Update On The Safety and Efficacy Of EXTENDed Treatment With Eltrombopag (EPAG) In Adults With Chronic Immune Thrombocytopenia (ITP)

Abstract Background EPAG, an oral thrombopoietin receptor agonist approved for cITP, increased platelets (plts) and reduced bleeding in 6 wk and 6 m placebo-controlled trials in previously treated cITP patients. EXTEND is an ongoing, open-label extension study, begun in Jun 2006, to assess the safety and efficacy of long-term treatment with EPAG in cITP patients who completed a previous EPAG study. Long-term safety and efficacy data up to Feb 2013 are presented. Methods EPAG was started at 50 mg and titrated to 25-75 mg/d or less often, based on plt counts. Patients who received ≥2 y of EPAG and transitioned off due to commercial availability of EPAG were considered to have completed EXTEND, whether or not they continued treatment with commercial EPAG. Results Of 302 patients enrolled, 43% (129) completed, 48% (146) withdrew, and 9% (27) remain on study. The most common reasons for withdrawal were adverse events (AEs; 15%), patient decision (13%), lack of efficacy (11%), and stable plts ≥6 m following interruption of EPAG (3%). The Table shows baseline patient characteristics and treatment duration. Doses of 75, 25, and 25 mg QOD were required by 62%, 51%, and 20% of patients, respectively, at some time during the study; 5% remained on 50 mg throughout the study (overall median duration of exposure, 122 wk; average dose, 50.8 mg/d). Overall, 85% (258/302) of patients achieved plts ≥50,000/µL in the absence of rescue therapy, and 61% achieved plts ≥50,000/µL for ≥50% of on-treatment assessments. Median plts increased to ≥50,000/µL by Wk 2, remaining consistently ≥50,000/µL throughout the treatment period. Nine of 10 patients who withdrew due to stable plts for ≥6 m following interruption of EPAG maintained plts ≥100,000/µL for ≥6 m without any ITP therapy. Incidence of bleeding symptoms (WHO grades 1-4) decreased from baseline to 1 y and thereafter (Figure). Of 101 patients receiving concomitant ITP treatment at baseline, 40 had a sustained reduction or permanently stopped ≥1 concomitant ITP treatment without ever receiving rescue therapy. The most frequently discontinued/reduced ITP medications were corticosteroids (35/40; 88%) and danazol and azathioprine (4/40 each; 10%). In 92% (277) of patients, AEs occurred. Serious AEs (SAEs) occurred in 31% (94) of patients, and 22 patients had 33 SAEs considered possibly drug related. Drug-related SAEs occurring in ≥2 patients were cataracts (7), alanine aminotransferase (ALT) (4) or aspartate aminotransferase (2) increased, deep vein thrombosis (DVT; 4), bilirubin increased (3), myocardial infarction (MI; 2), and pulmonary embolism (PE; 2). AEs leading to withdrawal occurred in 44 patients (15%), 29 (10%) of whom experienced SAEs. The most frequent AEs leading to withdrawal were increased ALT (7), increased bilirubin (5), cataracts (4), and DVT (4). In 19 patients (6%), 26 thromboembolic events (TEEs) were reported (incidence rate, 2.53/100 patient y; 95% CI, 1.52-3.95). Observed TEEs were DVT (11), central nervous system ischemic events (7), MI (5), and PE (3). No association with elevated plt counts was observed, as only 3/19 patients experienced the TEE at or shortly after achieving their maximum plt count. Hepatobiliary laboratory abnormalities (HBLAs) were reported in 37 patients (12%), and 8 were withdrawn because of HBLAs. No HBLAs were associated with signs of liver impairment; most resolved on treatment or after discontinuation. An independent central pathology review of bone marrow (BM) biopsies stained for reticulin from 115 patients treated with EPAG for ≤5.5 y found no clinically relevant increase in reticulin deposition. Two patients (2%) had maximum reticulin marrow fibrosis (MF) grade of ≥2 after >24 m on treatment; neither experienced any AE or hematologic parameter abnormality potentially related to impaired BM function. Conclusions Sustained plt increases and reduced bleeding symptoms were observed in EPAG-treated cITP patients throughout the study. Sustained increases in plt counts were maintained in a few patients after discontinuing EPAG. Concomitant ITP medications were reduced without requiring rescue medications. Eltrombopag was well tolerated with exposures ≤6.5 y. Rates of TEEs and HBLAs did not increase with longer treatment duration, and BM biopsies showed no clinically significant increase in MF grade. No new safety signals were observed. Long-term safety and efficacy continue to be assessed in this ongoing study. Disclosures: Bussel: Symphogen: Membership on an entity’s Board of Directors or advisory committees; Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Eisai Inc.: Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wong:GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau. Burgess:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Chan:GlaxoSmithKline: Employment. Bailey:GlaxoSmithKline: Employment, Equity Ownership.

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Long-Term Safety and Efficacy of Mitapivat (AG-348), a Pyruvate Kinase Activator, in Patients with Pyruvate Kinase Deficiency: The DRIVE PK Study

Blood ◽

10.1182/blood-2019-123406 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3512-3512

Author(s):

Rachael F. Grace ◽

D. Mark Layton ◽

Frédéric Galactéros ◽

Wilma Barcellini ◽

Eduard J. van Beers ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Employment Equity ◽

Advisory Committees ◽

Safety And Efficacy ◽

The Core ◽

Equity Ownership ◽

Extension Period

Background: Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by mutations in the PKLR gene, leading to a deficiency of the glycolytic enzyme red cell PK (PK-R). Current treatments for PK deficiency are supportive only. Mitapivat (AG-348) is an oral, small-molecule, allosteric PK-R activator in clinical trials for PK deficiency. We previously described results from DRIVE PK, a phase 2, randomized, open-label, dose-ranging study in adults with PK deficiency (N=52) treated with mitapivat for a median of 6 months. Aim: To report long-term safety and efficacy of mitapivat in patients who continue treatment in the ongoing Extension period of the DRIVE PK study (ClinicalTrials.gov NCT02476916). Methods: Patients were eligible to participate if ≥18 years of age with a confirmed diagnosis of PK deficiency (enzyme and molecular testing); baseline hemoglobin (Hb) levels ≤12.0 g/dL (males) or ≤11.0 g/dL (females); and if they had not received more than 3 units of red blood cells in the prior 12 months, with no transfusions in the prior 4 months. Patients were initially randomized 1:1 to receive mitapivat 50 mg twice daily (BID) or 300 mg BID for a 6-month Core period. Dose adjustment was allowed during the Core period based on safety and efficacy. Patients experiencing clinical benefit without concerning safety issues related to mitapivat (investigator discretion) could opt to enter the Extension period, with follow-up visits every 3 months. Safety (adverse events [AEs]) and efficacy (hematologic parameters including Hb) were assessed. Protocol amendments during the Extension period required that (1) patients who did not have an increase from baseline Hb of ≥1.0 g/dL for ≥3 of the prior 4 measurements withdraw from the study, and (2) patients treated with mitapivat doses >25 mg BID undergo a dose taper and continue on the dose that maintained their Hb level no lower than 1.0 g/dL below their pre-taper Hb level. Results: Fifty-two patients enrolled in this study and were treated in the 24-week Core period; 43 (83%) patients completed the Core period and 36 (69%) entered the Extension period. Eighteen patients discontinued from the Extension period: investigator decision (n=8), AEs (n=1), consent withdrawal (n=1), noncompliance (n=1), or other (n=7). Thus, 18 patients, all of whom received ≥29 months of treatment with mitapivat (median 35.6, range 28.7-41.9) have continued treatment. Ten of these 18 patients were male, 11 had a prior splenectomy, and 5 had a history of iron chelation. Median age was 33.5 (range 19-61) years; mean baseline Hb was 9.7 (range 7.9-12.0) g/dL. All patients had ≥1 missense PKLR mutation. The doses (post-taper) at which treatment was continued were (BID): ≤25 mg (n=12), 50 mg (n=5), and 200 mg (n=1). Improvements in Hb levels and markers of hemolysis (reticulocytes, indirect bilirubin, haptoglobin) were sustained (Figure). Among the 18 patients, headache was the most commonly reported AE during both the Extension (n=7, 38.9%) and Core (n=10, 55.6%) periods. Reports of insomnia and fatigue during the Extension period (n=5, 27.8% each) were the same as or similar to those during the Core period. There were fewer reports of nausea (2 vs 6) and hot flush (0 vs 5) in the Extension period. Nasopharyngitis was reported in 5 patients in the Extension period vs 1 patient in the Core period. These data are consistent with the AE profile for the 52 patients treated overall in the Core period, in that headache (44%), insomnia (40%), and nausea (38%) were the most commonly reported AEs and were transient (generally resolved within 7 days without intervention). Conclusion: Chronic daily dosing with mitapivat for a median of 3 years was well tolerated, with no new safety signals reported. Increased Hb levels and improvements in hemolysis markers were sustained at the optimized individual doses. These long-term data support the potential of mitapivat as the first disease-altering therapy for PK deficiency. Two phase 3 trials are underway to further study the effect of mitapivat in patients with PK deficiency. Disclosures Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Galactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Barcellini:Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Agios: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Sheth:Apopharma: Other: Clinical trial DSMB; CRSPR/Vertex: Other: Clinical Trial Steering committee; Celgene: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Agios: Consultancy. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hawkins:Bristol Myers Squibb: Equity Ownership; Infinity Pharma: Equity Ownership; Agios: Employment, Equity Ownership; Jazz Pharmaceuticals: Equity Ownership. Mix:Agios: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Long-Term Safety and Efficacy of Eltrombopag in Adults with Chronic Immune Thrombocytopenia (ITP): Report of up to 5.5 Years of Treatment in EXTEND.

Blood ◽

10.1182/blood.v120.21.2198.2198 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2198-2198

Author(s):

Mansoor N Saleh ◽

Gregory Cheng ◽

James B Bussel ◽

Paul Burgess ◽

Kalpana Bakshi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Drug Induced ◽

Advisory Committees ◽

Safety And Efficacy ◽

Platelet Counts ◽

Chronic Itp ◽

Equity Ownership

Abstract Abstract 2198 Background: Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of chronic ITP. Eltrombopag safely increased platelets and reduced bleeding in 6-week and 6-month placebo-controlled trials in patients with previously treated chronic ITP. EXTEND is an ongoing, open-label extension study of the safety and efficacy of long-term treatment with eltrombopag in chronic ITP patients who completed a previous eltrombopag study. Methods: Patients had received eltrombopag or placebo in a prior study. Eltrombopag was started at 50 mg and titrated to between 75 and 25 mg daily or less often, based on platelet counts. Patients were considered to have completed EXTEND if they had received ≥2 years of therapy and transitioned off due to commercial availability of eltrombopag, whether or not they continued with treatment. The study started in June 2006, and an update on long-term safety and efficacy up to February 2012 is presented. Results: Of 302 patients enrolled, 31% (95) completed the study, 48% (146) withdrew, and 20% (61) remain on study. The most common reasons for withdrawal were adverse events (AEs, 14%), patient decision (14%), and lack of efficacy (11%). Platelet counts at baseline were ≤15,000/μL (43%), >15,000-<30,000/μL (27%), 30,000–50,000/μL (17%), and >50,000/μL (13%); 38% were splenectomized, 33% were receiving concomitant ITP medication, and 53% had received ≥3 previous ITP therapies. 253 patients were treated for ≥6 months, 217 for ≥1 year, 176 for ≥2 years, and 59 for ≥4 years; 10 patients (3%) were treated for ≥5 years. Median duration of exposure was 121 weeks (range, 0.3–285 weeks), and median average daily dose was 51.4 mg. Overall, 85% (257/302) of patients achieved a platelet count ≥50,000/μL in the absence of rescue therapy, and 62% of patients achieved platelets ≥50,000/μL for ≥50% of on-treatment weeks. The proportion of patients achieving platelets ≥50,000/μL was similar regardless of baseline splenectomy status: splenectomy, 80% vs no splenectomy, 88%. Median platelet counts increased to ≥50,000/μL by Week 2 and remained consistently ≥50,000/μL through Week 241. The incidence of any bleeding symptoms (WHO grades 1–4) decreased from 57% at baseline to 16% at Week 52, 19% at Week 104, 12% at Week 156, and 14% at Week 208. Clinically significant bleeding (WHO grades 2–4) decreased from 17% at baseline to 4%, 5%, 0%, and 0% at Weeks 52, 104, 156, and 208, respectively. AEs and serious AEs (SAEs) occurred in 91% (275) and 29% (89) of patients, respectively. The most frequent AEs were headache (27%), nasopharyngitis (24%), and upper respiratory tract infection (22%). 43 patients (14%) were withdrawn due to AEs, 29 (10%) of which were SAEs. Twenty-five thromboembolic events (TEEs) were reported in 19 patients (6%); the incidence rate is 2.70/100 patient years (95% CI, 1.62–4.21). Observed TEEs were deep vein thrombosis (10), central nervous system ischemic events (7), myocardial infarction (5), and pulmonary embolism (3). No association has been observed with elevated platelet counts, as only 3/19 patients experienced the TEE at or shortly after their maximum platelet count achieved on study. Hepatobiliary laboratory abnormalities (HBLAs) meeting drug-induced liver injury screening criteria (FDA Guidance for Industry Drug-Induced Liver Injury, 2009) were reported in 36 patients (12%). None were associated with signs of liver impairment, and most resolved either while on treatment or after discontinuation. Eight patients were withdrawn as a result of HBLA. An independent central pathology review of bone marrow (BM) biopsies stained for reticulin from 113 patients treated with eltrombopag for up to 4.75 years revealed no clinically relevant increase in reticulin deposition. 2 patients (2%) had maximum reticulin grade of ≥MF-2 after >24 months on treatment; neither experienced any AE or abnormality in hematologic parameters potentially related to impaired BM function. Conclusions: Eltrombopag was effective in increasing and maintaining platelets ≥50,000/μL and reducing bleeding symptoms in patients with chronic ITP. Eltrombopag was well tolerated with exposures up to 5.5 years. Rates of TEE and HBLA have not increased with longer time on treatment, and analyses of BM biopsies revealed no clinically significant increase in reticulin deposition. No new safety signals were observed in this long-term study. Long-term safety and efficacy continue to be assessed. Disclosures: Cheng: GlaxoSmithKline: Honoraria, Speakers Bureau. Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shinogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Portola: Consultancy. Burgess:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties. Bailey:GlaskoSmithKline: Employment, Equity Ownership.

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Safety and Efficacy of Extended Treatment with Eltrombopag in Adults with Chronic Immune Thrombocytopenia (ITP) From June 2006 to February 2011,

Blood ◽

10.1182/blood.v118.21.3296.3296 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3296-3296 ◽

Cited By ~ 4

Author(s):

Mansoor N Saleh ◽

Gregory Cheng ◽

James B Bussel ◽

Paul Burgess ◽

Lisa Marcello ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Safety And Efficacy ◽

Platelet Counts ◽

Chronic Itp ◽

Equity Ownership ◽

Clinically Significant

Abstract Abstract 3296 Background: Eltrombopag is an oral, nonpeptide thrombopoietin receptor agonist approved for treatment of chronic immune thrombocytopenia (ITP). In 6-week, and 6-month, placebo-controlled trials, eltrombopag safely increased platelets and reduced bleeding in patients (pts) with previously treated chronic ITP. EXTEND is an ongoing, open-label extension study of the safety and efficacy of long-term treatment with eltrombopag in chronic ITP pts. Methods: Pts had received eltrombopag or placebo in one of the following studies: TRA100773A or B (6-weeks), RAISE (6-months), or REPEAT (intermittent treatment). The EXTEND study was designed to: 1) identify an individual dose that increases platelets to ≥100,000/μL to support reduction of concomitant ITP medications, 2) identify a minimal dose of eltrombopag and concomitant ITP medication to maintain platelets ≥50,000/μL, and 3) evaluate long-term safety and efficacy. Pts completed the study if they completed ≥2 years of therapy and transitioned off study due to commercial availability of eltrombopag. Results: Of 301 pts enrolled, 21% (63) completed the study, 48% (143) withdrew, and 32% (95) remain on study. The most common reasons for withdrawal were adverse events (AEs, 14%), pt decision (13%), and lack of efficacy (11%). At baseline, platelet counts were ≤15,000/μL, >15,000-<30,000/μL, 30,000–50,000/μL, and >50,000/μL in 43%, 27%, 17%, and 13% of pts, respectively; 38% were splenectomized, 34% were receiving concomitant ITP medication, and 53% had received ≥3 previous ITP therapies. As of this report, 252, 215, 176, and 84 pts had been treated for ≥6 months, 1 year, 2 years, and 3 years, respectively. Twenty-three pts (8%) were treated for ≥4 years. Median duration of exposure was 121 weeks (range, 0.3–237 weeks). Overall, 88% (264/301) of pts achieved a platelet count ≥50,000/μL at least once. The proportion of pts achieving on-treatment platelets ≥50,000/μL was similar regardless of the following baseline characteristics: splenectomy vs no splenectomy (85% vs 89%); use vs no use of ITP medication (89% vs 87%); and platelet counts (<30,000/μL, 84%; 30,000–50,000/μL, 98%; >50,000/μL, 95%). Median platelet counts increased to ≥50,000/μL by week 2 and remained consistently ≥50,000/μL through week 208. The incidence of any bleeding symptoms (WHO grades 1–4) decreased from 56% at baseline to 16%, 19%, and 9% at weeks 52, 104, and 156, respectively. Clinically significant bleeding (WHO grades 2–4) decreased from 16% at baseline to 3%, 5%, and 0% at weeks 52, 104, and 156, respectively. AEs and serious AEs (SAEs) occurred in 89% (269) and 29% (86) of pts, respectively. The most frequent AEs were headache (27%), nasopharyngitis (24%), and upper respiratory tract infection (21%). Forty pts (13%) had AEs leading to withdrawal; 28 (9%) had SAEs leading to withdrawal. Twenty-five thromboembolic events (TEEs) have been reported in 19 pts (6%); the incidence rate is 3.02/100 pt years (95% CI [1.82–4.71]). Observed TEEs were deep vein thrombosis (10), central nervous system ischemic events (7), myocardial infarction (5), and pulmonary embolism (3). No association has been observed with elevated platelet counts, as only 3/19 pts experienced the TEE at or closest to their maximum platelet count achieved on study. Hepatobiliary laboratory abnormalities (HBLAs) meeting drug-induced liver injury screening criteria (Center for Drug Evaluation and Research 2009 [FDA]) were reported in 34 pts (11%). None were associated with signs of liver impairment, and most (n=30) resolved either while on treatment or after discontinuation. Eight pts were withdrawn as a result of their HBLA. Two pts were diagnosed with lymphoma and none with leukemia during the 622 pt years of eltrombopag exposure during EXTEND. An independent central review of bone marrow biopsies from >100 pts treated with eltrombopag for 1–4 years, including 39 pts who had ≥2 biopsies during the study, revealed no clinically significant increase in reticulin deposition. Conclusions: Eltrombopag was effective in increasing and maintaining platelet counts ≥50,000/μL and reducing bleeding symptoms. Eltrombopag was well-tolerated during treatment of pts with chronic ITP with exposures up to 4.5 years. No new safety signals have been observed in this long-term study. Additional long-term safety data continue to be assessed, especially in terms of bone marrow reticulin, HBLAs, and TEEs. Disclosures: Saleh: GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau. Cheng:GlaxoSmithKline: Speakers Bureau. Bussel:Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Burgess:GlaxoSmithKline: Employment, Equity Ownership. Marcello:GlaxoSmithKline: Employment. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership.

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Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIFc) in Adults/Adolescents with Severe Hemophilia a

Blood ◽

10.1182/blood.v128.22.1413.1413 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1413-1413

Author(s):

Barbara Konkle ◽

K John Pasi ◽

David J Perry ◽

Johnny Mahlangu ◽

Savita Rangarajan ◽

...

Keyword(s):

Treatment Group ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Dosing Intervals

Abstract Background: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care for patients with hemophilia A; however, prophylaxis with conventional FVIII products usually requires frequent intravenous injections (3-4 times/week). The safety, efficacy, and prolonged half-life of rFVIIIFc in previously treated adults and adolescents (≥12 y) with severe hemophilia A were demonstrated in the phase 3 A-LONG study (NCT01181128, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in study participants as of the second interim data cut (8 Dec 2014). Methods: This longitudinal analysis includes cumulative data from A-LONG and ASPIRE (as of the second interim data cut 8 Dec 2014) for subjects treated with ≥1 dose of rFVIIIFc. A-LONG evaluated 2 prophylaxis regimens-individualized (IP): 25 IU/kg on Day 1 and 50 IU/kg on Day 4 to start, then 25-65 IU/kg every 3-5 days, to target a 1-3 IU/dL FVIII trough level, and weekly (WP): 65 IU/kg dosed once weekly-as well as episodic (on-demand) treatment (ET). Subjects completing A-LONG and meeting enrollment criteria for ASPIRE could participate in the IP, WP, or ET groups, or, if optimal dosing could not be achieved with IP or WP, in an additional modified prophylaxis (MP) group. Subjects could change treatment groups at any point during ASPIRE. Efficacy analyses were performed using data summarized according to the treatment group in which each subject participated, for the time period they were in that treatment group; thus, subjects may be included in the analysis of more than one group. Outcomes evaluated included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL identified and confirmed on 2 separate samples drawn approximately 2-4 weeks apart and performed by the central laboratory as measured by the Nijmegen-modified Bethesda assay), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and prophylactic consumption and dosing interval compared to pre-A-LONG (prestudy). Results: Of 164 subjects dosed with rFVIIIFc during A-LONG, 153 completed the study and 150 enrolled in ASPIRE; at the time of this second interim data cut, 97 subjects were ongoing in ASPIRE, 40 subjects had completed the study, and 13 subjects withdrew. Cumulatively, subjects had 38,662 rFVIIIFc exposure days (EDs), inclusive of surgery. As of this second interim data cut (8 Dec 2014), no inhibitors were observed; the type and incidence of adverse events (AEs) observed were typical of previous hemophilia A populations studied. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP and WP (MP was not an option during A-LONG) were lower with rFVIIIFc compared with prestudy FVIII for subjects on prestudy prophylaxis or ET (Figure). In the IP group, the median (interquartile range [IQR]) spontaneous ABRs in Years 1, 2, and 3 on-study were 0.0 (0.0, 2.0), 0.0 (0.0, 1.0), and 0.0 (0.0, 1.0), respectively. In the WP treatment group, the median (IQR) spontaneous ABRs in Years 1, 2, and 3 on-study were 1.0 (0.5, 3.0), 0.5 (0.0, 2.1), and 0.0 (0.0, 1.0), respectively. Overall, 88.5% and 97.0% of bleeding episodes were controlled with 1 or ≤2 intervenous injections, respectively. Among subjects treated with FVIII prophylaxis prestudy (n = 79), 86% were dosed at least 3 times/week prestudy. Compared with prestudy dosing intervals, dosing intervals with rFVIIIFc were extended in 96.2% of subjects, were shortened in 2.5% of subjects, and were unchanged in 1.3% of subjects. The median (IQR) total weekly prophylactic consumption was comparable (prestudy FVIII: 78.0 [60.0, 102.0] IU/kg; on-study rFVIIIFc: 75.0 [70.0, 113.8] IU/kg). Conclusions: Longitudinal data from patients with severe hemophilia A treated with rFVIIIFc in A-LONG and ASPIRE confirm long-term safety, with no inhibitors observed in any subject. Low median ABRs were maintained, and rFVIIIFc demonstrated efficacy in the prevention and treatment of bleeding episodes. Prophylactic dosing intervals were extended, without an increase in median prophylactic factor consumption. This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content. Disclosures Pasi: Biogen: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Mahlangu:Bayer: Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Roche: Consultancy, Research Funding; Baxalta: Consultancy. Rangarajan:Baxter: Research Funding; Baxalta, now part of Shire: Other: Investigator Clinical Studies, Research Funding; Biogen: Consultancy; Biotest: Research Funding; Grifols: Consultancy, Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding. Brown:Baxter: Consultancy; Biogen: Consultancy; Novo Nordisk: Consultancy. Hanabusa:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees; KaketsuKen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bayer: Honoraria; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pabinger:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cristiano:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Winding:Sobi: Employment. Glazebrook:Biogen: Employment, Equity Ownership. Lethagen:Sobi: Employment. Jackson:Biogen: Consultancy, Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Baxalta/Shire: Research Funding; Novo Nordisk: Research Funding; Baxter: Consultancy, Research Funding.

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Effects of Long-Term Ruxolitinib (RUX) on Bone Marrow (BM) Morphology in Patients with Myelofibrosis (MF) Enrolled in the COMFORT-I Study

Blood ◽

10.1182/blood.v128.22.1949.1949 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1949-1949 ◽

Cited By ~ 3

Author(s):

Hans Michael Kvasnicka ◽

Juergen Thiele ◽

Carlos E. Bueso-Ramos ◽

William Sun ◽

Ahmad Naim ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Rank Test ◽

Employment Equity ◽

Advisory Committees ◽

Signed Rank ◽

Signed Rank Test ◽

Equity Ownership ◽

Grade 3

Abstract Background: MF is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, cytopenias, debilitating symptoms, and progressive BM fibrosis The 2 phase 3 COMFORT studies have shown that RUX, an oral Janus kinase (JAK) 1/JAK2 inhibitor, improves splenomegaly, constitutional symptoms, and overall survival in patients with MF. Accumulating evidence suggests that RUX may also modulate the BM microenvironment. Aims: We evaluated the effects of long-term RUX treatment on changes in BM fibrosis in patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who were enrolled in the phase 3 COMFORT-I study. Methods: BM biopsies were obtained at baseline (BL), Weeks 48 and 72, and approximately every 48 weeks thereafter for up to 5 years of RUX treatment. Biopsies were reviewed independently in a blinded fashion (blinded for patient and treatment) by 3 hematopathologists (HMK, JT, and CEB-R). The final grading was based on consensus; no disagreements were recorded. The WHO grading system was used to grade BM fibrosis density based on a scale of 0-3 (Thiele et al, Haematologica 2005;90). Other details on the patient population and study design for the COMFORT-I study have been published previously (Verstovsek et al, N Engl J Med 2012;366). Biopsies from 59 patients were included in this exploratory analysis; patients who failed screening or received only 1 BM measurement were excluded. Three subgroups were defined for the analysis: 1) originally randomized to RUX (n=36); 2) randomized to placebo with BM measurements at BL and Week 48 (n=15); and 3) crossover to RUX with BM measurements at BL and ≥1 post-BL measurement after crossover (n=21). Changes from BL in BM fibrosis grades at various time points were categorized for each patient as improvement (-1 to -3), stabilization (0), or worsening (1 to 3). Patients with a BL score of 0 for improvement and 3 for worsening were excluded from the analysis. Patients who received placebo for ≥36 weeks were included in the crossover group, with Week 48 used as the BL BM measurement. RUX and crossover groups were combined for evaluation of RUX effect. Placebo effect in the crossover group was assessed by analyzing change from BL to Week 48. Change from BL was evaluated using a signed rank test. Change from BL to last grade, and time to the first occurrence of a ≥1 grade improvement from BL was assessed for RUX and crossover groups. KM analysis was used to estimate time to improvement in BM fibrosis for a subgroup of patients who had a BM fibrosis grade of ≥1 at BL. Results: BL characteristics for age, gender, International Prognostic Scoring System risk, spleen volume, hemoglobin, and platelet counts were similar between the 3 groups. At BL, of 36 patients originally randomized to RUX, 17% (n=6) presented with WHO-defined fibrosis grade 1, 39% (n=14) with grade 2, and 36% (n=13) with grade 3 (3 patients were grade 0). Of the 15 patients randomized to placebo, 20% (n=3) presented with grade 1, 40% (n=6) with grade 2, and 27% (n=4) with grade 3 WHO-defined fibrosis at BL (2 patients were grade 0). Mean exposure to RUX in the RUX and crossover groups was 136.0 (SD, 67.4) weeks and 129.1 (SD, 67.7) weeks, respectively. The proportion of evaluable patients with an improvement in BM fibrosis from BL to Week 48 was 26% (n=27) in the RUX group and 15.4% (n=13) in the placebo group. When evaluating all patients who received RUX (including placebo crossover), a significant shift was observed from BL to the last change in BM fibrosis grade (P=0.0119; signed rank test). For all RUX-treated patients (n=57), 33% (grade -1, n=11; -2, n=7; -3, n=1) had an improvement, 49% had no change or stabilization, and 18% had a worsening in BM fibrosis from BL to the last grade (Figure). At the final grading, 82% (n=47) of patients had improvement or stabilization while on RUX. Median time to a ≥1 grade improvement in BM fibrosis grade was approximately 3.5 years (95% CI, 2.5 to 4.5; n=51). Conclusions: This analysis from the COMFORT-I study showed that treatment with RUX was associated with improvement and stabilization in WHO-defined BM fibrosis in the majority of patients with MF in this study cohort. These results support evidence from other studies, suggesting that RUX treatment may contribute to disease-modifying effects in MF. The clinical effect of improvement and stabilization in BM fibrosis requires further study. Disclosures Kvasnicka: Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; AOP Pharma: Consultancy, Honoraria. Thiele:Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria. Sun:Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Svaraman:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Gotlib:Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dao:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Novartis: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Winton:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek:AstraZeneca: Research Funding; Roche: Research Funding; Celgene: Research Funding; Lilly Oncology: Research Funding; Galena BioPharma: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Geron: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

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Long-Term Safety and Efficacy of rFVIIIFc in Adults and Adolescents with Severe Hemophilia A: A Longitudinal Analysis of A-LONG and ASPIRE

Blood ◽

10.1182/blood.v126.23.1087.1087 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1087-1087 ◽

Cited By ~ 3

Author(s):

K John Pasi ◽

David J Perry ◽

Johnny Mahlangu ◽

Barbara A Konkle ◽

Savita Rangarajan ◽

...

Keyword(s):

Treatment Group ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Groups ◽

Equity Ownership

Abstract Background: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care for patients with hemophilia A; however, prophylactic treatment with conventional FVIII products usually requires frequent intravenous infusions (3-4 times/week). Recombinant FVIII Fc fusion protein (rFVIIIFc), which is produced in a human cell line, binds the neonatal Fc receptor and utilizes the natural IgG recycling pathway to prolong the half-life of FVIII. The safety, efficacy and prolonged half-life of rFVIIIFc in adults and adolescents with severe hemophilia A were demonstrated in the phase 3 A-LONG study (NCT01027377, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in participants in these studies. Methods: This longitudinal analysis includes cumulative data from A-LONG and ASPIRE (as of the interim data cut, 6 January 2014) for subjects treated with ≥1 dose of rFVIIIFc (n=164). A-LONG evaluated 2 prophylaxis regimens-individualized (IP): 25 IU/kg on day 1 and 50 IU/kg on day 4 to start, then 25-65 IU/kg every 3-5 days, to target a 1-3 IU/dL FVIII trough level, and weekly (WP): 65 IU/kg dosed once weekly-as well as episodic (on-demand) treatment. Subjects completing A-LONG and meeting enrollment criteria for ASPIRE could participate in the IP, WP, or episodic treatment groups, or, if optimal dosing could not be achieved with IP or WP, in an additional modified prophylaxis (MP) treatment group. Subjects could change treatment groups at any point during ASPIRE. For efficacy analyses, data were summarized according to the treatment group in which each subject participated, for the time period they were in that treatment group; thus, subjects may be included in the analysis of more than one treatment group. Outcomes evaluated included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL as measured by the Nijmegen-modified Bethesda assay at a central laboratory, confirmed upon retesting within 2 to 4 weeks), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and prophylactic dose and dosing interval. Results: Of the 164 subjects dosed with rFVIIIFc during A-LONG, 153 completed the study and 150 enrolled in ASPIRE. At the time of the interim data cut, 140 subjects were ongoing in ASPIRE. Cumulatively, subjects had a median (IQR) of 25.5 (24.6, 26.7) months of rFVIIIFc treatment, and a median (IQR) of 183.0 (120.5, 232.5) rFVIIIFc exposure days (EDs). No inhibitors were reported. The estimated inhibitor incidence rate (95% CI) was 0.0% (0.0, 2.2) overall (N=164), and 0.0% (0.0, 2.7) in subjects with ≥100 rFVIIIFc EDs (n=136). The type and incidence of AEs observed were consistent with those expected for the general hemophilia population. 84.8% of subjects reported ≥1 AE on study, with the majority assessed by the investigator as mild and unrelated to rFVIIIFc treatment. 17.7% of subjects experienced at least 1 SAE; none were assessed by the investigator as related to rFVIIIFc. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP and WP (MP was not an option during A-LONG) were generally lower with rFVIIIFc treatment compared with prestudy FVIII (Figure). In the IP treatment group, the year 1 and year 2 median spontaneous ABRs were 0.0. Overall, 89.1% of bleeding episodes were controlled with 1 infusion; 97.3% with 1 or 2 infusions. Among subjects treated with FVIII prophylaxis prior to entering A-LONG (n=79), 86% were dosed at least 3 times/week. With rFVIIIFc, 96% of these subjects extended their dosing interval compared with their prestudy product, while the median (IQR) total weekly prophylactic dose was comparable (prestudy FVIII: 78.0 [60.0, 102.0] IU/kg; on-study rFVIIIFc: 75.0 [70.0, 113.2] IU/kg). Conclusions: Longitudinal data from patients with severe hemophilia A treated with rFVIIIFc in A-LONG and ASPIRE demonstrate long-term safety, with no inhibitors observed in any subjects, and efficacy in the prevention and treatment of bleeding. Low median ABRs were maintained with extended prophylactic dosing intervals, without an increase in median prophylactic factor consumption. Figure 1. Figure 1. Disclosures Pasi: Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria; Octapharma: Research Funding. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Mahlangu:Roche: Research Funding; Biotest: Speakers Bureau; Bayer, CSL, Novo Nordisk, and Biogen: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Konkle:Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; CSL Behring: Consultancy, Other: IDMC chair; Pfizer: Other: IDMC member; Octapharma: Research Funding; Novo Nordisk: Consultancy. Rangarajan:Grifols, Pfizer, and Baxter: Research Funding; Grifols: Honoraria; Sobi: Membership on an entity's Board of Directors or advisory committees; LFB: Other: Conference support. Brown:Biogen, Novo Nordisk, Baxter, and Pfizer: Other: Sponsorship to meeting. Hanabusa:Novo Nordisk, Baxalta, Bayer, Pfizer, Biogen, and KaketsuKen: Honoraria; Novo Nordisk, Baxalta, KaketsuKen, and Biogen: Membership on an entity's Board of Directors or advisory committees. Jackson:Biogen: Honoraria, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Cristiano:Biogen: Employment, Equity Ownership. Dong:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Pierce:Biogen: Equity Ownership, Other: Former employee. Allen:Biogen: Employment, Equity Ownership.

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The Use of Erythropoietic-Stimulating Agents (ESAs) with Ruxolitinib in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), and Post-Essential Thrombocythemia Myelofibrosis (PET-MF).

Blood ◽

10.1182/blood.v120.21.2838.2838 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2838-2838 ◽

Cited By ~ 6

Author(s):

Mary Frances McMullin ◽

Claire N Harrison ◽

Dietger Niederwieser ◽

Hilde Demuynck ◽

Nadja Jakel ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Spleen Size ◽

Epoetin Alfa ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Safety And Efficacy ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 2838 Background: Ruxolitinib (rux), a potent oral JAK1 & 2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 COMFORT studies in MF patients (pts). Consistent with rux's known mechanism of action, anemia was one of the most frequently reported adverse events (AEs) and was generally transient and manageable leading to discontinuation in only 1 pt. In clinical practice, anemia can be managed with ESAs, which promote red blood cell proliferation via cytokine receptors that signal through the JAK pathway. Because these agents act upstream of rux in the JAK2 pathway, it is important to determine the effects of these medications on the safety and efficacy of rux. This post hoc analysis evaluated the safety and efficacy of rux in pts receiving concomitant ESA in COMFORT-II. Methods: COMFORT-II is an open-label, randomized, multicenter study. Pts were randomized (2:1) to receive rux 15 or 20 mg bid or best available therapy (BAT; as selected by the investigator). Use of ESAs (eg, darbepoetin alfa, epoetin alfa, epoetin nos), although not prohibited, was discouraged for pts randomized to rux because ESAs can increase spleen size, which could confound efficacy analyses. Spleen volume was assessed by MRI or CT every 12 wk. The rate of transfusions was calculated as the number of units transfused per exposure duration (typically 12 wk). Results: Concomitant use of ESA was reported for 13 (PMF, n = 10; PET-MF, n = 2; PPV-MF, n = 1) of the 146 pts who were treated with rux (darbepoetin alfa, 2% [n = 3]; epoetin alfa, 6% [n = 9]; epoetin nos, < 1% [n = 1]). The median exposure to rux was similar for pts who received an ESA (+ESA group; 500 d) vs those who did not receive ESA (468 d), and the median dose intensity of rux was the same for each group (30 mg/d). As shown in the table, 8 pts (62%) had no change, 2 pts (15%) had a decrease, and 3 pts (23%) had an increase in the rate of packed red blood cell (PRBC) transfusions per mo after the first administration of ESA compared with 12 wk before ESA use. Six wk prior to the first administration of ESA, 10/13 pts (77%) had grade 3/4 hemoglobin abnormalities; however, 6 wk after the administration of ESA, most pts' conditions improved to grade 2 (7/13 [54%]). The majority of pts (77%) did not have any change in their reticulocyte counts within the 6 wk before and after the administration of ESA; 1 pt (8%) had a marked increase; for 2 pts (15%), the data were not available. The AEs reported in pts who received ESA were similar to those previously reported with rux. Serious AEs were reported for 8 pts in the +ESA group (3 events in 2 pts that were possibly related to study drug). Within the last assessment prior to and the first assessment after the first administration of ESA, 7/9 evaluable pts (78%) had spleen volume reductions. Conclusions: In this analysis, although the sample size is small, rux was generally well tolerated in pts who received ESA, and the tolerability profile of rux was similar to that reported in previous studies. Rux-treated pts who received ESA generally did not have any change in their transfusion rates, but the rate of grade 3/4 hemoglobin abnormalities decreased within 6 wk of the first administration of ESA, suggesting that the use of ESA in combination with rux was beneficial in some pts. ESA did not appear to affect the efficacy of rux concerning spleen size reduction. The use of ESA for the treatment of anemia is common in clinical practice, and further analyses in combination with rux in this pt population are warranted. Disclosures: McMullin: Bristol Myers Squibb: Honoraria; Shire: Honoraria; Novartis: Honoraria. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. Recher:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, travel to ASH, travel to ASH Other; sunesis: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Gisslinger:Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; AOP Orphan Pharma AG: Consultancy, Speakers Bureau. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Al- Ali:Sanofi Aventis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria.

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The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Monotherapy Demonstrates Long-Term Safety and Durability Of Response In Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Patients In An Open-Label Extension Study

Blood ◽

10.1182/blood.v122.21.4163.4163 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4163-4163 ◽

Cited By ~ 5

Author(s):

Susan O'Brien ◽

Richard R. Furman ◽

Nathan Fowler ◽

Steven E. Coutre ◽

Jeff P. Sharman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Extension Study ◽

First Year ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Background Bruton’s Tyrosine Kinase (BTK) plays a critical role in chronic lymphocytic leukemia (CLL) cell survival by modulating B-cell receptor signaling. Ibrutinib (PCI-32765), a first-in-class oral inhibitor of BTK, inhibits proliferation, migration and adhesion in CLL cells. A total of 148 patients with CLL/SLL received ibrutinib monotherapy in a Phase 1 multiple ascending dose study (PCYC-04753) or Phase 1b/2 continuous dosing study (PCYC-1102-CA), after which a long-term extension study was available for continued follow-up for safety and efficacy with daily orally-administered ibrutinib monotherapy. The studies included patients with treatment-naïve (TN) and relapsed or refractory (RR) CLL/SLL. The aims of the present analysis were to evaluate safety based on time on ibrutinib therapy (≤ 1 year and > 1 year), summarize safety findings in the TN and RR patient populations, and assess duration of response (DOR). Methods Demographics and baseline characteristics were summarized according to parent study, comprising either TN patients or RR CLL/SLL patients who had received at least one dose of ibrutinib monotherapy. Patient disposition, treatment-emergent adverse events (AEs), best response, overall response rate (ORR), and DOR were determined for the time treated (beginning in the parent studies and extending into the long-term extension study). Results At a median treatment duration of 21.5 months, 109 out of 148 patients continued treatment with ibrutinib for over a year. The percentage of patients who had a grade 3 or higher serious adverse event (SAE) declined over time from 43% within the first year of study treatment to 32% after the first year of treatment. With respect to side effects determined to be related to study drug, the number of grade 3 AEs and SAEs also declined from within the first year of treatment (24% and 8%, respectively) to after the first year of treatment (7% and 0%, respectively). AEs leading to ibrutinib discontinuation occurred in 12 patients within the first year of treatment for all 148 patients and in 6 out of 109 patients after the first year of treatment. Overall, the most frequent AEs grade 3 or higher were pneumonia (16.9%), hypertension (13.5%), neutropenia (11.5%), thrombocytopenia (7.4%), and diarrhea (5.4%), regardless of relationship to study drug. Grade 3 or higher SAEs were reported in RR patients at 62% compared to TN patients at 29%. Pneumonia was reported in TN patients at 6.5% and in RR patients at 19.7%. Within the efficacy population (n = 140), the ORR was 86.2% for TN patients and 88.3% for RR patients who achieved a partial response (PR) or better. The ORR combined with PR with lymphocytosis suggests that 93.1% of TN patients and 93.7% of RR patients achieved an objective response to ibrutinib therapy based on Cheson JCO 2012. After a median follow up of 27.2 months (range 1.9-42 months) for TN and RR responders who achieved PR or better, the median DOR has not been reached. At landmark 30 months, 76.1% of the responders were alive without progression. Conclusions Ibrutinib as a single agent demonstrates long-term safety, tolerability, and durability of response in patients with TN and RR CLL/SLL. Indeed, a decrease in the number of patients experiencing SAEs or AEs grade 3 or higher after 1 year of treatment with ibrutinib resulted in low rates of treatment-related discontinuation after that time point. Grade 3 or higher SAEs were reported at a two-fold higher rate in patients who had received prior therapies, which may be reflective of disease state rather than relationship to ibrutinib. A majority of patients remain on ibrutinib monotherapy with the median DOR not yet reached in the ongoing extension study. Disclosures: O'Brien: Pharmacyclics: Research Funding. Furman:Genentech: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Gilead: Consultancy. Fowler:Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Coutre:Pharmacyclics: Consultancy, Research Funding. Burger:Pharmacyclics: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Jones:Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wierda:Abbott Laboratories: Research Funding; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, DSMB, DSMB Other, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Merck: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Tragara: Research Funding. Flinn:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding; Janssen: Research Funding. Kolibaba:Pharmacyclics: Research Funding. Shaw:Pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. James:Pharmacyclics: Employment, Equity Ownership. Chu:Pharmacyclics: Employment, Equity Ownership. Byrd:Celgene: Consultancy; Johnson and Johnson: Consultancy; Pharmacyclics: Research Funding.

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Analysis of Pomalidomide Plus Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma with Vs without Moderate Renal Impairment

Blood ◽

10.1182/blood.v126.23.3031.3031 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3031-3031 ◽

Cited By ~ 3

Author(s):

David S Siegel ◽

Katja C. Weisel ◽

Meletios A. Dimopoulos ◽

Rachid Baz ◽

Paul G. Richardson ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Pooled Analysis ◽

Employment Equity ◽

Advisory Committees ◽

Safety And Efficacy ◽

Equity Ownership ◽

Support Research

Abstract Introduction: Renal impairment (RI) occurs in ≈ 20% to 40% of patients (pts) with multiple myeloma (MM; Kastritis et al, Haematologica, 2007) and is a major comorbidity with this disease (Korbet et al, J Am Soc Nephrol, 2006). Pts with MM who relapse on or become refractory to treatment (Tx) experience shortened overall survival (OS; Kumar et al, Leukemia, 2012). Pomalidomide + low-dose dexamethasone (POM + LoDEX) is approved for the Tx of relapsed/refractory MM (RRMM) in pts who have had Tx failure with lenalidomide and/or bortezomib. POM + LoDEX demonstrated safety and efficacy in pts with RRMM (MM-010; Dimopoulos et al, EHA 2015) as well as extended progression-free survival (PFS) and OS vs high-dose dexamethasone (MM-003; San Miguel et al, Lancet Oncol, 2013) or POM alone (MM-002; Richardson et al, Blood, 2014). Each trial included pts with moderate RI, and this pooled analysis examines the safety and efficacy of POM + LoDEX in pts with moderate RI. Patients and Methods: Pts from MM-002, MM-003, and MM-010 who had received POM + LoDEX were grouped by RI status (with moderate RI [creatinine clearance (CrCl) ≥ 30 to < 60 mL/min] and without RI [CrCl ≥ 60 mL/min]) and assessed for safety and efficacy. Results: Overall, from the 3 trials, data from 356 pts with moderate RI and 716 pts without RI were analyzed. Pts with moderate RI were slightly older (70 vs 63 yrs) and more commonly had International Staging System stage III disease (45.8% vs 25.4% in the 271 and 544 pts with available data). Median time from diagnosis was similar, 5.2 yrs (with moderate RI) vs 5.3 years (without RI); pts in both subgroups had a median of 5 prior Tx. The proportions of pts with moderate RI vs without RI who were refractory to LEN (95.5% vs 93.0%), BORT (82.0% vs 80.7%), and both LEN and BORT (78.4% vs 76.1%) were similar. The median Tx duration was slightly shorter for pts with moderate RI vs without RI (16.6 vs 20.4 weeks), but the median average daily dose (4.0 mg/day) and median relative dose intensity (0.9) were the same between renal subgroups. There were similar frequencies of discontinuations (7.4% vs 5.8%), dose reductions (22.7% vs 21.1%), and interruptions (63.1% vs 63.5%) due to adverse events (AEs) between subgroups of pts with moderate RI vs without RI. The most common grade 3/4 AEs for pts with moderate RI vs without RI were neutropenia (45.5% vs 48.3%), anemia (34.9% vs 27.5%), infections (31.3% vs 32.3%), and thrombocytopenia (21.3% vs 22.6%). The frequency of deep vein thrombosis/pulmonary embolism or peripheral neuropathy was ≤ 2% in both subgroups. The overall response rate (ORR) was 32.0% vs 33.0%, the median PFS was 18.1 weeks (95% CI, 15.6-20.9 weeks) vs 21.1 weeks (95% CI, 19.0-24.3 weeks), and median time to progression (TTP) was 20.3 weeks (95% CI, 17.3-24.1 weeks) vs 24.0 weeks (95% CI, 20.1-25.6 weeks) in pts with vs without moderate RI, respectively. Consistent with the poor prognosis associated with RI, median OS was shorter for pts with moderate RI (45.6 weeks [95% CI, 37.9-50.1 weeks]) vs those without RI (62.7 weeks [95% CI, 54.9-70.3 weeks]). Conclusions: In a pooled analysis of 3 trials of pts with RRMM treated with POM + LoDEX, ORR, PFS, TTP, and tolerability results appeared to be independent of the presence or absence of moderate RI. This analysis supports the use of POM + LoDEX as a standard of care in RRMM for pts with or without moderate RI. Disclosures Siegel: Celgene Corporation: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Merck: Speakers Bureau; Novartis: Speakers Bureau. Weisel:Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Noxxon: Consultancy; BMS: Consultancy, Honoraria, Other: Travel Support. Dimopoulos:Genesis: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria. Baz:Karyopharm: Research Funding; Millennium: Research Funding; Celgene Corporation: Research Funding; Sanofi: Research Funding. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Delforge:Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Moreau:Millennium: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yu:Celgene Corporation: Employment, Equity Ownership. Hong:Celgene Corporation: Employment, Equity Ownership. Sternas:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

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Safety and Efficacy of Dasatinib (DAS) Vs. Imatinib (IM) by Baseline Comorbidity In Patients with Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Analysis of the DASISION Trial.

Blood ◽

10.1182/blood.v116.21.3421.3421 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3421-3421 ◽

Cited By ~ 7

Author(s):

H. Jean Khoury ◽

Jorge E. Cortes ◽

Hagop Kantarjian ◽

Michele Baccarani ◽

Neil P. Shah ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Age Groups ◽

Initial Therapy ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Once Daily ◽

Safety And Efficacy ◽

Equity Ownership

Abstract Abstract 3421 Background: BCR-ABL kinase inhibitors DAS, nilotinib and IM have become the primary treatment modality for patients (pts) with CML-CP. Pre-treatment comorbid conditions have been proposed to help select a second-line BCR-ABL inhibitor for IM-resistant CML-CP. The DASISION trial is a large Phase 3 trial comparing DAS with IM as initial treatment in pts with newly diagnosed CML-CP and has demonstrated superior efficacy of DAS 100 mg once daily after a minimum follow-up of 12 months (Kantarjian, H, et al. N Engl J Med 2010;362:2260). This analysis assessed the impact of baseline comorbidities on safety and efficacy of these agents when used as initial therapy for CML-CP. Methods: 519 pts with newly diagnosed CML-CP were randomized to either DAS 100 mg once daily (n = 259) or IM 400 mg once daily (n = 260). Key exclusion criteria included serious uncontrolled medical disorders or active infections; uncontrolled or serious cardiovascular disease; prior or concurrent malignancy; inadequate hepatic or renal function; and ECOG performance status of ≥ 3. Pts were analyzed according to the number (0, ≥ 1 and ≥ 2) and type of baseline comorbidity (allergic, dermatologic, diabetes, endocrine-metabolic, gastrointestinal, hematologic-lymphatic, hepatobiliary, hyperlipidemia, musculoskeletal, renal and respiratory), and age (< 46, 46–65 and > 65 y). Complete cytogenetic response (CCyR), major molecular response (MMR) and drug-related adverse events (AEs) were analyzed across these groups. Cardiovascular comorbidities were analyzed separately and are not included here. Results: Across the 2 treatment arms, 74% of the pts had 31 baseline comorbidity and 47% had 32. The distribution of comorbidities including allergic (n = 61), dermatologic (n = 62), diabetes (n = 31), endocrine/metabolic (n = 98), gastrointestinal (n = 176), hematologic/lymphatic (n = 57), hepatobiliary (n = 56), hyperlipidemia (n = 41), musculoskeletal (n = 150), neoplasia (n = 17), renal (n = 33) and respiratory (n = 72) was balanced across the 2 arms. Proportions of pts across 3 Hasford risk groups were similar between pts with baseline comorbidity and those without. Safety profiles of DAS and IM in pts with and without baseline comorbidities were comparable (Table). Proportions of pts with at least 1 dose interruption or dose reduction were also similar with or without any comorbidity (Table). Pts with 32 comorbidities and pt grouped by comorbidity type including diabetes mellitus, hepatobiliary conditions and hyperlipidemia also had generally similar safety profiles. In both arms, the 12-mo rates of CCyR and MMR were similar (Table). In DAS-treated pts with diabetes (n = 18), hepatobiliary conditions (n = 32) and hyperlipidemia (n = 22), CCyR rates were 67, 78 and 96%, respectively; the respective MMR rates were 44, 56 and 59%. IM pts with diabetes (n = 13), hepatobiliary conditions (n = 24) and hyperlipidemia (n = 19) had CCyR rates of 69, 75 and 79%, respectively; and MMR rates of 15, 29 and 32%, respectively. In DAS-treated pts, CCyR rates were 88% for pts aged < 46 y (n = 128), 78% for those aged 46–65 y (n = 111) and 85% for those aged > 65 y (n = 20); the corresponding MMR rates were 45, 47 and 50%, respectively. The corresponding IM age groups (n = 111, 125 and 24, respectively) had CCyR rates of 70, 70 and 83%, respectively; and MMR rates of 26, 30, 29%, respectively. Safety profiles were generally similar across age groups in both treatment arms, except that fluid retention rates in pts aged < 46, 46–65 and > 65 y were 13, 25 and 35%, respectively, for DAS; and 34, 45 and 67%, respectively, for IM. Conclusions: The presence of baseline comorbidities appeared to have no effect on the safety and efficacy of either DAS or IM as initial therapy for CML-CP. Disclosures: Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Baccarani:Brostol-Myers Squibb and Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees. Bradley-Garelik:Bristol-Myers Squibb: Employment, Equity Ownership. Dejardin:Bristol-Myers Squibb: Employment, Equity Ownership. Hochhaus:Brostol-Myers Squibb, Novartis: Consultancy, Research Funding.

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