Health-related quality of life in children with chronic immune thrombocytopenia treated with eltrombopag in the PETIT study.

The PETIT (Eltrombopag in Pediatric Patients with Thrombocytopenia from Chronic ITP) trial showed that in children aged 1-17 years with chronic or persistent immune thrombocytopenia (ITP), eltrombopag improved platelet counts, decreased clinically significant bleeding and reduced rescue medication need. We report the health-related quality of life (HRQoL) results from the PETIT study using the Kids' ITP Tools (KIT). A limitation was that PETIT was not powered for the HRQoL analysis. Eltrombopag did not impact children's HRQoL assessed by the KIT. Although median KIT scores in children treated with eltrombopag with platelet responses were numerically higher compared with non-responders in some age groups, the interquartile ranges overlapped.

Cost-Effectiveness of Eltrombopag versus Romiplostim for the Treatment of Chronic Immune Thrombocytopenia in England and Wales.

OBJECTIVES: To evaluate the cost-effectiveness of eltrombopag compared with romiplostim to be used in the treatment of chronic immune thrombocytopenia in patients in England and Wales who are splenectomized or ineligible for splenectomy and are refractory to other treatments. METHODS: A Markov cohort model in which patients were administered a sequence of treatments was used to predict long-term outcomes associated with each treatment. The model was informed by data from the eltrombopag clinical trial program and the available literature. The analysis was conducted from the perspective of the UK National Health Service, and a lifetime time horizon was used. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Eltrombopag dominated romiplostim (i.e., eltrombopag was as effective as but less costly than romiplostim) in both splenectomized and nonsplenectomized patients, assuming a class effect for the two treatments. Eltrombopag also dominated romiplostim in most deterministic sensitivity analyses with the exception of when indirect efficacy estimates were incorporated into the model. In this analysis, eltrombopag no longer dominated romiplostim but remained cost-effective versus romiplostim at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Probabilistic sensitivity analysis demonstrated that there was a 99% and 92% chance of eltrombopag being cost-effective at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year in splenectomized and nonsplenectomized patients, respectively. CONCLUSIONS: Results of this study demonstrate that eltrombopag is cost-effective when compared with romiplostim to be used in the treatment of chronic immune thrombocytopenia, representing good value for the UK National Health Service.

Health-related quality of life in thrombocytopenic patients with chronic hepatitis C with or without cirrhosis in the ENABLE-1 and ENABLE-2 studies.

BACKGROUND: Despite changes in the treatment paradigm towards non-interferon-based therapies, interferon-based treatments are still used in some geographical regions for treating patients with hepatitis C virus (HCV) infection. Use of eltrombopag with interferon-based treatment for patients with thrombocytopenia and HCV was assessed in two similarly designed phase 3 trials (Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects With Hepatitis C-Related Liver Disease [ENABLE-1 and ENABLE-2]). These trials also aimed to determine whether response to antiviral therapy (e.g., sustained virologic response [SVR]) is associated with changes in health-related quality of life (HRQoL). This pooled, post-hoc analysis aimed to (1) determine whether or not specific aspects of clinical response to treatment (i.e., achieving SVR) are associated with a significant change in HRQoL, and (2) to determine the magnitude and direction of the association between important changes in HRQoL, clinical response to interferon-based therapy (e.g., SVR) and treatment (eltrombopag or placebo), and patient and disease attributes. METHODS: The Short-Form 36 Health Survey version 2 and Chronic Liver Disease Questionnaire-Hepatitis C Virus version were administered at various time points during the studies. Results from both trials were pooled for the analyses. Logistic regression analysis was used to assess the influence of 5 clinical factors (SVR, early virologic response [EVR], genotype [2/3 vs. non-2/3], treatment [eltrombopag or placebo], and cumulative interferon dose), plus other factors including ethnicity, model of end-stage liver disease score, and platelets as predictors of meaningful changes in HRQoL. RESULTS: Between antiviral therapy baseline and the end of the 24-week post-treatment follow-up, declines in HRQoL were smaller in eltrombopag-treated patients than in placebo-treated patients, but the differences were not statistically significant. Mean changes among patients achieving SVR and EVR were small in comparison to thresholds of minimally important changes. Logistic models did not confirm the strength of the 5 clinical factors as predictors of meaningful changes in HRQoL during antiviral therapy, with the exception of the interaction between SVR and EVR (P = 0.0009). Asian ethnicity had a consistent effect on HRQoL, with East Asian patients being more likely to experience deterioration in HRQoL compared with white and/or other non-East Asian patients. CONCLUSIONS: While on active antiviral therapy, declines in HRQoL were not statistically different for eltrombopag-treated patients versus placebo-treated patients, suggesting that eltrombopag neither worsened HRQoL nor mitigated the effects of antiviral therapy on HRQoL.

Treatment patterns and clinical outcomes in patients with chronic immune thrombocytopenia (ITP) switched to eltrombopag or romiplostim.

This observational study aimed to assess real-world treatment patterns and clinical outcomes for patients with chronic immune thrombocytopenia (ITP) currently being treated with eltrombopag or romiplostim after switching from corticosteroids, rituximab, or the alternate thrombopoietin receptor agonist (TPO-RA). The study examined the rationale for switching to TPO-RA therapy using aided responses. Dosing patterns were also analyzed before and after switching. Treatment outcomes were assessed through platelet counts at multiple time points including treatment initiation and after switching at the last office visit. A total of 280 patients were enrolled whose active therapy for ITP was replaced with either eltrombopag (n = 130) or romiplostim (n = 150). Efficacy-related issues (desired platelet count not achieved and/or lack of response to prior therapy) were the main drivers for therapy switching among all patients (54 % for eltrombopag vs. 57 % for romiplostim). Platelet counts at the last office visit showed improvement compared with counts at the initiation of either eltrombopag or romiplostim treatment. No significant differences were noted when comparing clinical outcomes between the eltrombopag and romiplostim treatment cohorts. Our results suggest that switching to the other TPO-RA may be beneficial if there is inadequate response to treatment with the initial TPO-RA.

Incident severe thrombocytopenia in veterans treated with pegylated interferon plus ribavirin for chronic hepatitis C infection.

PURPOSE: We sought to determine the incidence and risks for severe thrombocytopenia (platelets < 50,000/µL) in United States Veteran patients treated with pegylated interferon (PEG-IFN) plus ribavirin for hepatitis C virus-positive (HCV) chronic liver disease (CLD). METHODS: Using a retrospective, observational cohort study design to analyze databases from the New England Veterans Healthcare System, we identified 979 patients diagnosed with HCV-positive CLD treated solely with PEG-IFN plus ribavirin. The cohort was stratified by pre-treatment platelet counts of 50,000-100,000/µL (N = 90), >100,000-150,000/µL (N = 162), and >150,000µL (N = 727). The cumulative incidence of severe thrombocytopenia and major bleeding events were determined for each baseline platelet group for 48 weeks following treatment initiation. Multivariable Cox regression was used to identify risk factors for incident severe thrombocytopenia. RESULTS: Overall, severe thrombocytopenia occurred in 6.1% (N = 60), but in 41.1% of patients with pre-treatment platelet counts 50, 000-100,000/µL compared with 11.7% (p < 0.001) and 0.55% (p < 0.001) in the two higher pre-treatment platelet groups. Most episodes occurred within the first 12 weeks of treatment. Median nadir count for these 60 patients was 35,000/µL (inter-quartile range 28,000, 44,000). Baseline platelet counts of 50,000-100,000/µL [adjusted hazard ratio (HR) = 3.81; 95%CI = 2.07-7.00] and hemoglobin <10 g/dL (adjusted HR = 3.39; 95%CI = 1.45-7.960) associated with severe thrombocytopenia. Major bleeding events during the 48-week observation period were rare (N = 5, 0.51%). CONCLUSIONS: The incidence of severe thrombocytopenia in a large, observational cohort of veteran patients with HCV CLD treated with PEG-IFN plus ribavirin was 6.1%. Low pre-treatment platelet counts and hemoglobin levels associated with early, incident severe thrombocytopenia.

Patient-reported treatment burden of chronic immune thrombocytopenia therapies.

BACKGROUND: Chronic immune thrombocytopenia (ITP) is a debilitating autoimmune disorder that causes a reduction in blood platelets and increased risk of bleeding. ITP is currently managed with various pharmacologic therapies and splenectomy.This study was conducted to assess patient perceived and reported treatment side effects, as well as the perceived burden or bother, and need to reduce or stop treatment, associated with these side effects among adult patients with chronic ITP. METHODS: A Web-enabled survey was administered to members of a US-based ITP patient support group. Patients reported demographic and clinical characteristics, ITP treatments' side effects for treatments received since diagnosed, level of bother (or distress), and need to reduce or stop treatment, associated with side effects. Current and past exposure was assessed for five specific treatment types: corticosteroids (CS), intravenous immunoglobulin (IVIg), anti-D immunoglobulin (anti-D), rituximab (RT), and splenectomy (SPL), as well as for other patient-referenced therapies (captured as "other"). RESULTS: The survey was completed by 589 patients; 78% female, 89% white, mean age 48 years (SD = 14.71), and 68% reported a typical low platelet count of < 50,000/µL. Current or past treatment with CS was reported by 92% (n = 542) of patients, 56% (n = 322) for IVIg, 36% (n = 209) for anti-D, 36% (n = 213) for RT, and 39% (n = 227) for SPL. A substantial proportion of CS-treated patients reported side effects (98%, P < 0.05), were highly bothered by their side effects (53.1%, P < 0.05), and reported the need to stop or reduce treatment due to side effects (37.8%, P < 0.05). Among patients reporting side effects of treatment, significant associations were noted for the number of side effects, aggregate bother of reported side effects, and the need to stop or reduce treatment (all P < 0.05). CONCLUSIONS: Current ITP treatments, particularly corticosteroids, are associated with multiple bothersome side effects that may lead to patients stopping or reducing therapy. Open, informed and complete communication between clinician and patient regarding both the benefits and the side effects of ITP treatment may better prepare patients for their prescribed regimens.

Selective validation of the WHO Bleeding Scale in patients with chronic immune thrombocytopenia.

OBJECTIVE: To evaluate the World Health Organization's (WHO) Bleeding Scale in two studies of eltrombopag in adults with chronic immune thrombocytopenia (ITP). RESEARCH DESIGN AND METHODS: Validated scales assessing bleeding in adults with ITP are lacking. Data from two long-term, phase 3 clinical trials (RAISE: NCT00370331; EXTEND: NCT00351468) that assessed eltrombopag in adults with chronic ITP were analyzed to evaluate the performance of the WHO Bleeding Scale. RESULTS: In RAISE, effect size (0.71), standardized response (0.75), and responsiveness statistics (0.57) were moderate for bleeding and bruising assessments. In EXTEND, effect size (0.62) and responsiveness statistics (0.59) were moderate; the standardized response statistic was 0.487. Intraclass correlation for test-retest reliability was 0.75 in RAISE and 0.71 in EXTEND. A positive correlation was observed between the WHO Bleeding Scale and the ITP Bleeding Scale. Bleeding scores and quality-of-life measures were inversely correlated (p < 0.05 for all). Minimal important differences for the WHO Bleeding Scale were 0.33-0.40 at baseline and last on-treatment assessment in both studies. LIMITATIONS: The majority of bleeding in these studies was mild to moderate, so this analysis cannot provide strong evidence of the validity of the WHO Bleeding Scale in patients with more severe bleeding. Potential limitations to the WHO Bleeding Scale itself include dependence on clinician interpretation of patient recall, inability to distinguish among bleeding events occurring at different anatomical sites, and an inherent assumption of linear increases in severity of bleeding across the response categories. CONCLUSIONS: These findings suggest potential usefulness of the WHO Bleeding Scale in adult patients with chronic ITP for standardizing grading of bleeding across research studies and in clinical practice.

Validation of the FACIT-fatigue subscale, selected items from FACT-thrombocytopenia, and the SF-36v2 in patients with chronic immune thrombocytopenia.

PURPOSE: To assess the validity and reliability of the fatigue subscale of the Functional Assessment of Chronic Illness Therapy (FACIT-F), a 6-item subset from the thrombocytopenia subscale of the Functional Assessment of Cancer Therapy (FACT-Th6) and the Short Form-36 Version 2 (SF-36v2) in 2 clinical trials of the thrombopoietin receptor agonist eltrombopag in chronic immune thrombocytopenia (ITP) patients. METHODS: In the 6-month, RAndomized placebo-controlled ITP Study with Eltrombopag (RAISE; n = 197), the FACIT-F, FACT-Th6, and SF-36v2 were administered at baseline, day 43, weeks 14 and 26, or early withdrawal. In the ongoing open-label extension study, Eltrombopag EXTENDed Dosing Study (EXTEND; n = 154), measures were administered at baseline, at the beginning of each stage, and at permanent discontinuation of study medication. RESULTS: FACIT-F, FACT-Th6, and SF-36v2 demonstrated acceptable internal consistency reliability (i.e., all Cronbach's alphas >0.70) and test-retest reliability (all intraclass correlation coefficients >0.70). Construct validity was supported by moderate (0.35 < r < 0.50) to strong (r > 0.50) inter-measure correlations for baseline and change scores. A small to medium magnitude of effect was captured by the FACIT-F and FACT-Th6 among patients who experienced sustained platelet responses. CONCLUSIONS: Results provide support for the validity, reliability, and responsiveness of the FACIT-F, FACT-Th6, and SF-36v2 in chronic ITP patients.

Patients' benefit-risk preferences for chronic idiopathic thrombocytopenic purpura therapies.

BACKGROUND: Idiopathic thrombocytopenic purpura (ITP) primarily is a disorder of adults characterized by autoantibody-induced platelet destruction and reduced platelet production, leading to a low peripheral blood platelet count. The long-term management of many patients with chronic ITP is unsatisfactory, largely due to the variable efficacy and risks of severe adverse effects associated with current treatment options. OBJECTIVE: To estimate patients' benefit-risk preferences for treatments for ITP. METHODS: Patients' adverse event risk tolerance and the levels of benefit required to offset possible risks were evaluated using choice-format conjoint analysis. Subjects chose between pairs of hypothetical treatment alternatives defined by probability of achieving safe platelet levels, need for corticosteroids, mode of administration, risk of rebound, risk of elevated liver enzyme levels, and risk of thromboembolism. RESULTS: In this study, we demonstrate that patients have clear and measurable benefit-risk preferences that physicians should consider when discussing treatment options with their patients. Patients were willing to accept significant risks of adverse events in return for an increase in the probability of achieving safe platelet levels, to avoid corticosteroids, and for more convenient administration. Patients were willing to accept significant risks of rebound and elevated liver enzymes for improvements in outcomes. CONCLUSIONS: These results demonstrate that patients with ITP are willing to accept treatment-related risks in exchange for improvements in treatment efficacy and administration attributes and suggest the importance of considering a patient's benefit-risk preferences during discussions of therapeutic options.

Analysis of the impact and burden of illness of adult chronic ITP in the US.

OBJECTIVE: Chronic idiopathic thrombocytopenic purpura (ITP), the predominant diagnosis in the ICD-9-CM category of primary thrombocytopenia in adults, is an autoimmune disease characterized by autoantibody-mediated platelet destruction and reduced platelet production. The objective of this study was to describe ITP patient demographics, treatment, medical care resource utilization, and costs from a real-world situation. RESEARCH DESIGN AND METHODS: Managed-care administrative claims data from January 1 2000 to February 29 2004 were used in a retrospective, longitudinal cohort study to evaluate the burden of illness of chronic idiopathic primary thrombocytopenia among adults in the US, with particular emphasis on chronic ITP. RESULTS: The annual prevalence of chronic, non-secondary, idiopathic thrombocytopenia in adults (out of >5.5 million patients) was 0.08% (i.e., 80 persons in 100 000). The mean age of the total cohort was 56.5 years (men, 60.2; women, 53.3); ratio of women to men was 1.1:1. The most frequently used thrombocytopenia-associated treatments were pharmacological therapy (e.g., immunoglobulins and corticosteroids) and whole blood transfusions; frequently used concomitant medications were antibiotics, antihypertensive agents, analgesics, and antidepressants. These data indicate that idiopathic thrombocytopenia-associated medical resource utilization and the corresponding expenditures for those services were substantive and constant over time. A large proportion of the overall patient care was directed to the treatment of bleeding and bruising symptoms. Although hospital and ER use was infrequent, these services accounted for the majority of ITP-attributable costs (46.1% were attributable to ITP-related hospital admissions; 45.0% were attributable to ER services for ITP). CONCLUSIONS: There is a need for patient-directed care plans, fuller consideration of available treatments, and the potential reduction in patient burden of illness. Study limitations included a broadly defined cohort and possible underreporting of certain medications. Introduction of highly effective and well-tolerated medications may reduce the cost and resource burden of ITP on the healthcare system.

Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer.

PURPOSE: This open-label, randomized, multicenter, phase III study compared oral topotecan versus intravenous (IV) docetaxel in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage III or IV NSCLC, performance status < or = 2, who had received only one prior chemotherapy regimen, were randomly assigned to treatment with oral topotecan 2.3 mg/m2/d on days 1 to 5 or IV docetaxel 75 mg/m2 day 1 every 21 days. RESULTS: A total of 829 patients were randomly assigned. In intent-to-treat analysis, 1-year survival rates were 25.1% with topotecan and 28.7% with docetaxel. The difference of -3.6% (95% CI, -9.59% to 2.48%) met the predefined criteria for noninferiority of topotecan relative to docetaxel because the lower limit of the 95% CI was above -10%. Median survival was 27.9 weeks with topotecan and 30.7 weeks with docetaxel. Although not statistically significant (log-rank P = .057), the higher survival rate with docetaxel was maintained across the entire treatment period. The median time to progression was 11.3 weeks with topotecan versus 13.1 weeks with docetaxel (log-rank P = .02). The overall response rate was 5% in each group. Grade 3/4 neutropenia occurred more frequently with docetaxel (60% v 50%). Grade 3/4 anemia and thrombocytopenia occurred more frequently with topotecan (26% v 10% and 26% v 7%, respectively). CONCLUSION: Oral topotecan provides activity in the treatment of relapsed, locally advanced, unresectable NSCLC. Both regimens were well tolerated with differing safety profiles. Topotecan may provide an option for patients who desire an orally available treatment after relapse.