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 ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1885-1885 ◽  
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.

Update of An Open-Label Extension Study Evaluating the Long-Term Safety and Efficacy of Romiplostim in Thrombocytopenic Patients with Myelodysplastic Syndromes (MDS)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2772-2772 ◽  
Author(s):  
Pierre Fenaux ◽  
Hagop M. Kantarjian ◽  
Petra Muus ◽  
Roger M. Lyons ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
Research Funding ◽  
Bleeding Event ◽  
Response Duration ◽  
Extension Study ◽  
Platelet Response ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Extension ◽  
Equity Ownership

Abstract Abstract 2772 Background: Thrombocytopenia, found in 40–65% of MDS patients, is an independent risk factor for survival. Romiplostim increases platelet production, with 46% of MDS patients in a phase 1/2 study having a durable platelet response [Kantarjian JCO 2010, 28:437–444]. MDS patients who completed a romiplostim clinical study could enroll in this open-label extension study. Interim results are reported to provide an update on continued, long-term romiplostim treatment in MDS patients. Methods: MDS patients who completed a prior romiplostim study with platelets ≤50×109/L and no evidence of disease progression were eligible to enroll. Prior studies were as follows: (1) romiplostim only for up to 52 weeks [Kantarjian JCO 2010, 28:437–444], (2) romiplostim or placebo plus decitabine for ≥4 cycles [Greenberg ASH 2009], (3) romiplostim or placebo plus lenalidomide for ≥4 cycles [Lyons ASH 2009], or (4) 58-week placebo-controlled study. The primary endpoint was adverse event incidence; secondary endpoints were bleeding event incidence, platelet transfusions, and platelet response duration. Based on previous dosing, patients received romiplostim at 250, 500, 750, 1000, or 1500 mcg weekly or biweekly, adjusting for platelet counts. If no response was observed after 4 weeks at 1000 mcg/week, treatment was discontinued. Results: As of May 31, 2011, 72 patients had enrolled; previous treatments were romiplostim or placebo (60), romiplostim with decitabine (7), or with lenalidomide (5). Patients (56% male) had median age 71.0 (Q1-Q3: 65.0–76.5) years, median baseline platelet count of 27×109/L (Q1-Q3:14–42×109/L), MDS subtypes: RA (22 patients), RARS (1), RAEB-1 (6), RAEB-2 (1), RCMD (25), RCMD-RS (2), and MDS-U (15), and IPSS status at prior study baseline: low (22), int-1 (44), int-2 (4), and unknown (2). Median duration of MDS (until last contact or AML progression) was 3.1 years (Q1-Q3:1.7–5.2 years). Median treatment duration during this extension study was 28 weeks (range: 2–181 weeks); for those patients who received romiplostim in prior studies, there was additional exposure for a median of 52 weeks (range: 7–74 weeks). The median average weekly dose was 750 mcg (Q1-Q3: 669–923 mcg). Romiplostim was well tolerated; the most common adverse events were epistaxis (32%), cough (25%), and fatigue (24%). No neutralizing antibodies to romiplostim or thrombopoietin were detected. Five cases of AML progression occurred (Table). There were a total of 11 deaths, 4 on-study and 7 post-study. The on-study deaths included cardiac arrest and intestinal obstruction after 83 weeks, congestive heart failure after 17 weeks, progressive muscle dystrophy after 153 weeks, and pulmonary fibrosis in a patient with a history of chronic obstructive pulmonary disease and congestive heart failure after 35 weeks. This last death was considered to be related to romiplostim by the investigator. The post-study deaths included four due to AML, one due to respiratory causes, one due to cerebral hemorrhage, and one due to unknown causes. The annual rate of AML or death was 14.3% (95% CI: 8.1%-25.2%). Fifty-two (72.2%) patients reported ≥1 bleeding event(s); the incidence rate was 23.3/100 patient-weeks; 23 patients (32%) reported ≥1 clinically significant bleeding event(s). The proportion of patients with significant bleeding events decreased over time. Platelet transfusions occurred in 32 (44%) patients, with none after 48 weeks of romiplostim. From Week 3 onwards, the median platelet count was ≥50×109/L; 60 patients (83%) had a platelet response (per IWG 2006). The median time to first platelet response was 2.1 weeks (Q1-Q3: 1.1–3.7 weeks) and the median platelet response duration was 20 weeks (Q1-Q3: 6.5–72 weeks). Shortly after this data cutoff, all patients were discontinued from romiplostim treatment and moved into the long-term observation portion of the study. Conclusion: In this study, long-term treatment of MDS patients with romiplostim for up to 3.5 years (5 years with prior studies) was well tolerated and resulted in platelet responses in 83% of patients. Among patients in this extension study, AML progression occurred at expected rates. Disclosures: Fenaux: Merck: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Off Label Use: Use of romiplostim, which is indicated for ITP, will be discussed in patients with MDS. Kantarjian:Amgen: Research Funding. Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. Lyons:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Larson:Amgen: Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Becker:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jia:Amgen: Employment, Equity Ownership. Yang:Amgen: Employment, Equity Ownership.

Efficacy, Safety and Tolerability of E5501 (AKR501) In a 6-Month Extension Study In Subjects with Chronic Immune Thrombocytopenia (ITP).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3695-3695 ◽  
Author(s):  
James B. Bussel ◽  
Jenny Zhang ◽  
Shande Tang ◽  
Joe McIntosh ◽  
David J. Kuter
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Extension Study ◽  
Dose Titration ◽  
Platelet Response ◽  
Open Label ◽  
Advisory Committees ◽  
Once Daily ◽  
Grade 3

Abstract Abstract 3695 The thrombopoietin (TPO) receptor agonist E5501 (AKR501) is one of a new class of oral TPO agents which increase platelet production. In a recent multicenter, randomized, double-blind, placebo-controlled Phase II study (501-CL-003) in subjects with chronic ITP who were refractory to, or relapsed after, at least one prior ITP therapy, E5501 (once-daily for 28 days) was well tolerated and, at higher dose, was effective at increasing platelet counts. Here, 53 of 57 subjects who completed 28 days of study treatment (placebo, 2.5, 5, 10 or 20 mg E5501) in 501-CL-003 were treated with E5501 in a 6-month extension study, 501-CL-004. Subjects classified as responders in 501-CL-003 (i.e. those whose platelet count had risen by a minimum of 20 ×109/L above baseline to ≥50 ×109/L at Day 28) continued to receive their original E5501 blinded dose when they entered 501-CL-004. Subjects who were nonresponders in 501-CL-003 initially received open-label E5501 10 mg once-daily. E5501 dose was titrated upwards in an open-label fashion in 10 mg increments every 14 days depending on subject response (to a maximum of 40 mg once-daily for nonresponders and blinded dose plus 20 mg once-daily for responders). Additionally, concomitant medications were reduced according to subject response. Effectiveness analyses included only the 53 subjects in 501-CL-004. Safety analyses were performed on combined data from 501-CL-003 and 501-CL-004 (n=64). Subjects were regarded as responders in 501-CL-004 if their platelet count was ≥50 ×109/L and had risen by a minimum of 20 ×109/L above baseline (from 501-CL-003). Subjects had an overall platelet response if, in the absence of rescue medication, they were responders for 75% of the time over the last 14 weeks of the 24 week study (‘durable platelet response’) or were responders on any 4 consecutive weeks (‘transient platelet response’). E5501 showed effectiveness as measured by durable and overall platelet response. The durable platelet response rate was 52.8% for all subjects, 72% for subjects who were responders in 501-CL-003, and 35.7% for subjects who had been nonresponders. The overall platelet response rate was 75.5% for all subjects, 88% for responders, and almost two thirds (64.3%) for nonresponders. Following treatment with E5501, median platelet counts were maintained for the duration of treatment (Figure 1). E5501 also showed effectiveness as measured by a reduction or withdrawal of concomitant steroid medications. Among subjects using steroids, 54.2% decreased their use by >50%, including 33.3% who discontinued their use permanently. Twenty of 25 (80%) responders from 501-CL-003 maintained a platelet response throughout 501-CL-004 without requiring an upward dose titration. Twenty-one of 28 nonresponders required, but only 10 subjects received, an upward dose titration; of these, 7 (70%) achieved an overall response. E5501 was well tolerated, with a favorable safety profile. All 64 subjects (100%) experienced one or more treatment-emergent adverse events (TEAEs); most were mild, transient, and resolved completely. The most common TEAEs were fatigue (37.5%), headache (32.8%) and epistaxis (25%). TEAEs leading to study discontinuation were reported in 10/64 (15.6%) subjects. Serious TEAEs were reported in 12/64 (18.8%) subjects (Table 1). Of these, only 4 (6.3%) were considered by the investigators to be treatment-related. Forty-three of 64 subjects (67.2%) reported a bleeding event; 3 had a clinically significant grade 3 bleed (epistaxis, hemorrhagic diathesis or intracranial bleed) and 1 had a grade 4 GI bleed related to hemorrhagic gastritis. None were considered to be related to study drug. All other bleeding events were grades 1 or 2. Nine subjects met the criteria for recurrence of thrombocytopenia, defined as a platelet count that decreased to <10 ×109/L upon discontinuation of E5501. Four of these were deemed serious; all 4 recovered. Thromboembolic events were reported in 4 of 64 subjects (6.3%). One had a grade 3 deep vein thrombosis, 1 had a grade 3 stroke, and 1 had TIA and MI (Day 20) and a grade 4 retinal artery occlusion (14 days posttreatment). All 3 of these subjects had multiple risk factors for thrombosis. The fourth subject had grade 1 superficial thrombophlebitis. In conclusion, results from this 6-month extension study are supportive of the long-term efficacy and safety of E5501 in adults with difficult-to-manage, relapsed or refractory ITP. Disclosures: 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; 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; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy. Zhang:Eisai: Employment. Tang:Eisai: Employment. McIntosh:Eisai: Employment. Kuter:Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; ONO: Consultancy; Shionogi: Consultancy, Research Funding; Pfizer: Consultancy; Protalix: Consultancy, Research Funding; Risk Managment Foundation: Consultancy.

An Open-Label Extension Study Evaluating the Long-Term Safety and Efficacy of Romiplostim in Thrombocytopenic Patients (Pts) with Myelodysplastic Syndromes (MDS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2765-2765 ◽  
Author(s):  
Pierre Fenaux ◽  
Hagop Kantarjian ◽  
Roger Lyons ◽  
Richard A. Larson ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Research Funding ◽  
Extension Study ◽  
Platelet Response ◽  
Bleeding Events ◽  
Open Label ◽  
Employment Equity ◽  
Open Label Extension ◽  
Equity Ownership

Abstract Abstract 2765 Poster Board II-741 Background: Romiplostim is a peptibody protein that increases platelet production by binding to and activating the thrombopoietin receptor. Currently, platelet transfusion is the only supportive treatment for thrombocytopenia in MDS. In a phase 1/2 study of romiplostim in lower-risk thrombocytopenic MDS pts receiving supportive care only, about half achieved a platelet response (Sekeres et al., ASCO 2009, Kantarjian et al, JCO 2009, in press). We report results from an interim analysis of the subsequent ongoing open-label extension study evaluating the long-term safety and efficacy of romiplostim in MDS pts. Methods: MDS pts who, after completing the parent study, had platelets '50×109/L and no evidence of disease progression were eligible to enroll in this extension. The primary endpoint of this extension was adverse event (AE) incidence with long-term use of romiplostim; incidence of bleeding events was a secondary endpoint. Pts received romiplostim at a dose of 250, 500, 750, 1000, or 1500 μg weekly or every two weeks based on previous dosing, with subsequent adjustment between 250 and 1000 μg. If after 4 weeks at the increased dose there was an inadequate platelet response (using IWG 2006 criteria), the dose could be further escalated (with 4 weeks at each dose) up to a maximum of 1000 μg/week. If no response was observed after 4 weeks at 1000 μg/week, treatment was discontinued. Results: At the reference date of Feb 18, 2009, 28 pts had enrolled in this open-label extension study: 68% male, median age 71.5 y [interquartile range (Q1-Q3): 63.5-76.5 y], median baseline platelets 31×109/L (Q1-Q3: 20–41×109/L), 32% with platelets <20×109/L. During the parent study, 24 of the 28 pts had a platelet response. At the end of the parent study, there was a 4-week washout period. At initiation of the open-label extension study, IPSS status was low (13 pts), int-1 (12), int-2 (1), or missing (2), and MDS subtypes were RA (11 pts), RCMD (7), MDS-U (4), RAEB-1 (2), RCMD-RS (1), RARS (1), or missing (2). Ten pts (36%) had bleeding events in the previous year. Median duration of treatment in the extension study was 41 weeks (Q1-Q3: 23–58 weeks), with a median weekly dose of 748 μg (Q1-Q3: 493–821 μg). All 28 pts received μ8 weeks of romiplostim. Most AEs were mild-to-moderate; the most common being epistaxis (36%), arthralgia (29%), anemia (21%), and cough (21%). No neutralizing antibodies to romiplostim or TPO were observed. Nine pts withdrew from the study, 6 of these due to AEs. By investigator assessment, five of these AEs were related to romiplostim: 3 pts with increased blast cells, 1 pt with early-stage chronic myeloid leukemia (CML) diagnosed 519 days after romiplostim initiation, with bcr-abl first detected 1 year after romiplostim initiation (negative at baseline), and 1 pt with a history of chronic obstructive pulmonary disease and congestive heart failure who subsequently experienced the acute and rapid development of fatal pulmonary fibrosis after treatment with romiplostim. Two of these AEs were severe (pulmonary fibrosis and CML). For the increased blast cells, in cases 1 and 2, peripheral blasts were detected: in case 1 bone marrow (bm) blasts of 7% fell to <1% after drug discontinuation, while in case 2, bm blasts were 3% (no follow-up blast count). In both cases 1 and 2, peripheral blasts disappeared after drug discontinuation. In case 3, increase in blasts was reported by the investigator, with no peripheral blasts detected (follow-up bm biopsy was not evaluable). One AE leading to study withdrawal was not related to romiplostim (follicular B-cell lymphoma). As of the reference date, no progression to AML was reported. Eighteen pts (64%) reported ≥1 bleeding events, with 6 pts (21%) reporting ≥1 clinically significant bleeding events (i.e., CTCAE grade ≥3, serious AE, or any bleeding AE requiring intervention). Eight pts (29%) received platelet transfusions. From Study Week 4 on, the median platelet count was ≥50×109/L. Twenty-three pts (82%) had a platelet response (per IWG 2006 guidelines), including 6 of 9 pts with baseline platelet counts <20×109/L. The median platelet response lasted 30 weeks (Q1-Q3: 16–52 weeks). Over half of pts (54%) demonstrated an initial platelet response by Study Week 3. Conclusion: In this long-term, follow-up, open-label extension study in thrombocytopenic MDS pts, romiplostim demonstrated an acceptable toxicity profile, with the majority of pts achieving a durable platelet response. Disclosures: Fenaux: Cephalon: Research Funding; Amgen Inc.: Research Funding; Merck: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Off Label Use: Nplate (romiplostim) is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Kantarjian:Amgen Inc.: Research Funding. Lyons:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy; Johnson&Johnson: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau. Larson:Amgen Inc.: Equity Ownership, Research Funding. Sekeres:Celgene: Honoraria, Research Funding, Speakers Bureau. Becker:Amgen Inc.: Research Funding, Speakers Bureau. Muus:Amgen Inc.: Speakers Bureau. Hu:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership.

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

Blood ◽  
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

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

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

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

Major Bleeding Complications Among Patients Treated with Ibrutinib and Concomitant Antiplatelet, Anticoagulant, or Supplemental Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4387-4387 ◽  
Author(s):  
Aaron Pavlik ◽  
Hallie Barr ◽  
Emily Dotson ◽  
John C. Byrd ◽  
Kristie A. Blum ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Major Bleeding ◽  
Research Funding ◽  
Bleeding Event ◽  
Antiplatelet Agents ◽  
Bleeding Complications ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Major Bleeding Events

Abstract Background: Ibrutinib, an orally bioavailable small molecular inhibitor of Bruton's tyrosine kinase (BTK), is an approved therapy for chronic lymphocytic leukemia (CLL), relapsed mantle cell lymphoma (MCL) and Waldenstrӧm's macroglobulinemia (WM). Beyond B lymphocytes, BTK signaling is important for collagen-mediated platelet activation, and BTK inhibition has been associated with primary hemostatic bleeding events (Levade et al Blood 2014). Although serious bleeding events have been uncommon (1-5%) in clinical trial populations, there is limited data describing the potential for increased serious bleeding incidence when ibrutinib is co-administered with other agents affecting the clotting cascade or platelet function. Methods: We conducted a retrospective cohort study to evaluate the incidence of major bleeding in patients receiving ibrutinib concomitantly with antiplatelet agents (non-steroidal anti-inflammatory agents, ADP inhibitors), anticoagulants (heparins, warfarin, novel oral anticoagulants), or supplements with potential anticoagulant activity (vitamin E and fish oil). Major bleeding events were identified using criteria developed by the International Society on Thrombosis and Haemostasis (Schulman et al J Thromb Haemost 2005). Patients 18-89 years of age and treated with ibrutinib for CLL, MCL, or WM between March 1, 2010 and March 1, 2015 were included. The primary endpoint of this study was the incidence of major bleeding events, but we also sought to identify risk factors associated with the development of major bleeding, focusing on potential drug interactions. Based on the historic prevalence of major bleeding in ibrutinib clinical studies, we calculated that at least 20 major bleeding events would need to be identified in order to perform blinded multinomial regression on the collected data of an estimated 400 patients. Results: 437 eligible patients were included in the analysis. Patients were overwhelmingly male (71.4%) and white (94.8%), with a mean age of 67.1 years (range: 29-89). 53.1% received ibrutinib as participants of a clinical trial, and the remainder received standard-of-care ibrutinib treatment. The table (upper panel) summarizes use of concomitant antihemostatic agents by presence or absence of major bleeding events. Characteristics of the major bleeding events are further detailed in the lower panel. The most commonly observed concomitant antihemostatic medication was aspirin, with 147 patients (33.6%) being exposed to aspirin within the study period. Fourteen instances of major bleeding were observed, corresponding to an overall incidence of 3.2%. These major bleeding events all occurred in CLL patients receiving ibrutinib at the standard dose of 420 mg daily. Two patients had platelet counts less than 50 k/µL at time of the bleeding event. One-half of the major bleeding events were observed in the absence of an antihemostatic medication, and 2 of the observed major bleeding events resulted in death (1 received concomitant warfarin). Fourteen patients (3.3%) in the group without major bleeding were on anticoagulation, 4 being warfarin. The most common sites of major bleeding were gastrointestinal (50%), intracranial (14.3%) and thoracic (14.3%). While most patients developing major bleeding permanently discontinued ibrutinib (57.1%), approximately one third of the patients who developed major bleeding subsequently resumed ibrutinib following resolution of the bleeding event. Subsequently, these patients did not experience a recurrent major bleeding event. The rate of major bleeding did not meet power to detect statistical differences in bleeding events when comparing concomitant therapy, Conclusions: Our observed incidence of major bleeding is consistent with previous controlled clinical trials, suggesting similar safety profile when ibrutinib is used outside of a controlled setting. Major bleeding events were uncommon despite the frequent co-administration of antiplatelet agents. However, because we modified practice early to avoid therapeutic anticoagulation during ibrutinib therapy whenever possible, the number of patients receiving such drugs in combination was small and precludes inferences regarding safety. Table Table. Disclosures Blum: Pharmacyclics: Research Funding. Awan:Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Woyach:Acerta: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding. Christian:Pharmacyclics: Research Funding; Janssen: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Safety and Efficacy of Romiplostim in over 200 Children with Immune Thrombocytopenia (ITP): Results of an Integrated Database of 5 Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2428-2428 ◽  
Author(s):  
Michael D. Tarantino ◽  
Jenny M. Despotovic ◽  
John Roy ◽  
John Grainger ◽  
Nichola Cooper ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Open Label ◽  
Advisory Committees ◽  
Baseline Platelet Count ◽  
Platelet Counts

Abstract Background: Romiplostim is approved globally for use in adults with ITP and in the EU for children with ITP. More comprehensive data are needed on the use of romiplostim in children with ITP. Objective: To examine the safety and efficacy of romiplostim in trials in children with ITP. Methods: Data were combined from 5 romiplostim trials in children with ITP, both placebo-controlled (a phase 1/2 and a phase 3 trial) and open-label (a 3-year trial and 2 extension trials); trial data have been reported previously (Bussel Blood 2011, Bussel PBC 2014, Tarantino Lancet 2016, Tarantino ASH 2017, Grainger ASH 2017). Platelet counts in the 4 weeks after use of rescue medication were excluded from analyses. Descriptive statistics were used. Number (n), mean, standard deviation (SD), median, quartile range (Q1, Q3), minimum (min), and maximum (max) for continuous variables, and number and percentage for categorical variables were provided. Results: Patients (N=286, 24 initially placebo and 262 initially romiplostim) had median (Q1, Q3) age of 10 (6, 13) years, ITP duration of 1.9 (1, 4) years, and baseline platelet count of 14 (8, 23)×109/L. Previously, 88% had received corticosteroids, 87% IVIg, and 21% rituximab; 23% had received >3 prior treatments and 7% had prior splenectomy. Of the 282 patients exposed to romiplostim (20 initially received placebo), the median (min, max) duration of treatment was 65 (8, 471) weeks, with a median (min, max) average weekly dose of 6.6 (0.1, 9.7) μg/kg; total exposure was 468 patient-years. The most common reasons for discontinuing the parent study for romiplostim-treated patients were per protocol (19%; eg, sponsor decision, death, lost to follow-up), consent withdrawn (3%), noncompliance (1%), and administrative decision (1%). Of romiplostim-treated patients, 24% had serious adverse events (SAEs), most commonly epistaxis, low platelet counts, and headache (Table). There were 7 cases of postbaseline neutralizing antibody against romiplostim: 2 transient and 5 persistent. There were no neutralizing antibodies against endogenous TPO. For patients undergoing bone marrow biopsies in the 3-year open-label trial, there were no findings of collagen or bone marrow abnormalities (Year 1 n=27, Year 2 n=5, vs. baseline) (Grainger et al, ASH 2017). One patient had an increase in modified Bauermeister bone marrow grade from 0 to 2 (fine reticulin fiber network) with no associated AEs (the only AEs were a cold and injection site pain); per protocol, there was no follow-up biopsy. Once at a steady dose of 10 μg/kg, most (11/16) of this patient's platelet counts were ≥30×109/L. Investigators reported thrombocytosis AEs; 1 patient had a platelet count of 1462×109/L at Week 14 for 1 week and another had elevated platelet counts 10 times between Weeks 20-172 (max of 872×109/L); there were no associated thrombotic events. Median platelet counts rose quickly and were over 50×109/L from Week 12 on (Figure). Platelet response rates also rose quickly. Overall, 89% of romiplostim-treated patients (vs 8% of placebo) had a platelet response (platelet counts ≥50×109/L; Figure). For romiplostim-treated patients, the first platelet responses occurred after a median of 6 weeks. The median % (Q1, Q3) of months responding was 76% (25%, 93%) and # of months responding was 11 (3, 20); from time of first monthly response, the median (Q1, Q3) % of months responding was 92% (75%, 100%) and # of months responding was 14 (7, 23). Nineteen romiplostim-treated patients discontinued all ITP therapies including romiplostim for ≥6 months while maintaining platelet counts ≥50×109/L (here defined as remission). These treatment-free periods lasted a median (Q1, Q3) of 12 (8, 14) months; no placebo patients remained free of treatment. There were no clear differences between those who did and did not enter remission (ie, age, sex, race, past treatment, ITP duration, baseline platelet count). Bleeding was reported for most (68%) patients: mostly grade 1/2, with 10% having grade 3 bleeding (most commonly epistaxis in 13 patients) and 2 patients having grade 4 bleeding (both reported as "ITP"). Conclusions: In this comprehensive database of romiplostim ITP trials in 286 children with 468 patient-years of romiplostim exposure, romiplostim was well tolerated. With romiplostim, the vast majority (89%) of patients had a platelet response, with some children able to discontinue all ITP treatments for ≥6 months. Disclosures Tarantino: Health Resources and Services Administration: Research Funding; Centers for Disease Control and Prevention: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Other: Reviews grants; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Grifols: Research Funding, Speakers Bureau. Despotovic:AmGen: Research Funding; Sanofi: Consultancy; Novartis: Research Funding. Grainger:Biotest: Consultancy; Ono Pharmaceuticals: Consultancy; Amgen: Consultancy, Honoraria, Other: Educational grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cooper:Amgen, Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.

Long-Term Use of Open-Label Romiplostim in Children with Chronic/Refractory Immune Thrombocytopenia (ITP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 621-621
Author(s):  
James B Bussel ◽  
George R. Buchanan ◽  
David J. Gnarra ◽  
Richard H. Ho ◽  
Kun Nie ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Pediatric Patients ◽  
Extension Study ◽  
Open Label ◽  
Advisory Committees ◽  
Bone Marrow Biopsies ◽  
Platelet Counts ◽  
Open Label Extension

Abstract Abstract 621 Background: Treatment options for children with chronic/refractory ITP are not well characterized. In a phase 1/2 16-week randomized double-blind placebo-controlled study of 22 patients (romiplostim n = 17, placebo n = 5), the thrombopoietin (TPO) receptor agonist romiplostim was well tolerated and 15 of 17 romiplostim-treated patients achieved platelet counts ≥50×109/L (Bussel et al, Blood 2011). Twenty-one of 22 patients from this phase 1/2 study subsequently entered an open-label extension study; 1/21 patients discontinued the extension study before receiving romiplostim. For the 20 patients who received romiplostim in the first extension study, the mean duration of treatment was 1.6 years (range, 0.1 to 2.1 years); all 20 achieved platelet counts >50×109/L (Nugent et al, 2011 ASPHO abstracts). Of the 17 patients who completed this extension study, 12 rolled over into a second open-label extension study for up to 2.5 years of further romiplostim treatment. Results from those 12 patients are described here. Objective: To investigate the safety and efficacy of long-term use of romiplostim in pediatric ITP. Methods: During the second extension study, patients received weekly subcutaneous injections of romiplostim with the initial dose being the same as the last dose in the prior study. Dose adjustment was allowed to maintain platelet counts in the target range of 50–200×109/L. The maximum allowed romiplostim dose was 10 μg/kg. The primary endpoint of this study was incidence of adverse events; platelet response was a secondary endpoint. The protocol did not require bone marrow biopsies to be conducted at pre-defined intervals, but any bone marrow biopsies performed as clinically indicated were to be analyzed. As deemed appropriate by investigators, patients or their caregivers had the option to administer romiplostim at home during this study; those patients who administered romiplostim at home used diary cards to record dosing date, time, volume administered, and any dosing errors. Patients who turned 18 years of age during this study were permitted to remain on study. Results: Baseline demographics for this second extension study included a median age of 12 years (range 3, 16 years), 67% male, and 33% with a prior splenectomy. Median romiplostim treatment duration in this second extension study was 118.9 weeks (range 100.1, 125.9 weeks); median average weekly romiplostim dose was 5.2 μg/kg (range 1, 10 μg/kg). Of the 3 patients who discontinued the study, 2 withdrew consent and 1 was noncompliant; no patients withdrew due to safety issues and 9 continued on study. Median platelet counts for all 12 patients were above 50×109/L throughout, and were in the target range of 50–200×109/L for all visits but Weeks 3 and 76 (Figure). Interestingly, the median dose decreased over time from a median (Q1, Q3) of 8.0 (5.5, 9.0) μg/kg at Week 1 to 1.0 (0.0, 6.0) μg/kg at Week 116 (last timepoint for which data are available) (Figure). Two patients received rescue medications (defined as medications used for platelet counts <10×109/L, bleeding/wet purpura, or investigator decision); one patient received platelet transfusions and another prednisone. Four patients (33.3%) had serious adverse events (asthma, epistaxis, hemangioma, hypotension, pyrexia, thrombocytopenia, and transfusion reaction) and one had a life-threatening adverse event (thrombocytopenia). None of the adverse events were deemed treatment-related by the investigators. There were no fatal adverse events. Eight patients had bleeding adverse events; one of which (gingival bleeding) was deemed treatment-related. These bleeding adverse events included epistaxis (4 patients), petechiae (3 patients), gingival bleeding (2 patients), and (in 1 patient each) bleeding from the anus, injection site, lip, and mouth; 1 patient also had unspecified bleeding. No bone marrow biopsies were reported to have been performed. Conclusion: In this open-label extension study, romiplostim increased platelet counts in pediatric patients with chronic ITP without significant toxicity. Thus, romiplostim has been well tolerated and shown to be of clinical benefit to pediatric patients with refractory severe chronic ITP. As this study is ongoing, future results will provide additional data regarding even longer-term use of TPO receptor agonists in this patient population. Disclosures: Bussel: Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, 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: 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; Portola: Consultancy; Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: The use of romiplostim in pediatric patients was examined in this study. Nie:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.

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 ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4163-4163 ◽  
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.

scholarly journals Trial in Progress: The Phase III, Randomized, Open-Label, Multicenter COMMODORE 2 Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Adult and Adolescent Patients with Paroxysmal Nocturnal Hemoglobinuria Not Previously Treated with Complement Inhibitors

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Austin Kulasekararaj ◽  
Guangsheng He ◽  
Talha Munir ◽  
Jeffrey Pu ◽  
Antonio Risitano ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Medical Writing ◽  
Third Party ◽  
Phase Iii ◽  
Publicly Traded ◽  
Open Label ◽  
Advisory Committees ◽  
Complement Inhibitors ◽  
Previously Treated

Background Crovalimab is a novel anti-human complement component 5 (C5) antibody engineered to significantly extend half-life and enable subcutaneous (SC) administration once every 4 weeks in C5-mediated diseases. Based on the promising results of the Phase I/II COMPOSER trial (NCT03157635; Röth et al. Blood. 2020), crovalimab is currently under investigation as a potential therapy for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disorder characterized by hemolytic anemia and thrombosis. Eculizumab and ravulizumab are C5 inhibitors currently approved for the treatment of patients with PNH, yet treatment limitations include breakthrough hemolysis due to unsustained C5 inhibition, lack of efficacy in patients with C5 mutational variants, and the treatment burden of regular intravenous (IV) infusions. Study Design and Methods The Phase III, randomized, open-label, active-controlled, multicenter COMMODORE 2 study (NCT04434092) is evaluating the efficacy and safety of crovalimab compared with eculizumab in patients aged ≥ 12 years with PNH not previously treated with complement inhibitors. Patients are randomized 2:1 to receive crovalimab or eculizumab (Figure 1). Two hundred patients in the crovalimab arm will receive a loading series of crovalimab (IV dose on Day 1, followed by weekly SC doses for 4 weeks starting on Day 2). This is followed by SC maintenance dosing every 4 weeks starting at Week 5. Patients in the eculizumab arm receive a weekly IV loading dose of eculizumab for the first 4 weeks, followed by IV maintenance dosing starting at Week 5 and then once every 2 weeks for 24 weeks. After 24 weeks of treatment, patients can continue crovalimab or switch from eculizumab to crovalimab if their physician determines this is in their best interest. The primary efficacy objective of COMMODORE 2 is to evaluate the noninferiority of crovalimab compared with eculizumab based on the co-primary endpoints of (1) the proportion of patients who achieve transfusion avoidance and (2) the proportion of patients with hemolysis control. Secondary efficacy objectives are to evaluate the noninferiority of crovalimab compared with eculizumab in regard to the (1) proportion of patients who experience breakthrough hemolysis, (2) proportion of patients who achieve stabilization of hemoglobin, and (3) mean change in fatigue, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. The safety objective is to evaluate the safety and tolerability of crovalimab compared with eculizumab based on the incidence and severity of adverse events, including infections (meningococcal meningitis and other infections), injection-site reactions, infusion-related reactions, hypersensitivity, and adverse events leading to study drug discontinuation. Pharmacokinetic, immunogenicity, biomarker, and health status utility objectives will also be assessed. Disclosures Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. He:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; LongBio Pharma: Consultancy, Research Funding. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Pu:SUNY Upstate Medical University: Current Employment; Pennsylvania State University: Patents & Royalties; F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; RA pharma: Research Funding. Röth:Roche: Consultancy, Honoraria, Research Funding; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria. Sima:F. Hoffmann-La Roche Ltd/Genentech: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Appius:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sreckovic:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Vignal:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

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