Randomized Double-Blind Study of Increasing Doses of Eltrombopag in Patients with Chronic ITP

Abstract Background: Eltrombopag (Epag) is an oral thrombopoietin receptor agonist used to increase platelet counts in patients with chronic immune thrombocytopenia (cITP). The maximum licensed Epag dose in cITP patients is 75 mg daily, yet some patients do not respond at this dose. Healthy individuals on escalated doses of eltrombopag (100-200 mg) demonstrated a dose dependent platelet response as did patients with thrombocytopenia secondary to chemotherapy. Doses of 100 mg and 150 mg have been approved for use in patients with hepatitis-C induced thrombocytopenia and aplastic anemia respectively. This is the final report of a double-blind, randomized controlled study to determine if Epag, administered at doses up to 150 mg daily, increases platelet counts in cITP patients who failed to respond to 75 mg. Methods: cITP patients³ 1 year old with platelet counts <50,000uL despite >3 weeks of 75mg of Epag daily), stratified by splenectomy status, were enrolled. Patients could continue stable doses of concomitant ITP medications. In the randomized blinded phase (Part 1), patients first received 75 mg daily of active Epag and 25 mg of study drug (Epag or placebo, 2:1). Every two weeks, study drug doses were increased in 25 mg increments to a maximum daily dose of 150 mg. After 8 weeks subjects were unblinded. If on active drug, they entered the open label phase (Part 2); if on placebo, they received open label Epag as per the study protocol escalating to a maximum dose of 150 mg. Two patients entered part 2 before 8 weeks because their counts were >100,000/uL in the blinded phase. Data analysis was descriptive. Mann Whitney U test estimated p-values (α<.05) or platelet count differences between groups. Imputation of platelet counts allowed omitting falsely high or low platelet counts resulting from rescue therapy (e.g. IVIG), or counts in3 patients discontinuing early with good responses after 2, 2, and 4 weeks who thereby did not have counts at weeks 4, 6, and 8. Interim analysis was pre-specified and data is included on 33 of the planned total of 36 patients. Results: As of July 31, 35 patients consented; 26 completed ³8 weeks on study medication. Two patients are in part 1 and 7 dis-enrolled before completing 8 weeks of study drug: 5 failed screening and never received medication; one had bleeding and low counts on placebo; and one had pre-existing reticulin fibrosis 2-3+, discovered after study drug was dispensed but not administered. The most common adverse event (AE) was minor bleeding. Two adults and 2 children developed transaminitis, which was life-threatening in 1 adult on 100mg. The 4 liver AEs occurred between 2 and 20 weeks of Epag dosing with 3/4 subjects on 150 mg daily; 2/4 discontinued Epag. No strokes or thromboembolic events were seen nor did any cataracts develop. Three patients underwent bone marrows: no grade 2-3 fibrosis was seen. Platelet counts for patients on active drug vs placebo separated by week 2 (Figure 1A) and the difference steadily increased until week 8 (p<0.07) reflecting the thrombopoietic effects of increased dose Epag. Increased eltrombopag doses had greater effect in children (avg age 13) than adults (avg age 51) [Figure 1B]. This may reflect more rapid drug metabolism or relative insensitivity to the effects of Epag in children or both; this was first noted in PETIT and PETIT2. Twenty-six patients entered the long-term open-label study. Three discontinued prior to 24 weeks because of transaminase elevation (1) and no response (2); 7 are not yet at 24 weeks; and 6 were also on other treatments, ie IVIG at increased intervals while on Epag, obscuring their responses. Ten patients were on open label medication for >24 weeks past the 8 weeks in part 1 up to 110 weeks. 72% of the long-term counts in these 10 patients were > 50,000/uL while 40% were > 100,000/uL. Six patients took 150 mg daily for >24 weeks while 4 reduced their doses, though not to <75mg daily. Conclusions: The results demonstrate that Eltrombopag at doses of 100-150mg daily can elevate platelet levels in most children and adults with cITP whose platelet counts were <50,000 on 75mg of Epag daily for >3 weeks. Children responded better to increased doses of Epag than did adults and high dose Epag can be used long term without development of cataracts, strokes or other thromboembolic events although an increased frequency of liver events, 12%, occurred. Although the 150 mg dose can be safely continued for many months, monitoring transaminases is essential. Disclosures Off Label Use: Increased doses of eltrombopag. McGuinn:Baxter: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bussel:Momenta: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; BiologicTx: Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees; 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; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Immunomedics: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Safety and Efficacy Of Eltrombopag At Escalated Doses Up To 150mg In Patients With Persistent and Chronic Immune Thrombocytopenia (ITP) Not Responsive To 75 Mg

Blood ◽

10.1182/blood.v122.21.3559.3559 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3559-3559

Author(s):

Catherine E. McGuinn ◽

Allison Imahiyerobo ◽

Micha Thompson ◽

Naznin Haq ◽

Claudia Tchatchouang ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Rescue Therapy ◽

Study Drug ◽

Controlled Study ◽

Open Label ◽

Advisory Committees ◽

Double Blind ◽

Platelet Counts ◽

Equity Ownership

Abstract Background Eltrombopag is an oral thrombopoietin receptor agonist which increases platelet counts in immune thrombocytopenia (ITP) patients by increasing proliferation of megakaryocyte (Mk) precursors and Mk. Maximal approved eltrombopag dosage in chronic ITP patients is 75mg daily, yet some patients do not respond at this dose. In a prior 6-week study, a numerically higher proportion of patients responded at 75mg vs. 50mg. Data of the pharmacokinetics, safety and tolerability of eltrombopag in healthy volunteers at an escalated dosage (100-200mg) showed a dose dependent platelet response. Doses > 75mg have been used in other settings without additional toxicity, including Aplastic Anemia and Chronic Hepatitis C associated thrombocytopenia. Taken in conjunction, a higher eltrombopag dose may be effective in treating ITP in non-responders without increased toxicity. The following double blind, randomized controlled study is in progress to determine if eltrombopag administered at up to 150mg daily increases platelet counts and lessens bleeding symptoms in ITP patients who failed to respond to 75 mg. Methods Non-responders (patients ≥ 12 years old with platelet counts<50,000 μL despite 3 weeks of 75mg of eltrombopag daily), stratified by splenectomy status, were enrolled into a double blind randomized controlled study. Patients were allowed to continue stable doses of concomitant medications at randomization. In Part 1 (blinded phase), all patients received 75 mg of eltrombopag with the addition of 25 mg of study drug (eltrombopag or placebo). Every two weeks, doses were increased in 25 mg increments to a maximum daily dose of 150mg. After 8 weeks subjects were unblinded. If on active drug, they can enter the open label (Part 2) phase; or if previously on placebo, subjects may receive open label eltrombopag as per the study protocol to a maximal daily dose of 150mg. Subjects are considered complete responders (CR) with 2 consecutive platelet counts >50,000 μL AND an overall increase from baseline >20,000 μL not attributable to rescue therapy in the 8 weeks from initiating dose escalation. Subjects are considered partial responders (PR) if they have 2 consecutive platelet counts of >50,000 μL OR an overall increase from baseline >20,000 μL not attributable to rescue therapy by 8 weeks (figure). Monitoring includes baseline cataract exams with additional eye exams at 6 and 18 months, bleeding evaluations every 2 weeks (Part 1) and bone marrow biopsy after 1 year (Part 2). Results 13 patients (2 adolescents and 11 adults) have been enrolled in the study. Of the 5 adult patients who completed ≥ 8 weeks on active medication, 3 achieved either CR (1) or PR (2). The 2 PRs had an increase from baseline to highest count ranging from 23-47,000 μL. 2/3 responders achieved higher platelet counts in the open label extension phase suggesting a longer term slow onset effect of eltrombopag. One PR decreased her daily prednisone dose from 30 mg to 10 mg, with platelet count fluctuations attributed to dietary guideline non-adherence. As of August 8, 6 patients are in Part 1, 4 patients are in Part 2, and 3 have been removed from the study (one patient had elevated transaminases in Part 2, week 12; one patient had pre-existing reticulin fibrosis 2-3+ without clinical symptoms. This pre-study bone marrow result was not available at randomization, but the patient was withdrawn prior to any study drug administration. She had previously received treatment with two other TPO agents; the third patient withdrew secondary to increased bleeding symptoms while on the placebo arm). Other adverse events related to eltrombopag have been mild or moderate. Rescue therapies include intravenous immunoglobulin (IVIG) and prednisone. Most patients have had pre-treatment or recent bone marrows biopsies with a follow up biopsy planned after one year of treatment at 150mg. Conclusions To date, the results demonstrate moderate responses to eltrombopag at increased doses to 150mg daily in the 3 responding patients who have been treated the longest. One subject achieved a CR and two a PR. Three subjects were removed for toxicity but in one it was for marrow findings that antedated study enrollment and another for bleeding while receiving placebo therapy. Interim analysis will be performed after 20 enrolled patients and younger patients might enter the study following completion of ongoing eltrombopag studies in pediatric patients with chronic ITP. Disclosures: Bussel: 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: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, 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.

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Hepatobiliary and Thromboembolic Events during Long-Term E.X.T.E.N.Ded Treatment with Eltrombopag in Adult Patients with Chronic Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v128.22.1368.1368 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1368-1368

Author(s):

Mansoor N. Saleh ◽

James B Bussel ◽

Raymond SM Wong ◽

Balkis Meddeb ◽

Abdulgabar Salama ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Adult Patients ◽

Phase Iii ◽

First Year ◽

Thromboembolic Events ◽

Advisory Committees ◽

Platelet Counts

Abstract Introduction: ITP, characterized by a reduction in platelets leading to thrombocytopenia, which persists for >12 months is considered chronic (cITP). Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of patients with cITP aged ≥1 year refractory to other treatments (eg corticosteroids, immunoglobulins). The recently completed Phase III EXTEND (Eltrombopag eXTENded Dosing) study was a global, open-label, extension study of patients with cITP, who received eltrombopag or placebo in prior eltrombopag clinical studies. The primary objective of EXTEND was to describe the long-term safety and tolerability of eltrombopag treatment in these patients. Here, we examine the occurrence of hepatobiliary and thromboembolic events (TEEs) as adverse events (AEs) of special interest in this study. Methods :Adult patients (≥18 years old) diagnosed with cITP according to ASH/BCSH guidelines were enrolled and received eltrombopag starting at 50 mg/day. Dose was titrated to 25-75 mg per day or less often as required, based on individual platelet count responses (targeted range ≥50-200x109/L). Patients who received 2 years of treatment and transitioned off eltrombopag due to commercial availability of eltrombopag were considered to have completed the study, whether or not they continued treatment with eltrombopag. The primary endpoint included detection and documentation of investigator-reported AEs, which included hepatobiliary AEs and TEEs. Analyses were conducted using the safety population, defined as all subjects who entered the study and had taken at least one dose of the study medication. Results:302 patients were enrolled and received at least one dose of eltrombopag: 67% were female; 38% splenectomized; 49% aged 18-49 years. Median duration of exposure was 2.4 years (range, 2 days to 8.8 years) and mean average daily dose was 50.2 (range, 1-75) mg/day. Overall, 259/302 (86%) achieved platelet counts of ≥50×109/L at least once during the study and 126/248 (51%) patients maintained continuous platelet counts ≥50×109/L for at least 31 weeks. Incidence of bleeding symptoms (WHO grades 1-4) generally decreased over time in patients with available data, from 57% (n=171/302) at baseline to 16% at 1 year (n=13/80), and 21% (12/58) at 2 years. 45 (15%) patients experienced at least one hepatobiliary AE, with the highest incidence within the first year of treatment (Figure A). AEs of increased ALT or AST led to the discontinuation of five and three patients, respectively and four patients discontinued due to an AE of increased blood bilirubin. Nine patients experienced ALT and/or AST >3 x upper limit of normal (ULN) and total bilirubin >1.5xULN. 19 (6.3%) patients experienced a total of 23 TEEs. Most events occurred in the first year (Figure B), and none after year 4. TEEs included deep vein thrombosis (n=6), cerebral infarction (stroke) [n=3], myocardial infarction (n=4), transient ischemic attack (n=2), others (n=8, 1 occurrence of each). A clear association with elevated platelet counts was not observed. Platelets >200x109/L at the time of the TEE were recorded in 8/19 patients; 6/19 experienced the TEE at or shortly after achieving their maximum platelet count. In total, 10 patients discontinued because of TEEs. Conclusions: Long-term treatment with eltrombopag in patients with cITP led to sustained platelet increases and reduced bleeding symptoms. The highest incidences of hepatobiliary AEs and TEEs occurred during the first year of treatment, though several events were recorded after 3 years of therapy. Long-term eltrombopag therapy was well-tolerated with a positive benefit-risk relationship in adults with cITP, with decreasing events after the first year of treatment. Disclosures Saleh: GSK: Consultancy, Research Funding, Speakers Bureau. Bussel:Amgen, Novartis & GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingleheim, Prophylix Pharma, Protalex, Rigel Pharmaceuticals: Research Funding; Momenta Pharmaceuticals, Novartis, Prophylix Pharma, Protalex, Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; UptoDate: Patents & Royalties; Physicians Education Resource: Speakers Bureau. Wong:Bayer, Biogen-Idec and Novartis: Consultancy; Bayer, Biogen-Idec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, and Roche: Research Funding; Biogen-Idec and Novartis: Membership on an entity's Board of Directors or advisory committees. El-Ali:Novartis: Employment. Quebe-Fehling:Novartis: Employment.

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Safety and Efficacy Of Long-Term Open-Label Romiplostim Dosing In Thrombocytopenic Pediatric Patients With Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v122.21.3530.3530 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3530-3530

Author(s):

Michael D. Tarantino ◽

James B. Bussel ◽

Amy Geddis ◽

Michael F. Guerrera ◽

Alan K. Ikeda ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Open Label ◽

Advisory Committees ◽

Safety And Efficacy ◽

Platelet Counts ◽

Equity Ownership

Abstract Background Chronic pediatric ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production, resulting in low platelet counts. Romiplostim is a peptibody that stimulates platelet production via activation of the thrombopoietin (TPO) receptor. Romiplostim increased and maintained platelet counts in thrombocytopenic children with ITP in a phase 1/2 trial. Patients who completed this study or an ongoing phase 3 trial were given the option of rolling over into an open-label long-term extension study. Objectives To evaluate the safety and efficacy of long-term use of romiplostim in pediatric ITP. Methods Patients received weekly subcutaneous injections of romiplostim; the starting dose was the last dose in the prior study. Patients who had received placebo started at 1 μg/kg. Dose adjustments targeted platelet counts in the range of 50–200 x 109/L. The maximum allowed romiplostim dose was 10 µg/kg. Assessments of adverse events, concomitant medications, and local platelet counts were performed weekly. The primary endpoint was incidence of adverse events. The protocol did not require bone marrow biopsies to be performed, but when performed, specimens were submitted to a central lab for analysis. Patients who were on a stable dose had the option to receive romiplostim at home; patients and their caregivers then recorded 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 Twenty-two patients (N = 12 from the phase 1/2 study and N = 10 from the phase 3 study) were treated with romiplostim for up to 172 weeks (3.3 years). Baseline demographics included a median age of 12.0 years (range 3–16), 50% male, and 18.2% with prior splenectomy. Median romiplostim treatment duration was 89.0 weeks (range 3–172); median total number of doses was 64 (range 3–171); median average weekly romiplostim dose was 4.0 µg/kg (range 1–10), including ramp up to stable dose; and median maximum dose was 8.0 µg/kg (range 1–10). Of the 4 patients who discontinued the study, 3 withdrew consent and 1 was noncompliant; no patients withdrew due to safety issues and 18 continued on study. After the first week of this extension study, which for some patients was the first week of romiplostim, median platelet counts remained above 50 x 109/L throughout the study, and were in the target range of 50–200 x 109/L for all visits but weeks 76 and 156 (Figure). The median romiplostim dose (Q1, Q3) was 6.0 (2.0, 8.0) µg/kg at week 1 and 3.5 (0.0, 7.0) µg/kg at week 168 (Figure). Four patients discontinued romiplostim. Eight patients received rescue medications (defined as medications used for platelet counts < 10 x 109/L, bleeding/wet purpura, or investigator decision) which included immunoglobulins (3 patients), tranexamic acid (3 patients), platelet transfusion (1 patient), aminocaproic acid (1 patient), and prednisone (1 patient). Four patients had serious adverse events (asthma, hemangioma, hypotension, infection, thrombocytopenia, and transfusion reaction) and 1 had life-threatening adverse events (infection and thrombocytopenia). None of the serious adverse events were deemed treatment-related by the investigators. There were no fatal adverse events. Twelve patients had bleeding adverse events; 2 of which were deemed treatment-related (gingival bleeding and petechiae). Bleeding adverse events included epistaxis (4 patients); petechiae (3 patients); gingival bleeding (2 patients); hemorrhage (2 patients); and bleeding from the anus, injection site, lip, and mouth (1 patient each). No bone marrow biopsies were performed as part of this study. Conclusion In this open-label extension study, long term treatment with romiplostim maintained platelet counts in pediatric patients with chronic ITP without significant toxicity. Future results from this ongoing study will provide additional safety and efficacy data regarding long-term use of romiplostim in children with ITP. Disclosures: Tarantino: Pfizer: Membership on an entity’s Board of Directors or advisory committees; Octapharma: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BPL: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Romiplostim is approved for the treatment of adults with chronic ITP. Romiplostim is not approved for the treatment of pediatric patients with chronic ITP. Bussel:Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: 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; Symphogen: Membership on an entity’s Board of Directors or advisory committees. Nie:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.

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First Analysis of an International Double-Blind Randomized Phase III Study of Lenalidomide Maintenance in Elderly Patients with DLBCL Treated with R-CHOP in First Line, the Remarc Study from Lysa

Blood ◽

10.1182/blood.v128.22.471.471 ◽

2016 ◽

Vol 128 (22) ◽

pp. 471-471 ◽

Cited By ~ 8

Author(s):

Catherine Thieblemont ◽

Hervé Tilly ◽

Maria Gomez da Silva ◽

Rene-Olivier Casasnovas ◽

Christophe Fruchart ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Phase Iii ◽

First Line ◽

Advisory Committees ◽

Double Blind

Abstract Background. R-CHOP is the standard first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). However 30% of patients will relapse and 70% of relapsed patients will die within 2 years of diagnosis. The REMARC study (clinicalTrials.gov NCT01122472) is an international, multicenter, double-blind, randomized, placebo controlled, phase III trial that assessed the benefit of lenalidomide (LEN) maintenance after response to R-CHOP in patients aged 60 to 80 years with untreated DLBCL, FL3b or transformed lymphoma. Patients achieving CR or PR at the end of 6 or 8 cycles of R-CHOP21 or R-CHOP14 were stratified by CR/PR status and country and randomized 1:1 to receive 2 years of LEN maintenance (25 mg/day for 21 of every 28 days) or placebo (PBO). The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints were safety, PR to CR conversion rate, and overall survival (OS). Diagnosis was retrospectively centrally reviewed. In patients with adequate samples, GCB/nonGCB profile was assessed by the Hans algorithm and GCB/ABC/unclassified profile was assessed using NanoString gene expression profiling technology. Methods. From 05/2009 to 05/2014, 784 patients were enrolled either before R-CHOP (n= 437) or after completion of 6 or 8 cycles of R-CHOP (n= 347). At the end of R-CHOP therapy, 650 patients were randomized to maintenance, either in CR (n= 495) or in PR (n= 152). Central review found that 3 patients were randomized in SD or PD, all in LEN arm. At time of diagnosis, median age was 68 y (range 58-80), 43.5% were older than 70 y, and 56% were male. aaIPI was low in 38.5% and high in 57.5% of patients (missing data 4%). COO analyses are ongoing for both Hans algorithm and NanoString technology. Results. With a median follow-up of 40 months, median PFS (according to independent centralized radiology review) was not reached in the LEN group versus 68 months in the PBO group (hazard ratio favoring the LEN group, 0.708 (95% CI 0.537-0.932; p=0.0135))(See Figure). In the LEN group, 18 patients (21%) converted from PR to CR during maintenance compared to 13 patients (14%) in the PBO group. Immature overall survival data did not show any benefit for LEN arm, a lack of difference not attributable to an excess of lymphoma relapse, secondary cancer or safety problems in LEN arm. Deaths generally occurred off study drug (median time from last dose of study drug to death was 277 days (range 20, 1291) in LEN arm and 334 (41, 1594) in control arm. During maintenance, the most common observed grade 3 or 4 AEs were neutropenia (56% vs. 22%), rash (5% vs. 1%), infections (8% vs. 6%), and thrombocytopenia (2.5% vs. 0.6%) in LEN and PBO arms, respectively. Dose adjustments were necessary in 72% of the LEN patients and 42% of PBO patients. 59% of patients stopped LEN and 40% stopped PBO for toxicity (p<0.001). Median number of cycles was 15 in LEN and 25 in PBO (p<0.001). Secondary primary malignancies occurred in 33 patients receiving LEN and in 42 patients on PBO. Conclusion. This analysis of the REMARC study shows that 2 years of LEN maintenance in patients responding to R-CHOP significantly improved PFS (primary endpoint) without an early significant impact on OS. The COO analysis is currently ongoing. This is the first report finding that using an immunomodulatory agent as maintenance therapy prolongs PFS for patients with DLBCL after first line treatment with R-CHOP. Figure 1. Progression-free survival of elderly patients with diffuse large B-cell lymphoma in response to R-CHOP treated in maintenance with either lenalidomide or placebo Figure 1 Figure 1. Disclosures Thieblemont: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gomez da Silva:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; ROche: Consultancy, Membership on an entity's Board of Directors or advisory committees; takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Haioun:Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cabecadas:celgene: Consultancy, Honoraria. Salles:Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Coiffier:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood-2018-99-109763 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2428-2428 ◽

Cited By ~ 1

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.

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Thromboembolic Events Observed in Eltrombopag Clinical Trials in Chronic Immune Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v114.22.2423.2423 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2423-2423 ◽

Cited By ~ 8

Author(s):

James B. Bussel ◽

Gregory Cheng ◽

Mansoor N. Saleh ◽

Sandra Vasey ◽

Manuel Aivado ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Thromboembolic Events ◽

Study Medication ◽

Normal Range ◽

Advisory Committees ◽

Thrombocytopenic Purpura ◽

Platelet Counts ◽

Equity Ownership

Abstract Abstract 2423 Poster Board II-400 BACKGROUND: Eltrombopag (PROMACTA®; GlaxoSmithKline, Collegeville, PA, USA), an oral, small molecule, thrombopoietin receptor agonist, was recently approved in the United States for the treatment of patients with chronic immune thrombocytopenic purpura (ITP). Limited published data indicate that patients with chronic ITP experience thromboembolic events (TEEs) with a frequency of 3% to 6%. (Aledort, Am J Hematol, 2004; Bennett, Haematologica, 2008). OBJECTIVE: To evaluate the incidence of TEEs in patients with chronic ITP treated with eltrombopag and to determine if the occurrence of TEEs was associated with elevated platelet counts. METHODS: Data from 446 patients from 3 placebo-controlled eltrombopag studies (TRA100773A, TRA100773B, and RAISE) and 2 open-label studies (REPEAT and EXTEND) were analyzed. The frequency of TEEs or suspected TEEs before and after the first dose of study medication (placebo or eltrombopag) was examined across the program. Potential risk factors, including platelet counts proximal to the event, were evaluated in patients experiencing a TEE. RESULTS: Prior to the initiation of study medication (placebo or eltrombopag), 16/493 (3.2%) of the patients entering the program had a history of TEEs (one of these patients experienced 2 additional TEEs [TIA, MI] while on treatment with eltrombopag). Across the ITP clinical program, 17/446 patients treated with eltrombopag (3.8%) experienced 22 TEEs. No patient treated with placebo experienced a TEE. The patient-years (PYs) of exposure to study medication was approximately 14 times greater for patients treated with eltrombopag compared to placebo (eltrombopag 377 PYs; placebo 26 PYs). Most patients (13/17) experienced 1 TEE; 3 patients experienced 2, and 1 patient experienced 3 (2 TEEs were 6 months off-therapy). The most common TEEs were deep vein thrombosis (n=8) and pulmonary embolism (n=6). A total of 18/22 events were resolved or resolving at the time of this analysis; all patients experiencing a TEE had at least 1 risk factor for these events other than ITP (eg, use of IVIg [n=3], hospitalization with no prophylactic anticoagulation [n=4], oral corticosteroids [n=6]). The platelet counts proximal to the event ranged from 14,000/μL to 420,000/μL. The majority of patients had platelet counts below 150,000/μL (9; 53%) or between 150,000/μL and 400,000/μL (5; 29%); 2 had platelet counts above 400,000/μL and the platelet count in 1 was unknown. All 446 patients were categorized by the maximum platelet count achieved during treatment with eltrombopag (above normal [>400,000/μL], normal range [150–400,000/μL], below normal range [<150,000/μ]; Table 1). The majority of patients (14; 82%) experienced the TEEs at a platelet count lower than their maximum platelet count, while 3 patients (18%) experienced a TEE proximal to their maximum platelet count. CONCLUSION: TEEs occurred with eltrombopag. None occurred with placebo; however, the PYs of exposure was considerably less with placebo than with eltrombopag. The frequency of TEEs observed during eltrombopag treatment (3.8%) is similar to that reported in the literature and prior to enrollment in the eltrombopag program (3.2%). No discernible correlation has been observed between platelet count increases and TEEs, and these events do not appear to be associated with maximum platelet counts during treatment with eltrombopag. Disclosures: Bussel: Sysmex: Research Funding; Eisai, Inc: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; 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; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees. Cheng:GlaxoSmithKline: Research Funding. Saleh:GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau. Vasey:GlaxoSmithKline: Employment. Aivado:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.

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

Blood ◽

10.1182/blood.v120.21.621.621 ◽

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.

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Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years

Blood ◽

10.1182/blood.v122.21.2310.2310 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2310-2310 ◽

Cited By ~ 11

Author(s):

Christina S Lee ◽

Allison Imahiyerobo ◽

Micha Thompson ◽

Marina Izak Karaev ◽

Waleed Ghanima ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Response Rate ◽

Newly Diagnosed ◽

Advisory Committees ◽

Platelet Counts ◽

Best Response

Abstract Background Adults with newly-diagnosed and persistent ITP usually respond to steroid based treatments such as prednisone but relapse with tapering. One 4-day cycle of Dexamethasone (dex) at 40 mg/day in newly diagnosed ITP resulted in a lasting effect in 50% of patients (pts) in 1 study. An Italian study showed that 3 cycles of dex are better than 1 cycle. Approximately 50% of pts with chronic ITP experience a complete or partial response (CR & PR) to rituximab, yet only 20% of pts have a lasting, unmaintained response after 3 years. Mechanistically, rituximab (which depletes B cells but not plasma cells) and dexamethasone (which may be the most potent anti-plasma cell agent) are a logical combination in treatment of antibody-mediated diseases such as ITP. In 2 studies of newly-diagnosed pts, dex 40mg/day x 4 followed by rituximab was more effective than dex alone (one study added more dex half way through). In our pilot study, pts at Weill Cornell Medical College (WCMC) with all stages of ITP were treated with a combination of rituximab (R) and usually 3 cycles of dex. The outcome of this combination was retrospectively analyzed. Methods Combination of standard-dose rituximab (weekly x 4) and usually 3 4-day cycles of 28mg/m2 (max. 40mg) dex at 2-week intervals (R+3Dex) was explored in 67 pediatric and adult pts with ITP at WCMC. Patients were monitored with CBCs obtained weekly and then at less frequent intervals if a response was achieved. Best response (after 8 weeks to avoid transient effects of dex) was determined. Patients were categorized as CR (platelet count≥100x109/L) or PR (50-100x109/L). Relapse was defined as either two consecutive platelet counts <50x109/L and/or need for additional therapy. The duration of response was calculated from date of first rituximab administration to relapse or latest follow-up as of July 31st 2013. Results Overall, 50 of 67 pts treated with R+3Dex achieved a best response of either a CR (n=43) or a PR (n=7) at 8 weeks or later from start of therapy for an overall response rate of 75%. Seventy-three percent of pts received R+3Dex; variations were primarily in the timing and amount of dex given. Fifteen responders, 9 CRs and 6 PRs, relapsed at a median of 9 months. Seventy percent of the responders (or 52% of all pts treated) maintain a continuous response with platelet counts ≥ 50 x 109/L as of their last visit at a median f/u of 20 months. Kaplan Meier Analysis estimates 44% of all pts treated (Figure) and 59% of responders (Figure) maintained a best response without relapse at 67 months after initiating treatment. If only those with ITP ≤ 24 months are included, the estimated long term response rate is 59% (p=0.0017) versus only 19% for those with a duration of ITP > 24 months (Figure). Of 36 responding children and adults who had ITP ≤ 24 months, 29 continued to respond as of last follow up. Adults initially responded better than children (p=0.0019) but the long-term responses were not different (Figure). Pts achieving a CR had longer response than those achieving a PR. Adverse events related to R+Dex were usually mild-moderate, although 3 pts had serum sickness and 2 had transient colitis. IgG levels fell to below the lower limit of normal for age in 14 of 67 pts, 10 of whom had their IgG levels return to normal. In 6 of 14, IgG levels were < 400 mg/dl, some of whom received IVIG. Fifteen patients had serial BK/JC levels without ever detecting virus. Conclusions R+3Dex provides clearly superior results to rituximab alone. Notably, there was a 75% response rate overall (50/67 pts) compared to 50% with R alone. The 5 year response rate was almost 50% of all patients and 3/5 of responders. In patients who had had ITP for ≤ 2 years, the response is comparable to what has been reported with splenectomy. Specifically the results in the ≤ 2 year group suggest that R+3Dex is an effective way to induce indefinitely normal platelet counts in pts with a “short” duration of ITP. R+3Dex was tolerable although patients had difficulty with 3 cycles of dex. The 21% rate of hypogammaglobulinemia, higher than that seen with R alone, is also evidence of the mechanism of R+3Dex affecting both B cells and plasma cells. The lasting, long-lived, unmaintained responses observed in this study suggest that this combination therapeutic strategy should be further tested in a controlled trial in patients with newly diagnosed, persistent, and early chronic ITP, whether or not they have been previously treated with other agents. Disclosures: Bussel: Sysmex: Research Funding; Cangene: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees; Shionogi: 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; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2021-147335 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3675-3675

Author(s):

David M Ross ◽

Alejandro Arbelaez ◽

Lynette C.Y. Chee ◽

Chun Yew Fong ◽

Devendra Hiwase ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Phase 2 ◽

Publicly Traded ◽

Open Label ◽

Advisory Committees ◽

Maximum Increase ◽

Phase 2 Study ◽

Dose Levels

Abstract Background: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias, including anemia and thrombocytopenia. KER-050, a modified activin receptor type IIA inhibitor, is designed to target transforming growth factor-β ligands, including activin A. In preclinical studies, KER-050 promoted the maturation of progenitors across the full spectrum of erythropoiesis and thrombopoiesis and elicited bone anabolic effects. In a Phase 1 study in healthy participants, KER-050 treatment resulted in robust and sustained increases in reticulocytes (RETs), hemoglobin (HGB), and platelets. Increases in the bone formation marker bone specific alkaline phosphatase were also observed. Here we report results of an ongoing Phase 2 study to evaluate whether KER-050 provides therapeutic benefit in MDS patients with anemia. Aims: Evaluate safety, tolerability, pharmacodynamics and efficacy of ascending doses of KER-050 in participants with MDS in an open-label, 2-part Phase 2 study. Methods: IPSS-R very low-to-intermediate risk MDS patients (both RS+ and non-RS) with anemia (HGB <10g/dL or requiring RBC transfusions) are enrolled. In Part 1, ascending dose cohorts receive KER-050 subcutaneously every 4 weeks for 4 doses starting at 0.75mg/kg until a recommended Part 2 dose is determined. Part 2 dose expansion will begin following Part 1, with treatment extended to 2 years. Safety endpoints include incidence of adverse events (AEs); erythroid efficacy endpoints (≥8 weeks duration) include rates of transfusion independence (TI) in transfused participants, reduction in RBC transfusions by ≥4 units or ≥50% reduction in high transfusion burden participants (HTB) and HGB increase ≥1.5g/dL in non-transfused (NT) and low transfusion burden (LTB) participants. Results are reported for efficacy-evaluable participants in cohorts 1 and 2 of Part 1 dose escalation, defined as having ≥8 weeks of HGB and transfusion data. Results: At data cut-off (July 10, 2021) with median follow-up of 140 days (range 1 to 169 days), 17 participants had received ≥1 dose of KER-050 across 3 dose levels: 0.75 mg/kg, 1.5 mg/kg and 2.5 mg/kg. Baseline characteristics are described in Table 1. No related serious AEs, dose-limiting toxicities, or dose modifications were reported. One participant developed grade 2 maculopapular rash after the first dose which was considered treatment related, resolved and did not recur with subsequent doses. No other related AEs were reported. Two discontinued study drug prior to end of treatment: 1 due to participant decision, 1 due to death unrelated to study drug. None developed high risk MDS or AML. In 10 efficacy-evaluable participants, overall erythroid response rate was 60% (n=6/10). 33% (n=1/3) NT participants had a HGB increase of ≥1.5g/dL sustained ≥ 8 weeks. 5 of 7 transfused participants (71%) (n=1/2 LTB and n=4/5 HTB; n=2/3 non-RS and n=3/4 RS+) had erythroid responses sustained ≥8 weeks (range 8-20 weeks, ongoing) and 57% (n=4/7) achieved TI (Figure 1, Panel A). Maximum increase from baseline in RETs observed in transfused responders (TR) (n=5) was 24.6 x10 9/L (mean), range 10.5- 41.6 x10 9/L from day 1-29 with increases in RETs seen after each dose (Panel B). Maximum reduction in serum ferritin in TR was 40.4% (mean), range 10-66%, and maximum increase in soluble transferrin receptor (sTfR) was 52.8% (mean), range 29.8-116.4%. Increases in platelets were observed in TR (Panel C). Mean baseline platelet count for TR was 234 x10 9/L (range 104-401 x10 9/L), and maximum increase from baseline was 130 x10 9/L (mean), range 32-235 x10 9/L. No participants required dose reduction due to thrombocytosis. Summary: Erythroid responses have been observed in RS+ and non-RS MDS patients including reduction in transfusion burden at the initial dose levels. Observed increases in RETs and sTfR and observed decreases in ferritin suggest that KER-050 treatment is potentially associated with increased erythropoiesis. Increases in platelets have been observed in TR. These data support the potential of KER-050 as a treatment for multilineage cytopenias in MDS by potentially targeting multiple stages of hematopoiesis. As of data cut-off, KER-050 has been well tolerated. Dose escalation is ongoing in this Phase 2 study of anemic patients with MDS; data from planned cohorts from Part 1 will be presented. Part 2 dose expansion phase is expected to initiate prior to the meeting. Figure 1 Figure 1. Disclosures Ross: Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Keros Therapeutics: Consultancy, Honoraria. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fong: AbbVie: Consultancy; Amgen: Consultancy; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Phizer: Consultancy; Novotech: Honoraria; Specialised Therapeutics: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Wight: Jannsen: Honoraria, Other: Travel subsidies; Abbvie: Honoraria, Other: Travel subsidies. Rovaldi: Keros Therapeutics: Current equity holder in publicly-traded company. Furutani: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gaggi: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jiang: Keros Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Natarajan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ordonez: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

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