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In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 569-569

Abstract: Abstract 569 Introduction: Romiplostim, a novel peptibody that increases platelet production, is approved for the treatment of adult chronic ITP. Positive results from a previous study suggest the potential that romiplostim could improve QOL (Kuter, ASH 2009, #679). Immunosuppressive therapies for ITP may adversely affect patient QOL. We compared QOL between SOC- and romiplostim-treated pts from this study, and examined changes among subgroups of pts. Methods: This was an open-label study of nonsplenectomized ITP pts who were randomized to receive either once-weekly subcutaneous romiplostim or SOC. SOC treatments were prescribed according to standard institutional practices or therapeutic guidelines. QOL was assessed using the ITP patient assessment questionnaire (ITP-PAQ; consisting of 10 scales scored from 0–100); assessments were taken at baseline and every 12 weeks to week 52. Scores were also assessed for subgroups of pts with the following favorable outcomes: (1) did not receive blood transfusions or rescue medications, (2) did not experience bleeding ≥ grade 2, (3) did not experience a platelet count 〈 20 × 109/L. Mean and change from baseline scores were computed, and differences between treatment groups and among subgroups were assessed. Clinical significance was determined from the minimal important difference (MID), which is the smallest difference in QOL considered clinically meaningful (Mathias et al., CMRO 375-83) and corresponds to an 8–15 point improvement depending on the scale. The time to MID was also computed for Symptoms, Bother, Activity and Fatigue. Results: In total, 157 pts were randomized to receive romiplostim and 77 to receive SOC. At baseline, no statistically significant differences were found between the romiplostim and the SOC group on any of the scales. At 52-weeks, change scores for both the romiplostim group and the SOC group showed improvements that exceeded the MID with the exception of Fatigue in both arms and Activity in the SOC arm (Table). In comparison to the SOC group, the romiplostim group showed statistically significantly greater improvements from baseline for all scales except Fatigue. The differences between treatment groups did not exceed the MID for any of the scales. The time to MID was significantly shorter for the romiplostim group vs the SOC group on the Symptoms and Bother (p 〈 0.0001), and Fatigue (p=0.0068) scales. Among subgroups with favorable clinical outcomes, statistically significantly greater improvements were seen in the romiplostim group compared with the SOC group in many of the scales. The difference between treatment groups exceeded the MID only once: romiplostim-treated pts in the subgroup who did not experience platelet counts 〈 20 × 109/L had a 12.6 point greater improvement in Activity score compared to SOC pts. Conclusions: Nonsplenectomized ITP pts receiving romiplostim had greater improvements in QOL than pts receiving SOC. These improvements were maintained even among subgroups of pts with favorable clinical outcomes. However, the open-label study design limits our ability to make conclusions, and the clinical significance of the QOL improvements in romiplostim-treated pts relative to those receiving SOC remains uncertain. Disclosures: Kuter: Amgen Inc.: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; ONO: Consultancy; Pfizer: Consultancy, Research Funding; Shionogi: Consultancy, Research Funding. Mandanas:Celgene: Honoraria; Genentech/Roche: Honoraria; Amgen Inc.: Honoraria; GlaxoSmithKline: Speakers Bureau; Pfizer: Speakers Bureau; Genomic Health: Speakers Bureau. Giagounidis:Celgene: Consultancy, Honoraria. Wang:Amgen Inc.: Employment, Equity Ownership. Mathias:Amgen Inc.: Consultancy. Deuson:Amgen Inc.: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.569.569

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1430-1430

Abstract: Abstract 1430 Introduction: It is commonly accepted that antibody-mediated removal of platelets represents the major mechanism of platelet destruction in immune thrombocytopenic purpura (ITP). However, both the clinical course and the response to various treatments vary largely between ITP patients, suggesting a multi-factorial pathogenesis of thrombocytopenia in ITP. Ineffective thrombopoiesis and direct T-cell cytotoxicity have been described as additional immune-mediated mechanisms. In contrast, although some promising early studies were performed in the 1980s, the role of the complement system in ITP is still not well defined. The present pilot study investigated the possible contribution of the complement system in ITP. Material and Methods: We examined blood samples from 240 patients with ITP. First, all samples were assessed for the presence of free and bound platelet autoantibodies by a standard glycoprotein-specific assay (MAIPA). Second, the ability of all sera to fix complement to a panel of human platelets was investigated in a complement fixation assay. Third, fixation of C1q to immunobeads coated with platelet-derived GP IIb/IIIa as well as the generation of microparticles from test platelets were assessed by flow cytometry. The study was approved by the local research ethics committee. Results: Glycoprotein-specific autoantibodies were detected as platelet-bound antibodies in 129 (54%); as additional free antibodies in 26 (11%); and were undetectable in 111 (46%) of all patients. When sera from these patients where then assessed for their ability to fix complement to a panel of 5 test platelets, 103 (65%), 21 (81%), and 33 (30%) sera gave positive results. When studied in the presence of test platelets lacking either GP IIb/IIIa or GPIb/IX, 72% and 25% of all sera lost their ability to fix complement, respectively. Fixation of C1q to immunobeads covered with GP IIb/IIIa was observed in 70% of sera that had fixed complement to platelets. Half of these sera induced the production of platelet microparticles. In a group of 50 controls, platelet-reactive antibodies were undetectable, fixation of complement to platelets and fixation of C1q to immunobeads was observed in 2/50 (4%), and there were no sera inducing the production of micoparticles. Discussion: In a significant number of patients with chronic ITP, platelet autoantibodies are capable of activating the classical complement pathway. Complement fixation is even present in ITP sera without detectable autoantibodies, indicating that current techniques for autoantibody detection may be insufficient. The major target for complement-fixing autoantibodies in ITP is GP IIb/IIIa. In vitro, however, only 50% of sera that can fix complement in a GP IIb/IIIa-dependent manner are also capable of inducing platelet lysis. We conclude that complement fixation may contribute to thrombocytopenia by directly damaging platelets and/or by enhancing platelet clearance via complement-receptor mediated phagocytosis. It will thus be relevant to study the influence of complement-mediated platelet destruction on treatment responses, particularly in the light of newly developed approved and non-approved therapies, such as, thrombopoietin receptor agonists and inhibitors of complement activation. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.1430.1430

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 104, No. 6 ( 2019-06), p. 1237-1243

Type of Medium: Online Resource

ISSN: 0390-6078 , 1592-8721

URL: Article

DOI: 10.3324/haematol.2018.211086

Language: English

Publisher: Ferrata Storti Foundation (Haematologica)

Publication Date: 2019

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detail.hit.zdb_id: 2030158-3

detail.hit.zdb_id: 2805244-4

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 569-569

Abstract: Immune thrombocytopenia (ITP) is a bleeding disorder caused by IgG autoantibodies (AAbs) directed against platelets. The IgG effector functions of autoantibodies depend on their Fc-constant region which undergoes posttranslational glycosylation. We investigated the role of Asn279-linked N-glycan of AAbs in vitro and in vivo. Material and Methods AAbs were purified from ITP patients (n=15) and controls (n=10) and N-glycans were enzymatically cleaved by endoglycosidase F. The effects of native AAbs and deglycosylated AAbs (deAAbs) were compared in vitro on enhancement of phagocytosis of platelets by monocytes and complement fixation and activation applying flow cytometry, laser scanning microscopy, and a complement consumption assay. The capability of AAbs and deAAbs to eliminate human platelets in vivo was studied in a NOD/SCID mouse model in presence and absence of a complement source. Results AAb-induced platelet phagocytosis was inhibited by N-glycan cleavage (median phagocytic activity: 8% vs. 0.8%, p=0.004). Seven out of 15 native AAbs bound C1q and induced complement consumption. N-glycan cleavage significantly reduced C1q binding (MFI 16.4 vs. 4.9, p=0.017) and complement consumption. In vivo survival of human PLTs was assessed after cotransfusion with native or deAAbs in NOD/SCID mice. Injection of AAbs resulted in rapid clearance of human platelets compared to control (platelet clearance after 5h (CL5h) 75% vs. 30%, p 〈 0.001). AAbs that were able to activate complement induced more pronounced platelet clearance in the presence of complement compared to the clearance in the absence of complement (CL5h 82% vs. 62%, p=0.003). AAbs lost their ability to destroy platelets in vivo after deglycosylation (CL5h42%, p 〈 0.001). Conclusion Removal of N-glycan from AAbs interferes with Fc-mediated phagocytosis and complement activation and thereby prolongs platelet survival in vivo. Our study provides tools for better characterizing ITP AAbs and sheds light on the heterogeneity of AAbs in ITP. Clinical studies should aim to assess such additional characteristics, since this could lead to the identification of ITP patient subgroups with increased responses to specific or new interventions such as, targetting complement factors. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.569.569

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3701-3701

Abstract: Abstract 3701 Introduction: ITP is an autoimmune disease characterized by increased platelet destruction and suboptimal platelet production. ITP pts are at increased risk of bleeding, and those with persistently low platelet counts are at increased risk of fatal bleeding (Cohen, Arch Intern Med, 2000). Romiplostim increases platelet production and offers an alternative treatment option to chronic immune suppression in pts with ITP. We analyzed mortality rates in ITP pts who participated in randomized, controlled romiplostim clinical studies (in which pts received either romiplostim or placebo/standard of care [SOC] ) and their subsequent time in an open-label extension study (in which all pts received romiplostim). Methods: Data were pooled from two 24-week placebo-controlled phase 3 studies and a 52-week SOC-controlled study, which included an off-treatment safety follow-up period for those pts who did not enter the extension study. Additional analyses included data from pts' subsequent time in an extension study. The Cox regression model was used to estimate mortality rates. Results: In total, 354 pts (238 romiplostim, 41 placebo, 75 SOC) from the controlled studies were included in the analysis. Of these, 238 enrolled into the extension study (187 romiplostim, 33 placebo, 18 SOC). At the time of enrolment into the controlled study, the median age was 55 years (Q1 –Q3, 42 – 68), and 22% were splenectomized; their median time since diagnosis was 3.5 years (range, 0.02 – 45); pts had received a median of 3 prior ITP therapies (range, 1 – 9), and 24% were receiving baseline concurrent ITP treatment. Pts were followed for up to 87 weeks in the controlled studies; 0.8% (2/238) of pts in the romiplostim arm died and 6.9% (8/116) of pts in the placebo/SOC arm died. Pts who entered the extension study were followed for up to 215 weeks; 5.9% (14/238) of pts died during this time. Pts died from various causes (see Table). The median age of the pts who died was 73 years (Q1 – Q3, 58 – 78). When data from the controlled studies were pooled, mortality rates in the romiplostim arm were approximately 5-fold less than those in the placebo/SOC arm (HR, 0.187; 95% CI, 0.048–0.931; p=0.04). The survival benefit in the romiplostim arm was maintained when time spent in the extension study was added to the analysis (HR, 0.120; 95% CI, 0.035–0.410; p=0.0007) [see Figure]. Factors predicting increased mortality risk in a multiple Cox regression model were: treatment with placebo/SOC vs romiplostim (p 〈 0.0001), age ≥ 65 years (p=0.002), greater number of prior ITP treatments (p=0.064), and concurrent baseline ITP treatment (p=0.016). Furthermore, there was a positive correlation between the grade of worst bleeding event and risk of death (p 〈 0.0001), and there was an association between mortality and experiencing a bleeding event with a worst grade of ≥2 (p=0.0154), ≥3 (p=0.0002), and ≥4 (p=0.0002). Conclusions: In this large retrospective analysis of an ITP pt study population, the mortality rate was significantly lower in pts receiving romiplostim than in those receiving placebo or other ITP therapies. Associations were found between mortality risk and age, prior treatment with other ITP therapies, and on-study bleeding; however, there was no clear pattern of disease-related or treatment-related cause of death, and determining the mechanism for increased survival in the romiplostim arm requires further study. Disclosures: Gernsheimer: Amgen Inc.: Consultancy; Cangene: Consultancy; Baxter: Honoraria; Shionogi Corp.: Research Funding. Kuter:Amgen Inc.: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; ONO: Consultancy, Research Funding; Eisai: Consultancy, Research Funding. Cines:Amgen Inc.: Consultancy; GlaxoSmithKline: Consultancy. Stasi:Amgen Inc.: Honoraria, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau. Godeau:Amgen France: Consultancy, Research Funding; Roche France: Consultancy, Research Funding; LFB France: Consultancy. Guo:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.3701.3701

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1141-1141

Abstract: Immune thrombocytopenia (ITP) results from autoimmunization against platelet antigens. Autoantibodies (aabs) are considered to represent a major mechanism of thrombocytopenia in ITP by inducing platelet clearance from the circulation. Several lines of evidence demonstrate that aabs against glycoproteins (GP) IIb/IIIa and Ib/IX are predominant in ITP patients. Both disease severity and treatment response rates to specific therapeutics have been associated with aabs patterns. GP V is a well characterized immune target in Varicella-associated and drug-induced thrombocytopenia, but has never been studied systematically in ITP. In this study, patients with a suspected diagnosis of primary ITP were included once they met pre-defined clinical inclusion criteria. The presence of GP IIb/IIIa-, GP Ib/IX, and GP V-specific aabs was investigated by monoclonal antibody immobilization of platelet antigens (MAIPA) assay, both on patients' autologous platelets (direct MAIPA) and in serum (indirect MAIPA). In addition, serum IgG fractions were prepared from all patients with a positive direct MAIPA. IgG fractions were tested by surface plasmon resonance (SPR) technology for the presence of anti-GP V aabs. Complete data sets were obtained from 1,140 qualified patients. Platelet-bound aabs were detected in 343/1,140 patients (30.1%). Of these, 222 (64.7%) had platelet-bound anti-GP V aabs, either alone (10/222), or together with other specificities (211/222). Free anti-GP V aabs were detected in 30/222 patients by indirect MAIPA, but in 88/222 by SPR. The avidity of aabs detected by both methods (n=29; R700/R350=0.73±0.14) was significantly higher than the avidity for aabs detected by SPR only (n=59; R700/R350=0.32±0.13, p 〈 0.001). In order to study the potential biological relevance of anti-GP V, a phagocytosis assay using CD14+ positively-selected macrophages from spleen specimens from splenectomized ITP patients was performed. Anti-GPV aabs induced a modest amount of platelet uptake above the normal human serum-incubated control. No difference was observed between high avidity and low avidity anti-GP V. The effect of anti-GPV on platelet clearance was further studied in a NOD/SCID mouse model. Freshly isolated human platelets were injected into the lateral mouse tail vein; after 30 min, IgG fractions isolated from human sera containing anti-GPV antibodies or control sera from healthy donors were injected into the other lateral tail vein, and the survival of human platelets in the mouse circulation was analyzed by taking murine blood 60, 120, 300 min and 24h after baseline. High avidity and low avidity anti-GP V aabs (n=3 per group) eliminated human platelets with no detectable difference between the groups (mean platelet survival at t=300 min: 40% [range 27-55] versus 35% [range, 16-46]). A comparable, dose-dependent platelet clearance was also obtained with monoclonal antibody SW16 against GP V. In summary, we have demonstrated that anti-GP V autoantibodies are regularly detectable in ITP patients; and that they are able to induce phagocytosis and platelet clearance. Our findings have implications for both, further development of laboratory testing, and guidance for clinical decision making. First, comparison between MAIPA and SPR reveals that free aabs may be more frequent than reported, since aabs appear to escape detection by standard laboratory methods because of low avidity. Better test methods are required. Second, predicting disease severity and/or tailoring ITP therapy can possibly not be restricted to the postulated difference between anti-GP IIb/IIIa and anti-GP Ib/IX. Prospective studies are required to understand the impact of different GP-specific platelet aabs on the clinical course of ITP including, anti-GP V. Disclosures Rummel: Celgene: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria. Bakchoul:Aspen Germany gGmbH, CLS Behring, Stago gGmbH: Honoraria; German Research Society (DFG): Research Funding; Robert Bosch gGmbH: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-118090

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 679-679

Abstract: Abstract 679 Chronic ITP is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production. Immunosuppressive ITP therapies have variable response rates and may be associated with substantial side effects, limiting their use for long-term treatment. Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to thrombopoietin, and is approved for the treatment of chronic ITP. We present final results from a phase 3b, randomized, open-label study, comparing the incidence of splenectomy and treatment failure in adult nonsplenectomized ITP patients receiving either romiplostim or medical standard of care (SOC). Patients were randomized (2:1) to romiplostim or SOC. Eligible patients had a platelet count 〈 50 × 109/L. Once-weekly subcutaneous romiplostim was administered with dose adjustments to target a platelet count between 50 and 200 × 109/L. SOC treatments were prescribed according to standard institutional practices or therapeutic guidelines; the only treatments not allowed were investigational agents (rituximab was allowed) or other thrombopoietic agents. Patients received romiplostim or SOC for 52 weeks, and those who did not subsequently transfer to another romiplostim study completed a 6-month off-treatment safety follow-up. Co-primary endpoints of the study were: the incidence of splenectomy and the incidence of treatment failure (defined as: platelet count ≤20 × 109/L for 4 consecutive weeks at the highest recommended dose and schedule, or major bleeding event, or change in therapy due to intolerable side-effect or bleeding symptoms). Patients who discontinued study during the treatment period were counted as having had splenectomy or treatment failure. To assess the impact of treatment discontinuation on the primary endpoints, a sensitivity analysis was conducted to determine the actual incidence of splenectomy or treatment failure. A total of 234 patients were randomized (romiplostim, 157; SOC, 77); 83% of romiplostim and 66% of SOC patients completed the study. Patients had been diagnosed with ITP for a median of 2 years (range 0.01 to 44 years) and 73% had received ≥2 prior ITP therapies. Patient characteristics were similar between treatment groups. The efficacy of romiplostim was significantly greater than that of SOC in both primary endpoint analyses. The incidence of splenectomy was 9% (14/157) in the romiplostim group compared to 36% (28/77) in the SOC group (OR, 0.17; 0.08, 0.35; p 〈 0.0001), and the incidence of treatment failure was 12% (18/157) in the romiplostim group compared to 30% (23/77) in the SOC group (OR, 0.31; 0.15, 0.61; p=0.0005). Sensitivity analyses confirmed the primary endpoint analyses: the actual incidence of splenectomy was significantly lower in the romiplostim group (2/157, 1%) than the SOC group (15/77, 20%) [p 〈 0.0001], and the actual incidence of treatment failure was significantly lower in the romiplostim group (6/157, 4%) than the SOC group (10/77, 13%) [p=0.009] . The incidence of bleeding events with a worst grade score ≥3 appeared lower for patients in the romiplostim group (3%) than the SOC group (7%). Safety analyses included only patients who received ≥1 dose of romiplostim or 1 type of SOC. During the 52-week treatment period, adverse events occurred in 96% (147/154) of patients receiving romiplostim and 92% (69/75) of patients receiving SOC. Serious adverse events occurred in 23% (35/154) of romiplostim and 37% (28/75) of SOC patients; serious adverse events were considered treatment-related in 5% (7/154) of romiplostim and 8% (6/75) of SOC patients. During the 6-month safety follow-up period, 36% (11/31) of romiplostim and 43% (18/42) of SOC patients experienced an adverse event; treatment-related adverse events occurred in none of the romiplostim patients and 2 of the SOC patients. Overall, 6 patients died: 1 (1%) in the romiplostim group and 5 (7%) in the SOC group. None of the deaths were considered related to study treatment or the underlying ITP. No patients tested positive for neutralizing antibodies to romiplostim or TPO. One romiplostim-treated patient showed an increase in bone marrow reticulin that was still within the normal range (Grade 2). In summary, romiplostim significantly reduced incidences of splenectomy and treatment failure in nonsplenectomized ITP patients compared to SOC. The safety profile of romiplostim was similar to SOC. Disclosures: Kuter: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Esehi: Consultancy; Shionagi: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria, Speakers Bureau; MGI Pharma: Consultancy, Research Funding; Ligand: Honoraria, Speakers Bureau. Rummel:Amgen Inc.: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Boccia:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Macik:Amgen Inc.: Research Funding; Eisai Inc.: Research Funding. Pabinger:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Selleslag:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodeghiero:Amgen Inc.: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Shionogi: Speakers Bureau. Chong:Commonwealth Serum Laboratory (CSL): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 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. Müller-Beiβenhirtz:Amgen Inc.: Consultancy. Gehl:Amgen Inc.: Employment, Equity Ownership. Wang:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.679.679

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3702-3702

Abstract: 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; p 〈 0.0001]. In addition, romiplostim-treated patients had a significantly longer time to splenectomy than SOC patients (p=0.0001) (Figure). The sensitivity analysis showed that the actual incidence of treatment failure was similar between treatment groups (romiplostim, 5%, 3/56; SOC, 10%, 3/29) [p=0.5589] and the actual incidence of splenectomy was significantly lower in romiplostim-treated patients (4%, 2/56) than in SOC-treated patients (35%, 10/29) [p=.0002]. The percentage of patients experiencing a serious bleeding event was similar (romiplostim, 6%; SOC, 4%). Serious adverse events occurred in 24% (13/55) of romiplostim patients and 46% (13/28) of SOC patients with the most common event being thrombocytopenia. No adverse events led to study withdrawal. Thromboembolic events occurred in one romiplostim-treated patient (pulmonary embolism) and one SOC patient (cerebral microangiopathy). There were no reports of increased reticulin, and no patients tested positive for neutralizing antibodies to romiplostim or TPO. Conclusion: The results from this ad-hoc analysis of this subgroup indicate romiplostim may reduce the incidence of treatment failure and splenectomy in patients who have been diagnosed with ITP for 1 year or less, although the enrollment of patients with platelet counts 〉 20 × 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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.3702.3702

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7

In: European Journal of Haematology, Wiley, Vol. 88, No. 2 ( 2012-02), p. 167-174

Type of Medium: Online Resource

ISSN: 0902-4441

URL: Issue

URL: Article

DOI: 10.1111/ejh.2012.88.issue-2

DOI: 10.1111/j.1600-0609.2011.01718.x

Language: English

Publisher: Wiley

Publication Date: 2012

detail.hit.zdb_id: 2027114-1

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. TPS8617-TPS8617

Abstract: TPS8617 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). Phase 1 trials demonstrated that idelalisib is highly active in pts with heavily pretreated iNHL: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with acceptable safety profile (de Vos et al, 2011). Methods: 375 pts with previously treated iNHL, who have measurable lymphadenopathy, have received prior anti-CD20-antibody-containing therapy, and who have iNHL that is not refractory to rituximab (R) are randomized in a 2:1 ratio into Arm A or Arm B. In Arm A, pts receive idelalisib at 150 mg BID continuously + R at 375 mg/m 2 (weekly x 4 then every 8 weeks x 4). In Arm B, pts receive placebo BID instead of idelalisib. Stratification factors include tumor type (follicular lymphoma vs others), tumor burden (high vs low), and time since completion of last prior therapy for iNHL ( 〈 18 months vs ≥18 months). The primary endpoint is PFS and key secondary endpoints include ORR, lymph node response rate, CR rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test. The study opened for enrollment in Dec 2012 (NCT01732913). Clinical trial information: NCT01732913.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2013.31.15_suppl.tps8617

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2013

detail.hit.zdb_id: 2005181-5