molecular response by Dasatinib. We retrospectively investigated thirty-one patients who were treated with Dasatinib for the first-line treatment of CML at Tokai university school of medicine between 2011 and 2015. Patients with HNK1 haplotype tended to achieve MR4.5 more frequently (not significant), and these patients accomplished MR4.5significantly faster than others. Next, we harvested NK cells from healthy volunteers, and investigated NK cell responses by Dasatinib in vitro. There were differences in the degree of NK cell proliferation capacity among subjects after DA treatment in vitro. We found that NK cells with NKG2D LNK1/LNK1 haplotype exhibited significantly lower proliferation capacity than others in the population. NK cells of higher proliferation capacity exhibited Vav-1 Tyr174 phosphorylation, but they didn't show any differences in cytotoxicity capacity. In this study, our data suggest that DA may stimulate NK cells with NKG2D HNK1 haplotype more strongly than LNK1 haplotype, and therefore patients with HNK1 haplotype can achieve deep molecular response faster than others. So, personalized medicine according to their NKG2D haplotype may be useful to the treatment of CML, especially when they are considered to discontinue DA in stop TKI trials. Disclosures No relevant conflicts of interest to declare.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder caused by the clonal expansion of the phosphatidylinositol glycan class A (PIGA) mutant hematopoietic stem cells, which results in a deficiency in glycosylphosphatidylinositol-anchored proteins (GPI-APs). Through the high-resolution flow cytometry-based method, GPI-APs deficient blood cells (i.e., PNH-type cells) are often detectable in patients with bone marrow failure syndromes (BMF), such as aplastic anemia (AA) and low-risk types of myelodysplastic syndromes (MDS). Sugimori et al reported that when BMF patients possessed increased PNH-type cells, the patients had a good prognosis and showed a high response rate to immunosuppressive therapies, suggesting that detection of PNH-type cells is potentially useful in determining an optimal treatment for BMF patients. Thus, we conducted a nationwide, multi-center prospective observational investigation, the OPTIMA study. Methods: From July 2011, we start recruiting the patients with BMF that were diagnosed at various hematology clinics throughout Japan to the OPTIMA study. The primary endpoint of this study was to determine the prevalence of BMF patients with PNH-type cells and to clarify the clinical significance of the presence and quantitative changes of these cells with regard to the clinical features. Six different university laboratories were assigned as regional analyzing centers. The percentage of PNH-type cells was measured by the high-resolution flow cytometry-based method, originally established in Kanazawa University. At six individual laboratories, cross validations were conducted twice a year to minimize the inter-laboratory variations in the detection sensitivities, cutoff values, etc. The liquid FLAER method (≥0.003%) and cocktail method (≥0.005%) with CD55 and CD59 antibodies were used for the detection of PNH-type granulocytes and erythrocytes, respectively. Results Between July 2011 and May 2015, a total of 2328 patients were enrolled to this study, and we analyzed 2212 patients who were eligible for the interim analysis. Of these patients, 74 (3.3%) were diagnosed with PNH, 690 (31.2%) with AA, 592 (26.8%) with MDS, and 856 (38.7%) with undiagnosed BMF. Using high-resolution flow cytometry-based method, 755 (34.1%; 95.9% in PNH, 52.8% in AA, 18.2% in MDS, and 24.8% in undiagnosed BMT) patients had ≥0.005% PNH-type erythrocytes and ≥0.003% PNH-type granulocytes. Overall, 181(8.2%) patients had ≥1% of both PNH-type erythrocytes and granulocytes; the prevalence in each disease subset was 68/74 (91.9%) in PNH, 67/690 (9.7%) in AA, 22/592 (3.7%) in MDS, and 24/856 (2.8%) in undiagnosed BMF. Regarding FAB and WHO classifications of MDS subtype, no patients with RARS (0/22), RAEB-1 (0/37) or RAEB-2 (0/23) had PNH-type cells. In contrast, 20.4% (56/275) patients with RCMD, 18.3% (26/153) patients with RCUD and 50% (2/4) patients with del (5q) MDS possessed increased PNH-type cells. Blood samples from 75 (65 with and 10 without PNH-type cells) patients were analyzed three years after the first examination. Of 65 PNH (+) patients, PNH-type cells disappeared in 4 (6.2%), while the percentage remained stable in 61 (93.8%). All of the 10 PNH (-) at the enrollment were also negative for PNH-type cells in 3 years. Conclusions: A high-resolution flow cytometry-based method that enables the detection of minimal PNH-type cells below 0.01% was successfully transferred from Kanazawa University to other laboratories in Japan. Our interim analysis confirmed previous findings that PNH-type cells were detectable in patients with 52.8% of AA and 18.2% of MDS patients. Regarding FAB and WHO classifications of MDS subtype, PNH-type cells were not detected in any of MDS RARS, RAEB-1 or RAEB-2 patients. Further analysis are required to determine the clinical significance of the minimal level of PNH-type cells as well as chronological changes in the PNH-type cell percentage, especially in terms of their relation to response to immunosuppressive therapy. Disclosures Ninomiya: Alexion Pharmaceuticals: Honoraria. Ando:Eisai Co., Ltd.: Honoraria, Research Funding. Yonemura:1. Chugai Pharma, 2. Alexion Pharma, 3. Japan Blood Products Organization, 4. OHARA Pharma: Research Funding. Kawaguchi:Alexion Pharmaceuticals: Honoraria. Ueda:Alexion Pharma: Research Funding. Nishimura:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

The American Society of Hematology guidelines recommend rituximab as second-line treatment, as well as splenectomy and thrombopoietin receptor agonists (TPO-RAs), for chronic immune thrombocytopenia (ITP). However, rituximab has not been approved for the treatment of chronic ITP in Japan. To establish chronic ITP as a new indication for rituximab, we conducted an investigator-initiated clinical trial to clarify the efficacy and safety of rituximab for Japanese patients with ITP. This study was designed as a single-arm, multicenter phase III study. Patients diagnosed with chronic ITP who were previously treated with at least one therapy for ITP and whose platelet count was ≤ 30,000/μL were included. Patients with a past history or current hepatitis B virus, hepatitis C virus or HIV infection, who were treated with splenectomy within 12 weeks or with TPO-RA within 4 weeks were excluded. Rituximab at a dose of 375 mg/m2was intravenously infused once weekly for 4 weeks. Patients were premedicated with acetaminophen, restamin and hydrocortisone to prevent infusion reactions. Platelet counts, bleeding symptoms, and B lymphocyte counts were observed once monthly following the protocol. The primary endpoint was the proportion of patients whose platelet count was ≥ 50,000/μL 24 weeks after treatment with rituximab. Between October 2011 and January 2013, 26 patients were enrolled in this study from 10 hospitals in Japan. Median age of the patients was 40 years and 89% were female. Baseline platelet counts were 23,000/μL. Median interval from diagnosis of ITP to commencing rituximab therapy was 5.9 years. Previous treatment of ITP was corticosteroids (69%), splenectomy (15%), TPO-RA (27%) and intravenous immunoglobulins (39%). At baseline, 58% of patients had some bleeding symptoms. Median number of previous ITP treatments was two. All patients completed the study. At 24 weeks after treatment, 30.8% (95% CI: 14.3–51.8%) of patients achieved platelet counts > 50,000/μL. Seven of eight responders demonstrated improvement until 8 weeks. Platelet count was significantly increased compared with baseline (P We demonstrated the efficacy and safety of rituximab in Japanese patients with chronic ITP. The response rate was similar to that in previous reports in the US and Europe. We plan to propose that the Japanese government approve chronic ITP as a new indication for rituximab. Disclosures: Miyakawa: Fuji film: Consultancy; Alexion pharmaceuticals: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; KyowaHakkoKirin: Consultancy, Honoraria; Shire: Honoraria. Off Label Use: rituximab, clinical trial. Nishiwaki:Chugai pharmaceutical: Research Funding; Zenyaku Kogyo: Research Funding. Higashihara:Alexion: Honoraria; Asahi Kasei Pharma: Honoraria; Janssen pharma: Honoraria, Research Funding; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Shionogi: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; KyowaHakkoKirin: Honoraria, Research Funding; Boehringer-Ingeheim: Honoraria; Daiichi Sankyo: Honoraria; Yakurt: Honoraria; Astellas: Research Funding; Pfizer: Research Funding; Teijin: Research Funding; Meiji Seika pharma: Research Funding; Venesis: Research Funding; Baxter: Research Funding; Torii pharmaceutical: Research Funding; Bristol-Myers Squibb: Research Funding; Dainippon Sumitomo: Research Funding; Taiho: Research Funding; Taisho Tomiyama: Research Funding; MSD: Research Funding. Nishikawa:Daiichi-Sankyo: Research Funding. Ozaki:Chugai pharmaceutical: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria. Kanakura:Alexion Pharmaceuticals: Research Funding, Speakers Bureau. Okamoto:Novartis : Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; GlaxoSmithKlein: Honoraria, Research Funding; KyowaHakkoKirin: Honoraria, Research Funding; Chugai: Honoraria, Research Funding.

Abstract 691 Background: Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for patients with chronic phase chronic myelogenous leukemia (CML-CP). Compared with imatinib, dasatinib is known to induce a faster and better response as a first- and second-line treatment. A unique effect of dasatinib treatment is the induction of clonal lymphocytosis with large granular lymphocyte (LGL) morphology, presumed to be the effect of off-target kinase inhibition. These LGLs are known to possess either cytotoxic T-cell (CTL) or natural-killer (NK) cell phenotype. Several reports have shown that this clonal LGL expansion is associated with a better response to dasatinib treatment. Purpose: To prospectively analyze the immunoprofile of Japanese patients treated with dasatinib, and to correlate the increase of lymphocytes and their subsets (LGL, CTL and NK cells) with the clinical efficacy of dasatinib. Method and Patients: Japanese patients with CML-CP who were resistant or intolerant to first-line imatinib therapy participated in the prospective phase II study assessing the efficacy and safety of dasatinib. Peripheral blood LGL, CTL and NK cell counts before and 2 weeks, 1 month (M), 3M, and 6M after the initiation of treatment were analyzed at the central laboratory (BML Inc.) by flow cytometry. LGL, CTL and NK cells were defined as CD57+/CD14-, CD8+/CD4- and CD56+/CD3- cells, respectively. Lymphocytosis was defined as a lymphocyte count of >3.0×109/L. The clinical efficacy of dasatinib was evaluated at 12M as complete molecular response (CMR) or less than CMR by peripheral blood quantitative RT-PCR (BML Inc.). The full data set was available for 50 out of 65 patients and was included in this analysis. Results: The median age of the patients enrolled was 57 years (range: 16 – 87 years). There were 37 male and 13 female patients. Twenty patients were switched to dasatinib due to intolerance to imatinib and 30 due to resistance. Lymphocytosis was observed in 19 patients (38%) at 3M. Of those 19 patients, 14 (73.7%) had lymphocytosis persisting at 6M. In total, 21 patients (42%) achieved CMR at 12M. The absolute count of lymphocytes, LGL, CTL or NK cells, did not differ significantly between patients who achieved CMR at 12M and those who did not (p>0.05). However, there were significant differences between these two groups in the relative increase of these cell counts. Relative increase of lymphocytes compared to baseline as early as 2 weeks after initiation of treatment was identified by univariate analysis as a significant factor associated with CMR at 12M (p=0.0348). This increase persisted at each time point observed until 6M. As for the different subsets of lymphocytes, the relative increase of CTL at 3 and 6M and LGL at 1, 3 and 6M were also significantly associated with a higher rate of CMR at 12M. When adjusted for possible confounding factors (age, sex, performance status, whether 1st or 2nd CP, resistance or intolerance to imatinib), the relative increase of lymphocytes at 1, 3 and 6M, CTL and LGL at 3 and 6M remained significant (Fig a-c). Patients who showed an increase of lymphocytes of over 1.5-fold at 1M showed a significantly higher rate of CMR at 12M (66.7% vs 25.8%, p=0.0007). Similar differences were seen in patients with increases of over 2-fold in CTL, LGL and NK cells (70.6% vs 22.6%, p=0.0011; 74% vs 21%, p=0.0003; and 57.9% vs 28.6%, p=0.0444). Detailed analysis at 3M showed a further significant difference in the treatment effect. An increase of over 2-fold in lymphocytes (81.3% vs 21.2%, p Conclusion: Lymphocytosis after the initiation of dasatinib was seen in a substantial proportion of Japanese patients treated with dasatinib. A relative increase of lymphocytes together with LGL, CTL and NK cells, uniformly defined by flow cytometry, at 1 and 3M after the initiation of treatment were associated with a higher rate of CMR at 12M. To our knowledge, this is the first large prospective study analyzing the clinical significance of lymphocytosis associated with dasatinib therapy in Japanese patients with CML-CP using flow cytometry. Our results suggest that a relative increase of lymphocytes as early as 1M after the initiation of dasatinib is a reliable predictive marker for achieving CMR at 12M. Disclosures: No relevant conflicts of interest to declare.

Abstract 4448 Background Dasatinib is a potent tyrosine kinase inhibitor and is highly effective against chronic myeloid leukemia (CML). In Japan, dasatinib was approved in 2009 as a second-line therapy for CML after imatinib failure. Therefore, we conducted a phase II study to investigate the efficacy and safety of dasatinib treatment in Japanese CML-chronic phase (CP) patients with intolerance or resistance to imatinib. Patients and method CML-CP patients who were unable to continue imatinib therapy (400 mg/day) because of adverse events were registered as being intolerant to imatinib. Resistance to imatinib was defined as failure to achieve a partial cytogenetic response (PCyR) after three months of therapy or a complete cytogenetic response (CCyR) after six months of therapy or the expression of over 100 copies/μg RNA of BCR-ABL after 12 months of therapy. For these patients, dasatinib (100 mg) was administered once daily. Patients with T315I and F317I mutations in BCR-ABL were excluded. Major and complete molecular responses (MMR and CMR) were centrally evaluated using RQ-PCR at the BML laboratory. When the study was designed, a conversion factor (CF) had not been introduced to Japan for the adoption of international scale (IS). Subsequently, 0.1% IS (MMR) was defined as being equivalent to 731 copies/μg RNA based on the BML laboratory specific CF obtained in 2011, and 11 patients were identified as having an MMR at the time of study enrollment. Results A total of 61 patients were accrued from 21 centers: 26 with intolerance, and 35 with resistance. The median age was 58 years (range, 16 – 91 years). The median follow-up duration was nine months (range, 0.5 – 18 months). An MMR+CMR was observed in 27 out of 45 patients (60.0%, 13 CMR and 14 MMR) at six months and in 22 out of 31 patients (71.0%, 8 CMR and 14 MMR) at nine months after treatment with dasatinib, respectively. Excluding the patients with an MMR at the time of registration, dasatinib had induced an MMR+CMR in 21 out of 39 patients (53.9%, 11 CMR and 10 MMR) at six months and 19 out of 28 patients (67.9%, 7 CMR and 12 MMR) at nine months, respectively. The response rates in intolerant and resistant patients were comparable. Twelve patients discontinued dasatinib treatment because of drug toxicity (four patients), patient request (one), disease progression or the development of a T315I mutation (three), or unknown causes (four). Although grade 1 – 2 pleural effusion was observed in five patients, no severe cases were observed. Ten mutations in BCR-ABL occurred in eight patients during dasatinib treatment; a low IC50 of dasatinib against tumor cells in five of these mutations (M244V, M351T, F359I, F359V, H396R), an intermediate value against tumor cells in one of these mutations (Q252H), a high value against tumor cells in two of these mutations in three patients (T315I in two patients and E459K), and an unknown sensitivity against tumor cells in one of these mutations (A397P). Patients with M244V+Q252H, H396R, or T315I did not respond to dasatinib treatment. Conclusion Dasatinib is a safe and efficacious alternative for the treatment of CML following imatinib failure. Because MMR rate in the global study was 31% at one year and 44% at 5 years, the molecular response rate among Japanese patients was higher than that in western populations. Mutation in BCR-ABL remains a major issue. Disclosures: Okamoto: Bristol-Myers Squibb: Research Funding.

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. Table 1 . Study Efficacy Endpoints Romiplostim N = 22 Placebo N = 12 p Value Primary end point Weekly platelet response: platelet count of ≥ 50 × 109/L, median (Q1, Q3) 11.0 wk (9, 12) 0.0 wk (0, 0) Secondary end points Proportion of patients with increase of platelet count ≥ 20 × 109/L from baseline, incidence rate, n (%) 21 (96) 3 (25) Change from baseline in mean of last 4 platelet counts during weeks 2–13, mean (SD) 110 (89) × 109/L 2 (7) × 109/L 0.0003 Number of weeks with platelet counts in target range of ≥ 50 to ≤ 200 × 109/L, median (Q1, Q3) 7 (3, 9) wk 0 (0, 0) wk Proportion of patients requiring rescue medications, incidence rate, n (%) 2u(9) 2u(17) 0.6015 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.

AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin (TPO) receptor. This phase 2 study was conducted to identify the appropriate starting dose of AMG 531 for treatment of chronic ITP in adult Japanese patients. The study consisted of 2 phases: a 2-week cohort dose-escalation phase to determine the starting dose for subsequent phase 3 evaluation, and a treatment continuation phase (that lasted until completion of the dose-escalation phase) which provided continuation of treatment for those with a platelet response. Patients in the continuation phase received the dose of AMG 531 they had received in the dose-escalation phase with the option for subsequent dose adjustments. Twelve patients were enrolled with a mean platelet count of 11.8x109/L and a median age of 60.5 years (range 32 to 63); 8 were female. Four patients enrolled into each of 1μg/kg, 3μg/kg, or 6μg/kg dose cohorts and received AMG 531 by subcutaneous injection on days 1 and 8 with no dose adjustments. Cohort dose escalation was to be stopped in the event of an observed platelet count >1000x109/L. Comparison of dose cohorts showed that the proportion of patients achieving a platelet response (doubling of baseline counts and ≥50x109/L) was greater in cohorts receiving higher doses of AMG 531 (see Table). A dose response was also observed in the mean peak platelet counts, the mean fold changes from baseline in peak platelet counts, and the maximum platelet count. Because one patient in the 6μg/kg cohort had an excessively high platelet count (980x109/L), this dose was eliminated from consideration as the starting dose in phase 3 and further dose escalation to 10μg/kg dose cohort was stopped. Five of 7 eligible patients (3μg/kg, 1/4; 6μg/kg, 4/4) elected to enter the treatment continuation phase. There were no study withdrawals, and no serious adverse events (AEs) were reported during the study in either phase. The most common treatment-related AE in the cohort phase was headache (25%), and in the treatment continuation phase were arthralgia, contact dermatitis, and malaise (each 20%). No patients received rescue medications during the entire treatment period. No antibodies against either AMG 531 or endogenous TPO were detected. AMG 531 was well-tolerated and produced a dose-responsive increase in platelet counts. The phase 3 study in Japanese patients with ITP will be initiated with a starting dose of 3μg/kg based on the outcome of this study. Key Measures of Platelet Response