scholarly journals Comparative Effectiveness of Fedratinib and Pacritinib for the Treatment of Myelofibrosis in Patients with Low Platelet Counts: A Simulated Treatment Comparison Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 5034-5034
Author(s):  
Patrick Daniele ◽  
Pranav Abraham ◽  
Arianna Kee ◽  
Gabriel Tremblay ◽  
Shelonitda Rose ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Platelet Count ◽  
Literature Review ◽  
Comparative Efficacy ◽  
Mutation Status ◽  
Baseline Platelet Count ◽  
Platelet Counts ◽  
Median Baseline ◽  
Treatment Comparisons ◽  
Privately Held

Abstract Introduction: Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm with an estimated prevalence of 4-6/100,000 persons in the USA. Patients with MF experience aberrant hematopoiesis, bone marrow fibrosis, splenomegaly, and cytopenias, including thrombocytopenia, as well as diminished survival ranging from months to years, depending on risk status. Symptoms progressively worsen, underscoring the need for effective treatments across heterogeneous risk statuses and patient dispositions. Among intermediate- to high-risk patients, Janus kinase 2 (JAK2) inhibitors are the primary treatment for MF. Fedratinib was approved by the US Food and Drug Administration (FDA) based on the results of the JAKARTA trials (NCT01437787; NCT01523171), and a new drug application for pacritinib has been submitted to the FDA for the treatment of MF in patients with severe thrombocytopenia. A head-to-head trial of fedratinib and pacritinib for the treatment of MF has not been conducted. Moreover, there is a paucity of evidence evaluating these agents in patients with MF and thrombocytopenia (platelets < 100 × 10 9/L). Therefore, indirect treatment comparisons (ITCs) are required to assess the comparative efficacy of fedratinib and pacritinib in this population. Methods: A systematic literature review (SLR) was conducted to identify all clinical evidence in patients with MF and thrombocytopenia. Based on the SLR results, the JAKARTA, JAKARTA-2, and PERSIST-2 (NCT01773187) trials were identified as the studies to form the basis of the ITC. A pooled analysis data set was developed based on individual patient-level data from the fedratinib 400-mg arms of the JAKARTA and JAKARTA-2 trials including patients with platelets < 100 × 10 9/L. Published summary data from the pacritinib 200-mg arm of the PERSIST-2 trial served as the comparator. Simulated treatment comparisons (STCs) were used to compare spleen volume reduction (SVR) ≥ 35% while adjusting for mutually reported baseline patient characteristics such as age, sex, Dynamic International Prognostic Scoring System, Eastern Cooperative Oncology Group (ECOG) performance status (PS), JAK2 V617F mutation status, prior ruxolitinib exposure, and laboratory tests. Final adjustment models were selected based on fit statistics and the literature review. Indirect relative risk (RR) was estimated with 95% confidence intervals (CIs) using unanchored naive ITC (unadjusted) and STC (adjusted) methodologies. The PERSIST-2 trial included patients with baseline platelets < 50 × 10 9/L, but did not report median baseline counts. Therefore, a sensitivity analysis was conducted to evaluate the impact of differential median baseline platelet counts. In the sensitivity analysis, an outcome model was generated in the full pooled JAKARTA trial population irrespective of platelet count, and platelet count was forced into the multivariable adjustment model. Outcomes were simulated at 3 median baseline platelet counts (25, 50, and 75 × 10 9/L) and compared using similar methodology to the main analysis. Results: The main analysis suggests that fedratinib is associated with a greater proportion of SVR ≥ 35% than pacritinib (Table, A). According to the naive ITC, fedratinib was numerically favored over pacritinib in terms of SVR ≥ 35% (RR, 1.67 [95% CI, 0.94-2.97]). After adjustment for ECOG PS, JAK2 V6127F mutation status, and prior ruxolitinib exposure, fedratinib was statistically favored relative to pacritinib for SVR ≥ 35% (RR, 1.76 [95% CI, 1.00-3.10]). Results of the platelet-count-adjusted sensitivity analysis showed that a significant difference was observed in favor of fedratinib with respect to SVR ≥ 35% (Table, B). The resulting indirect RRs were similar regardless of simulated median baseline platelet count, which suggest that differential baseline platelet count has a minimal impact on the ITC results. Conclusion: This analysis used a population-adjusted ITC to assess the comparative efficacy of pacritinib and fedratinib in patients with MF and thrombocytopenia. Following population adjustment, fedratinib was associated with a greater proportion of patients achieving SVR ≥ 35% than pacritinib. In lieu of a head-to-head clinical trial, further real-world evidence studies should be conducted to assess the effectiveness of these treatments in the clinical setting. Figure 1 Figure 1. Disclosures Daniele: BMS/Celgene: Consultancy; Purple Squirrel Economics: Current Employment. Abraham: Bristol Myers Squibb: Current Employment. Kee: Bristol Myers Squibb: Current Employment. Tremblay: Cytel: Consultancy; Purple Squirrel Economics: Current Employment. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. McBride: BMS: Current Employment.

Platelet Counts Following Eltrombopag Discontinuation in Patients with Chronic Immune Thrombocytopenic Purpura.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3517-3517
Author(s):  
Gregory Cheng ◽  
Michael Tarantino ◽  
Terry Gernsheimer ◽  
Oliver Meyer ◽  
Andres Brainsky ◽  
...  
Keyword(s):  
Platelet Count ◽  
Immune Thrombocytopenic Purpura ◽  
Research Funding ◽  
Rescue Medication ◽  
Study Medication ◽  
Bleeding Events ◽  
Thrombocytopenic Purpura ◽  
Baseline Platelet Count ◽  
Platelet Counts ◽  
Transient Decrease

Abstract Abstract 3517 Poster Board III-454 BACKGROUND Eltrombopag (PROMACTA®; GlaxoSmithKline, Collegeville, PA, USA) is an oral, small molecule (565 Da), thrombopoietin receptor agonist that has been approved in the United States for the treatment of patients with chronic immune thrombocytopenic purpura (ITP). It is also being studied in thrombocytopenic patients with chronic liver disease, hepatitis C, myelodysplastic syndromes, and cancer. Withdrawal of treatments that stimulate platelet production may theoretically result in recurrent thrombocytopenia below pretreatment levels (below baseline). OBJECTIVE: To determine whether worsening of thrombocytopenia (ie, platelet count decrease below baseline) occurs after discontinuation of eltrombopag in patients with chronic ITP. METHODS: The lowest median platelet counts during the first 4 weeks posttherapy were compared with median baseline platelet counts. Data from 369 patients treated in 3 randomized, double-blind, placebo-controlled studies were analyzed: TRA100773A and TRA100773B were 6-week studies, and RAISE was a 6-month study. For all 3 studies, a baseline platelet count <30,000/μL was required. Platelet counts, bleeding events, and the use of ITP medication were examined in the 4 weeks following the discontinuation of eltrombopag or placebo. A transient decrease in platelet counts (ie, worsening of thrombocytopenia) was defined as a platelet count below 10,000/μL and at least 10,000/μL below each patient's baseline platelet count (Bussel N Eng J Med 2006). RESULTS: Using pooled data from the 3 studies, no decreases below baseline median platelet counts (placebo, 16,300/μL; eltrombopag, 16,000/μL) were observed compared to the lowest median platelet counts within the first 4 weeks posttherapy (placebo, 14,000/μL; eltrombopag, 17,000/μL). Across the pooled studies, a total of 10/128 (8%) of placebo-treated patients and 20/241 (8%) of eltrombopag-treated patients had a transient decrease in platelet counts in the 4 weeks following discontinuation or interruption of treatment. None of the 10 placebo-treated patients had bleeding events associated with posttreatment platelet nadirs. Three of the 20 eltrombopag-treated patients had bleeding events and/or rescue treatment associated with the platelet nadir in the 4-week posttreatment period. One patient discontinued eltrombopag after achieving platelet counts >200,000/μL following on-therapy rescue medication (corticosteroid 0.5 mg/kg/day); 9 days after discontinuing study medication, the patient had grade 1 gum bleeding and resumed daily corticosteroids at an increased dose. The second patient had grade 3 menorrhagia and was administered vincristine (patient had a history of similar symptoms). The third patient had Henoch-Schoenlein purpura, interrupted eltrombopag due to platelet counts >400,000/μL, and 7 days after holding eltrombopag had a platelet count of 2000/μL, experienced grade 1 mouth hemorrhage and grade 2 petechiae, and did not require rescue medication. The patient continued in the study for the full 6 months and following permanent discontinuation of eltrombopag, this patient did not experience a transient decrease in platelet counts or any bleeding. CONCLUSION: Across 3 placebo-controlled studies, the incidence of transient decreases in platelet counts following discontinuation or interruption of study medication was similar in patients receiving eltrombopag or placebo. Therefore, these decreases may be unrelated to study medication and may represent normal fluctuations in platelet counts in patients with chronic ITP. Transient platelet count decreases were generally not associated with bleeding events. Disclosures: Cheng: GlaxoSmithKline: Research Funding. Tarantino:GlaxoSmithKline: Speakers Bureau; Lundbeck: Speakers Bureau; Baxter: Membership on an entity's Board of Directors or advisory committees. Gernsheimer:GlaxoSmithKline: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Meyer:GlaxoSmithKline: Consultancy, Honoraria. Brainsky:GlaxoSmithKline: Employment. Stone:GlaxoSmithKline: Employment.

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

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

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

An Individual Platelet Count Set-Point in ITP: A Concept Learned from Patients with Mild Thrombocytopenia and a Good Response to IVIg or Corticosteroids.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3926-3926
Author(s):  
Donald M. Arnold ◽  
Jane C. Moore ◽  
James W. Smith ◽  
John G. Kelton
Keyword(s):  
Platelet Count ◽  
Invasive Procedure ◽  
Platelet Glycoprotein ◽  
Platelet Destruction ◽  
Specific Test ◽  
Baseline Platelet Count ◽  
Set Point ◽  
Platelet Counts ◽  
Count Response ◽  
Platelet Autoantibodies

Abstract Background: Immune thrombocytopenic purpura (ITP) is a heterogeneous disease caused by both increased platelet destruction and decreased platelet production. Thrombocytopenia is typically severe, and in the absence of a sensitive and specific test, a platelet count response to intravenous immune globulin (IVIg) or corticosteroids is diagnostic. Patients with mild thrombocytopenia (platelets 50 – 150 × 109/L) may have ITP, non-immune thrombocytopenia or a low-normal platelet count. The diagnostic value of platelet autoantibodies for such patients is not known. Methods: We studied the platelet count responses of 6 patients with mild thrombocytopenia who were treated with either IVIg or corticosteroids. Baseline platelet count was defined as the mean of the 2 lowest, consecutive platelet counts that were within 15% of each other. The peak platelet count was the highest recorded platelet count measured within 1 month of treatment. For most patients, the dose of IVIg was 1g/kg ×1, and the dose of prednisone was 1mg/kg for 2 – 4 weeks. Complete response was defined as a peak platelet count that was at least 2x baseline; a partial response was defined as a peak platelet count 1.5 – 2x baseline; below that was not considered a response. Platelet glycoprotein IIb/IIIa and Ib/IX autoantibodies were determined by the antigen capture assay using platelet lysates prepared from samples collected prior to treatment. An OD &gt;0.4 was considered positive. Results: Five patients with mild thrombocytopenia received 5 treatments with IVIg and 2 treatments with corticosteroid (2 patients received IVIg on 2 separate occasions). The indications for treatment were: planned invasive procedure (n=5), pregnancy/delivery (n=1), and treatment of multiple sclerosis (n=1). Patients were followed for a median of 1.6 years (range 0.6 – 3 years). Median baseline platelet count prior to treatment was 70 ×109/L (range 57 – 79 ×109/L). A platelet count response was observed following all 7 treatments; including 5 complete responses and 2 partial responses. Median peak platelet count was 180 ×109/L (range 115 – 297 ×109/L). Post-treatment platelet counts returned to within 15% of pre-treatment values following 6 of 7 treatments after a median of 3 months (range 1 week – 5 months). Of the 3 patient tested, none had anti-GP IIb/IIIa or anti-Ib/IX autoantibodies. Interpretation: A good response to IVIg (or steroid) treatment confirmed the immune nature of mild thrombocytopenia in this cohort and should be used as the gold standard to evaluate the test characteristics of platelet autoantibodies. We observed that some patients with mild ITP have an individual platelet count “set-point” which remained relatively stable over time. Although further testing is required, this concept implies that in some patients, there is a regulated balance between platelet destruction and underproduction.

scholarly journals Real-World Experience with Fostamatinib in Patients with Immune Thrombocytopenia at an Academic Medical Center

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4912-4912 ◽  
Author(s):  
David Hughes ◽  
Frances Blevins ◽  
Bhavesh Shah ◽  
Shayna Sarosiek ◽  
Adam Lerner ◽  
...  
Keyword(s):  
Platelet Count ◽  
Immune Thrombocytopenia ◽  
Medical Center ◽  
Rescue Therapy ◽  
Academic Medical Center ◽  
Baseline Platelet Count ◽  
Platelet Counts ◽  
Therapy Initiation ◽  
Academic Medical ◽  
Insufficient Response

Introduction Fostamatinib is a first in its class oral inhibitor of spleen tyrosine kinase (Syk) pathway for treatment of adults with immune thrombocytopenia (ITP) with insufficient response to previous treatment. Choice of treatment for relapsed ITP varies greatly according to clinician and patient preference. It is common for patients to switch between available thrombopoietin (TPO) agonists and now fostamatinib. Titration of these agents is often cumbersome and labor intensive; romiplostim in particular requires weekly visits with lab draws and consumes nurse, pharmacy and provider effort. Here we present real world experience with fostamatinib use in an academic medical center. Methods. We retrospectively identified four patients who were prescribed fostamatinib within the past nine months at Boston Medical Center Health System. All patients had a diagnosis of chronic ITP and were previously treated with corticosteroids, intravenous immunoglobulin (IVIG), and rituximab. With respect to previous TPO receptor use, two of four patients had received both eltrombopag and romiplostim. Patients were started on fostamatinib at a dose of 100 mg by mouth twice daily and titrated up to 150 mg by mouth twice daily if platelet counts were <50 10x9 /L after 4 weeks of therapy. All patients were seen by a pharmacist and provider for initiation of the drug and seen in clinic weekly for the first month on therapy to assess toxicity and efficacy. The duration of follow up for the patients is between 2 and 9 months on therapy. Results. Three of four patients initiated on fostamatinib had a baseline platelet count 100K or greater and the fourth patient had ITP refractory to multiple lines of therapy with a baseline platelet count of 7K at therapy initiation. Three patients sought alternative therapy given side effects from TPO agonists or inconvenience of romiplostim. Three patients had platelets counts >50K at 4 weeks and one patient had a platelet count <30K. Recent platelet counts of the two patients that have been on therapy for 7 and 8 months were 123K and 108K, respectively. The third patient that responded initially discontinued therapy due to lack of stable response. Both of the patients with stable responses were well controlled on previous therapy with romiplostim. One patient required rescue therapy with IVIG and romiplostim due to petechiae 15 days after therapy initiation but continued on therapy thereafter. Two patients that discontinued therapy had platelet counts of 10K and 88K upon discontinuation due to inadequate response and toxicity, respectively. One patient was romiplostim naïve and the other patient had not received romiplostim for four years prior. Two patients developed diarrhea that was managed with loperamide and one led to treatment discontinuation (in combination with insufficient response). One patient experienced hypertension that was managed accordingly. Conclusion. The ideal place in therapy for fostamatinib in ITP therapy is not yet clear. However, the availability as an oral option for patients with refractory disease is appealing. One of our patients required rescue therapy which should be considered when transitioning patients to fostamatinib from TPO agonists. Additionally, side effect management with anti-hypertensives and anti-diarrheal agents may be required to continue therapy. Effectiveness of romiplostim may predict responsiveness to fostamatinib, although additional data are needed. Table Disclosures Shah: Rigel Pharmaceutical: Consultancy, Speakers Bureau. Sarosiek:Acrotech: Research Funding. Sloan:Merck: Other: endpoint review commitee; Abbvie: Other: Endpoint Review Committee; Stemline: Consultancy.

A Randomized, Double-Blind, Placebo-Controlled Phase II Trial on the Efficacy, Safety and Tolerability of E5501 (AKR501) In Subjects with Chronic Immune Thrombocytopenia (ITP)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 71-71 ◽  
Author(s):  
James B. Bussel ◽  
Jenny Zhang ◽  
Shande Tang ◽  
Joe McIntosh ◽  
David J. Kuter
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Responder Rate ◽  
Dependent Manner ◽  
Advisory Committees ◽  
Double Blind ◽  
Baseline Platelet Count ◽  
Platelet Counts ◽  
Dose Dependent

Abstract Abstract 71 Chronic immune thrombocytopenia (ITP) is a condition of low platelet counts due to increased autoimmune-mediated platelet destruction and suboptimal platelet production. Thrombopoietin (TPO) receptor agonists are a novel class of agents which increase platelet counts by mimicking the principal physiologic regulator of platelet production, TPO. TPO agonists have demonstrated efficacy in randomized controlled trials in patients with ITP who are refractory to 1st and 2nd line agents. E5501 (previously AKR501) is a novel, orally-active, once-a-day TPO agonist which increased platelet counts in healthy volunteers. Here, we report data from a Phase II, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, parallel group 4-week study (501-CL-003) of E5501 in subjects with ITP whose disease was refractory to, or had relapsed after, at least one prior ITP therapy. Subjects were enrolled if they had a baseline platelet count of <30 x109/L, or if they had a baseline platelet count of <50 x109/L and were on stable corticosteroid therapy. Sixty-four subjects were randomized to E5501 (2.5, 5, 10 or 20 mg) or placebo in a 3:3:3:3:1 randomization ratio, respectively. E5501 or placebo was administered orally, once daily for 28 days. Response to E5501 was based on weekly platelet counts. The primary endpoint was responder rate at Day 28. Responders were defined as subjects whose platelet count was ≥50 x109/L and had risen by a minimum of 20 x109/L above baseline. Responder rate increased in subjects receiving E5501 in a dose-dependent manner (Table 1). At Day 28, the responder rate in the E5501 20 mg group was 80% (12 of 15 subjects) vs 0% in the placebo group (p=0.0036). The responder rate was also significantly higher with E5501 20 mg than with E5501 2.5 mg (80% vs 13.3%; p=0.0007). In non-splenectomized subjects, the responder rate at Day 28 was 51.2% in the combined E5501 group and 88.9% in the E5501 20 mg group, compared with 44.4% and 66.7% respectively in splenectomized subjects. Median platelet counts at Day 28, and change in platelet counts above baseline, increased in subjects receiving E5501 in a dose-dependent manner (Table 2). The majority (57.6%) of subjects responded to a dose of ≥5 mg E5501 by Day 7. Subjects treated with E5501 20 mg achieved a 93.3% response rate on Day 7. None of the 5 placebo-treated subjects responded at any time during the study. E5501 was well tolerated, with a similar proportion of subjects showing treatment-emergent adverse events (TEAEs) across all dose groups. Most TEAEs were mild, transient, and resolved completely. TEAEs occurring in ≥10% of E5501-treated subjects were fatigue (20.3%), headache (20.3%) and epistaxis (15.3%). There were no clinically relevant changes in vital signs or physical examination findings. Three subjects (2 in the 2.5 mg and 1 in the 10 mg E5501 group) reported serious TEAEs. Of the two subjects in the 2.5 mg E5501 group, one reported thrombocytopenia and one reported a GI bleed; both had platelet counts <10 x109/L. The one subject in the 10 mg E5501 group, a 72-year-old Hispanic male with a significant history of cardiovascular disease (including myocardial infarction [MI], coronary artery vein bypass graft, 3 prior transient ischemic attacks [TIAs], chronic obstructive pulmonary disease, hypertension, systolic ejection murmur, angioplasty, stent placement, hyperlipidemia, and small vessel disease), had TIA and MI on Day 20 and a retinal artery occlusion 14 days after E5501 was discontinued. At the time of the events his platelet counts were 40–47 x109/L. Three other E5501-treated subjects (6.8% in total) experienced TEAEs leading to study drug withdrawal: 1 receiving 5 mg E5501 had Grade 2 musculoskeletal chest pain; 2 receiving 20 mg E5501 had excessively increased platelet counts with no clinical sequellae. In conclusion, E5501 was effective in increasing platelet counts in subjects with ITP. At 20 mg E5501, 80% of patients had responded at Day 28, with a median platelet count of 95 x109/L, and >90% of patients had responded by Day 7. E5501 was generally well tolerated and had a favorable safety profile. These data support continued development of E5501 as a potentially effective treatment with an acceptable safety profile in non-splenectomized and splenectomized patients with ITP. Disclosures: Bussel: Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy. Zhang:Eisai: Employment. Tang:Eisai: Employment. McIntosh:Eisai: Employment. Kuter:Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; ONO: Consultancy; Shionogi: Consultancy, Research Funding; Pfizer: Consultancy; Protalix: Consultancy, Research Funding; Risk Managment Foundation: Consultancy.

EXTEND Study Update: Safety and Efficacy of Eltrombopag In Adults with Chronic Immune Thrombocytopenia (ITP) From June 2006 to February 2010

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 67-67 ◽  
Author(s):  
Mansoor N. Saleh ◽  
Gregory Cheng ◽  
James B. Bussel ◽  
Huiping Sun ◽  
Bhabita Mayer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Immune Thrombocytopenia ◽  
Thromboembolic Events ◽  
Bone Marrow Biopsies ◽  
Baseline Platelet Count ◽  
Safety And Efficacy ◽  
Platelet Counts ◽  
Equity Ownership ◽  
Chronic Immune Thrombocytopenia

Abstract Abstract 67 Background: Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of chronic immune thrombocytopenia (ITP) in the US and other countries. In 6-week and 6-month placebo-controlled trials, eltrombopag safely increased platelet counts and reduced bleeding symptoms in patients with previously treated chronic ITP. The safety and efficacy of eltrombopag treatment are being evaluated in EXTEND, an ongoing open-label, extension study in ITP patients who completed a previous eltrombopag study. Methods: Enrolled patients had previously received eltrombopag or placebo in one of the following studies: two 6-week studies (773A and B), RAISE (6-month), or REPEAT (intermittent treatment). In EXTEND, specific goals include: 1) identification of a dose of eltrombopag that increases platelet counts (≥100,000/μ L) to support reduction of concomitant ITP medications (if taken); 2) identification of minimally effective doses of eltrombopag and concomitant ITP medication to maintain platelet counts ≥50,000/μ L; and 3) evaluation of the safety and efficacy of eltrombopag. Patients who completed at least 2 years of therapy and transitioned off study due to commercial availability of eltrombopag were considered to have completed the study. Results: Of 299 patients enrolled, 8% (23) completed the study, 41% (122) withdrew, and 52% (154) remain on study. The main reasons for withdrawal were adverse events (AEs, 11%), patient decision (11%), and lack of efficacy (10%). At baseline, platelet counts were ≤15, >15–<30, 30–50, and >50,000/μ L in 43%, 27%, 17%, and 13% of patients, respectively; 38% of patients were splenectomized; 33% were receiving concomitant ITP medication at baseline, and 53% had received ≥3 previous ITP therapies. 249, 210, 138, and 24 patients had been taking eltrombopag for ≥26, 52, 104, and 156 weeks, respectively, with a median duration of exposure of 100 weeks at the time of data analysis. The proportion of patients achieving a platelet count ≥50,000/μ L was similar regardless of the following baseline characteristics: splenectomy (84%) vs no splenectomy (89%); use of ITP medication (88%) vs no use of ITP medication (87%); and baseline platelet count <30,000/μ L (83%) vs 30–50,000/μ L (98%) vs >50,000/μ L (95%). Overall, 87% (261/299) of patients achieved a platelet count ≥50,000/μ L on treatment; 37 of these had a baseline platelet count of ≥50,000/μ L. Median platelet counts increased to ≥50,000/μ L by week 2 and remained consistently ≥50,000/μ L through week 164. The incidence of any bleeding symptoms (WHO grades 1–4) declined from 56% at baseline to 16% and 20% at weeks 52 and 104, respectively. Clinically significant bleeding (WHO grades 2–4) was reduced from 16% (47/299) at baseline to 3% (2/77) and 7% (3/41) at weeks 52 and 104, respectively. AEs and SAEs occurred in 88% (262) and 26% (79) of patients, respectively. The most frequent AEs were headache (26%), nasopharyngitis (23%), and upper respiratory tract infection (21%). AEs led to withdrawal of 13% (38) of patients, 9% (27) of which were due to SAEs. Twenty-one thromboembolic events (TEE) have been reported in 5% (16) of patients; the incidence rate is 3.17/100 patient years (95% CI [1.81, 5.15]). The most common TEEs were DVT (8) and MI (4). No association has been observed with elevated platelet counts, as only 3/16 patients experienced the TEE closest to their maximum platelet count achieved on study. Hepatobiliary laboratory abnormalities were reported in 29 patients (10%). All were reversible; the majority while on therapy. Of 299 patients enrolled, 6 (2%) have been withdrawn due to a hepatobiliary AE. After examining bone marrow biopsies from >150 patients treated with eltrombopag for >1 year, no clinically relevant increase in reticulin fiber deposition has been observed. Conclusions: Eltrombopag was effective in increasing and maintaining platelet counts ≥50,000/μ L and reducing bleeding symptoms. Eltrombopag has an overall positive risk/benefit assessment and was well tolerated during treatment of patients with chronic ITP even with exposures of more than 3 years. Bone marrow biopsies will continue to be assessed. Hepatobiliary laboratory abnormalities and thromboembolic events are risks that need to be monitored. Disclosures: Saleh: GlaxoSmithKline, Novartis, Imcoline, Celgene: Honoraria, Speakers Bureau. Cheng:GlaxoSmithKline: Consultancy, Honoraria, Speakers Bureau. Bussel:GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mayer:GlaxoSmithKline: Employment, Equity Ownership. Bailey:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.

Sustained Complete Remission Of Corticosteroid-Resistant Immune Thrombocytopenia With a Short Course Of Recombinant Human Thrombopoietin

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4746-4746 ◽  
Author(s):  
Hai Zhou ◽  
Ping Qin ◽  
Jihua Qiu ◽  
Linlin Shao ◽  
Yawen Wang ◽  
...  
Keyword(s):  
Platelet Count ◽  
Complete Remission ◽  
Fold Increase ◽  
Complete Response ◽  
Baseline Platelet Count ◽  
Platelet Counts ◽  
Time To Peak ◽  
Short Course ◽  
Daily Dose ◽  
Recombinant Human Thrombopoietin

Thrombopoietin (TPO) and TPO receptor agonists have substantially broadened the therapeutic options for patients with immune thrombocytopenia (ITP). Platelet count response of ITP is usually maintained during the medication; however, once it is stopped, platelet counts commonly drop to pretreatment levels. We report three corticosteroid-resistant ITP patients achieving sustained complete remission with one short-term application of recombinant human thrombopoietin (rhTPO). Thirty-two adult ITP patients (18 females and 14 males; age range 18-72 years, median 45 years) were enrolled between December, 2011 and July, 2013 at the Department of Hematology, Qilu Hospital, Shandong University. Patients were diagnosed according to the recently published criteria (Rodeghiero F et al, Blood 2009). All patients had a baseline platelet count (PC) of < 30 x 109/L and bleeding symptoms, and were resistant to prior corticosteroid therapy or splenectomy. Recombinant human thrombopoietin (rhTPO, a truncated and non-glycosylated TPO developed by 3SBIO Pharmaceutical Co., LTD, Shenyang, China, approved by China State Food and Drug Administration) was given subcutaneously at a daily dose of 1.0 µg/kg for 14 days. Withdrawal of rhTPO could be performed while platelet count rose to above 100 x 109/L in less than 14 days. Responses were required to be independent of supportive medications. The criteria for response were defined as follows: (1) complete response (CR): platelet count > 100 x 109/L; (2) response (R): platelet count > 30 x 109/L and at least 2-fold increase of the baseline platelet count and absence of bleeding; (3) no response (NR): platelet count < 30 x 109/L or less than 2-fold increase of the baseline platelet count or bleeding. Of the 32 ITP patients treated with rhTPO, the complete response (CR), response (R), overall response (OR) and no response (NR) rates were 37.50% (12/32), 28.12% (9/32), 65.62% (21/32) and 34.38% (11/32), respectively. Among the 32 patients, three (9.38%) acquired sustained complete response (i.e., platelet count > 100 x 109/L and no clinical symptoms for at least six months after the medication). Of these three patients, the time to peak response was 28, 20 and 28 days, and the peak values of platelet counts were 215 x 109/L, 245 x 109/L and 296 x 109/L, respectively. These three patients’ information was shown in Table 1. Their platelet count responses sustained for 56, 40 and 28 weeks without any ITP-specific treatments after the cessation of rhTPO (Figure 1). In addition, only mild adverse events (WHO grades 1-2) were observed, including fever, fatigue and insomnia.Table 1Characteristics of the three ITP patients who achieved a durable complete response associated with the use of rhTPO.PatientAge(years)SexBaseline Platelet Count (x109/L)rhTPO Daily Dose(µg/kg)rhTPO Duration(days)Time to Peak Response(days)Peak Value of Platelet Count(x109/L)Complete Remission off rhTPO(Weeks)172Female21122821556234Female51102024540354Male81142829628Figure 1Serial platelet counts of three ITP patients who achieved a definite rhTPO-induced sustained remission.Figure 1. Serial platelet counts of three ITP patients who achieved a definite rhTPO-induced sustained remission. In conclusion, some ITP patients can achieve sustained complete remission after a short-course of rhTPO. However, the mechanism behind this is unclear. Disclosures: No relevant conflicts of interest to declare.

Eltrombopag Is Efficacious in Patients with Refractory Chronic Idiopathic Thrombocytopenic Purpura (ITP) - Data from the EXTEND Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 401-401 ◽  
Author(s):  
Mansoor N Saleh ◽  
James B Bussel ◽  
Gregory Cheng ◽  
Balkis Meddeb ◽  
Paul M Burgess ◽  
...  
Keyword(s):  
Platelet Count ◽  
Clinical Benefit ◽  
Baseline Platelet Count ◽  
Platelet Counts ◽  
Prior Therapy ◽  
Chronic Itp ◽  
Significant Difference ◽  
Previously Treated ◽  
Clinically Significant ◽  
Refractory Itp

Abstract INTRODUCTION: Refractory ITP patients have an unmet medical need for new treatment options. It is unknown how novel therapeutic agents such as eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline), the first oral, small-molecule, non-peptide thrombopoietin receptor agonist, may help ITP patients refractory to standard therapies. Eltrombopag was shown to substantially increase platelet counts during 2 placebo-controlled trials including &gt;200 previously treated chronic ITP patients. EXTEND is an ongoing, open-label study designed to assess the long-term safety and clinical benefit of eltrombopag in patients with chronic ITP. METHODS: A post hoc analysis of EXTEND data assessed the efficacy of eltrombopag treatment in 165 chronic ITP patients, by refractoriness to prior therapy. Patients included had to have been on study ≥6 weeks. Refractory patients were defined as those with no response to a prior therapy (corticosteroids, IVIg, anti-D, or rituximab), and non-refractory patients were those previously treated patients who had either relapsed or become intolerant to their prior therapy. Specifically, corticosteroid-refractory patients had to have either no prior response to corticosteroids, or if there had been at least 1 documented response, there was subsequently nonresponse to all corticosteroids attempted. To determine whether outcome of prior therapy impacts a patient’s response to eltrombopag, refractory ITP patients were compared to non-refractory ITP patients with regard to 3 measures of clinical benefit: 1) the proportion of patients who achieved platelet counts ≥50,000/μL and 2X baseline, 2) median weekly platelet counts on therapy through 39 weeks (9 mo.), and 3) the proportion of patients with clinically significant bleeding symptoms (WHO Grades 2–4) at each week on therapy through 39 weeks (9 mo.). Bleeding symptoms were prospectively evaluated using the WHO Bleeding Scale: Grade 0 = no bleeding, Grade 1 = mild bleeding, Grade 2 = moderate bleeding, Grade 3 = gross bleeding, and Grade 4 = debilitating blood loss. RESULTS: Of the 165 patients included, 68 were refractory to at least 1 of the following medications: corticosteroids (no response, n = 36; no response following prior response, n = 7), IVIg (n = 20), anti-D (n = 12), or rituximab (n = 23). The median baseline platelet count was 17,000/μL in both the refractory and non-refractory patients. Overall, 75% (n = 51/68) of refractory patients achieved platelet counts ≥50,000/μL and 2X baseline, compared to 84% (n = 81/97) of non-refractory patients. A logistic regression model, adjusted for baseline splenectomy status, ITP medication use, and baseline platelet count showed no significant difference in this response between refractory and non-refractory patients (p = 0.1425). In addition, weekly median platelet counts in both refractory and non-refractory patients generally remained at or above 50,000/μL from week 1 through week 39 (9 mo.). While refractory patients had more clinically significant bleeding at baseline than non-refractory patients: 32% (n = 22/68) and 14% (n = 14/97), respectively, the proportion of patients with clinically significant bleeding in both groups was lower than baseline at any point from weeks 1 to 39. The proportion of patients with clinically significant bleeding in both groups was generally reduced 50% from baseline throughout this period. CONCLUSION: Eltrombopag induces long lasting platelet count increases and reduces clinically significant bleeding symptoms in refractory and non-refractory chronic ITP patients. We hypothesize that eltrombopag’s novel mechanism of action, stimulation of platelet production, underlies its ability to successfully treat patients refractory to treatments which impede platelet destruction.

Optimizing Dose Titration Of Ruxolitinib: The COMFORT-I Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4062-4062 ◽  
Author(s):  
Ruben A. Mesa ◽  
Rami S. Komrokji ◽  
William Sun ◽  
Victor A. Sandor ◽  
Srdan Verstovsek
Keyword(s):  
Platelet Count ◽  
Research Funding ◽  
Dose Adjustment ◽  
Janus Kinase ◽  
Dose Titration ◽  
Baseline Platelet Count ◽  
Platelet Counts ◽  
Starting Dose ◽  
Positive Rate ◽  
Equity Ownership

Abstract Background The Janus-kinase (JAK) pathway plays a critical role in normal hematopoiesis. In two phase 3 studies, the JAK1/JAK2 inhibitor ruxolitinib (RUX) demonstrated clinical benefit over placebo (COMFORT-I) or best available therapy (COMFORT-II) in patients with intermediate-2 or high-risk myelofibrosis (MF). Anemia and thrombocytopenia, the most common adverse events associated with RUX treatment, were dose-dependent and expected based on RUX's mechanism of action. These events were successfully managed and few RUX-treated patients discontinued for anemia or thrombocytopenia (<1% for each event). The ability to identify patients who would most likely benefit from a dose adjustment may contribute to improved patient management. Therefore, an analysis was conducted in patients who received RUX in COMFORT-I to identify patient characteristics that could help select patients who would potentially benefit from closer monitoring and dose titration in the early period after initiation of therapy. Methods In COMFORT-I, starting doses in the patients randomized to RUX were 15 mg twice daily (BID) for patients with baseline platelet counts of 100–200 ×109/L (n=55) and 20 mg BID for those with platelet counts >200 ×109/L (n=100). Dose reductions were required for protocol-defined decreases in platelet counts; there was no protocol-mandated dose change for anemia. The time course of dose adjustments and the most common titrated doses by starting dose were evaluated. Logistic regression analyses with baseline hemoglobin (Hgb) level, platelet count, IPSS risk category, sex, and MF type as model effects were conducted to determine predictors of: 1) titration to a RUX dose of ≤10 mg BID within 8 weeks of starting therapy (early dose titration event); or 2) development of grade ≥3 anemia or new need for RBC transfusions (≥2 units of packed RBCs) within 12 weeks of therapy initiation (anemia event). Only baseline platelet count and Hgb emerged as significant predictors (alpha=0.05). Receiver operating characteristics (ROC) analyses were also conducted for these two predictors to determine a clinically relevant cutoff of the underlying predictor variable with a positive predictive value (PPV), true positive rate (TPR), and false positive rate (FPR) obtained at all possible cutoffs and a general goal of obtaining a TPR ≥ 50%, an FPR ≤ 10%, and a high PPV. Results Approximately 70% of patients had a dose adjustment within the first 12 weeks of initiating RUX treatment. At week 24, 77% of patients with baseline platelet counts of 100–200 ×109/L and 39% of those with baseline platelet counts >200 ×109/L had titrated to a reduced RUX dose relative to their starting dose. With longer-term follow-up (median 149 weeks), the mean dose over time in patients who continued on study was ∼10 mg BID for patients starting at 15 mg BID and ∼15 mg BID for those starting at 20 mg BID (Figure). ROC analyses identified that a baseline platelet count range of less than 150–175 x109/L may predict which patients would experience an early titration event, while a baseline Hgb level of less than 10 mg/dL may predict which patients would experience an anemia event (Table). Conclusions In COMFORT-I, most patients experienced a RUX dose adjustment in the first 12 weeks of treatment and stable doses were achieved with long-term therapy. Dose titration allowed most patients to maintain adequate platelet counts. After starting therapy at 15 or 20 mg BID, the majority of patients titrated to RUX doses of 10 mg BID or higher, which have been previously been shown to produce meaningful spleen volume reductions and symptom improvements (Mesa et al. 8th Annual Hematologic Malignancies Conference. Abstract 305; Verstovsek et al. ASH 2012. Abstract 800; Talpaz et al. ASH 2012. Abstract 176). A baseline platelet count of less than 150 ×109/L and baseline Hgb level of less than 10 g/dL may be clinically useful cutoffs for predicting which patients may benefit from closer monitoring shortly after treatment initiation of RUX and appropriate dose adjustments as needed. Disclosures: Mesa: Lilly: Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding. Komrokji:Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees. Sun:Incyte Corporation: Equity Ownership; Incyte Corporation: Employment. Sandor:Incyte Corporation: Equity Ownership; Incyte Corporation: Employment. Verstovsek:Incyte Corporation: Research Funding.

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