Thrombocytopenia in the Absence of Splenomegaly in Patients with Type 1 Gaucher Disease: A Preliminary Analysis From the ICGG Gaucher Registry,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4217-4217
Author(s):  
Barry E Rosenbloom ◽  
Sarah Kulke ◽  
John Taylor ◽  
Neal J. Weinreb
Keyword(s):  
Board Of Directors ◽  
Gaucher Disease ◽  
Research Funding ◽  
Diagnostic Delay ◽  
Clinical Signs ◽  
Severe Thrombocytopenia ◽  
Advisory Committees ◽  
Delay In Diagnosis ◽  
Platelet Counts

Abstract Abstract 4217 Background: Patients with Gaucher disease frequently experience a delay in diagnosis despite clinical signs and/or symptoms. This delay is thought to stem from the rarity of the disease and physicians' inexperience with the constellation of disease manifestations that often overlap those of more common hematological illnesses. It has been the authors' experience that, in the absence of palpable splenomegaly, physicians are even less likely to consider the possibility of Gaucher disease in patients who have other typical manifestations such as chronic bone pain or hematological cytopenias. Using data submitted to the International Collaborative Gaucher Group (ICGG) Gaucher Registry, the largest single repository of Gaucher disease clinical information in existence, we sought to determine how commonly such patients are likely to be encountered. Purpose: To determine the frequency of patients with Gaucher disease who have little to no splenomegaly at diagnosis despite having concurrent moderate or severe thrombocytopenia. Methods: Data were evaluated from all patients with Gaucher disease type 1 enrolled in the ICGG Gaucher Registry as of June 3, 2011 who had not been splenectomized before diagnosis and whose spleen volumes and platelet counts at the time of diagnosis were reported to the Registry. Splenomegaly was quantitated by MRI, CT or ultrasonic volumetric measurements and categorized as mild/none (≤5 multiples of normal [MN] based on a normal value of 0.2% of body weight), moderate (>5 to ≤15 MN) and severe (> 15 MN). Platelet counts were categorized according to thrombocytopenia categories of mild/none (≥120 ×103/mm3), moderate (>60 to ≤120 × 103/mm3) and severe (<60 × 103/mm3). Results: A total of 612 patients with platelet counts and spleen volumes were identified. Of these, 96/612 (15.7%) had mild or no splenomegaly at the time of Gaucher diagnosis. Of these 96 patients, 37 (38.5%) had moderate thrombocytopenia and 6 (6.3%) had severe thrombocytopenia. Conclusions: Type 1 Gaucher patients often present with moderate to severe thrombocytopenia but with either normal spleen volumes or with splenomegaly that is not likely to be clinically apparent. These patients may be at particular risk for diagnostic delay but no less susceptible to Gaucher disease morbidity than patients with a more typical presentation. Further description of this cohort with respect to genotype, demographics, and other disease manifestations will be presented. Disclosures: Rosenbloom: Genzyme Corporation ; Shire Pharmaceuticals: Research Funding, Speakers Bureau; Genzyme Corp: Research Funding, Speakers Bureau. Kulke:Genzyme, a Sanofi Company: Employment. Taylor:Genzyme, a Sanofi Company: Employment. Weinreb:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire HGT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Actelion Corporation: Speakers Bureau.

scholarly journals Pacifica: A Randomized, Controlled Phase 3 Study of Pacritinib Vs. Physician's Choice in Patients with Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post Essential Thrombocytopenia Myelofibrosis with Severe Thrombocytopenia (Platelet Count <50,000/mL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4175-4175 ◽  
Author(s):  
Claire N Harrison ◽  
Aaron T. Gerds ◽  
Jean-Jacques Kiladjian ◽  
Konstanze Döhner ◽  
Sarah A Buckley ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Severe Thrombocytopenia ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Jak2 Inhibitor ◽  
Oncology Research ◽  
Equity Ownership

Background: Myelofibrosis (MF) is a life-limiting condition with severe morbidity in advanced stages. Patients with MF and severe thrombocytopenia (platelet counts <50,000/mL) have a particularly poor prognosis, with more frequent anemia and leukopenia, higher rates of hemorrhagic and thrombotic complications, and worse overall survival (~15 months) compared to the overall MF population (Scotch AH, et al, Leuk Res. 2017; Masarova L, et al, Eur J Haematol. 2018). Moreover, effective treatment options are limited in this high-risk population as the currently approved JAK inhibitor, ruxolitinib (RUX), is associated with treatment-related thrombocytopenia and often requires dose reductions for patients with platelet counts <100,000/mL, with reduced efficacy compared to patients able to tolerate higher doses. Further, there is no approved dose of RUX for patients with platelet counts <50,000/mL, and NCCN guidelines encourage physicians to consider clinical trials for such patients given the lack of approved therapies. Pacritinib (PAC) is an oral JAK2/IRAK1 inhibitor that has demonstrated clinical activity in MF patients in two prior Phase 3 studies (PERSIST-1, PERSIST-2) as well as a Phase 2 dose-finding study (PAC203), including patients with severe thrombocytopenia. The PACIFICA trial has been designed to evaluate the efficacy and safety of PAC 200 mg BID vs. physician's choice (P/C) therapy in patients with MF and severe thrombocytopenia. Study Design and Methods: PACIFICA is a randomized, controlled Phase 3 trial of PAC vs. P/C in adult patients with primary or secondary MF who are not candidates for stem cell transplant, with DIPSS intermediate- or high-risk disease, ECOG PS ≤2, and platelet counts <50,000/mL, who have had up to 90 days of prior treatment with a JAK2 inhibitor or are JAK2 inhibitor-naïve. Additional exclusion criteria exist for patients with recent cardiac or hemorrhagic events, ejection fraction <50%, QTc >450 msec, or use of medications that increase the risk of hemorrhage or QT prolongation. On the PAC arm, patients receive continuous PAC 200mg BID. On the P/C arm, one of the following agents is selected prior to randomization: low-dose ruxolitinib (no more than 5 mg BID while platelet counts remain <50,000/mL), thalidomide, lenalidomide, corticosteroids, or hydroxyurea. The primary objective is to compare the efficacy of PAC vs. P/C based on the proportion of patients achieving a ≥35% spleen volume response (SVR) at Week 24. Secondary objectives include comparisons of the proportion of patients achieving a ≥50% reduction in total symptom score (TSS) at Week 24, overall survival, and proportion of patients who self-assess as "very much improved" or "much improved" as measured by the patient global impression of change (PGIC). Tertiary endpoints include alternative methods of evaluating SVR improvement, hematologic improvement (transfusion independence and improvement in anemia and thrombocytopenia), improvement in fatigue as measured by the PROMIS - Fatigue - Short form 7a, and changes in mutated allelic burden and gene expression (including correlation with response data). The study will enroll ~180 patients in a 2:1 ratio (PAC to P/C), which will have >80% power to achieve the primary endpoint. Enrollment is anticipated to begin in Q3 2019, as PACIFICA is expected to open as an amendment to the Phase 2 PAC203 study (NCT03165734) in select sites. Disclosures Harrison: Janssen: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Gilead: Speakers Bureau; AOP: Honoraria; Promedior: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Sierra Oncology: Honoraria. Gerds:Roche: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Incyte: Consultancy, Research Funding. Kiladjian:Novartis: Honoraria, Research Funding; Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Buckley:CTI BioPharma: Employment, Equity Ownership. Smith:CTI BioPharma: Employment, Equity Ownership. Craig:CTI BioPharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Mascarenhas:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Verstovsek:Incyte: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; NS Pharma: Research Funding; Roche: Research Funding.

Engage: A Phase 3, Randomized, Double-blind, Placebo-controlled, Multi-center Study To Investigate The Efficacy and Safety Of Eliglustat In Adults With Gaucher Disease Type 1: 9 Month Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2275-2275 ◽  
Author(s):  
Suma Shankar ◽  
Elena Lukina ◽  
Dominick J Amato ◽  
Majed Dasouki ◽  
Seymour Packman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Gaucher Disease ◽  
Research Funding ◽  
Liver Volume ◽  
Disease Type ◽  
Spleen Volume ◽  
Advisory Committees ◽  
Gaucher Disease Type 1

Abstract Background Gaucher disease type 1 is one of the most common lysosomal storage disorders. Deficiency of the lysosomal enzyme acid-β-glucosidase leads to accumulation of glucosylceramide (GL-1) in the spleen, liver, and bone marrow. Enzyme replacement therapy has been the mainstay of therapy for the last 20 years. Substrate reduction therapy is another treatment approach that inhibits GL-1 synthase and ultimately restores the balance between synthesis and degradation of the substrate. Eliglustat is a novel oral substrate reduction therapy that is currently in development for the treatment of Gaucher disease type 1. ENGAGE (NCT00891202) is a randomized, double-blind, placebo-controlled, Phase 3 trial sponsored by Genzyme, a Sanofi company investigating the efficacy and safety of eliglustat in untreated adults with Gaucher disease type 1. Method Forty patients (mean age: 31.8 years; 20 males) with splenomegaly and thrombocytopenia and/or anemia were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg BID depending on plasma levels) or placebo for 9 months. The primary efficacy endpoint was percent change in spleen volume (multiples of normal). Other efficacy measures included hemoglobin, liver volume, and platelets. Bone endpoints included bone marrow burden (BMB) scores and bone mineral density changes (DXA). Quality of life assessments included the Gaucher Disease Severity Scoring System (DS3). Safety monitoring included adverse event reporting, and lab and electrocardiogram evaluations. Results In patients receiving eliglustat vs. placebo, mean spleen volume decreased (-28% vs. +2%, P<0.0001), mean hemoglobin increased (0.69 vs. -0.54 g/dL, P<0.0006), liver volume decreased (-5.20% vs. +1.44%, P<0.0072), and platelets increased (+32% vs. -9.06%, P<0.0001). Significant improvements (eliglustat vs. placebo) were observed for total (-1.1 vs. 0.0, p=0.002), spine (-0.6 vs. 0.1, p=0.002), and femur (-0.5 vs. 0.0, p=0.026) BMB scores. Although patients with symptomatic bone disease were excluded, absolute change in total spine DXA Z-scores approached significance (least square mean treatment difference=0.2, p=0.06). Burden of disease, as measured by the Gaucher DS3, was significantly reduced following treatment with eliglustat vs. placebo (least square mean treatment difference=-0.3, p=0.0452). No patients discontinued due to an adverse event, all of which were classified as mild to moderate, and 39/40 patients transitioned into the ongoing open-label trial. Arthralgia and nasopharyngitis occurred in >10% of eliglustat vs. placebo patients. Conclusion ENGAGE met its primary and secondary efficacy endpoints. Significant effects on bone marrow and a trend toward BMD improvement in spine were observed. Eliglustat treatment was effective and well-tolerated in untreated adults with Gaucher disease type 1. Disclosures: Shankar: Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Lukina:Genzyme, a Sanofi company: Consultancy, Honoraria, Speakers Bureau. Amato:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Packman:Genzyme, a Sanofi company: Consultancy, Research Funding. Pastores:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Balwani:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Mistry:Genzyme, a Sanofi company: Consultancy, Honoraria, Research Funding. Ross:Genzyme, a Sanofi company: Employment. Marulkar:Genzyme, a Sanofi company: Employment. Peterschmitt:Genzyme, a Sanofi company: Employment.

scholarly journals Biomarker Response to Oral Eliglustat in Adults with Gaucher Disease Type 1: Results from 4 Completed Clinical Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4859-4859
Author(s):  
Neal J Weinreb ◽  
Timothy M Cox ◽  
Pramod K. Mistry ◽  
Joel Charrow ◽  
Elena Lukina ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Gaucher Disease ◽  
Research Funding ◽  
Phase 2 ◽  
Phase 3 ◽  
Advisory Committees ◽  
Therapeutic Goals ◽  
Treatment Naïve ◽  
Gaucher Disease Type 1

INTRODUCTION: Gaucher disease type 1 (GD1) is caused by hereditary deficiency in activity of lysosomal acid β-glucosidase and lysosomal dysfunction due to abnormal recycling and storage of glycosphingolipids especially in tissue macrophages. Clinical manifestations can include anemia, thrombocytopenia, hepatosplenomegaly, and debilitating bone disease. Hematologists care for most patients with GD1 but may be unaware of the importance of plasma biomarkers not only as tissue response surrogates that are useful for monitoring treatment efficacy but also as pathogenic molecules that can directly contribute to disease manifestations. These biomarkers include chitotriosidase, macrophage inflammatory protein 1β (MIP-1β), glucosylceramide, glucosylsphingosine, and monosialodihexosyl ganglioside (GM3). Here we show differing changes in biomarker levels after inception of eliglustat therapy in treatment-naïve GD1 patients and in patients previously treated with enzyme replacement therapy (ERT). Eliglustat is an oral inhibitor of glucosylceramide biosynthesis approved by FDA as a first-line treatment of adults with GD1 who have extensive, intermediate, or poor CYP2D6 metabolizer phenotypes (>90% of patients). METHODS: We evaluated percent change from baseline in biomarker levels during time on eliglustat in the 4 completed clinical trials of oral eliglustat for GD1 adults (Sanofi Genzyme): Phase 2/NCT00358150 (treatment-naïve patients with moderate to severe baseline disease, N=26); Phase 3 ENGAGE/NCT00891202 (treatment-naïve patients with mild to moderate baseline disease, N=40); Phase 3 ENCORE/NCT00943111 (switch patients at prespecified therapeutic goals stabilized after a mean of 10 years of ERT], N=159); Phase 3 EDGE/NCT01074944 (mixture of treatment-naïve [N=22] and ERT-switch patients [N=148] with mild to moderate baseline disease and variable prior time on ERT). All percentages were calculated in the subset of patients with biomarkers measured at baseline and the reported timepoint. The attrition of patients with data at the longer-term time points is attributable primarily to a combination of 2-year enrollment periods, trial design, and protocol-mandated switches to commercial therapy for US patients. Most patients (81%) continued until eliglustat became commercially available or completion of their trial; 9 patients (2.3% overall) withdrew due to adverse events reported as drug-related. For Phase 2, ENGAGE, and ENCORE, chitotriosidase genotypes were obtained and values were normalized; patients homozygous for the CHIT null mutation were excluded and values for heterozygous patients were doubled. For EDGE patients, chitotriosidase genotype data were not obtained but patients with ≥4 zero values (n=12) were excluded. RESULTS: In treatment-naïve patients, all biomarkers were elevated at baseline. Median levels of glucosylceramide, GM3, and MIP-1β normalized within 1 year of starting eliglustat. Chitotriosidase and glucosylsphingosine levels markedly decreased but did not normalize. After 3-8 years on treatment, median percent reduction in chitotriosidase and glucosylsphingosine (Phase 2 and ENGAGE) was 85-92% (Table) but values did not normalize. In patients switching from ERT, median chitotriosidase was still modestly elevated at baseline. Median values for other biomarkers were normal or near normal. After 1 year of treatment, chitotriosidase decreased (Table). Median glucosylceramide, GM3, and MIP-1β remained normal or normalized. After 3-4 years, GM3 and MIP-1β remained normal. Median percent reduction in chitotriosidase from baseline was 60-63% but values did not normalize. Eliglustat was generally well-tolerated in all 4 trials; 97% of adverse events were mild/moderate and 86% considered unrelated to eliglustat by the investigator. CONCLUSIONS: Gaucher disease biomarkers decreased substantially in treatment-naïve patients after eliglustat treatment. In switch patients, including very stable patients after a mean of 10 years on ERT, chitotriosidase and MIP-1β also decreased substantively after eliglustat treatment. Future longitudinal follow-up of eliglustat-treated patients should indicate whether the biomarker and plasma glycosphingolipid responses reported here in stable patients at long-term therapeutic goals are associated with immunological and clinical improvements. Disclosures Weinreb: Shire HGT: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cox:Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Reimbursement, Research Funding. Mistry:Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Reimbursement, Research Funding; NIH NIMS: Research Funding; Shire: Honoraria, Other: Travel Reimbursement, Research Funding; Pfizer: Honoraria, Other: Travel Reimbursement; Synageva: Honoraria, Other: Travel Reimbursement. Charrow:BioMarin: Research Funding; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amicus: Research Funding. Lukina:JSC GENERIUM: Research Funding; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Reimbursement, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Reimbursement. Foster:Sanofi Genzyme: Employment. Peterschmitt:Sanofi Genzyme: Employment.

Report on the Safety of Velaglucerase Alfa Enzyme Replacement Therapy in Patients with Type 1 Gaucher Disease and the Transition From Clinic to Home Infusions During Treatment Protocol HGT-GCB-058

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1101-1101
Author(s):  
Gregory M Pastores ◽  
Barry E Rosenbloom ◽  
Neal J Weinreb ◽  
Ozlem Goker-Alpan ◽  
Rebecca Mardach ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Gaucher Disease ◽  
Research Funding ◽  
Treatment Protocol ◽  
Home Therapy ◽  
Advisory Committees ◽  
Enzyme Replacement ◽  
Home Infusion ◽  
Type 1 Gaucher Disease

Abstract Abstract 1101 BACKGROUND: Type 1 Gaucher disease (GD) is an inherited storage disease characterized by acid-β-glucosidase deficiency and the accumulation of glucosylceramide in the mononuclear phagocyte system. Hematologists are commonly the specialists to whom affected individuals present; findings may include anemia, thrombocytopenia, splenomegaly, hepatomegaly, and skeletal and bone marrow pathology. HGT-GCB-058 was a multicenter treatment protocol initiated at the request of the US Food and Drug Administration (FDA) in 2009 (ClinicalTrials.gov identifier NCT00954460). It provided velaglucerase alfa, then an investigational drug, to patients with type 1 GD who would otherwise have experienced a disruption or delay in receiving enzyme replacement therapy (ERT) due to a global supply shortage of imiglucerase at that time. OBJECTIVE: We report safety results in patients who received up to 12 months of velaglucerase alfa in protocol HGT-GCB-058, and the transition from administration at the clinical site to home infusions. METHODS: To enroll, patients had to be aged >2 years, with a documented diagnosis of type 1 GD and no history of an anaphylactic or anaphylactoid reaction to ERT. Patients who were treatment-naïve received 60 U/kg (body weight) of velaglucerase alfa as an intravenous infusion every other week (EOW). Patients who were previously treated with imiglucerase (switch patients) received the same EOW dose of velaglucerase alfa as their prior imiglucerase treatment. Each patient could continue in the protocol until commercial therapy was available to him or her. Adverse events (AEs) were monitored throughout the patient's participation in the protocol. Switch patients were eligible for home therapy if they received their first 3 infusions, at the clinical site, in the absence of an infusion-related AE or treatment-related, serious AE (SAE). RESULTS: Across 23 centers, 211 patients were enrolled. The median age was 54 years (range 6–89 years); 8 patients were aged <18 years; 48% were male; 34% were splenectomized. There were 205 switch patients (the median prior imiglucerase exposure was 145 months [range 1–231 months]) and 6 treatment-naïve patients. All 211 patients received ≥1 infusion of velaglucerase alfa. By the end of 12 months, 203 patients had left the protocol; most patients transitioned to commercial velaglucerase alfa, which was approved by the FDA in 2010. The median duration of velaglucerase alfa treatment in the protocol was 182 days (range 1–365 days) for switch patients and 106 days (range 27–232 days) for treatment-naïve patients. Over 12 months, most AEs were mild or moderate in severity. Twenty severe AEs were reported in 11 patients, of which 5 – pain in extremity and fatigue in 1 patient, fatigue in 1 patient, and 2 instances of generalized pain in 1 patient – were considered treatment-related Table). Ten SAEs were reported in 7 patients, of which 1 (migraine) was considered treatment-related. The AEs leading to protocol discontinuation were: nausea, increased blood pressure (both treatment-related), and hip fracture (not treatment-related). The most common AEs were nasopharyngitis (n=15), headache (n=15), and nausea (n=12). After the first 3 infusions, 187 of the 205 switch patients were eligible for home therapy based on safety criteria. During the protocol, 54 patients received ≥1 home infusion. Home infusions were administered by qualified and trained medical personnel under the direction of the investigator. Patients' and investigators' preferences for home therapy were not captured in the protocol. CONCLUSIONS: Velaglucerase alfa was generally well-tolerated in a large, clinically heterogeneous group of patients with type 1 GD. Of 205 patients in treatment protocol HGT-GCB-058 who switched from imiglucerase, 91% met the safety criteria for early transition to home infusions and 26% received ≥1 home infusion, which supports home therapy as a treatment option depending on the patient's response and the recommendation of the treating physician. Disclosures: Pastores: Actelion: Research Funding; Amicus: Research Funding; Biomarin: Research Funding; Genzyme Corp: Research Funding; Protalix: Research Funding; Shire HGT: Research Funding. Rosenbloom:Genzyme Corporation: Educational Grant; Shire Pharmaceuticals: Research Funding, Speakers Bureau; Genzyme Corp: Research Funding, Speakers Bureau. Weinreb:Shire HGT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amicus: Research Funding; Actelion: Speakers Bureau. Goker-Alpan:Shire HGT: Consultancy, Research Funding; Genzyme Corp: Research Funding, Speakers Bureau; Amicus: Research Funding; Pfizer-Protalix Biotherapeutics: Consultancy, Research Funding. Lipson:Kaiser-Permanente: Employment. Ibrahim:Shire HGT: Research Funding. Cohn:Shire HGT: Employment. Zahrieh:Shire HGT: Employment. Mistry:Shire: Research Funding.

Causes of Death in 184 Patients with Type 1 Gaucher Disease From the United States Who Were Never Treated with Enzyme Replacement Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3128-3128
Author(s):  
Neal J. Weinreb ◽  
Deborah Barbouth ◽  
Robert E Lee
Keyword(s):  
Liver Disease ◽  
Chronic Liver Disease ◽  
Board Of Directors ◽  
Gaucher Disease ◽  
Research Funding ◽  
Causes Of Death ◽  
Chronic Liver ◽  
Death Certificates ◽  
Advisory Committees

Abstract Abstract 3128 Type 1 Gaucher disease (GD1) is caused by deficient lysosomal glucocerebrosidase activity with resultant accumulation of glucosylceramide predominantly within hepatic, splenic, pulmonary and bone marrow macrophages. Intravenous recombinant glucocerebrosidase (ERT) is generally safe and effective in decreasing morbidity due to the heterogeneous manifestations of GD1: hematological cytopenias, hepatosplenomegaly, bone pain, osteonecrosis, osteopenia and fractures. There are other complications whose responsiveness to conventional treatment is yet undetermined: atypical Parkinsonism and an increased risk for cancer (CA), particularly plasma cell and other hematological and lymphoid malignancies and hepatocellular carcinoma. Because of the widespread use of ERT during the past 20 years and attrition of older medical records, a phenotypically representative control group of untreated symptomatic patients for study of these late outcome events is hard to find. From 1961–97, one of us (REL) collected information on 395 US patients with GD1. We determined through public records that 217 died from 1950–2010 of whom 184 never received ERT. Here, we report confirmed causes of death (COD) for the untreated GD1 patients compared to COD reported for this time period in an age comparable overall US population. Methods: After IRB approval, COD recorded in death certificates were accessed via the National Death Index for available years 1979–2008. COD prior to 1979 were determined based on autopsy or physician communication with REL and, where possible, by death certificates obtained from State Bureaus of Vital Records. Information on COD (1950–2008) for the general US population is from US National Vital Statistics Reports. The analysis included descriptive statistics, calculation of proportional mortality ratios (PMR), and 2-tailed Fisher exact test calculations based on absolute death numbers in the GD1 and general populations. Results: COD is unknown for 9 patients who died before 1979. 111 pts were male (60.3%); 124 (67.4%) were Ashkenazi Jewish. Median age at death was 66y (2–97y). Median age at GD1 diagnosis (N=102): 39y (1–83y). Spleen status: Splenectomy 94 (51.1%); Intact 56 (30.4%); Unknown 34 (18.5%). Median age at splenectomy: 36y (1.3–78y). Symptomatic bone disease was present in 74 (40.2%), absent in 7 (3.8%) and undocumented for 103 (60.0%). COD for which the PMR was significantly increased (P<0.01): malignant neoplasms (PMR 1.57), suicide/drug overdose (PMR 3.86), chronic liver disease (PMR 4.76) and septicemia (PMR 9.22). Other COD that were disproportionately high included CNS and gastrointestinal bleeding, post-splenectomy complications, pulmonary hypertension (PHT), and Parkinsonism. Heart disease/atherosclerosis was the only COD for which PMR was very significantly decreased (0.33). PMR for cerebrovascular disease was 0.48 (P=0.027). For 57 pts with a CA COD, PMRs for myeloma (9.66), kidney CA (4.63), liver CA (4.36), NHL (4.13), and all leukemia (3.19) were significantly elevated (P<0.01). Conversely, the PMR for lung CA was 0.32 (P=0.002). There was 1 death from breast CA and none from gynecological CA. PMR for colorectal, pancreatic and prostate CA were not divergent from expected. Compared to the control population, the age distribution of deaths was identical for heart disease, septicemia, and suicide. Age at death was not younger than expected in pts with myeloma but there was a tendency for death at a younger age for GD pts with NHL, chronic liver disease and Parkinsonism. COD significantly more prevalent in surgically asplenic pts included chronic liver disease, septicemia, GI bleeding, PHT and post-splenectomy complications. Spleen status was statistically irrelevant to CA deaths including myeloma except for hepatocellular CA (splenectomy) and CLL (intact spleen). Conclusions: With earlier diagnosis, improved risk assessment and phase-out of splenectomy, COD that we encountered (chronic liver disease, GI bleeding, septicemia, PHT, suicide and drug dependency) should be increasingly rare with timely institution of appropriate treatment. Our study population of untreated pts (estimated at 5% of all US GD1 deaths from 1950–2008 but a substantially greater percentage of GD1 deaths over age 60y), should serve as a valuable control for future studies of the effect of GD1 treatment on mortality due to malignancy or other later course events. Disclosures: Weinreb: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire HGT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Actelion Corporation: Speakers Bureau.

Peripheral Neuropathy in MGUS and Progression to Amyloid Light-Chain Amyloidosis: A Population-Based Study Including 15,351 MGUS Cases

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5444-5444
Author(s):  
Sæmundur Rögnvaldsson ◽  
Ingemar Turesson ◽  
Magnus Björkholm ◽  
Ola Landgren ◽  
Sigurður Yngvi Kristinsson
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Large Population ◽  
Diagnostic Delay ◽  
Population Based ◽  
Lymphoproliferative Disorders ◽  
First Year ◽  
Advisory Committees ◽  
Population Based Study ◽  
Increased Risk

Introduction Peripheral neuropathy (PN) is a common disorder that can be caused by amyloid light-chain amyloidosis (AL). AL is a rare disorder caused by the deposition of amyloid fibers, originating from malignant plasma cells. Amyloid deposition in peripheral nerves causes PN and is present in 35% of patients with newly diagnosed AL. Diagnosis of AL can be difficult, leading to under-recognition, diagnostic delay, and delayed treatment. Virtually all instances of AL are preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common with a reported prevalence of 4.2% in the general Caucasian population over the age of 50 years. Although MGUS is usually considered asymptomatic, a significant proportion of affected individuals develop PN. However, we are not aware of any studies assessing how PN affects risk of MGUS progression to AL. We were therefore motivated to conduct a large population-based study including 15,351 Swedish individuals with MGUS diagnosed 1986-2013. Methods Participants diagnosed with MGUS between 1986-2013 were recruited from a registry of a nationwide network of hematology- and oncology centers and the Swedish Patient Registry. We then cross-linked data on recorded diagnoses of AL and PN from the Swedish Patient Registry, diagnoses of lymphoproliferative disorders form the Swedish Cancer Registry, and dates of death from the Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. A multi-state survival model was created. At inclusion, participants started providing person time into the PN or the non-PN states depending on whether they had a previous diagnosis of PN. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time in the PN state after that. We then created a Cox proportional hazard regression model with AL as the endpoint. Participants were censored at diagnosis of other lymphoproliferative disorders. We adjusted for sex, age, and year of MGUS diagnosis. Results We included 15,351 participants with MGUS. Of those, 996 participants provided person-time with PN (6.5%). About half of those had PN at MGUS diagnosis (55%). A total of 174 cases of AL were recorded, with AL being more common among those who had PN (2.1% vs 1.0% p=0.002). Those who had PN had a 2.3-fold increased risk of AL as compared to those who did not have PN (hazard ratio (HR): 2.3; 95% confidence interval (95% CI): 1.5-3.7; p<0.001). The results were similar for those who had PN at MGUS diagnosis and those who did not. More than half of AL cases (53%) were diagnosed within one year after MGUS diagnosis. The rate was even higher among those with PN, with 82% of AL cases among those who presented with PN being diagnosed within one year after MGUS diagnosis. In the first year after inclusion, the incidence of AL was 15.2 and 6.1 per 1000 person-years for participants with and without PN respectively (HR: 1.8; 95% CI:1.0-3.4; p=0.04). Participants with PN continued to have an increased risk of progression to AL after the first year with an incidence of AL of 2.6 per 1000 person-years as compared to 1.1 per 1000 person-years among participants who did not have PN (HR:2.4; 95% CI: 1.1-5.0; p=0.02) (Figure). Discussion In this large population-based study, including 15,351 individuals with MGUS, we found that individuals with MGUS who develop PN have an increased risk of progression to AL. In fact, individuals with MGUS who have PN at MGUS diagnosis might already have AL. This risk of AL was highest during the first year after MGUS diagnosis with participants with PN having a higher risk than those who did not have PN. PN continued to be associated with a higher risk of MGUS progression to AL throughout the study period. This is the largest study that we are aware of assessing the association of PN and MGUS progression to AL. Since this is a registry-based study based on recorded diagnoses, some clinical data, including MGUS isotype, is not available. These findings suggest that increased awareness of PN as a feature of MGUS might decrease diagnostic delay and improve outcomes for patients with AL. Figure Disclosures Landgren: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Plerixafor (Mozobil ®)Plus G-CSF Is Effective in Mobilizing Hematopoietic Stem Cells in Patients with Concurrent Thrombocytopenia Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3229-3229 ◽  
Author(s):  
Ivana N Micallef ◽  
Eric Jacobsen ◽  
Paul Shaughnessy ◽  
Sachin Marulkar ◽  
Purvi Mody ◽  
...  
Keyword(s):  
Stem Cell ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Platelet Counts ◽  
Cd34 Cells ◽  
Low Platelet Count ◽  
Equity Ownership

Abstract Abstract 3229 Poster Board III-166 Introduction Low platelet count prior to mobilization is a significant predictive factor for mobilization failure in patients with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) undergoing autologous hematopoietic stem cell (HSC) transplantation (auto-HSCT; Hosing C, et al, Am J Hematol. 2009). The purpose of this study is to assess the efficacy of HSC mobilization with plerixafor plus G-CSF in patients with concomitant thrombocytopenia undergoing auto-HSCT. Methods Patients who had failed successful HSC collection with any mobilization regimen were remobilized with plerixafor plus G-CSF as part of a compassionate use program (CUP). Mobilization failure was defined as the inability to collect 2 ×106 CD34+ cells/kg or inability to achieve a peripheral blood count of ≥10 CD34+ cells/μl without having undergone apheresis. As part of the CUP, G-CSF (10μg/kg) was administered subcutaneously (SC) every morning for 4 days. Plerixafor (0.24 mg/kg SC) was administered in the evening on Day 4, approximately 11 hours prior to the initiation of apheresis the following day. On Day 5, G-CSF was administered and apheresis was initiated. Plerixafor, G-CSF and apheresis were repeated daily until patients collected the minimum of 2 × 106 CD34+ cells/kg for auto-HSCT. Patients in the CUP with available data on pre-mobilization platelet counts were included in this analysis. While patients with a platelet count <85 × 109/L were excluded from the CUP, some patients received waivers and were included in this analysis. Efficacy of remobilization with plerixafor + G-CSF was evaluated in patients with platelet counts ≤ 100 × 109/L or ≤ 150 × 109/L. Results Of the 833 patients in the plerixafor CUP database, pre-mobilization platelet counts were available for 219 patients (NHL=115, MM=66, HD=20 and other=18.). Of these, 92 patients (NHL=49, MM=25, HD=8 and other=10) had pre-mobilization platelet counts ≤ 150 × 109/L; the median platelet count was 115 × 109/L (range, 50-150). The median age was 60 years (range 20-76) and 60.4% of the patients were male. Fifty-nine patients (64.1%) collected ≥2 × 109 CD34+ cells/kg and 13 patients (14.1%) achieved ≥5 × 106 CD34+ cells/kg. The median CD34+ cell yield was 2.56 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 68.5%. The median time to neutrophil and platelet engraftment was 12 days and 22 days, respectively. Similar results were obtained when efficacy of plerixafor + G-CSF was evaluated in 29 patients with platelet counts ≤ 100 × 109/L (NHL=12, MM=10, HD=3 and other=4). The median platelet count in these patients was 83 × 109/L (range, 50-100). The median age was 59 years (range 23-73) and 60.4% of the patients were male. The minimal and optimal cell dose was achieved in 19(65.5%) and 3(10.3%) patients, respectively. The median CD34+ cell yield was 2.92 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 62.1%. The median time to neutrophil and platelet engraftment was 12 days and 23 days, respectively. Conclusions For patients mobilized with G-CSF alone or chemotherapy ±G-CSF, a low platelet count prior to mobilization is a significant predictor of mobilization failure. These data demonstrate that in patients with thrombocytopenia who have failed prior mobilization attempts, remobilization with plerixafor plus G-CSF allows ∼65% of the patients to collect the minimal cell dose to proceed to transplantation. Thus, in patients predicted or proven to be poor mobilizers, addition of plerixafor may increase stem cell yields. Future studies should investigate the efficacy of plerixafor + G-CSF in front line mobilization in patients with low platelet counts prior to mobilization. Disclosures Micallef: Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jacobsen:Genzyme Corporation: Research Funding. Shaughnessy:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Mody:Genzyme Corporation: Employment, Equity Ownership. van Rhee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Evaluation of Bleeding-Related Episodes in Patients with Chronic Immune Thrombocytopenia (ITP) Treated with Romiplostim in Two Phase 3 Placebo-Controlled Clinical Trials.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 891-891 ◽  
Author(s):  
Ilene Ceil Weitz ◽  
Miguel A Sanz ◽  
David H. Henry ◽  
Martin Schipperus ◽  
Bertrand Godeau ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Rescue Medication ◽  
Bleeding Event ◽  
Bleeding Events ◽  
Phase 3 ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Chronic Itp

Abstract Abstract 891 Background: Chronic Immune thrombocytopenia (ITP) is characterized by low platelet counts and increased risk of bleeding. Rescue medications used to treat or prevent bleeding produce transient increases in platelet counts but may be associated with additional toxicities and costs. Romiplostim, approved for the treatment of adult chronic ITP, is a TPO mimetic peptibody protein that increases platelet production. Previously published data from phase 3 romiplostim trials showed that despite the increased use of rescue medication in the placebo arm, patient (pt) incidence of bleeding was reduced in the romiplostim arm vs placebo arm: 15% vs 34% (p = 0.02) for bleeding of grade ≥2 severity and 7% vs 12% (p=0.36) for grade ≥3 severity. Objective: To evaluate the effects of romiplostim treatment on bleeding outcomes in the phase 3 placebo controlled studies in chronic ITP pts with and without previous splenectomy. Bleeding events were captured as adverse events making it difficult to identify a single event reported multiple times versus persistent or recurrent bleeding. Further, we have developed a composite endpoint, termed bleeding-related episodes (BREs), which combines bleeding events and rescue medication administration to account for use of rescue medications to prevent bleeding. Methods: Adults with chronic ITP and a mean baseline platelet count <30 × 109/L were eligible. The previously published studies were conducted separately in splenectomized and nonsplenectomized populations. Pts were randomized (2:1) to receive romiplostim or placebo by subcutaneous injection once weekly for 24 weeks, with dose adjustments to maintain platelet counts between 50-200 × 109/L. Rescue medications were permitted to treat or prevent bleeding and included immunoglobulins, platelet transfusions, corticosteroids, or an increase in dose or frequency of a concurrent ITP medication. A BRE was defined as an actual bleeding event and/or the use of rescue medication. To collapse related events into episodes, events (bleeding events and/or the use of rescue medication) that occurred concurrently or within 3 days of each other were considered a single BRE. Bleeding events beginning 7 or more days after the start of the initial bleeding event were considered a new BRE. To account for differences in time spent on-study, rates of BRE per 100 pt-weeks were calculated. Results: A total of 125 pts (41 placebo, 84 romiplostim) were enrolled in the two studies. Baseline characteristics were well-balanced between the placebo and romiplostim-treated groups. During the treatment period, the rate of BREs was lower in the romiplostim group than in the placebo group, and results were consistent between splenectomized and nonsplenectomized pts (Table). Across both studies, the rate of BREs was reduced by 55% in pts receiving romiplostim compared to those receiving placebo (95% CI, 41% to 65%). BREs were more frequent at platelet counts <50 × 109/L (Table). BREs associated with hospitalizations were less common among romiplostim- than placebo-treated pts, and occurred at platelet counts <50 × 109/L in 10 of 11 cases. Corticosteroids (58 romiplostim, 38 placebo) and immunoglobulins (30 romiplostim, 73 placebo), were the most commonly used rescue medications and the rate of BREs including immunoglobulins was reduced by 88% in pts receiving romiplostim compared to placebo. Conclusions: In adults with chronic ITP, romiplostim was associated with a significant reduction in BREs compared to placebo. There was a marked reduction in BREs requiring immunoglobulins in the romiplostim arm compared to the placebo arm. Results were comparable in splenectomized and nonsplenectomized populations. The platelet count for a BRE starting ≥1 day after a platelet count measurement was calculated from the 2 proximal weekly measurements. Disclosures: Weitz: Amgen Inc.: Speakers Bureau. Sanz:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Henry:Amgen Inc.: Research Funding, Speakers Bureau; Orthobiotech: Research Funding, Speakers Bureau; Watson Pharma: Research Funding, Speakers Bureau. Schipperus:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Godeau:Amgen Inc.: Consultancy, Research Funding; Laboratoire Français de Fractionnement et de Biotechnologies (LFB): Consultancy; Roche: Research Funding. Gleeson:Amgen Inc.: Consultancy, Research Funding. Danese:Amgen Inc.: Consultancy, Research Funding. Deuson:Amgen Inc.: Employment, Equity Ownership.

Final Results from an International, Multi-Center, Single-Arm Study Evaluating the Safety and Efficacy of Romiplostim in Adults with Primary Immune Thrombocytopenia (ITP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3279-3279 ◽  
Author(s):  
Ann Janssens ◽  
Michael D. Tarantino ◽  
Robert Bird ◽  
Maria Gabriella Mazzucconi ◽  
Ralph Vincent V. Boccia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Production ◽  
Platelet Counts ◽  
Equity Ownership

Abstract 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.

Improvements in Skeletal Manifestations in Gaucher Disease Type 1 Patients After 3 Years of Treatment with Oral Eliglustat During a Phase 2 Trial,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3216-3216
Author(s):  
M. Judith Peterschmitt ◽  
Ravi S Kamath ◽  
Elena Lukina ◽  
Nora Watman ◽  
Marta Dragosky ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Disease Type ◽  
Phase 2 ◽  
Z Score ◽  
Advisory Committees ◽  
Lytic Lesions ◽  
Skeletal Complications ◽  
Gaucher Disease Type 1

Abstract Abstract 3216 Introduction: In Gaucher disease type 1 (GD1), deficient lysosomal acid β-glucosidase leads to accumulation of undegraded glucosylceramide in lysosomes of tissue macrophages known as Gaucher cells. Skeletal complications are a major cause of morbidity and include bone marrow infiltration by Gaucher cells, osteopenia/osteoporosis, lytic lesions, fractures, avascular necrosis, and bone pain. Eliglustat, a novel, oral inhibitor of glucosylceramide synthase, is under investigation for the treatment of GD1. Objective: To report skeletal changes after 3 years of eliglustat therapy. Methods: This ongoing, open-label, uncontrolled, multicenter, Phase 2 clinical trial enrolled 26 adults with GD1 not on treatment for the previous 12 months, who had splenomegaly with thrombocytopenia and/or anemia. Study entry criteria also required that patients had no new pathologic bone involvement or bone crises within the preceding 12 months and not have used bisphosphonates during the previous 3 months. Changes from baseline were reported for centrally reviewed skeletal x-rays, dual-energy x-ray absorptiometry (DXA) and MRI assessments. Results: Of 26 enrolled patients, 19 completed 3 years of treatment. In 15 patients with evaluable DXA results at baseline and at 1, 2, and 3 years, mean lumbar spine BMD increased by 0.6±0.69 Z-score (baseline, −1.28), with greatest increases seen in osteoporotic patients. Mean femur BMD (T- and Z-score) remained normal through 3 years. Femur dark marrow on MRI, which reflects bone marrow infiltration by Gaucher cells, was reduced in 56% (10/18) or stable in 44% (8/18) of patients with findings at baseline. No bone crises or reductions in mobility occurred. On baseline radiographs, no patients had fractures, 42% (8/19 patients) had femoral lytic lesions, and 37% (7/19 patients) had bone infarcts. After 3 years, the lumbar spine and femurs showed no new lytic lesions, bone infarcts, fractures, or areas of osteonecrosis and no worsening of pre-existing lytic lesions or bone infarcts. One patient had worsening of asymptomatic osteonecrosis after 1 year noted retrospectively at baseline. Eliglustat was well-tolerated. Most adverse events (AEs) were mild and unrelated to treatment; the most common were viral infections (6 patients); urinary and upper respiratory tract infections (4 patients each); and headache, increased blood pressure, abdominal pain, diarrhea (3 patients each). Eight drug-related AEs, all mild, occurred in 6 patients. Conclusions: During 3 years of eliglustat treatment, radiologic monitoring showed improvement or stabilization of GD1 bony manifestations with no noted safety-related trends, suggesting that eliglustat may be a promising treatment for skeletal complications of GD1. Ongoing Phase 3 studies will provide more information on the bone effects of eliglustat. Disclosures: Peterschmitt: Genzyme: Employment. Kamath:Genzyme: Consultancy. Lukina:Genzyme: Honoraria. Watman:Genzyme: Membership on an entity's Board of Directors or advisory committees. Pastores:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Actelion: Research Funding; Amicus: Research Funding; Biomarin: Research Funding; Shire HGT: Research Funding; Protalix: Research Funding. Arreguin:Genzyme: Research Funding. Aguzzi:Genzyme: Employment. Ross:Genzyme: Employment. Puga:Genzyme: Employment. Rosenthal:Genzyme: Consultancy.

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