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 ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 176-176 ◽  
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.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3279-3279 ◽  
Author(s):  
Ann Janssens ◽  
Michael D. Tarantino ◽  
Robert Bird ◽  
Maria Gabriella Mazzucconi ◽  
Ralph Vincent V. Boccia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Production ◽  
Platelet Counts ◽  
Equity Ownership

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.

scholarly journals PETIT and PETIT 2: Treatment with Eltrombopag in 171 Children with Chronic Immune Thrombocytopenia (ITP)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1450-1450 ◽  
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.

scholarly journals A Phase 2a Study of the LSD1 Inhibitor Img-7289 (bomedemstat) for the Treatment of Myelofibrosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 556-556 ◽  
Author(s):  
Kristen Pettit ◽  
Aaron T. Gerds ◽  
Abdulraheem Yacoub ◽  
Justin M. Watts ◽  
Maciej Tartaczuch ◽  
...  
Keyword(s):  
Platelet Count ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Once Daily ◽  
Equity Ownership

Ruxolitinib (Jakafi®) is the one approved therapy for myelofibrosis (MF) based on reduction of splenomegaly and symptoms but JAK inhibition has not proven to significantly modify disease progression. There remains the need for novel therapies with distinct modes of action that can improve the patient experience of MF and impact progression. Lysine-specific demethylase, LSD1, is an epigenetic enzyme critical for self-renewal of malignant myeloid cells and differentiation of myeloid progenitors. LSD1 bound to GFI1b permits maturation of progenitors to megakaryocytes and enables their normal function. IMG-7289 (bomedemstat) is an orally available LSD1 inhibitor. In mouse models of myeloproliferative neoplasms (MPN), IMG-7289 reduced elevated peripheral cell counts, spleen size, inflammatory cytokines, mutant allele frequencies, and marrow fibrosis (Jutzi et al. 2018) supporting its clinical development. IMG-7289-CTP-102 is an ongoing, multi-center, open-label study that recently transitioned from a Phase 1/2a dose-range finding study to a Phase 2b study of IMG-7289 administered orally once-daily in adult patients with intermediate-2 or high-risk MF resistant to or intolerant of ruxolitinib. The key objectives are safety, PD, changes in spleen volume (MRI/CT) and total symptoms scores (TSS) using the MPN-SAF instrument. Inclusion criteria included a platelet count ≥100K/μL. Bone marrow (BM) biopsies and imaging studies (both centrally-read) were conducted at baseline and during washout (post-Day 84). The MPN-SAF was self-administered weekly. Phase 1/2a patients were treated for 84 days followed by a washout of up to 28 days. Patients demonstrating clinical benefit could resume treatment for additional 12 week cycles. Dosing was individually tailored using platelet count as a biomarker of effective thrombopoiesis. Patients were started at a presumed sub-therapeutic dose of 0.25 mg/kg/d and up-titrated weekly until the platelet count rested between 50 and 100K/μL. This preliminary analysis includes 20 patients; 18 enrolled in the Phase 1/2a study, 2 in the Phase 2b portion. 50% had PMF, 35% Post-ET-MF, 15% Post-PV-MF. The median age was 65 (48-89) with 70% males. The median baseline platelet count was 197 k/μL (102-1309k/μL). 12 patients (56%) were transfusion-dependent at baseline. Sixty percent were IPSS-classified as high risk, the remainder, intermediate risk-2. 71% had more than 1 mutation of the 261 AML/MPN genes sequenced of which 63% were high molecular risk (ASXL1, U2AF1, SRSF2) mutations; 31% had abnormal karyotypes. Sixteen patients completed the first 12 weeks; 4 patients withdrew, one due to fatigue (Day 33), one for progressive disease (Day 39), one due to physician decision (Day 76), one for an unrelated SAE of cellulitis (Day 83). All patients were up-titrated from the starting dose 0.25 mg/kg to an average daily dose of 0.89 mg/kg ± 0.20 mg/kg, the dose needed to achieve the target platelet count range; 17 achieved the target platelet range in a mean time of 45 days. Of patients evaluable for response after cycle 1 in Phase1/2a (N=14), 50% had a reduction in spleen volume from baseline (median SVR: -14%; -2% to -30%). Further, 79% (N=11) recorded a reduction in TSS (mean change -28%; -13% to -69%); for 21% of patients (N=3), the change was &gt;-50%. Improved BM fibrosis scores at Day 84 were observed in 2/13 patients. Two patients had improvement in transfusion requirements. Plasma IL-8 levels were significantly elevated in 6/14 patients at baseline and dropped in a dose-dependent manner over 21 days in 5/6 patients. The mean duration of treatment is 166 days (14-539) at the census point in this ongoing study. Nineteen patients (95%) reported 358 AEs of which 22 were SAEs. Of the SAEs, 2 were deemed by investigators as possibly related: painful splenomegaly and heart failure. There have been no safety signals, DLTs, progression to AML, or deaths. This is the first clinical study of an LSD1 inhibitor in patients with MPNs. Once-daily IMG-7289 was well-tolerated in a heterogeneous population of patients with advanced MF and limited therapeutic options. Despite under-dosing and slow dose escalation, IMG-7289 improved symptom burdens in most patients and modestly reduced spleen volumes in a subset of patients. The Phase 2b 24-week expansion study with more aggressive dosing aimed at preserving safety and enhancing efficacy is open for enrollment in the US, UK and EU. Figure Disclosures Pettit: Samus Therapeutics: Research Funding. Gerds:Imago Biosciences: Research Funding; Celgene Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche: Research Funding; Sierra Oncology: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy. Yacoub:Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bradley:AbbVie: Other: Advisory Board. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Natsoulis:Imago BioSciences: Consultancy, Equity Ownership. Jones:Imago BioSciences: Employment, Equity Ownership. Talpaz:Samus Therapeutics: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Constellation: Research Funding; Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding. Peppe:Imago BioSciences: Employment, Equity Ownership. Ross:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rienhoff:Imago Biosciences: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

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 ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 680-680 ◽  
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.

scholarly journals Predictors of Remission in Adults with Immune Thrombocytopenia Treated with Romiplostim

Blood ◽  
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.

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

Blood ◽  
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.

Plerixafor (Mozobil ®)Plus G-CSF Is Effective in Mobilizing Hematopoietic Stem Cells in Patients with Concurrent Thrombocytopenia Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3229-3229 ◽  
Author(s):  
Ivana N Micallef ◽  
Eric Jacobsen ◽  
Paul Shaughnessy ◽  
Sachin Marulkar ◽  
Purvi Mody ◽  
...  
Keyword(s):  
Stem Cell ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Platelet Counts ◽  
Cd34 Cells ◽  
Low Platelet Count ◽  
Equity Ownership

Abstract Abstract 3229 Poster Board III-166 Introduction Low platelet count prior to mobilization is a significant predictive factor for mobilization failure in patients with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) undergoing autologous hematopoietic stem cell (HSC) transplantation (auto-HSCT; Hosing C, et al, Am J Hematol. 2009). The purpose of this study is to assess the efficacy of HSC mobilization with plerixafor plus G-CSF in patients with concomitant thrombocytopenia undergoing auto-HSCT. Methods Patients who had failed successful HSC collection with any mobilization regimen were remobilized with plerixafor plus G-CSF as part of a compassionate use program (CUP). Mobilization failure was defined as the inability to collect 2 ×106 CD34+ cells/kg or inability to achieve a peripheral blood count of ≥10 CD34+ cells/μl without having undergone apheresis. As part of the CUP, G-CSF (10μg/kg) was administered subcutaneously (SC) every morning for 4 days. Plerixafor (0.24 mg/kg SC) was administered in the evening on Day 4, approximately 11 hours prior to the initiation of apheresis the following day. On Day 5, G-CSF was administered and apheresis was initiated. Plerixafor, G-CSF and apheresis were repeated daily until patients collected the minimum of 2 × 106 CD34+ cells/kg for auto-HSCT. Patients in the CUP with available data on pre-mobilization platelet counts were included in this analysis. While patients with a platelet count <85 × 109/L were excluded from the CUP, some patients received waivers and were included in this analysis. Efficacy of remobilization with plerixafor + G-CSF was evaluated in patients with platelet counts ≤ 100 × 109/L or ≤ 150 × 109/L. Results Of the 833 patients in the plerixafor CUP database, pre-mobilization platelet counts were available for 219 patients (NHL=115, MM=66, HD=20 and other=18.). Of these, 92 patients (NHL=49, MM=25, HD=8 and other=10) had pre-mobilization platelet counts ≤ 150 × 109/L; the median platelet count was 115 × 109/L (range, 50-150). The median age was 60 years (range 20-76) and 60.4% of the patients were male. Fifty-nine patients (64.1%) collected ≥2 × 109 CD34+ cells/kg and 13 patients (14.1%) achieved ≥5 × 106 CD34+ cells/kg. The median CD34+ cell yield was 2.56 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 68.5%. The median time to neutrophil and platelet engraftment was 12 days and 22 days, respectively. Similar results were obtained when efficacy of plerixafor + G-CSF was evaluated in 29 patients with platelet counts ≤ 100 × 109/L (NHL=12, MM=10, HD=3 and other=4). The median platelet count in these patients was 83 × 109/L (range, 50-100). The median age was 59 years (range 23-73) and 60.4% of the patients were male. The minimal and optimal cell dose was achieved in 19(65.5%) and 3(10.3%) patients, respectively. The median CD34+ cell yield was 2.92 × 106 CD34+ cells/kg. The proportion of patients proceeding to transplant was 62.1%. The median time to neutrophil and platelet engraftment was 12 days and 23 days, respectively. Conclusions For patients mobilized with G-CSF alone or chemotherapy ±G-CSF, a low platelet count prior to mobilization is a significant predictor of mobilization failure. These data demonstrate that in patients with thrombocytopenia who have failed prior mobilization attempts, remobilization with plerixafor plus G-CSF allows ∼65% of the patients to collect the minimal cell dose to proceed to transplantation. Thus, in patients predicted or proven to be poor mobilizers, addition of plerixafor may increase stem cell yields. Future studies should investigate the efficacy of plerixafor + G-CSF in front line mobilization in patients with low platelet counts prior to mobilization. Disclosures Micallef: Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jacobsen:Genzyme Corporation: Research Funding. Shaughnessy:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Mody:Genzyme Corporation: Employment, Equity Ownership. van Rhee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 801-801 ◽  
Author(s):  
Francisco Cervantes ◽  
Jean-Jacques Kiladjian ◽  
Dietger Niederwieser ◽  
Andres Sirulnik ◽  
Viktoriya Stalbovskaya ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Extension Phase ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Case Studies Of Remission In Adults With Immune Thrombocytopenia (ITP) Following Cessation Of Treatment With The TPO Receptor Agonist Romiplostim

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 328-328
Author(s):  
James B. Bussel ◽  
Xuena Wang ◽  
Melissa Eisen
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Regulatory Cell ◽  
Platelet Counts ◽  
Long Term Treatment ◽  
Wide Range ◽  
Equity Ownership

Abstract Background In adults, ITP (characterized by platelet counts <100x109/L) is typically chronic, with remission reported infrequently ≥3 y post-diagnosis (Sailer, Haematol 2006). The TPO-mimetic romiplostim increases platelet counts and reduces use of concomitant ITP medications in chronic ITP. While often perceived as a long-term treatment, dose adjustment rules allow romiplostim to be discontinued when hemostatic platelet counts are reached, as reported in Amgen trials (pivotal trials, 2011 EHA, 2011 ASH) and case reports. Methods Data from 8 romiplostim trials (4 phase 3, 2 single-arm, and 2 extension trials) were examined for cases in which patients receiving romiplostim subsequently had ≥26 consecutive wks of platelet counts ≥50x109/L without romiplostim or any other ITP medications. The number of evaluable patients could not be calculated as many trials had dosing rules that did not allow for the reduction of romiplostim in patients with platelet counts <400x109/L (making remission unlikely), treatment durations varied by study, and follow-up data were not always available. Results Twenty-seven patients had ≥26 wk of platelet counts ≥50x109/L without romiplostim or any other ITP medications (Table; data from 4 of these patients were presented at ASH 2011). These patients had characteristics of median (Q1, Q3) time since ITP diagnosis of 2.1 (0.5, 4.2) y, with 17/27 having ITP >1 y, mean (SD) baseline platelet count of 20.9 (15.41) x109/L, median (Q1, Q3) age of 49.0 (36.0, 67.0) y, and mean (SD) maximum dose prior to remission of 4.6 (3.6) µg/kg. Of the 27 patients, 12 (44%) were splenectomized at baseline and 15 (56%) were male. Patients had from 40 to 276 cumulative wks of romiplostim with doses ranging from 0.1 to 4.3 µg/kg. Prior to romiplostim treatment, minimum platelet counts ranged from 1-37x109/L and individual average platelet counts ranged from 1-152x109/L. On treatment, minimum (1-182x109/L) and average (121-654x109/L) platelet counts ranged widely. The median (Q1, Q3) time to remission was 7.1 (1.9, 12.7) months. Only 3 patients (3, 6, 15) had bleeding of grade 3; the remainder had either bleeding of grade 1 or 2 or none. Conclusions The patient population who entered clinical remission (platelet counts ≥50x109/L for 26 wks) after treatment with romiplostim generally had: ITP of less than 5 y duration, a wide range of ages (23-78 y), about equal proportions of men and women, were as likely to be splenectomized as not, and no significant bleeding. Therefore, it is difficult to predict which patients would have this response. Reporting of these cases was not predefined, so a prospective assessment, such as the phase 2 single-arm study currently underway (NCT01143038), will provide a more comprehensive evaluation of remission with romiplostim. Potential mechanisms for the phenomenon of remission, both in early and late stages of ITP, may involve T-regulatory cell function, increased numbers/activity of natural killer T-cells, or increased B-regulatory cell activity. Disclosures: Bussel: Amgen: 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; GSK: Equity Ownership, 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; 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. Wang:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.

Efficacy of Ruxolitinib By Baseline Spleen Volume in Patients with Polycythemia Vera Resistant to or Intolerant of Hydroxyurea

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1840-1840 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Srdan Verstovsek ◽  
Mark M Jones ◽  
Shui He ◽  
Jingjin Li ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Linear Regression ◽  
Polycythemia Vera ◽  
Board Of Directors ◽  
Research Funding ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Response Trial

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm defined by erythrocytosis; patients may also have increased platelets and white blood cells as well as splenomegaly and disease-related symptoms. JAK/STAT activation is the primary driver of PV pathogenesis, in most cases resulting from the JAK2V617F mutation. The RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV and splenomegaly who were intolerant of or resistant to hydroxyurea (HU) according to modified European LeukemiaNet criteria. At the time of the primary analysis, RUX demonstrated superior improvements in hematocrit (HCT) control, symptom burden, and spleen volume compared with BAT. This post hoc analysis of RESPONSE was conducted to determine if treatment outcomes were influenced by baseline spleen volume. Methods : Patients with PV ≥18 years of age who were resistant to or intolerant of HU with palpable spleen (confirmed by MRI/CT to be ≥450 cm3) and phlebotomy requirement were randomized 1:1 to receive open-label RUX 10 mg BID or BAT. The primary endpoint was a composite that required a ≥35% reduction in spleen volume at Week 32 and hematocrit (HCT) control. HCT control was defined as lack of phlebotomy eligibility (based on HCT values) between Weeks 8–32 with no more than 1 phlebotomy eligibility between randomization and Week 8. A linear regression was conducted to determine the effect of baseline spleen volume on the percent change in spleen volume at Week 32. A logistic regression was conducted to determine the effect of baseline spleen volume on HCT control through Week 32. Spleen volume was measured by MRI at screening and Weeks 16 and 32. Hematocrit was assessed at screening, prerandomization, and every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32. Results :The RESPONSE trial enrolled 222 patients (RUX, 110; BAT, 112). Median (range) spleen volume at baseline was 1195 cm3 (396–4631 cm3) in the RUX arm and 1322 cm3 (254–5147 cm3) in the BAT arm. Baseline median (range) spleen length by palpation was 7.0 cm (0.0–24.0 cm) in the RUX arm and 7.0 cm (0.0–25.0 cm) in the BAT arm. In the 24 weeks prior to screening, most patients in both arms had ≥2 phlebotomy procedures (RUX, 87%; BAT, 80%). There was no correlation between the percentage change in spleen volume at Week 32 and baseline spleen volume; linear regression showed no significant effect of baseline spleen volume on the percentage change in spleen volume at Week 32 (P=0.40). No significant effect of baseline spleen volume on HCT control through Week 32 was identified based on logistic regression analysis (P=0.37). Conclusion : In PV patients with inadequate response to or intolerant of HU, the degree of splenomegaly at baseline did not influence achievement of HCT control or reduction in spleen volume with RUX therapy. Disclosures Vannucchi: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Verstovsek:Incyte Corporation: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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