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

Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study

Background: Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period. Methods: We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months’ duration who had baseline platelet counts lower than 30 000 per μL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a computer-generated randomisation schedule and was stratified by baseline platelet count (≤15 000 per μL), use of treatment for immune thrombocytopenia, and splenectomy status. Patients, investigators, and those assessing data were masked to allocation. Dose modifications were made on the basis of platelet response. Patients were assessed for response to treatment (defined as a platelet count of 50 000–400 000 per μL) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00370331. Findings: Between Nov 22, 2006, and July 31, 2007, 197 patients were randomly allocated to treatment groups and were included in the intention-to-treat analysis (135 eltrombopag, 62 placebo). 106 (79%) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 (28%) patients in the placebo group. The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period (odds ratio 8·2, 99% CI 3·59–18·73; p\u3c0·0001). 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0·016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0·001). Three (2%) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo. Nine (7%) eltrombopag- treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients (vs none allocated to placebo) had increases in total bilirubin. Four (7%) patients taking placebo had serious bleeding events, compared with one (\u3c1%) patient treated with eltrombopag. Interpretation: Eltrombopag is effective for management of chronic immune thrombocytopenia, and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment. These benefits should be balanced with the potential risks associated with eltrombopag treatmen

Proteomic Identification of Interleukin-2 Therapy Response in Metastatic Renal Cell Cancer

Introduction—To detect a predictive protein profile that distinguishes between IL-2 therapy responders and non-responders among metastatic RCC patients we used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI TOF-MS). Materials and Methods—Protein extracts of 56 metastatic clear cell RCC patients obtained from radical nephrectomy specimens and prior to IL-2 therapy were applied to protein chip arrays of different chromatographic properties and analyzed using SELDI TOF-MS. A class prediction algorithm was applied to identify a subset of protein peaks whose expression values were associated with IL-2 response status. Multivariate analysis was performed to assess the association between the proteomic profile and the IL-2 response status controlling for the effect of lymphadenopathy. Results—From a total of 513 protein peaks we discovered a predictor set of 11 peaks that performed optimally for predicting IL-2 response status (86 % accuracy, Fisher’s p\u3c0.004, permutation p\u3c0.01). The results were validated on an independent data set with an overall accuracy of 72% (p \u3c 0.05, permutation p\u3c0.01). On multivariate analysis the proteomic profile was significantly associated with IL-2 response when corrected for lymph node status (p\u3c 0.04). Conclusions—We have identified and validated a proteomic pattern that is an independent predictor of IL-2 response. The ability to predict the probability of IL-2 response could permit targeted selection of patients most likely to respond to IL-2, while avoiding unwanted toxicities in patients less likely to respond. This proteomic predictor has the potential to significantly aid clinicians in the decision making of appropriate therapy for metastatic RCC patients

Thromboembolic events observed in eltrombopag clinical trials in chronic immune thrombocytopenic purpura.

BACKGROUND: Eltrombopag (PROMACTA®; GlaxoSmithKline, Collegeville, PA, USA), an oral, small molecule, thrombopoietin receptor agonist, was recently approved in the United States for the treatment of patients with chronic immune thrombocytopenic purpura (ITP). Limited published data indicate that patients with chronic ITP experience thromboembolic events (TEEs) with a frequency of 3% to 6%. (Aledort, Am J Hematol, 2004; Bennett, Haematologica, 2008). OBJECTIVE: To evaluate the incidence of TEEs in patients with chronic ITP treated with eltrombopag and to determine if the occurrence of TEEs was associated with elevated platelet counts. METHODS: Data from 446 patients from 3 placebo-controlled eltrombopag studies (TRA100773A, TRA100773B, and RAISE) and 2 open-label studies (REPEAT and EXTEND) were analyzed. The frequency of TEEs or suspected TEEs before and after the first dose of study medication (placebo or eltrombopag) was examined across the program. Potential risk factors, including platelet counts proximal to the event, were evaluated in patients experiencing a TEE. RESULTS: Prior to the initiation of study medication (placebo or eltrombopag), 16/493 (3.2%) of the patients entering the program had a history of TEEs (one of these patients experienced 2 additional TEEs [TIA, MI] while on treatment with eltrombopag). Across the ITP clinical program, 17/446 patients treated with eltrombopag (3.8%) experienced 22 TEEs. No patient treated with placebo experienced a TEE. The patient-years (PYs) of exposure to study medication was approximately 14 times greater for patients treated with eltrombopag compared to placebo (eltrombopag 377 PYs; placebo 26 PYs). Most patients (13/17) experienced 1 TEE; 3 patients experienced 2, and 1 patient experienced 3 (2 TEEs were 6 months off-therapy). The most common TEEs were deep vein thrombosis (n=8) and pulmonary embolism (n=6). A total of 18/22 events were resolved or resolving at the time of this analysis; all patients experiencing a TEE had at least 1 risk factor for these events other than ITP (eg, use of IVIg [n=3], hospitalization with no prophylactic anticoagulation [n=4], oral corticosteroids [n=6]). The platelet counts proximal to the event ranged from 14,000/μL to 420,000/μL. The majority of patients had platelet counts below 150,000/μL (9; 53%) or between 150,000/μL and 400,000/μL (5; 29%); 2 had platelet counts above 400,000/μL and the platelet count in 1 was unknown. All 446 patients were categorized by the maximum platelet count achieved during treatment with eltrombopag (above normal [\u3e400,000/μL], normal range [150–400,000/μL], below normal range [\u3c150,000/μ]; Table 1). The majority of patients (14; 82%) experienced the TEEs at a platelet count lower than their maximum platelet count, while 3 patients (18%) experienced a TEE proximal to their maximum platelet count. CONCLUSION: TEEs occurred with eltrombopag. None occurred with placebo; however, the PYs of exposure was considerably less with placebo than with eltrombopag. The frequency of TEEs observed during eltrombopag treatment (3.8%) is similar to that reported in the literature and prior to enrollment in the eltrombopag program (3.2%). No discernible correlation has been observed between platelet count increases and TEEs, and these events do not appear to be associated with maximum platelet counts during treatment with eltrombopag

Proteomic Identification of Interleukin-2 Therapy Response in Metastatic Renal Cell Cancer

Introduction—To detect a predictive protein profile that distinguishes between IL-2 therapy responders and non-responders among metastatic RCC patients we used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI TOF-MS). Materials and Methods—Protein extracts of 56 metastatic clear cell RCC patients obtained from radical nephrectomy specimens and prior to IL-2 therapy were applied to protein chip arrays of different chromatographic properties and analyzed using SELDI TOF-MS. A class prediction algorithm was applied to identify a subset of protein peaks whose expression values were associated with IL-2 response status. Multivariate analysis was performed to assess the association between the proteomic profile and the IL-2 response status controlling for the effect of lymphadenopathy. Results—From a total of 513 protein peaks we discovered a predictor set of 11 peaks that performed optimally for predicting IL-2 response status (86 % accuracy, Fisher’s p\u3c0.004, permutation p\u3c0.01). The results were validated on an independent data set with an overall accuracy of 72% (p \u3c 0.05, permutation p\u3c0.01). On multivariate analysis the proteomic profile was significantly associated with IL-2 response when corrected for lymph node status (p\u3c 0.04). Conclusions—We have identified and validated a proteomic pattern that is an independent predictor of IL-2 response. The ability to predict the probability of IL-2 response could permit targeted selection of patients most likely to respond to IL-2, while avoiding unwanted toxicities in patients less likely to respond. This proteomic predictor has the potential to significantly aid clinicians in the decision making of appropriate therapy for metastatic RCC patients

Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura.

Introduction: Eltrombopag (PROMACTA/REVOLADE; GlaxoSmithKline, Collegeville, PA) is the first oral, small molecule, non-peptide thrombopoietin receptor agonist under investigation for the treatment of thrombocytopenia due to various causes, including idiopathic thrombocytopenic purpura (ITP). Chronic ITP is characterized by autoantibody-induced platelet destruction and reduced platelet production, leading to chronically low peripheral platelet counts. Eltrombopag treatment has previously demonstrated a significant increase in platelet counts and a reduction in clinically relevant bleeding symptoms in 2 placebo-controlled trials evaluating a total of \u3e200 patients with chronic ITP 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 in ITP patients that have previously completed an eltrombopag trial. Methods: 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 in order 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. Patients who achieved platelet counts ≥ 50,000/μL during treatment with eltrombopag were considered responders. Bleeding events 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: At the time of this analysis, 207 patients (median age, 50 years; 67% female) had received eltrombopag on this study. At baseline, 33% were receiving concomitant ITP medication and 40% were splenectomized. The majority of patients (70%) enrolled with baseline platelet counts \u3c30,000/μL, followed by 18% and 12% with baseline platelet counts from ≥ 30,000/μL to ≤ 50,000/μL, and \u3e50,000/μL, respectively. The duration of eltrombopag treatment ranged from 3 to 523 days. Seventy-nine percent (159/201) of patients achieved a platelet count ≥ 50,000/μL, and 24% (18/75) of patients who had received eltrombopag for at least 25 weeks maintained platelet counts ≥ 50,000/μL continuously for ≥ 25 weeks. Patients responded to eltrombopag regardless of splenectomy status (non-splenectomized: 78%, splenectomized: 81%) and use of baseline concomitant ITP medications (no baseline ITP medications: 79%, baseline ITP medications: 80%). Median platelet counts remained ≥ 50,000/μL throughout the observation period of the study (Figure 1) with only 3 exceptions, when the median platelet counts remained \u3e40,000/μL. At baseline, 59% of patients reported bleeding symptoms (WHO Grades 1–4) compared with approximately 30% at months 1, 3, and 6. Adverse events (AEs) were reported in 150 patients (72%) while on therapy, the majority of which were mild to moderate. Headache (15%) was the most commonly reported on-therapy AE, followed by upper respiratory tract infection (13%), diarrhea (10%), and nasopharyngitis (9%). Six thromboembolic events were reported during the study. No clinically relevant effects of eltrombopag on patient bone marrow were detected. Thirty-nine serious AEs were reported by 17 patients (8%) while on therapy +1 day. Four deaths were reported in the study (2 deaths on therapy and 2 deaths \u3e30 days after the last dose of eltrombopag); none were considered related to study medication. Conclusion: Oral eltrombopag is effective at raising platelet counts and decreasing bleeding symptoms during long-term treatment, regardless of splenectomy status or the use of baseline ITP medications. Eltrombopag is well tolerated during long-term treatment in patients with previously treated chronic ITP

Hepatobiliary laboratory abnormalities among patients with chronic or persistent immune thrombocytopenia (ITP)

Therapies for immune thrombocytopenia (ITP) may be associated with abnormal hepatobiliary laboratory (HBL) values, but the epidemiology of these abnormalities is unknown in the ITP population. The study aim was to provide prevalence and incidence rates, as well as risk factors for abnormal HBL values among a cohort of patients with chronic or persistent primary ITP. Health insurance claims data from 3,244 patients with chronic or persistent ITP was examined to estimate the prevalence of abnormal HBL values: elevated levels of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), total bilirubin, and Alkaline Phosphatase (ALP). Incidence of abnormal HBL values was estimated in a sub cohort of 2557 (79%) patients without evidence of comorbidities related to secondary thrombocytopenia, liver disease, or abnormal HBL values during the 12-month baseline period. The baseline prevalence of ALT and AST > 3x the upper limit of normal (ULN) was 4.6 and 3.7%, respectively. The baseline prevalence of total bilirubin and ALP >1.5x ULN was 4.2 and 3.2%, respectively. The incidence rate of new HBL abnormalities (HBLA) was 1.24/1,000 person- years (95% CI: 0.52-2.56) for ALT>3x ULN and 0.41/1,000 person-years (95% CI: 0.08-1.32) for AST>3x ULN. HBLAs were significantly associated with male gender, liver disease, diabetes, congestive heart failure, lupus, hematological cancers, and HIV infection. In conclusion, the prevalence of HBLA, specifically ALT>3x ULN, among the ITP population is relatively high compared with atrial fibrillation, though within the confidence interval for that estimate. HBLAs were significantly associated with male gender, liver disease, and several other comorbidities, thus, distinguishing drug-induced liver injury in this population is clinically challenging

Long-term treatment of chronic immune thrombocytopenic purpura with oral eltrombopag: results from the EXTEND Study.

Introduction: Eltrombopag (PROMACTA; GlaxoSmithKline, Collegeville, PA) is the first oral, small molecule, thrombopoietin receptor agonist approved in the US for the treatment of chronic immune thrombocytopenic purpura (ITP). Eltrombopag is also being evaluated for the treatment of thrombocytopenia due to other causes (eg, hepatitis C, MDS). Chronic ITP is characterized by autoantibody-induced platelet destruction and reduced platelet production, leading to chronically low platelet counts. Eltrombopag has been shown to significantly increase platelet counts and reduce clinically relevant bleeding symptoms in 3 placebo-controlled ITP trials evaluating a total of 429 patients. EXTEND is an ongoing open-label, phase 3 extension study to assess the long-term safety and efficacy of eltrombopag in chronic ITP. Method: 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 between ≥50,000/μL and \u3c200,000/μL, with doses between 75 mg and 25 mg once daily (or less often if necessary). Patients who achieved platelet counts ≥50,000/μL were considered responders. Bleeding events were prospectively evaluated using the World Health Organization (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. Bone marrow (BM) biopsy was required after 1 year on treatment. Results: At the time of this analysis, 299 patients (median age 50 years; 66% female) had received eltrombopag (240, 126, 48, and 17 patients exposed for ≥6, 12, 18, and 24 months, respectively). The median duration of eltrombopag treatment was 204 days and ranged from 2–861 days. At baseline, 33% were receiving concomitant ITP medication and 38% had been splenectomized. The majority of patients (70%) had baseline platelet counts \u3c30,000/μL, followed by 17% and 13% with baseline platelet counts from μ30,000/μL to \u3c50,000/μL, and μ50,000/μL, respectively; all had baseline platelet counts \u3c50,000/μL at the time of entry into their previous study. Overall, 86% of patients (257/299) achieved a platelet count μ50,000/μL. Splenectomized and non-splenectomized patients responded equally well (89% and 82%, respectively). Patients responded to eltrombopag regardless of baseline use of concomitant ITP medications (no baseline ITP medications and baseline ITP medications: 86% each). Median platelet counts increased to μ50,000/μL by week 2, and remained μ50,000/μL throughout the observation period of the study (Figure 1). Patients on treatment for μ6 months or μ12 months achieved platelet counts of μ50,000/μL and 2x baseline for 69% (18/26 weeks) and 71% (37/52 weeks) of the time on treatment, respectively. At baseline, 56% of patients reported bleeding symptoms (WHO grades 1–4) compared to 27%, 21%, 40%, and 25% at 6, 12, 18, and 24 months, respectively. Adverse events (AEs) were reported in 248 patients (83%) while on therapy, the majority being mild to moderate. The most common AEs reported were headache (23%), upper respiratory tract infection (17%), nasopharyngitis (17%), fatigue (13%), arthralgia (12%), and diarrhea (11%). Five deaths were reported: 2 occurred on therapy and 3 occurred more than 30 days posttherapy; none considered related to study medication. A total of 24 patients (8%) met any of the hepatobiliary laboratory abnormality screening criteria (ALT ≥3x ULN, AST ≥3x ULN, total bilirubin \u3e1.5x ULN, or alkaline phosphatase \u3e1.5x ULN). Thirteen patients (4%) experienced 16 thromboembolic events (TEEs); 11/13 (85%) experienced the event at a platelet count lower than the maximum platelet count achieved during eltrombopag treatment. Platelet counts proximal to the TEEs ranged from 14,000–407,000/μL. Eighty-six BM biopsies were performed. No clinically relevant effects of eltrombopag on BM were detected. Conclusion: Oral eltrombopag treatment for up to 2 years effectively raised platelet counts, decreased bleeding symptoms, and was generally well-tolerated in chronic ITP

Eltrombopag Delivers Clinical Benefit in Chronic Idiopathic Thrombocytopenic Purpura (ITP) Patients Not Achieving Platelet Counts ≥50,000/μL - Data from the EXTEND Study.

Introduction: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline, Collegeville, PA) is the first oral small molecule, non-peptide thrombopoietin receptor agonist shown to increase platelets and reduce bleeding symptoms during placebo-controlled trials in 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. While eltrombopag has been shown to raise platelet counts above the recognized goal of ≥50,000/μL in the majority of patients, it unknown whether patients who do not achieve this level of elevation derive other clinical benefit from eltrombopag therapy. Methods: For this analysis, patients who were enrolled in EXTEND for at least 6 weeks were evaluated to determine what percentage achieved platelet counts ≥50,000/μL from baseline platelet counts ≤30,000/μL. Furthermore, clinical benefit, in terms of doubled platelet counts, reduced bleeding symptoms, or reduced concomitant ITP medication use, was evaluated in the subgroup of patients who did not achieve platelet counts ≥50,000/μL during the study. 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 117 patients with baseline platelet counts ≤30,000/μL evaluated, 91 patients (78%) achieved platelet counts ≥50,000/μL at least once during the study; whereas, 26 patients (22%) did not achieve platelet counts ≥50,000/μL. The majority of patients not achieving platelet counts ≥50,000/μL had baseline platelet counts ≤15,000/μL (96%, n = 24/26); however, 69% of all patients with baseline platelet counts ≤15,000/μL on study for at least 6 weeks achieved platelet counts ≥50,000/μL. The majority of patients not achieving platelet counts ≥50,000/μL during the study doubled their platelet count from baseline at least once (62%, n = 16/26). Among patients whose platelet counts doubled, the median baseline platelet count was 4,000/μL, compared to the median maximum platelet count of 29,000/μL achieved during treatment with eltrombopag. Nineteen of the 26 patients not achieving platelet counts ≥50,000/μL had bleeding symptoms at baseline (WHO Grades 1–4). The majority of the 19 patients with bleeding symptoms at baseline reduced their bleeding symptoms during treatment with eltrombopag (68%, n = 13/19). Eleven of the 26 patients not achieving platelet counts ≥50,000/μL were receiving concomitant ITP medications at baseline. Five of the 11 (45%) were able to reduce or discontinue at least 1 baseline concomitant ITP medication while receiving eltrombopag. A total of 24 of the 26 patients (92%) not achieving platelet counts ≥50,000/μL during the study derived clinical benefit (doubling of platelet count, reduction in bleeding, and/or reduction in use of concomitant ITP medications) following treatment with eltrombopag. Conclusion: Approximately 80% of evaluated patients with baseline platelet counts ≤30,000/μL achieved platelet counts ≥50,000/μL during the study. In the subgroup of patients who did not achieve platelet counts ≥50,000/μL, clinical benefit was achieved by 92% of patients and consisted of doubled platelet counts, reduced bleeding symptoms, and/or reduced concomitant medication use

Long-term safety and efficacy of oral eltrombopag for the treatment of subjects with Idiopathic Thrombocytopenic purpura (ITP): Preliminary data from the EXTEND study.

Idiopathic thrombocytopenic purpura (ITP) is a disease caused by inadequate platelet production as well as increased platelet destruction. Eltrombopag is a first-in-class, oral, non-peptide platelet growth factor that increases platelet counts by interacting with the thrombopoietin receptor on megakaryocytes and their precursors. Accordingly, in two completed 6-week, randomized, double-blind, placebo-controlled studies of adult subjects with chronic ITP, eltrombopag produced a substantial dose-dependent increase in platelet counts. EXTEND is an ongoing, open-label extension study designed to assess the long-term safety and efficacy of oral eltrombopag. Subjects previously enrolled in an eltrombopag study are eligible to enroll in EXTEND after an intervening washout period of at least 4 weeks. Subjects are administered a starting dose of 50 mg/day (which could be increased to 75 mg/day at any time after 3 weeks) in order to reach a platelet count of ≥50,000/uL (stage 1). Then, concomitant ITP medications, if taken at study entry, are tapered to a minimal dose or discontinued entirely (stage 2), whilst maintaining a platelet count of ≥50,000/uL. Eltrombopag is then titrated to a minimal effective dose (25–75 mg/day) required to maintain platelet counts of 50,000/uL-200,000/uL (stage 3). Eltrombopag is continued for as long as the subject continues to benefit (stage 4). Bleeding incidence and severity is assessed using the WHO bleeding scale (Grade 0–4). As of August 6, 2007, data were available on 96 subjects. Ninety-four subjects were administered eltrombopag. Evaluable subjects (n=89) had a median treatment duration of 151 days (2–333 days). At baseline, 42 (44%) subjects had a platelet count ≤15,000/uL, 60 (63%) had evidence of bleeding (WHO Grade 1-4), 44 (46%) were splenectomized, and 35 (36%) were receiving concomitant ITP treatment. Of the sixty-one subjects who entered into the study with a platelet count \u3c30,000/uL, 43 (73%) achieved a platelet count of ≥50,000/uL while on study; 10 of the 61 subjects had at least one count ≥400,000/mL during the study. Of the 94 subjects who received at least one dose of eltrombopag, 78 (83%) reported at least one adverse event; 30 (32%) reported a drug-related adverse event (AE). Most AEs were mild in severity with the most common being headache (20%). Twelve (13%) subjects reported a serious adverse event. Two deaths were reported (traffic accident and hypovolaemic shock), both not related to study medication. To date, these findings of the EXTEND study suggest that eltrombopag is well tolerated and sustains increased platelets counts during long-term treatment