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

Abstract Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were > 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

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Novel Protein Agonist of Thrombopoiesis Acts Via a Physiocrine Pathway Distinct From That of Thrombopoietin

Blood ◽

10.1182/blood.v118.21.2376.2376 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2376-2376

Author(s):

Minh-Ha T Do ◽

Wei Zhang ◽

Kyle Chiang ◽

Chi-Fang Wu ◽

Chulho Park ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Production ◽

Platelet Counts ◽

Normal Platelet ◽

Naturally Occurring ◽

Equity Ownership

Abstract Abstract 2376 Thrombopoietin (TPO) is recognized as the main regulator of platelet production, yet its genetic ablation in mice does not completely obliterate thrombopoiesis, suggesting that alternate pathways could lead to platelet formation. We recently identified a naturally-occurring protein that acts as a potent agonist of platelet production by a mechanism distinct from that of TPO. This protein belongs to a novel class of human extracellular signaling proteins called physiocrines that are generated from tRNA synthetases by alternative splicing or proteolysis. Physiocrines interact with several classes of receptors through unique mechanisms to modulate cellular differentiation and tissue homeostasis in normal and pathological processes. The newly identified thrombopoietic physiocrine, termed ATYR0030, is an engineered version of a naturally-occurring physiocrine derived from the tyrosyl tRNA synthetase (YRS). In vivo, systemic administration of ATYR0030 or YRS physiocrine to rats led to an increase in platelets counts comparable to that seen with TPO treatment, but with a greater effect in animals with low baseline platelet levels. When injected into normal animals preselected for low platelet counts, ATYR0030 treatment resulted in an increase in platelets up to, but not beyond, normal levels (Figure 1), suggesting a role in platelet homeostasis and differentiating its effects from the known activity of TPO. Intravenous administration of ATYR0030 also accelerated recovery of platelet counts in carboplatin-treated rats, indicating a possible role in bone marrow reconstitution after chemical insult. Consistent with homeostatic properties, no toxicity was seen in a repeat-dose 28-day non-GLP safety study in rats dosed up to 100-fold above the efficacious range. Histopathology assessment revealed no tissue abnormalities, no increase in bone marrow reticulin and no hyperplasia of myeloid precursors. Clinical chemistry and hematology parameters were in the normal range with a modest increase in platelet counts, as anticipated in animals with normal platelet levels. Our in vitro data suggest that ATYR0030 may play a role in megakaryopoiesis by facilitating cell migration and adhesion to the vasculature. In contrast to TPO, ATYR0030 does not directly signal through the TPO receptor and does not activate the JAK/STAT pathway but rather appears to engage specific G-protein coupled receptors. In vitro, ATYR0030 does not stimulate proliferation of cultured M07e human megakaryoblasts or primary bone marrow cells isolated from AML patients (Figure 2). The parent synthetase is present in human platelets and is secreted in response to platelet activation, perhaps providing a feedback mechanism to stimulate the release of new platelets. In an effort to link the biological activity of ATYR0030 and the role that the parent synthetase plays in human physiology, we have begun to analyze samples from patients with abnormal platelets counts to determine circulating levels of the parent synthetase. The unique thrombopoietic activity of ATYR0030 may lead to an orthogonal approach to restoring normal platelet levels in thrombocytopenic patients who currently have limited treatment options. For example, in the myelodysplastic syndrome population, TPO-receptor agonists carry a risk of stimulating blast proliferation and accelerating disease progression to acute myeloid leukemia (AML). The distinct proliferation profile of ATYR0030 may translate into important safety benefits by reducing the risk of progression to AML. In addition, the potential role of ATYR0030 in regulating platelet homeostasis may provide a greater safety margin in the normalization of platelet levels, thereby also limiting the risk of thrombosis. Leveraging the therapeutic potential of this thrombopoietic physiocrine may lead to the development of a novel treatment option with a favorable safety profile. Disclosures: Do: aTyr Pharma: Employment, Equity Ownership, Patents & Royalties. Zhang:aTyr Pharma: Employment, Equity Ownership. Chiang:aTyr Pharma: Employment, Equity Ownership. Wu:aTyr Pharma: Employment, Equity Ownership, Patents & Royalties. Park:aTyr Pharma: Equity Ownership. Yang:aTyr Pharma: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Kunkel:aTyr Pharma: Consultancy, Stock Ownership. Ashlock:aTyr Pharma: Employment, Equity Ownership. Mendlein:aTyr Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Belani:Atyr Pahrma: Consultancy, Equity Ownership, Patents & Royalties. Vasserot:aTyr Pharma: Employment, Equity Ownership, Patents & Royalties. Watkins:aTyr Pharma: Employment, Equity Ownership, 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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PETIT and PETIT 2: Treatment with Eltrombopag in 171 Children with Chronic Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v124.21.1450.1450 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1450-1450 ◽

Cited By ~ 1

Author(s):

James B. Bussel ◽

John D. Grainger ◽

Purificacion Garcia de Miguel ◽

Jenny M. Despotovic ◽

Franco Locatelli ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Counts ◽

Chronic Itp ◽

Thrombopoietin Receptor ◽

Count Response ◽

Equity Ownership

Abstract Background: Eltrombopag (EPAG), an oral thrombopoietin receptor agonist, is approved for treating thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) with insufficient response to prior therapy. Pooled data from 2 similarly designed, randomized, double-blind, placebo (PBO)-controlled studies investigating safety and efficacy of EPAG in pediatric ITP are presented here. Methods: Subjects aged 1 to <18 years with a confirmed diagnosis of persistent or chronic ITP and a platelet count <30 Gi/L at day 1 were randomized 2:1 to EPAG or PBO and stratified by age: 12–17 years (Cohort 1), 6–11 years (Cohort 2), and 1–5 years (Cohort 3). Subjects could continue baseline ITP medications. After the PBO-controlled randomized phase, subjects were permitted to complete 17 or 24 weeks of treatment with open-label (OL) EPAG. Dose was adjusted based on platelet counts to a maximum of 75 mg daily. Results: A total of 174 subjects were enrolled in both studies; 171 received ≥1 dose of EPAG. 159 subjects were randomized (intent-to-treat population), and 157 received ≥1 dose of randomized study treatment (safety population). In the randomized period, 3 EPAG and 1 PBO subject discontinued study treatment, of which 2 EPAG and 1 PBO discontinued due to adverse events (AEs). In the OL-EPAG period, an additional 14 EPAG subjects discontinued study treatment, 6 due to AEs. Males comprised 47% of the EPAG and PBO groups and 20% and 24% were East Asians, respectively. Most subjects (93%) were diagnosed with ITP for ≥12 months, and 13% were receiving ITP medications at baseline. The majority of subjects (81%) received ≥2 prior ITP therapies. Most subjects (59%) had a baseline platelet count <15 Gi/L. All 9 (6%) splenectomized subjects were randomized to the EPAG group. Randomized Period A higher proportion of EPAG versus PBO subjects (62% vs 24%; P < 0.001) achieved a response with platelet counts ≥50 Gi/L at least once between weeks 1–6 (Cohort 1, 64% vs 11%; Cohort 2, 64% vs 27%; Cohort 3, 54% vs 36%, respectively). At each week, a higher proportion of EPAG subjects had a response versus PBO (Fig. 1). A lower proportion of EPAG subjects (13%) received rescue treatment compared with PBO subjects (31%; P = 0.009). The odds of having World Health Organization (WHO) bleeding grades 1–4 (0.19; P = 0.011) and clinically significant (WHO grades 2–4) bleeding (0.29; P = 0.007) were lower for EPAG versus PBO subjects. EPAG-Only Period Sustained reduction or discontinuation of baseline ITP medications, primarily corticosteroids, was achieved by 50% of subjects; 81% of subjects had a platelet count response at least once; 52% (n = 80/154) had a platelet count response for ≥50% of assessments; and 38% (n = 58/154) responded for ≥75% of assessments. For >13 of 24 weeks, 47% of subjects achieved responses (Fig. 2). The median average daily dose for EPAG-exposed patients in Cohorts 1, 2, and 3 were 64.0 mg (0.93 mg/kg), 57.6 mg (1.50 mg/kg), and 37.0 mg (2.02 mg/kg), respectively. AEs Similar proportions of subjects in the EPAG and PBO groups reported an AE during the randomization period. The most common AEs (≥10% of subjects) were headache, upper respiratory tract infection, and nasopharyngitis in the EPAG group, and headache, epistaxis, and vomiting in the PBO group. Serious AEs (SAEs) were reported in 8% of EPAG subjects versus 12% of PBO subjects. No SAEs were reported by >1 subject in either treatment group except epistaxis, which was reported by 2 subjects in the PBO group. No SAEs were common to both treatment groups. In the randomized period, an ALT elevation of ³3 x ULN occurred in 5 (4.7%) subjects in the EPAG group and no subjects in the PBO group. In the OL period, there were an additional 7 subjects with ALT ³3 x ULN. All elevations resolved either while still on treatment or after discontinuation of study treatment. Overall, the hepatobiliary laboratory findings were mostly mild, reversible, and not accompanied by impaired liver function. Fewer EPAG than PBO subjects reported bleeding AEs (17% vs 36%, respectively). No thromboembolic events were reported. Cataract events were experienced by 2 subjects who received EPAG; both had used corticosteroids and 1 had pre-existing cataracts. Conclusions: EPAG was safe and raised platelet counts in 62% of pediatric patients with persistent and chronic ITP during the randomized phase. Treatment with EPAG was well tolerated in both studies as evidenced by the low incidence of treatment discontinuations due to AEs. Disclosures Bussel: Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Honoraria; Novartis: Honoraria; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; GlaxoSmithKline: Equity Ownership, Honoraria, Research Funding; Genzyme: Research Funding; Eisai, Inc.: Research Funding; Cangene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Amgen: Equity Ownership, Honoraria, 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. Off Label Use: Eltrombopag is a thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in adults with chronic ITP. Use in children and adolescents will be discussed.. Grainger:GlaxoSmithKline: Honoraria; Baxter: Honoraria, Research Funding; Amgen: Honoraria. Pongtanakul:GlaxoSmithKline: Research Funding. Komvilaisak:GlaxoSmithKline: I am an investigator on this study. Other. Sosothikul:CSL Behring: Research Funding; GlaxoSmithKline: Research Funding. Drelichman:GlaxoSmithKline: I am investigator on this study. Other. David:GlaxoSmithKline: Research Funding. Marcello:GlaxoSmithKline: Employment. Iyengar:GlaxoSmithKline: Employment. Chan:GlaxoSmithKline: Employment. Chagin:GlaxoSmithKline: Employment. Theodore:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Bailey:GlaxoSmithKline: Employment, Equity Ownership.

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A Randomized, Double-Blind, Placebo-Controlled Phase 1/2 Study to Determine the Safety and Efficacy of Romiplostim in Children with Chronic Immune (Idiopathic) Thrombocytopenic Purpura (ITP).

Blood ◽

10.1182/blood.v114.22.680.680 ◽

2009 ◽

Vol 114 (22) ◽

pp. 680-680 ◽

Cited By ~ 1

Author(s):

George R. Buchanan ◽

Lisa Bomgaars ◽

James B. Bussel ◽

Diane J. Nugent ◽

David J. Gnarra ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Treatment Period ◽

Research Funding ◽

Bleeding Events ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Counts ◽

Chronic Itp ◽

Equity Ownership

Abstract Abstract 680 Introduction: ITP is an autoimmune disorder characterized by thrombocytopenia due to accelerated destruction as well as suboptimal platelet production. Childhood ITP is most commonly an acute illness; however, chronic ITP (duration > 6 months) develops in 20%–30% of ITP cases. Romiplostim, a peptibody protein designed to increase platelet production, is approved for treating chronic ITP in adults. The objective of this study was to evaluate the safety and efficacy of romiplostim in the treatment of thrombocytopenia in children with chronic ITP. Patients and Methods: ITP patients aged 12 months to <18 years with persistent severe thrombocytopenia for at least six months before enrollment (mean of 2 platelet counts ≥ 30 × 109/L at baseline) were included in this study. Patients were randomized (3:1) to receive romiplostim or placebo and stratified by age: 12 months - <3 years (N=4), 3 - <12 years (N=8), and 12 - <18 years (N=8). Treatment for a 12 week period was followed by a 4 week pharmacokinetic (PK) assessment period for responding patients (those who achieved a platelet count of >20 × 109/L above baseline for 2 consecutive weeks without rescue therapy at any point during the treatment period). Treatment was initiated at 1 μg/kg once weekly by subcutaneous injection. The dose was adjusted in 2 μg/kg increments every two weeks, to a maximum dose of 10 μg/kg/week based on weekly platelet counts. The incidence of adverse events (AEs) during the 12-week treatment period and the number of patients achieving platelet counts >50 × 109/L for 2 consecutive weeks during the treatment period, or achieving an increase in platelet count >20 × 109/L above baseline for 2 consecutive weeks during the treatment period was recorded. Results: A total of 22 (romiplostim, 17; placebo, 5) patients were randomized; 16 (73%) were boys and 6 (27%) were girls. Eight patients had undergone splenectomy. The mean age was 9.5 (SD: 5.1) years, with 4 subjects aged 12 months - <3 years, 10 aged 3 - <12 years, and 8 aged 12 - <18 years. The median baseline platelet count was 13 × 109/L (range 2 to 29 × 109/L) and the median duration of ITP was 2.4 years (range 0.6 to 14 years). All patients completed the study. Sixteen of 17 patients in the romiplostim arm (94%) and 5/5 in the placebo arm (100%) had at least 1 AE during the treatment period. The most common AEs were (romiplostim, placebo, respectively) headache (35%, 40%), epistaxis (35%, 20%), cough (12%, 40%), and vomiting (12%, 40%). Serious AEs were experienced by 1 patient in the romiplostim arm (moderate influenza and sepsis) and none in the placebo arm. AEs considered to be treatment related were reported for 3 (18%) and 1 (20%) subjects in the romiplostim and placebo arms, respectively; none of the treatment-related AEs were serious or of ≥3 grade severity. No patients died during the study and none tested positive for neutralizing antibodies to romiplostim or thrombopoietin. The same group of patients in the romiplostim-treated arm (15/17, 88.2%, 95% CI: 63.6%, 98.5%) achieved both efficacy endpoints during the treatment period. The median platelet count in the romiplostim-treated arm after 6 weeks of treatment was ≥50 × 109/L. The median weekly platelet count in the placebo arm remained stable at approximately 10 × 109/L. None of the placebo-treated patients achieved either platelet count endpoint. Rescue medication was administered to 2/17 (12%) of romiplostim- and 2/5 (40%) of placebo-treated patients during the 12 week treatment period. Twelve (71%) and 2 (40%) subjects in the romiplostim and placebo arms, respectively, experienced bleeding events. The majority of bleeding events (15/17) in the romiplostim arm occurred in the first 6 weeks of treatment. Most bleeding events (14/17) in the romiplostim arm and all bleeding events in the placebo arm occurred when the platelet count was < 30 × 109/L. A total of 14 patients treated with romiplostim entered the PK assessment period. The romiplostim serum concentration results were not different among the 3 age cohorts. The mean weekly dose of romiplostim in the treatment period was 3.4 (SD: 1.6) μg/kg. Conclusion: Treatment with romiplostim appeared to be well tolerated in pediatric ITP patients, with no new safety concerns observed in this study as compared to adults with chronic ITP. Romiplostim was effective in treating thrombocytopenia in children with chronic ITP. Disclosures: Buchanan: Amgen Inc.: Research Funding. Off Label Use: Use of romiplostim, a thrombopoietin mimetic, in treatment of thrombocytopenia in pediatric ITP patients. . Bomgaars:Novartis: Research Funding. Bussel:Eisai, Inc: Research Funding; Sysmex: Research Funding; Shionogi: 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; Immunomedics: Research Funding; 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; Scienta: Speakers Bureau. Nie:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

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Use of Rituximab in a Study Comparing the Thrombopoietin Mimetic Romiplostim with Standard of Care (SOC) in Patients with Immune Thrombocytopenia (ITP),

Blood ◽

10.1182/blood.v118.21.3282.3282 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3282-3282

Author(s):

Jeffrey Wasser ◽

Ralph Vincent V. Boccia ◽

Roger M. Lyons ◽

Romeo Mandanas ◽

Ingrid Pabinger ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Platelet Response ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Term Response

Abstract Abstract 3282 Background/Methods: The relative safety and efficacy of romiplostim and rituximab in ITP have not been compared in clinical trials. In an open-label 52-week trial of SOC (N = 77) and romiplostim (N = 157) in ITP patients without prior splenectomy (Kuter et al, NEJM 2010), treatment failure was lower with romiplostim vs SOC (11% vs 30%, P<0.001). Within the SOC arm, 16 patients (21%) received rituximab; most (11/16) at QW × 4 (dose: 219–363 mg/m2), other rituximab dosing regimens varied considerably. We examine here outcomes of those 16 patients as compared with the romiplostim arm (in which 1 patient received rituximab) and the SOC arm as a whole. Results: All 3 groups had comparable age, sex, and baseline platelet count (Table). Median ITP duration was somewhat shorter for romiplostim-treated patients and the SOC arm vs. SOC-rituximab patients (2.1, 2.3 vs 3.4 years). More romiplostim patients completed the 52-week treatment phase vs SOC-rituximab patients and the SOC arm (78% vs 44%, 56%). Fewer romiplostim patients vs. SOC-rituximab and SOC patients experienced treatment failure (4% vs 13%, 13%). Adverse events (AE), serious AE (SAE), treatment-related AE, and treatment-related SAE rates were similar for all 3 groups. Platelet response rates (platelet count >50×109/L, excluding 8 weeks after rescue medication) were higher with romiplostim than with SOC-rituximab or SOC as a whole (Graph). When comparing concomitant ITP medications prior to rituximab and during or after rituximab treatment in the SOC-rituximab patients, there was no change in the proportion of patients receiving ITP medications (9/16 vs 10/16) or the number of medications per patient [median (range) of 1 (0, 3) vs 1 (0, 4)]. The most common prior to rituximab treatment were prednisone (7/16), IVIg (3/16) and anti-D (2/16); during or after rituximab treatment, the most common were prednisone (6/16), IVIg (4/16), anti-D (2/16), and methylprednisone (2/16). Conclusion: This post hoc non-randomized comparison indicates that romiplostim may have greater effects on platelet responses than SOC-rituximab or SOC, with similar safety profiles. However, different treatment goals – ongoing use of romiplostim to maintain platelet response as opposed to one or more courses of rituximab which may result in a long-term response in the absence of other therapies (∼20% response rate at 5 years, Patel, ASH 2010) – makes efficacy comparisons problematic, particularly as the long-term response rate was not measured in this one-year study. Also not analyzed was how the use of concomitant ITP medications changed over the course of the study. As splenectomy and many immunosuppressive ITP medications are associated with significant morbidity and mortality over time, this is an important consideration. Most importantly, patients were selected for rituximab treatment by the investigators in a non-random way, as evidenced by the longer duration of ITP, making any generalizations difficult. Prospective controlled studies of romiplostim and rituximab in patients with ITP would be needed to provide further information. Disclosures: Wasser: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Rituximab is not indicated for ITP. Boccia:Amgen: Equity Ownership, Speakers Bureau. Lyons:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mandanas:Amgen: Membership on an entity's Board of Directors or advisory committees. Pabinger:Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Michel:Roche: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Viallard:Amgen: Consultancy. Wang:Amgen: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

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Pooled Analysis of Safety and Efficacy of Romiplostim in Splenectomized and Nonsplenectomized Patients (pts) with Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v124.21.4199.4199 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4199-4199

Author(s):

Francesco Rodeghiero ◽

Andrew Provan ◽

Michael Steurer ◽

Bertrand Godeau ◽

Nancy Carpenter ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Clinical Studies ◽

Research Funding ◽

Platelet Response ◽

Employment Equity ◽

Advisory Committees ◽

Safety And Efficacy ◽

First Response ◽

Equity Ownership

Abstract Introduction: Romiplostim is a thrombopoietin receptor agonist approved for use in adult pts with ITP. Pooled analyses of combined pt data from romiplostim ITP clinical studies have previously been reported. Here we report updated safety and efficacy data according to baseline splenectomy status. Methods: Data from adult pts in 13 completed ITP studies with romiplostim were analysed up to June 2014. Pts received romiplostim, placebo or medical standard of care (SOC) and data from the placebo/SOC arms were pooled. All 13 studies were included in analyses of baseline pt characteristics and safety endpoints; 4 early dose-finding studies were excluded from analyses of efficacy endpoints as they do not reflect the current dosing of romiplostim. Adverse events were adjusted for time spent on study and reported as rates per 100 pt-years. For pts who started their parent study in the placebo/SOC group and then went on to receive romiplostim in an extension study, all data from the first dose of romiplostim were included in the romiplostim group. A platelet response was defined as a platelet count ≥50x109/L without rescue medication in the previous 8 weeks; a platelet response for 9 out of any 12 consecutive weeks on-study was considered a sustained platelet response. All analyses were descriptive and no statistical testing was performed. Results: Data from 1,111 pts were analysed, 395 splenectomized and 716 nonsplenectomized. The splenectomized and nonsplenectomized groups were similar in age (median 52 vs 53 years) and sex (female 64% vs 60%), but in the splenectomized group median baseline platelet counts were slightly lower (14 vs 19x109/L) and a higher proportion of pts were known to have received >3 prior ITP treatments (38% vs 12%) than the nonsplenectomized group. Rates of AEs, serious AEs, fatal AEs, treatment-related AEs, thrombotic events, and hemorrhages were lower in nonsplenectomized than splenectomized pts and were in general lower in romiplostim than placebo/SOC-treated pts in both groups. Bone marrow reticulin occurred in 17 romiplostim-treated pts and one placebo-treated pt, at a slightly increased rate in splenectomized vs nonsplenectomized pts. Bone marrow collagen was reported in one romiplostim-treated nonsplenectomised pt. Data from 1,024 pts were analysed for efficacy (376 splenectomized, 648 nonsplenectomized). The median (Q1, Q3) most frequent weekly dose was 4 µg/kg (2, 9) in splenectomized and 3 µg/kg (2, 7) in nonsplenectomized pts. A platelet response was achieved in 82% of splenectomized and 91% of nonsplenectomized pts and a sustained platelet response in 66% and 79%, respectively. The median time to first response was 2.1 weeks for splenectomized and 2.0 weeks for nonsplenectomized pts. Platelet responses were maintained in those who responded: after the first response the median (Q1, Q3) proportion of time with a response was 97% (79%, 100%) for splenectomized and 100% (91%, 100%) for nonsplenectomized pts. Conclusions: A relatively large number of nonsplenectomized pts have received romiplostim in clinical studies. Safety of romiplostim was comparable in splenectomized and nonsplenectomized patients with no new safety signals observed, and platelet response rates were high and of sustained duration in both groups. Abstract 4199. Table Number of events (rate per 100 pt-years) Splenectomized Nonsplenectomized Placebo/SOC N=27 Pt-yr=11.2 Romiplostim N=391 Pt-yr=702.0 Placebo/SOC N=106 Pt-yr=97.7 Romiplostim N=655 Pt-yr=1129.7 All AE 208 (1861.1) 8609 (1226.3) 1028 (1052.6) 9624 (851.9) Serious AE 15 (134.2) 478 (68.1) 92 (94.2) 498 (44.1) Fatal AE 3 (26.8) 11 (1.6) 5 (5.1) 31 (2.7) Treatment-related AE 15 (134.2) 864 (123.1) 152 (155.6) 928 (82.1) Treatment-related serious AE 0 (0) 65 (9.3) 18 (18.4) 59 (5.2) Treatment-related fatal AE 0 (0) 2 (0.3) 0 (0) 3 (0.3) Thrombotic events 1 (8.9) 44 (6.3) 5 (5.1) 52 (4.6) Hemorrhage events 54 (483.2) 1868 (266.1) 233 (238.6) 1591 (140.8) Fatal hemorrhage events 1 (3.7) 0 (0) 0 (0) 5 (0.8) Bone marrow reticulin /collagen events* 1 (8.9) 11 (2.0) 0 (0) 7 (0.8) Hematologic malignancies/MDS 0 (0) 6 (0.9) 4 (4.1) 8 (0.7) Any malignancies 0 (0) 24 (3.4) 9 (9.2) 43 (3.8) * Bone marrow collagen reported in one romiplostim-treated nonsplenectomized pt. Excludes study NCT00907478 as bone marrow evaluations were collected differently than in other studies; in the romiplostim arms the N/pt-yrs were 331/560.6 for splenectomised and 546/866.7 for nonsplenectomised pts. Disclosures Rodeghiero: GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Suppremol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Steurer:Amgen: Honoraria. Godeau:Amgen: Consultancy. Carpenter:Amgen: Employment, Equity Ownership. Kreuzbauer:Amgen: Employment, Equity Ownership.

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Predictors of Remission in Adults with Immune Thrombocytopenia Treated with Romiplostim

Blood ◽

10.1182/blood-2018-99-109791 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 735-735

Author(s):

Adrian Newland ◽

James B. Bussel ◽

Robert Bird ◽

Donald M. Arnold ◽

Craig M. Kessler ◽

...

Keyword(s):

Multivariate Analysis ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Counts ◽

Equity Ownership

Abstract Background: In adults with ITP, thrombopoietin receptor agonists (TPO-RA) are often assumed to be lifelong therapy. However, some patients achieve treatment-free remission (TFR) by maintaining hemostatic platelet counts after discontinuing TPO-RA, despite not replacing them with other ITP medications. Predictors of safely discontinuing romiplostim have varied across studies. In an analysis of 8 romiplostim studies, 27 patients achieved TFR; more remitters than nonremitters had ITP for <12 months but there were no unequivocal predictors of TFR (Bussel et. al. Hematology 2016;21:257). In a phase 2 study with forced romiplostim taper after 12 months, 24 (32%) of 75 patients achieved TFR; a higher platelet count in the first 2 months was associated with TFR (P<.05; Newland et. al. Br J Haematol 2016;172:262). Differences between remitters and nonremitters for baseline patient characteristics and time to first platelet response were not statistically significant. Analysis of romiplostim treatment at 2 centers found that 12 (28%) of 43 patients achieved TFR; splenectomized patients were more likely than nonsplenectomized patients to achieve TFR (P=.05; Marshall et. al. Haematologica 2016;101:e476). Aim: This multivariate analysis integrated data across multiple romiplostim studies in adults with ITP to explore predictors of TFR. Methods: Data were pooled for 911 romiplostim-treated patients in 13 ITP studies conducted from 2002 to 2014. All patients failed first-line treatments before study enrollment. Secondary thrombocytopenia patients were excluded. Romiplostim treatment was discontinued per dosing rules; 1 study included a forced taper after 1 year of romiplostim. Typically, the romiplostim dose was reduced for platelet counts >200×109/L and withheld, then reduced, for platelet counts >400×109/L. Concomitant ITP medication could be reduced for platelet counts >50×109/L. TFR was defined as a ≥6-month treatment-free period with platelet counts consistently ≥50×109/L. Univariate analysis with logistic regression examined potential predictors of TFR, including age, sex, ITP duration, prior splenectomy, platelet count (baseline and first 4 weeks), bleeding in the first 6 months, and baseline concurrent therapy. Multivariate analysis with logistic regression evaluated significant predictors from the univariate analysis. Results: TFR was achieved by 61 ITP study patients who received romiplostim. For remitters vs nonremitters, median baseline age was 53 years in both cohorts; 57% vs 61% were female; and 93% vs 88% were Caucasian (Table 1). Median ITP duration at study baseline was 0.5 years among remitters and 3.5 years among nonremitters. Prior splenectomy occurred in 21% of remitters and 36% of nonremitters. The number of prior ITP treatments was ≤3 for 74% of remitters and 39% of nonremitters. Baseline platelet count was <30×109/L for 80% of remitters and 78% of nonremitters. Median platelet counts on treatment during the romiplostim studies were often higher among remitters than nonremitters, despite increasing median doses of romiplostim over time for nonremitters (Figure). During the first 6 months on study, 30% of remitters and 43% of nonremitters had a bleeding event. Prior splenectomy and bleeding in the first 6 study months were significant predictors of lower odds of TFR in the univariate model but not in the multivariate model. In the multivariate model, shorter ITP duration predicted significantly higher odds of TFR, either <3 months (newly diagnosed) vs >12 months (chronic; odds ratio [OR], 4.275; P<.0001) or 3-12 months (persistent) vs chronic (OR, 2.171; P=.0408; Table 2). One limitation of this analysis was 19 of 61 patients entering TFR were from one study of newly diagnosed and persistent patients; the protocol included a forced romiplostim taper. Number of previous treatments was not included in the multivariate analysis. Conclusions: In this integrated analysis of 911 adult ITP patients across 13 studies, shorter ITP duration at baseline (≤12 months) was an independent predictor of TFR. Neither previous splenectomy (which predicted TFR in 1 study) nor bleeding were independent predictors of TFR in this much larger analysis. In total, these results imply that earlier use of romiplostim in adults with ITP could be associated with greater likelihood of achieving TFR. Future studies should also explore biologic variables as predictors of TFR. Disclosures Newland: Amgen Inc., Angle, Dova Pharmaceuticals, Argenx, Rigel, Shionogi, Novartis: Consultancy; Amgen Inc., GlaxoSmithKline, and Novartis: Research Funding; Novartis: Speakers Bureau. Bussel:Uptodate: Honoraria; Protalex: Consultancy; Momenta: Consultancy; Rigel: Consultancy, Research Funding; Prophylix: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding. Bird:Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Arnold:Novartis: Consultancy, Research Funding; UCB: Consultancy; UCB: Consultancy; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Kessler:Novo Nordisk: Honoraria, Research Funding; Biomarin: Research Funding; Genentech: Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; DSMB: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mayer:Novartis: Research Funding; Amgen: Research Funding. Janssens:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Sanofi-Genzyme: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Wang:Amgen: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.

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Cumulative Response to Eltrombopag and Impact of the Number of Prior ITP Therapies: Interim Results of a Long-Term Extension Study,

Blood ◽

10.1182/blood.v118.21.3297.3297 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3297-3297

Author(s):

James B Bussel ◽

Christine K Bailey ◽

Andres Brainsky

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Platelet Counts ◽

Chronic Itp ◽

Equity Ownership

Abstract Abstract 3297 Background: Patients with chronic immune thrombocytopenia (ITP) have an increased risk of bleeding, ranging from minor to life-threatening. The goal of treatment is to increase and maintain platelets in a safe range to prevent bleeding. Guidelines state that achieving platelet counts of 30,000/μL to 50,000/μL in patients without other risk factors avoids the most serious complications of ITP, namely intra-cerebral or gastrointestinal hemorrhage (George 1996; Provan 2010). Many patients are refractory or relapse after multiple treatments. Eltrombopag is an oral, nonpeptide thrombopoietin receptor agonist approved for the treatment of chronic ITP. In 6-week, and 6-month, placebo-controlled trials in patients with heavily pre-treated chronic ITP, eltrombopag increased platelets and reduced bleeding and the need for concomitant ITP therapy (Bussel 2007; Bussel 2009; Cheng 2011). Long-term treatment with eltrombopag is being evaluated in EXTEND, an extension study in chronic ITP patients who completed a previous eltrombopag study (Saleh 2010). Aims: To analyze in EXTEND the ability of eltrombopag to increase platelet counts to ≥50,000/μL in >50% and >75% of assessments and to determine whether the number of prior ITP therapies influences this ability. Methods: Patients in EXTEND received eltrombopag or placebo in 1 of the following prior studies of eltrombopag in chronic ITP: a 6-week phase 2 (TRA100773A; Bussel 2007) or phase 3 (TRA100773B; Bussel 2009) study, a 6-month phase 3 study (RAISE; Cheng 2011), or a phase 3 study of intermittent treatment (REPEAT; Psaila 2008). Dosing in EXTEND is individualized in order to maintain platelet counts ≥50,000/μL and <200,000/μL while minimizing the use of concomitant ITP medications. For the purpose of this analysis, response is defined as a platelet count ≥50,000/μL. Results: Among the 299 patients enrolled in EXTEND between June 2006 and February 2010, 67 (22%), 73 (24%), 47 (16%), and 112 (37%) patients had received 1, 2, 3, and ≥4 prior therapies (excluding eltrombopag). The most commonly used prior therapies were corticosteroids (81%), IVIg (45%), splenectomy (38%), and rituximab (23%). Of the 299 patients enrolled, 70% achieved response in >50% of study assessments and 46% achieved response in >75% of assessments. Among 210 patients treated ≥12 months, 79% achieved response in >50% of assessments and 56% in >75% of assessments. Among 138 patients treated for ≥24 months, 82% achieved response in >50% and 59% in >75% of assessments. Response in >50% and >75% of assessments by the number of prior therapies was similar between the groups (Figure 1). The proportion of patients who achieved a response in >50% of assessments was similar between splenectomized and non-splenectomized patients (65% and 73%, respectively). Conclusion: The majority of patients treated with eltrombopag for ≥12 months achieved a platelet count of ≥50,000/μL in >50% of study assessments. This response was observed even among patients previously treated with 4 or more ITP therapies, suggesting that eltrombopag may be a viable treatment option even for more refractory chronic ITP patients. Disclosures: Bussel: Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership.

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Efficacy, Hematologic Effects, and Dose of Ruxolitinib in Myelofibrosis Patients with Low Starting Platelet Counts (50–100 × 109/L): A Comparison to Patients with Normal or High Starting Platelet Counts

Blood ◽

10.1182/blood.v120.21.176.176 ◽

2012 ◽

Vol 120 (21) ◽

pp. 176-176 ◽

Cited By ~ 4

Author(s):

Moshe Talpaz ◽

Ronald Paquette ◽

Lawrence Afrin ◽

Solomon Hamburg ◽

Katarzyna Jamieson ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Counts ◽

Equity Ownership ◽

Eortc Qlq

Abstract Abstract 176 Background: Ruxolitinib (RUX) has demonstrated clinical benefit for patients with myelofibrosis (MF) with or without the JAK2V617F mutation at starting doses of 15 or 20 mg PO BID by alleviating symptoms, improving quality of life measures, reducing spleen volume and exhibiting an apparent increase in overall survival in the phase III placebo (PBO)-controlled COMFORT-I study. Reversible declines in platelet count and hemoglobin (Hgb) can occur with ruxolitinib but are rarely treatment-limiting. Patients with MF who have low platelet counts represent an important subset of MF patients; given the potential risk of bleeding complications, a dosing strategy for such patients is needed. We assessed an alternative strategy using lower starting doses of ruxolitinib with subsequent dose escalation in patients with MF who have platelet counts of 50–100 × 109/L (Study INCB018424-258; NCT01348490). Methods: RUX dosing started at 5 mg BID. With adequate platelet count, doses could increase by 5 mg once daily every 4 weeks to 10 mg BID. Further increases required evidence of suboptimal efficacy. Assessments include measurement of MF symptoms (MF Symptom Assessment Form v2.0 Total Symptom Score [TSS]); Patient Global Impression of Change (PGIC); EORTC QLQ-C30, measurement of spleen volume by MRI, and safety/tolerability. Results: A total of 50 patients have enrolled, with data available for 41 patients. Nineteen have completed 24 weeks of treatment; >70% of these patients attained a final dose of ≥10 mg BID of RUX. Treatment was generally well tolerated in this study population with no withdrawals for thrombocytopenia or bleeding events. Based on analysis of adverse events, no new safety signals were observed in this population of MF patients with low platelet counts. Data for efficacy parameters, including spleen volume reduction, TSS reduction, and improvement in EORTC-QLQ-C30 subscales and PGIC were consistent with RUX treatment in the COMFORT-I study, and demonstrated clinically meaningful efficacy compared with the COMFORT-I PBO arm (Table). Of 19 patients with platelet count data through Week 24, 5 showed increased platelet count over the duration of the study (range of increase: 20 to 95 x109/L); all 5 patients had optimized dosing to ≥10 mg BID. Compared with the 14 patients showing smaller increases or modest decreases in platelet count, these 5 patients were younger (mean age: 63 years vs. 71 years), had been diagnosed with MF more recently (2.2 years vs. 5.2 years) and had lower DIPSS scores (60% Intermediate-1; 20% Intermediate-2; 20% High vs. 0% Intermediate-1; 79% Intermediate-2; 21% High). Four patients (9.8%) reported adverse events of bleeding (excluding events related to bruising) of any grade (all events were Grade 1 except one Grade 2 hematochezia), consistent with previously reported hemorrhage frequency in the COMFORT-I study (16.8%, RUX; 12.6%, PBO). Conclusions: These preliminary findings suggest that a dosing strategy of a low starting dose of RUX with escalation to 10 mg BID may be appropriate in MF patients who have low platelet counts. Most patients were able to titrate to a dose of ≥10 mg BID of RUX, a dose showing efficacy for both spleen volume and patient-reported outcomes generally consistent with previously reported data from Phase III trials. An increase in platelet counts was observed in approximately one-fourth of patients who completed 24 weeks of RUX treatment. Escalation to, and subsequent maintenance of, a 10 mg BID dose of RUX also preserves both Hgb and platelet count which may be beneficial for MF patients with anemia or thrombocytopenia. Disclosures: Talpaz: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Paquette:Incyte: Consultancy. Jamieson:Sunesis: Membership on an entity's Board of Directors or advisory committees; Blue Distinction Centers for Transplants BlueCross BlueShield Association: Consultancy. Lyons:Amgen: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Novartis: Research Funding. Tiu:Incyte: Honoraria, Speakers Bureau. Winton:Incyte Corporation: Consultancy, Honoraria. Odenike:Incyte: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis:Membership on an entity's Board of Directors or advisory committees. Peng:Incyte: Employment, Equity Ownership. Sandor:Incyte: Employment, Equity Ownership. O'Neill:Incyte: Employment, Equity Ownership. Erickson-Viitanen:Incyte: Employment, Equity Ownership. Leopold:Incyte: Employment, Equity Ownership. Levy:Incyte: Employment, Equity Ownership. Kantarjian:Incyte Corporation: grant support Other. Verstovsek:Incyte Corporation: Research Funding.

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EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-114421 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1528-1528

Author(s):

Sebastian Stasik ◽

Jan Moritz Middeke ◽

Michael Kramer ◽

Christoph Rollig ◽

Alwin Krämer ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Mutational Status ◽

Equity Ownership ◽

Acute Myeloid

Abstract Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: 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; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

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