Results of bone marrow examinations in patients with chronic immune thrombocytopenic purpura treated with eltrombopag

Background: Bone marrow (BM) reticulin fibers can be increased in conditions such as neoplasms and autoimmune diseases (Frisch Haematol [Budap] 1982; Aharon Lupus 1997) and can lead to a clinical situation similar to osteomyelofibrosis. In healthy individuals, grade 1 and 2 reticulin have been reported in 27–70% and 4–20% of BM biopsies, respectively (Hultdin Med Onc 2007; Beckman Arch Path Int Med 1990; Bauermeister Am J Clin Path 1971). The presence of grade 1/2 reticulin was reported in the BM of up to 67% of patients with immune thrombocytopenic purpura (ITP) (Mufti J Supp Onc 2007). Theoretically, prolonged stimulation of megakaryocytes with TPO-R agonists might increase the risk of myelofibrosis (MF). Increased reticulin and peripheral nucleated RBCs have been reported in chronic ITP patients treated with romiplostim (Bussel Blood 2009). Eltrombopag, an oral, small molecule, TPO-R agonist, is approved in the United States for the treatment of chronic ITP. Objective: To determine whether eltrombopag treatment is associated with an increase in BM reticulin. METHODS Reports of BM biopsies performed prior to eltrombopag treatment were reviewed. In eltrombopag studies, complete blood counts (CBC) including white blood cell (WBC) differentials were performed at each visit. If a WBC differential indicated the presence of immature or dysplastic cells in the RAISE, REPEAT, and EXTEND studies, then a peripheral blood smear was performed. If the presence of immature or dysplastic cells on the blood smear was not consistent with the chronic ITP diagnosis, then a BM biopsy was performed. Additionally, a BM biopsy could be performed at any time at the investigator\u27s discretion. In EXTEND, a BM biopsy was required after 1 year on treatment. Reticulin was quantified using the modified MF scale (Thiele Haematologica 2005). Results: Prestudy BM biopsies were available for 64/446 patients subsequently exposed to eltrombopag; 51 reports did not mention reticulin or fibrosis. Of the 13 remaining prestudy reports, 4 (31%) had increased reticulin. Ninety-one patients (5 patients RAISE; 86 patients EXTEND) had a BM biopsy following treatment initiation; none of the BM biopsies were prompted by an abnormal peripheral blood smear. In a 6-month placebo-controlled study (RAISE), 1 placebo-treated patient had an on-treatment BM examination that showed myelodysplastic syndrome, and 4 eltrombopag-treated patients (2 on-treatment and 2 posttreatment) had BM examinations. One patient treated with eltrombopag for 41 days had a posttreatment marrow examination that showed grade 2 (Bauermeister) reticulin. None of the 4 showed hematologically relevant BM alterations. In an open-label extension study (EXTEND), 86 patients treated for a median of 12 months (range: 1–18 months) at the time of the procedure had BM biopsies; 83 had mention of reticulin fibers in the report and were evaluable for this analysis. Five patients had MF grade 2 reticulin with no clinical signs or symptoms of BM dysfunction (eg, abnormal WBC differential or peripheral blood smear); 2 reported collagen. One patient had a biopsy 2 years prior to EXTEND (grade 1/3). After 15 months on study, a biopsy showed grade 2/3; this patient was withdrawn. Of note, while on treatment the patient was not considered a responder (platelets \u3c50,000/μL) but did have decreased bleeding. The second patient was 81 years old with a history of 3 cancers. A similar degree of reticulin was observed when comparing the biopsy taken 6 years prior to EXTEND and after 14 months on study, but collagen was noted on the second BM. A patient with MF grade 1 reticulin reported collagen, but did not experience any adverse event or significant change in CBC and is continuing on study with good platelet response. Conclusion: There was no evidence of clinically relevant BM abnormalities or clinical findings typically associated with MF in patients treated for up to 18 months with eltrombopag. Systematic longitudinal evaluation of BMs in EXTEND will provide meaningful data regarding incidence of fibrosis during long-term treatment

Coagulation Factor Plasma Levels Following Administration of a 4-Factor Prothrombin Complex Concentrate for Rapid Vitamin K Antagonist Reversal in Japanese Patients

ABSTRACT: Background: Four-factor prothrombin complex concentrates (4F-PCCs) have been approved for urgent vitamin K antagonist reversal in Western countries for many years. Ethnicity and genetic variations between populations may influence the pharmacokinetic profile of 4F-PCC treatments. Objective: To report plasma levels of vitamin K-dependent coagulation factors and proteins C and S in Japanese patients following administration of a 4F-PCC approved recently in Japan. Methods: This was a subanalysis of a prospective, open-label, Phase IIIb study in Japanese patients requiring rapid vitamin K antagonist reversal owing to major bleeding (n = 6) or need for urgent surgery (n = 5). International normalized ratio and plasma levels of factors II, VII, IX, and X, and proteins C and S were measured before PCC infusion and at specific time points for the next 24 hours. Adverse events and serious adverse events were recorded up to Day 14 and 45, respectively. Results: Rapid increases in plasma concentrations 30 minutes following 4F-PCC infusion were seen for all factors and proteins C and S, with median concentrations compared with baseline increasing by ≥100% and 70% in the bleeding and surgical groups, respectively. A concurrent decrease in international normalized ratio was observed. Plasma levels for each factor and protein remained within physiologic levels throughout the assessment period. No relationship between thromboembolic events and elevated plasma levels was identified. Conclusions: Administration of 4F-PCC in Japanese patients receiving vitamin K antagonist anticoagulation therapy resulted in rapid and sustained increases in plasma levels and was well tolerated, indicating that this treatment is effective for the urgent reversal of vitamin K antagonist therapy in this population. Key words: Coagulation factor, Hemorrhage, Prothrombin complex concentrate, Surgery, Vitamin K antagonis

Oral eltrombopag treatment reduces the need for concomitant medications in patients with chronic idiopathic thrombocytopenic purpura.

Introduction: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline, Collegeville, PA) is the first oral, small molecule, non-peptide thrombopoietin receptor agonist developed as a treatment for thrombocytopenia of various etiologies, including chronic idiopathic thrombocytopenic purpura (ITP). In 2 placebo-controlled studies totaling over 200 patients with chronic ITP, eltrombopag has demonstrated a significant increase in platelet counts and a reduction in clinically relevant bleeding after up to 6 weeks of treatment. EXTEND is an ongoing open-label, phase III extension study to assess the long-term safety and efficacy of oral eltrombopag. Although the primary objective of this study was to raise platelet counts to a safe level (≥50,000/μL), the ability of eltrombopag treatment to allow patients to reduce concomitant ITP medications and avoid the adverse events associated with those therapies was also of interest. Methods: Adult patients with previously treated chronic ITP who completed a prior eltrombopag study were eligible to participate in EXTEND. Eltrombopag treatment was initiated at 50 mg once daily and then adjusted to maintain platelet counts ≥50,000/μL and \u3c400,000/μL, with doses between 75 mg once daily and 25 mg once daily or less often than once daily, if necessary. The effect of eltrombopag treatment on the ability of patients to reduce and/or discontinue baseline concomitant ITP medications was evaluated. Results: As of the clinical cut-off date (January 7, 2008), 207 patients (median age, 50 years; 67% female) had received eltrombopag. At baseline, 69 (33%) patients reported the use of ITP medications; of these, 65 patients had at least 1 post-baseline visit by the clinical cut-off date and were evaluable for response status. Eighty percent (52/65) of these patients responded to eltrombopag with a platelet count of ≥50,000/μL during the study. Forty-eight percent (33/69) of patients attempted to reduce or discontinue their concomitant ITP medications during the study. Seventy percent (23/33) of these patients discontinued or had a sustained reduction of their baseline ITP medication and did not require any subsequent rescue treatment as of the clinical cut-off date; of these, 65% (15/23) had maintained the discontinuation or reduction for at least 24 weeks as of the clinical cut-off date. Sixty-one percent (20/33) of patients discontinued at least 1 baseline ITP medication, and 55% (18/33) discontinued all baseline ITP medications, without subsequent rescue treatment. Discontinued or reduced medications included prednisone (n = 11); prednisolone (n = 8); danazol (n = 5); and azathioprine, dexamethasone, mycophenolic acid, and oxymetholone (n = 1 each). Only 12% (8/69) of patients increased the dose of concomitant ITP medication from baseline. Conclusion: In this study, long-term therapy with oral eltrombopag allowed 80% of patients with chronic ITP who were also receiving a concomitant ITP medication at baseline to maintain elevated platelet counts sufficient to permit a reduction in the use of concomitant ITP medications without the need for rescue therapy

Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study

Patients with chronic immune thrombocytopenia may have bleeding resulting from low platelet counts. Eltrombopag increases and maintains hemostatic platelet counts; however, to date, outcome has been reported only for treatment lasting ≤ 6 months. This interim analysis of the ongoing open-label EXTEND (Eltrombopag eXTENded Dosing) study evaluates the safety and efficacy of eltrombopag in 299 patients treated up to 3 years. Splenectomized and nonsplenectomized patients achieved platelets ≥ 50 000/μL at least once (80% and 88%, respectively). Platelets ≥ 50 000/μL and 2 × baseline were maintained for a median of 73 of 104 and 109 of 156 cumulative study weeks, respectively. Bleeding symptoms (World Health Organization Grades 1-4) decreased from 56% of patients at baseline to 20% at 2 years and 11% at 3 years. One hundred (33%) patients were receiving concomitant treatments at study entry, 69 of whom attempted to reduce them; 65% (45 of 69) had a sustained reduction or permanently stopped ≥ 1 concomitant treatment. Thirty-eight patients (13%) experienced ≥ 1 adverse events leading to study withdrawal, including patients meeting protocol-defined withdrawal criteria (11 [4%] thromboembolic events, 5 [2%] exceeding liver enzyme thresholds). No new or increased incidence of safety issues was identified. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts in the desired rang