Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life in Previously Treated Pediatric Patients with Hemophilia Α: Efficacy of Prophylaxis and Treatment By Time (of Day/of Week) of Occurrence of Bleeding

Abstract Introduction: Hemophilia A (HA) is an X linked recessive bleeding disorder characterized by frequent bleeding predominantly in joints. To avoid the sequelae of hemarthroses (e.g., target joints and arthropathy), timing of factor VIII (FVIII) infusions to cover periods of physical activity and adherence to a prophylactic schedule are particularly important in children with HA. BAX 8551, a polyethylene glycol (peg)ylated, extended half-life, full-length, recombinant FVIII built on ADVATE2, was developed to reduce infusion frequency while maintaining or improving therapeutic efficacy. Methods: Efficacy of twice-weekly prophylaxis with BAX 855 was evaluated in a phase 3, prospective, uncontrolled, multicenter study in pediatric previously treated patients with severe HA (FVIII level <1%) without inhibitors (<0.6 BU using the Nijmegen modification). Annualized bleeding rates (ABRs) and efficacy of bleed treatment were analyzed by time of day (morning [04:00 - 11:59], afternoon [12:00 - 17:59], evening [18:00 - 03:59]) and period of the week (weekday [Monday - Friday], weekend [Saturday, Sunday]). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results: Sixty-six patients, 32 aged <6 and 34 aged 6 to <12 years, were treated with a mean (SD) prophylactic BAX 855 dose of 51.1 (5.5) IU/kg at a frequency of 1.8 (0.2) infusions per week for 48.5 (7.7) exposure days. ABRs were highest in the evening with point estimates (95% CIs) of the mean of 1.0 (0.7 - 1.5) compared to 0.6 (0.4 - 1.0) in the afternoon and 0.5 (0.3 - 1.1) in the morning. On weekdays, the point estimate (95% CI) of the mean ABR was 2.4 (1.7 - 3.5), on weekends it was 0.9 (0.6 - 1.2). For all periods assessed except for mornings, ABRs were higher in the older than in the younger cohort (Table 1). Seventy minor or moderate bleeding events in 34/66 (51.5%) patients were treated with a mean (SD) dose of 57.9 (31.0) IU/kg of BAX 855. Most treated bleeds occurred in the evening (34.3%; 24/70), fewer in the afternoon (22.9%; 16/70) and in the morning (14.3%; 10/70). The proportion of moderate bleeds increased during the day from 20.0% (2/10) in the morning to 31.3% (5/16) in the afternoon and 70.8% (17/24) in the evening. For 28.6% (20/70) of treated bleeds, the time of day of occurrence was unknown. The mean interval between the preceding prophylactic infusion and the bleeding event was similar for all times of day, ranging from 51.0 h to 54.6 h (median 51.4 h to 57.8 h). On weekends, the mean interval between prophylactic dose and bleeding event was lower (38.8 h; median 35.7 h) than on weekdays (54.6 h; median 52.9 h), suggesting that the time of infusion was chosen to cover for weekend activities. Bleeding severity was similar on weekdays and on weekends. Efficacy of bleed treatment with BAX 855 was rated excellent or good for ≥85% of bleeds and ≥85% were treated with 1 or 2 infusions, irrespective of the time of day/period of the week the bleeds occurred. Conclusions: In this study in pediatric patients with severe HA, bleeding was observed more frequently in the evening than during other times of day and more frequently on weekdays than on weekends. BAX 855 was shown to be effective for the prevention and treatment of bleeding in this patient population. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trademark of Baxalta US Inc., now part of Shire. Disclosures Mullins: Baxalta (now part of Shire): Honoraria; US WorldMeds: Membership on an entity's Board of Directors or advisory committees. Dunn:Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Kedrion: Research Funding; NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

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Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽

10.1182/blood.v128.22.3778.3778 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3778-3778

Author(s):

Amy L. Dunn ◽

Alexis A. Thompson ◽

Werner Engl ◽

Marlies Sharkhawy ◽

Brigitt E. Abbuehl

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Pediatric Patients ◽

Hemophilia A ◽

Point Estimate ◽

Severe Hemophilia ◽

Advisory Committees ◽

The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

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Joint Bleeding Patterns in Patients Treated Prophylactically with an Extended Half-Life, Pegylated, Full-Length Recombinant Factor VIII (BAX 855)

Blood ◽

10.1182/blood.v126.23.2300.2300 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2300-2300 ◽

Cited By ~ 1

Author(s):

Marilyn J. Manco-Johnson ◽

Alice D. Ma ◽

Robert Klamroth ◽

Werner Engl ◽

Lorena Griparic ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Recombinant Factor Viii ◽

Employment Equity ◽

Advisory Committees ◽

Bleeding Episodes ◽

Equity Ownership ◽

The Mean

Abstract BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on ADVATE with an extended half-life and is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. In a pivotal trial, 101 previously treated patients (PTPs) received BAX 855 for prophylaxis twice weekly (in the per protocol analysis set). At screening, 67/101 (66.3%) of patients had arthropathy (reported in medical history or history of joint surgery) and 69/101 (68.3%) had at least 1 target joint. A target joint was defined as a single joint (ankle, knee, hip, or elbow) with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period. Overall, among these 101 PTPs, the mean (standard deviation) annualized joint bleeding rate (AJBR) was 1.8 (3.0) and 57.4% of patients had zero joint bleeding episodes. There were 32, 40, and 29 subjects with 0, 1-2, and ≥3 target joints, respectively, at screening. Patients with more target joints at screening experienced higher AJBRs: with mean AJBRs of 1.15, 1.84, and 2.58 for patients with 0, 1-2, and ≥3 target joints, respectively, at screening. Of the individual joints, ankle and knee joints had highest AJBRs. BAX 855 demonstrated efficacy in the treatment of joint bleeding, with the majority of joint bleeding episodes, irrespective of target joint status, treated with 1-2 infusions: 92.8%, 91.9% and 94.4% for patients with 0, 1-2, and ≥3 target joints, respectively, at screening. Hemostatic efficacy of BAX 855 at 24 hours was rated as excellent or good in >90% of patients, regardless of target joint status at screening. Patients with 0 target joints at screening had 57.1% of joint bleeding episodes considered mild in severity, while patients with 1-2 or ≥3 target joints had 59.5% and 66.7% of joint bleeding episodes, respectively, rated moderate in severity. There were few joint bleeding episodes considered severe. Similar doses per infusion of BAX 855 were used to treat joint bleeding episodes: the mean dose per BAX 855 infusion was 35, 33.8, and 36.2 IU/kg for patients with 0, 1-2, and ≥3 target joints, respectively. In conclusion, BAX 855 demonstrated a favorable efficacy profile in the treatment of breakthrough joint bleeding episodes, and twice-weekly use was efficacious in prevention of bleeding, with the lowest overall AJBRs achieved in patients in the trial without target joints. Disclosures Manco-Johnson: Baxter/Baxalta, Bayer, CSL Behring, Biogen NovoNordisk: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding. Ma:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees. Klamroth:Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau; Biogen and SOBI: Honoraria, Speakers Bureau. Engl:Baxalta: Employment, Equity Ownership. Griparic:Baxalta: Employment. Dyck-Jones:Baxalta: Employment. Abbuehl:Baxalta: Employment, Equity Ownership.

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Lack of Inhibitor Development in the American Thrombosis and Hemostasis Network (ATHN)-2 Factor Switching Study: Preliminary Report of Primary Outcome

Blood ◽

10.1182/blood-2019-128612 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1114-1114

Author(s):

Robert F. Sidonio ◽

Dunlei Cheng ◽

Christine Guelcher ◽

Janna M. Journeycake ◽

Susan U Lattimore ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Primary Outcome ◽

Hemophilia A ◽

Advisory Board ◽

Severe Hemophilia ◽

Advisory Committees ◽

Inhibitor Development

Introduction: With many standard half-life (SHL) and extended half-life (EHL) recombinant factor VIII and factor IX products licensed in the US over the last 6 years, it is likely that previously treated patients (PTPs) will consider switching to a new EHL FVIII or FIX product. Although past product switching surveillance suggests no increased inhibitor development risk, there is the need for a real-world data on the incidence of inhibitor development following switching from SHL to EHL rFVIII or rFIX in PTPs with hemophilia A and B. Methods: A longitudinal, observational study of participants with Hemophilia A or B who switched to a rFVIII or rFIX concentrate licensed after Jan 1, 2013. The study included retrospective (switched within 50 exposure days (EDs) and prospective arms. Participants were recruited from ATHN-affiliated Hemophilia Treatment Centers (HTCs). The primary outcome measure was the development of a new inhibitor (i.e. neutralizing antibodies to factor VIII or IX) a 1 year or during the 50 EDs following the product switch. Plasma samples were collected at baseline, 10 EDs and 50 EDs. Inclusion criteria include moderate or severe hemophilia A/B currently on a plasma-derived or recombinant FVIII or FIX concentrate with planned or recent switch to an EHL FVIII or FIX concentrate approved after Jan 1, 2013. Participants with an active inhibitor at time of enrollment or undergoing ITI or switched to a non-factor product were excluded. Results: 303 hemophilia participants from 27 treatment centers were enrolled from 2015 to June 2019. The median age at enrollment was 17 years (IQR 10-32 years). 300 of 303 participants were male, Caucasian (72.6%) and had private insurance (44.9%). 74.3% were FVIII deficient and 25.7% were FIX deficient. Most had severe hemophilia A or B, 82.3% (n=237) and 12.8% (n=37) had a prior history of inhibitor but were negative at the time of enrollment. Prior to the switching, 92.1% (n=197) and 7.9% (n=17) of hemophilia A participants took standard rFVIII or pdFVIII respectively, while 87.8% (n=65) and 12.2% (n=9) of hemophilia B participants took standard rFIX or pdFIX, respectively. The three most frequent switching reasons were extended half-life consideration (n=192; 66.7%), a desire for a longer acting version (n=55; 19.1%) and less than expected clinical response to the current product (n=15; 5.2%). Among 214 participants with hemophilia A, 182 (85.0%) switched to FVIII EHL products while 23 (10.7%) switched to new SHL FVIII. For nine patients (4.2%) switching product information was not available. 72 out of 74 (97.3%) participants with hemophilia B that switched products, switched to an EHL rFIX. Eleven hemophilia participants (six A and five B) entered a second cycle of switching after the completion of the first switching cycle. Following that, four switched to FVIII EHL products, two to new SHL rFVIII and five to rFIX EHL products. A total of 193 (63.7%; 148 FVIII, 45 FIX) participants completed the clinical trial while 36 (11.9%; 26 FVIII, 10 FIX) did not complete the trial and 74 (24.4%) are ongoing in the trial. None of 303 (0%) enrolled participants developed an inhibitor, the primary outcome for this study, through data updated 6/2019. Variability was noted in per-site enrollment. The median enrollment per Hemophilia Treatment Center (HTC) was 10, the IQR was 7-16 with a range of 1-31. The types of factors associated with patients switches are summarized in the figure. Conclusion: No new inhibitors were noted among 303 moderate/severe hemophilia A/B PTPs without active inhibitors at entry, who switched factor VIII or IX products over 50 exposure days or 12 months. This result provides real-world evidence of the rarity of inhibitor development after a product switch in PTPs. The study also achieved a key logistical objective: to demonstrate feasibility of a prospective observational study across ATHN sites. Figure Legend: Factor types to which ATHN-2 patients switched during the study. Disclosures Sidonio: Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Guelcher:Takeda: Other: Advisory Board; Genetech: Other: Advisory Board; NovoNordisk: Other: Advisory Board; Octapharma: Other: Advisory Board. Takemoto:genentech: Membership on an entity's Board of Directors or advisory committees; novartis: Other: DSMB membership. Tarantino:Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Michael Tarantino, MD SC: Other: President, Owner- Private Practice ; Magellan Healthcare: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial PI, Speakers Bureau; Roche: Consultancy; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bleeding and Clotting Disorders Institute: Employment; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Grant Reviewer , Research Funding; Octapharma: Consultancy, Speakers Bureau. Neufeld:Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored).

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Baseline Characteristics of Patients in Peak: A Global, Longitudinal Registry of Patients with Pyruvate Kinase Deficiency

Blood ◽

10.1182/blood-2020-136634 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Rachael F. Grace ◽

Audra Boscoe ◽

Chris Bowden ◽

Bertil Glader ◽

Hitoshi Kanno ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Chelation Therapy ◽

Treatment Patterns ◽

Missense Mutations ◽

Private Company ◽

Advisory Committees ◽

The Mean

Background: Pyruvate kinase (PK) deficiency is a rare, inherited hemolytic anemia caused by autosomal recessive mutations in the PKLR gene, whereby a glycolytic defect causes a reduction in adenosine triphosphate generation. Current treatment options are supportive and include splenectomy, blood transfusions, and iron chelation therapy. To better understand the natural history, treatment patterns, and burden of disease, the observational PK Deficiency Natural History Study (NHS) (NCT02053480) enrolled 254 adult and pediatric patients with PK deficiency at 30 sites in 6 countries between 2014 and 2017 and followed patients for 2 years. The Peak Registry (NCT03481738) was developed to continue and expand on this research. This retrospective and prospective observational registry aims to enroll 500 adult and pediatric patients at ~ 60 sites in up to 20 countries over 7 years, with 2-9 years of follow-up. Objective: This analysis aimed to characterize the baseline demographics and clinical characteristics of patients with PK deficiency enrolled in the Peak Registry as of 24March2020. Methods: Demographic, diagnostic, medical history, laboratory, treatment, and other relevant data were collected from participating clinicians via electronic case report forms. To be eligible for inclusion in this analysis, patients were required to have genetically confirmed PK deficiency and available demographic information. All analyses reported here are descriptive and based on data as of the date of enrollment in the registry. Continuous variables are summarized by the number of non-missing observations, mean, standard deviation (SD), median, and range. Categorical variables are summarized as counts and percentages. Results: A total of 141 patients met the inclusion criteria, across 11 countries in North America and Europe. A summary of baseline demographics and clinical characteristics is shown in the Table. Fifty patients (35.5%) had completed 2 years of follow-up in the NHS and then moved to the Peak Registry; the remainder were newly recruited to the Peak Registry. The mean age of study participants at enrollment was 25.5 years (SD 19.1); 78 patients (55.3%) were female. Mean reported age at first symptoms was 5.8 years (SD 13.2) and mean age at diagnosis was 11.7 years (SD 16.0). Fifty-seven percent of patients were classified as having missense/missense mutations, 34.4% as having missense/non-missense mutations, and 8.6% as having non-missense/non-missense mutations. The mean hemoglobin at enrollment was 8.8 g/dL (range: 5.8-12.9 g/dL). Mean reticulocyte count was 19.8% (range: 2.2-42.4%), mean lactate dehydrogenase was 382 IU/L (range: 135-849 IU/L), and mean indirect bilirubin was 4.3 mg/dL (range: 0.8-23.1 mg/dL). Among the 45.2% of patients who had been splenectomized, the mean age at splenectomy was 7.2 years. Chelation therapy had been previously prescribed to 40.3% of patients. Among the 27 patients for whom ferritin data were available, the mean was 867.9 ng/L (range: 78.1-2499.0 ng/L), and 18 patients (66.7%) had a level > 500 ng/L. Ninety-nine patients (70.2%) had received at least one transfusion in their lifetime. Among the 45 patients who were known to have received at ≥ 1 transfusion in the 12 months prior to enrollment, the mean number of transfusions during that period was 5 (SD 4.3), with 18 of those patients (40.0%) having received ≥ 6 transfusions. Conclusions: New data emerging from the Peak Registry will provide valuable insights into the patient characteristics, treatment patterns, and burden associated with PK deficiency. The population is demographically heterogenous and represents a broad geography. Patients have a wide range of hemoglobin levels, and iron overload is common. The substantial rates of splenectomy, cholecystectomy, transfusions, and chelation use are indicative of a high disease and treatment burden in patients with PK deficiency. This abstract is presented on behalf of the Peak Registry Steering Committee and Peak Registry Investigators. Disclosures Grace: Novartis: Research Funding; Pfizer: Research Funding; Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees. Boscoe:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Bowden:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Glader:Agios Pharmaceuticals, Inc.: Consultancy. Layton:Cerus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. van Beers:Novartis: Research Funding; Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yan:Agios Pharmaceuticals: Consultancy. Bianchi:Agios Pharmaceuticals: Other: Scientific Advisor.

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Cross-Sectional Comparative Study of PK-Guided Switch between Standard Half-Life and Extended Half-Life Factor VIII Products

Blood ◽

10.1182/blood-2019-127946 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2405-2405

Author(s):

Juan Eduardo Megias ◽

Santiago Bonanad Boix ◽

María Fernanda Martínez García ◽

Rubén Berrueco ◽

Maria Eva Mingot-Castellano ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Small Subset ◽

Weekly Dose ◽

Advisory Committees ◽

Full Cohort ◽

Cross Sectional ◽

Weekly Infusion

Background The high inter-individual variability in pharmacokinetics (PK) of factor VIII (FVIII) justifies the use of PK-guided prophylaxis, especially in switching between different products. A proposed definition of extended half-life (EHL) FVIII requires improvements of at least 1.3 times in half-life (t1/2) and 1.25 times the area under the curve (AUC) compared to standard half-life (SHL) products (Mahlangu et al. Haemophilia. 2018;24(3):348-358). The objective of this multicenter study was to analyze the results of a PK-guided switch from SHL to EHL in patients with hemophilia A (HA). Methods Multicenter comparative, cross-sectional, prospective study in HA severe/moderate patients in prophylaxis analyzing PK differences after switch from SHL to EHL (efmoroctocog alfa [rFVIII-Fc] and rurioctocog alfa pegol [PEG-rFVIII]). WAPPS-Hemo® was used to analyze PK parameters with 2-3 samples: t1/2; AUC, peak level (PL); trough level at 24, 48 and 72 h (TL24, TL48, TL72); and time to reach FVIII levels of 1, 2, 5% (T1%, T2%, T5%). We have also compared the ratio of t1/2 and AUC, the number of weekly doses and the dose/kg/week before and after the switch. Wilcoxon and Kruskal-Wallis tests (SPSS®) were used to compare the PK parameters. Results are expressed with the median and interquartile range (IQR) or range, and mean and standard deviation (SD). Results Eighty-one patients from 8 Spanish hospitals were analyzed (61 rFVIII-Fc; 20 PEG-rFVIII), 78 had severe HA and 3 moderate HA. Mean age was 30 years (range=3-64) and no differences in weight were observed between both periods [70 (range=12-116) vs 70 (13.7-116) kg; p=0,141]. Dose/kg/week and weekly infusion frequency were reduced after the switch to EHL, and significant improvements were observed in all PK parameters after the change from SHL to EHL (Table 1). These results were similar in adult and pediatric patients switching to rFVIII-Fc. The median ratios of t1/2 and AUC were 1.3 (IQR:1.2-1.6) and 1.5 (IQR:1.3-2.3) in the entire cohort. These results were reproduced in the subset of patients with ≥12 years treated with rFVIII-Fc and PEG-rFVIII (ratio t1/2: 1.4 [IQR:1.3-1.6]; ratio AUC: 1.6 [IQR:1.3-2.3]), and were slightly in the cohort of 15 patients <12 years treated with rFVIII-Fc (ratio t1/2: 1.3 [IQR:0.9-1.3]; ratio AUC: 1.3 [IQR:1.1-1.9]), the only EHL approved in Europe for children. After the switch to EHL, weekly dose frequency (median 23.3%, IQR:0-33.3%) and dose/kg/week (median 16%, IQR:5.3-30%) were reduced. In a small subset of 17 patients the dose/kg/week increased a median of 31.4%, and this subset was younger than the patients with dose/kg/week reduction or no changes (median age 18 [IQR:8-22] vs. 33 [IQR:16.5-42.5]). No differences were observed in any of the PK parameters and median ratios of t1/2 and AUC in patients aged ≥12 years treated with rFVIII-Fc vs. PEG-rFVIII (46 rFVIII-Fc; 20 PEG-rFVIII; Table 2). Conclusions EHL FVIII have shown significant PK improvements in clinical real practice, allowing to reduce weekly infusion number and dose/kg/week, especially in adult patients. Outside the clinical trial setting, we have observed an increase in t1/2 and AUC ratios accordingly to EHL definition. Comparisons regarding clinical outcomes (bleeding rate after switch) will be performed after a follow-up of 1 year with EHL for the full cohort. WAPPS-Hemo PK-guided switch easily facilitates individualization of prophylaxis with a potential reduction in the cost of treatment and patient perceived outcomes. Disclosures Megias: Baxalta US INC.: Research Funding; Grifols: Research Funding. Bonanad Boix:Baxalta US INC.: Research Funding. Berrueco:NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL-Bering: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mingot-Castellano:Sobi: Consultancy; Bayer: Consultancy; Amgen: Consultancy; Roche: Consultancy; Novartis: Consultancy; Novonordisk: Consultancy; Takeda: Consultancy; CSL Behring: Consultancy. Cid:Shire, a Takeda company: Honoraria; Novo Nordisk: Honoraria. Sanz:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: 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; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen - Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman - La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Update from an Open-Label Extension Study Evaluating the Long-Term Safety and Efficacy of Romiplostim In Thrombocytopenic Patients (Pts) with Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v116.21.1885.1885 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1885-1885 ◽

Cited By ~ 2

Author(s):

Pierre Fenaux ◽

Hagop Kantarjian ◽

Roger M Lyons ◽

Richard A Larson ◽

Mikkael A Sekeres ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Bleeding Event ◽

Extension Study ◽

Platelet Response ◽

Bleeding Events ◽

Open Label ◽

Advisory Committees ◽

Previously Treated

Abstract Abstract 1885 Background: Thrombocytopenia is a significant clinical problem in MDS, found in approximately 35% to 65% of pts, and is an independent risk factor for survival. Romiplostim increases platelet production by binding to and activating the thrombopoietin receptor. MDS pts who completed a romiplostim clinical study could continue romiplostim treatment in an open-label extension study. Interim results from this ongoing study are reported to provide updated safety and efficacy information on the effects of continued, long-term romiplostim treatment in pts with MDS. Methods: MDS pts who had completed a prior romiplostim study and had platelets ≤50 × 109/L with no evidence of disease progression were eligible. Pts enrolled into the extension study from 3 prior studies with the following study designs: (1) romiplostim only for up to 52 weeks [Kantarjian JCO 2009], (2) romiplostim or placebo plus decitabine for ≥4 cycles [Greenberg ASH 2009], and (3) romiplostim or placebo plus lenalidomide for ≥4 cycles [Lyons ASH 2009]. The primary endpoint was adverse event (AE) incidence; secondary endpoints were incidence of bleeding events, platelet transfusions, and platelet response durations. On the basis of previous dosing, pts received romiplostim at 250, 500, 750, 1000, or 1500 mcg weekly, with subsequent adjustments based on platelet count. If no response was observed after 4 weeks at 1000 mcg/week, treatment was discontinued. Results: As of July 2, 2010, 40 pts had enrolled: 28 from 72 previously treated with romiplostim only, 7 from 29 previously treated with decitabine plus romiplostim or placebo, and 5 from 39 previously treated with lenalidomide plus romiplostim. In the extension study, 3 pts continued receiving decitabine and 3 pts continued receiving lenalidomide. Twenty-eight pts (70%) were male, the median age was 72 (Q1-Q3: 64–77) years, median baseline platelets were 31 × 109/L (Q1-Q3: 19–45 × 109/L), 11 pts (28%) had platelets < 20 × 109/L. At the end of their prior study, IPSS status was low (19 pts), int-1 (15), int-2 (1), or missing (5), and MDS subtypes at diagnosis were RA (11 pts), RCMD (10), MDS-U (6), RAEB-1 (8), MDS del 5q (2), RAEB-2 (1), RCMD-RS (1), and RARS (1). Twenty-one pts (53%) had bleeding events during the year before entering this study. Median duration of treatment in the extension study was 50 weeks (range: 6–134 weeks), with a median average weekly dose of 729 mcg (Q1-Q3: 593–893 mcg). The incidence of all AEs during 12-week study periods ranged from 60% to 92% and did not increase with time on study. Most AEs were mild-to-moderate; the most common being epistaxis (40%), fatigue (33%), and cough (30%). No neutralizing antibodies to romiplostim or endogenous TPO were detected. No pts died during the study; one pt died 3 months after withdrawing from the study (causality was uncertain). Peripheral blasts were increased in 2 pts (MDS-U and RA at baseline) and resolved in both cases after discontinuation of romiplostim. Three cases of progression to AML were reported, corresponding to an annual on-study event rate of 5.9% (95% CI: 1.9% to 18.3%). These pts were IPSS-risk low or int-1 at baseline and had a WHO classification of RAEB-1 or RCMD. During this study, they received 750 mcg romiplostim for 6, 49, and 36 weeks. Bone marrow blasts were 39%, 65%, and 40% at AML diagnosis. Thirty pts (75%) reported ≥1 bleeding event(s), with 17 pts (43%) reporting ≥1 clinically significant bleeding event(s) [CTCAE grade ≥3, serious AE, or any bleeding AE requiring intervention]. The proportion of pts experiencing a significant bleeding event decreased from 23% (9/40) during weeks 1–12 to 0% (0/21) during weeks 48–60. Similarly, the proportion of pts receiving a platelet transfusion decreased from 28% (11/40) during weeks 1–12 to 0% (0/21) during weeks 48–60. From week 3 onwards, the median platelet count was ≥ 50 × 109/L (Figure). Thirty-four pts (85%) had a platelet response (per IWG 2006). The median duration of platelet response was 41 weeks (Q1-Q3: 15–87 weeks). Conclusion: In this study, long-term treatment of MDS pts with romiplostim demonstrated a toxicity profile consistent with published data and disease progression was consistent with expected rates. Most pts achieved a sustained platelet response while receiving romiplostim. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Off Label Use: Romiplostim is approved for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP). Kantarjian:Amgen Inc.: Research Funding. Lyons:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Larson:Amgen Inc.: Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy. Becker:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Jia:Amgen Inc.: Employment, Equity Ownership. Yang:Amgen Inc: Employment, Equity Ownership.

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The Effects of Romiplostim or Standard of Care (SOC) on Splenectomy and Treatment Failure of Patients Who Had Immune Thrombocytopenia (ITP) for Less Than or Equal to One Year.

Blood ◽

10.1182/blood.v116.21.3702.3702 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3702-3702

Author(s):

Ralph Boccia ◽

David J. Kuter ◽

Mathias J. Rummel ◽

B. Gail Macik ◽

Ingrid Pabinger ◽

...

Keyword(s):

Treatment Failure ◽

Board Of Directors ◽

Research Funding ◽

Ad Hoc ◽

Bleeding Event ◽

Advisory Committees ◽

Platelet Counts ◽

Equity Ownership ◽

The Mean ◽

Actual Incidence

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.

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Is There a Clinical Benefit to Switch Hydroxyurea (HU) Drug in Sickle Cell Disease (SCD)?

Blood ◽

10.1182/blood-2020-140265 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-5

Author(s):

Frédéric Galactéros ◽

Ersi Voskaridou ◽

Anoosha Habibi ◽

Giovanna Cannas ◽

Laure Joseph ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Clinical Benefit ◽

Research Funding ◽

Fine Tuning ◽

Cell Disease ◽

Advisory Committees ◽

Previously Treated ◽

The Mean

The European Sickle Cell Disease Cohort - Hydroxyurea (ESCORT-HU) study was initiated when HU got an approval in SCD in Europe. This non-interventional prospective cohort study conducted in patients treated with HU according to current clinical practice with SCD was terminated in 2019 after enrolment of 1906 patients in 4 European countries. The main objective was to refine the safety profile of hydroxycarbamide, as well as to identify unexpected toxicities, especially after long-term treatment. However clinical effectiveness evaluated by recording painful crises lasting more than 48 hours, episodes of ACS, number of hospitalisations related to SCD, and biological parameters were also regularly recorded according to the frequency of the hospital visits. At inclusion, 926 (48.7%) patients had been previously treated off the label with HU (as HU was only approved for myeloproliferative disorders at the time), with mean duration of HU treatment of 5.74 ± 4.98 years. The mean age of this subgroup was 27.60 ± 14.81 years compared to 19.75 ± 15.79 years of the patients never been treated with HU before enrolment Of the 926 patients, 299 (32%) were younger than 18 years. As showed in the table 1, hemoglobin level remains unchanged during the first two years but the HbF% increased in the HU-pretreated subgroup. In the "HU-naïve group", despite lower baseline Hb level et HbF% at baseline , similar outcome were obtained after 12 or 24 months. In terms of clinical outcomes, after 1 year of treatment the number of vaso-occlusive crises (VOC), acute chest syndrome (ACS) or hospitalizations decreased dramatically (table 2) in both group. The median duration of follow-up in the cohort was 45 months (0-128). 123.7 ± 62.7 months was the mean total exposure to HU in the HU-pretreated subgroup. In term of safety, neutropenia, thrombocytopenia and dry skin were the most frequent HU- related adverse events reported but with comparable cumulated incidence between the HU-pretreated subgroup and HU-naïve subgroup (Table 3). Conclusion: In real life setting, a significant improvement of the vasoocclusive symptoms was observed. Improvement of the compliance thanks to a treatment dedicated to the disease is probably one reason for better effectiveness; as suggested bythe lower red blood cell MCV was lower than expected at baseline in patients previously treated with HU. It is also possible that the increase in HbF% observed during the treatment could be another reason for clinical benefit. Paule and al (2011) demonstrated that daily regimen of HU were superior to weekly regimen. The fine tuning of the daily dose possible with HU tablets might be another reason of clinical optimization. Disclosures Galactéros: Addmedica:Membership on an entity's Board of Directors or advisory committees.Voskaridou:BMS:Consultancy, Research Funding;ADDMEDICA Company:Consultancy, Research Funding;NOVARTIS Company:Research Funding;GENESIS Company:Consultancy, Research Funding;PROTAGONIST Company:Research Funding;ACCELERON Company:Consultancy, Research Funding.Habibi:Pfizer:Consultancy;Bluebird:Consultancy;Novartis:Consultancy;Addmedica:Consultancy.De Montalembert:bluebird bio:Honoraria, Membership on an entity's Board of Directors or advisory committees;Vertex:Honoraria, Membership on an entity's Board of Directors or advisory committees;Addmedica:Honoraria, Membership on an entity's Board of Directors or advisory committees;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Long-Term Outcomes and Organ Responses with Daratumumab Therapy in Previously Treated Patients with AL Amyloidosis

Blood ◽

10.1182/blood-2019-122152 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1828-1828

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

Erik Eckhert ◽

Stanley Schrier ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cardiac Response ◽

Al Amyloidosis ◽

Long Term Outcomes ◽

Advisory Committees ◽

Renal Response ◽

Cardiac Responses ◽

Previously Treated

Introduction: AL amyloidosis involves deposition of abnormally folded light chains into a wide range of tissues causing end-organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously relapsed/refractory disease. However, data on long-term outcomes to daratumumab, including organ responses, are lacking. Here we present the largest retrospective study to date on patients with previously treated AL amyloidosis treated with daratumumab. Methods: We conducted a retrospective analysis of relapsed/refractory AL amyloidosis patients treated at Stanford University from January 2016 to January 2019. Patients treated with daratumumab, either as monotherapy with dexamethasone (DMT) or in combination with other plasma-cell directed therapies (DCT) were included. Hematologic and organ responses were assessed by consensus guidelines. Hematologic responses were based on the maximal change in the difference between involved and uninvolved free light chains (dFLC). For cardiac response, a >30% and >300 pg/mL decrease in NT-proBNP for patients with initial baseline NT-proBNP ≥650 pg/mL was considered a response. A graded cardiac response metric was also explored with partial response (PR) representing 30-59% reduction, very good partial response (VGPR) ≥60% reduction, and complete response (CR) NT-proBNP <450 pg/mL as previously reported. For renal response, a >30% decrease (by at least 0.5 g/day) in 24-hour urine protein without worsening in creatinine or creatinine clearance by more than 25% in patients with at least 0.5 g/day pretreatment was considered a response. A graded renal response metric was also explored with PR representing 30-59% reduction in proteinuria, VGPR ≥60%, and CR ≤ 200 mg per 24-hour period. Survival data was analyzed using the Kaplan-Meier method. All time-to-event outcomes, including survival and organ responses, were determined from initiation of daratumumab. Results: Eighty-four patients were identified with baseline characteristics at start of daratumumab shown in Table 1. Median duration of follow-up was 16 months. Two-year overall survival (OS) was 83% and median OS was not reached. Median time-to-next-treatment or death was 31 months. Sixty-seven out of 80 evaluable patients (84%) achieved a hematologic response, with 47 patients (59%) achieving a VGPR or better (Figure 1). Sixty-eight patients (81%) had cardiac involvement, and among the 34 evaluable patients, 18 (53%) of evaluable patients achieved a cardiac response with a median response time of 2 months among responders. In terms of a graded cardiac response, 6 patients (18%) were able to achieve cardiac CR, 5 patients (15%) cardiac VGPR, and 7 patients (21%) PR (Figure 2). The median NT-proBNP percent reduction was 64.5% (IQR: 48.3 - 81.1%) and the median absolute reduction was 2395 pg/mL (IQR 1279.5 - 4089.5 pg/mL). Cardiac responses were associated with an improvement in OS (p<0.001, Figure 3), with landmark analysis for cardiac responses at 6-month trending towards statistical significance (100% vs. 51% at 30 months, p=0.052). Fifty-three patients (63%) had renal involvement, and among the 26 evaluable patients, 12 patients (46%) achieved a renal response with a median initial response time of 6 months among responders. Using graded response, 1 patient (4%) achieved renal CR, 7 patients (27%) renal VGPR, 4 patients (15%) renal PR, and 14 patients had no response, worsening creatinine, or were subsequently started on hemodialysis (54%) (Figure 4). The median percent reduction in proteinuria was 74.1% (IQR: 49.2 - 83.1%) and the median absolute reduction in proteinuria was 3.1 g/24 hours (IQR 2.1 - 4.9 g) among responders. There were no significant differences in OS between renal responders and non-responders. Conclusion: Daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve durable hematologic responses as well as improvements in organ function. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding. OffLabel Disclosure: Daratumumab in AL amyloidosis

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

Blood ◽

10.1182/blood.v114.22.891.891 ◽

2009 ◽

Vol 114 (22) ◽

pp. 891-891 ◽

Cited By ~ 1

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.

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