Real-World Characteristics of Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy: An Analysis of Electronic Healthcare Records in the United States.

BACKGROUND: Tafamidis was approved for the treatment of hereditary and wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) in May 2019, based on findings from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). METHODS: This retrospective cohort study evaluated the factors associated with tafamidis prescription after diagnosis of ATTRwt-CM in the real world. Between May 2019 and December 2020, 430 patients with 6 months' database activity were indexed from the de-identified US Optum electronic healthcare records at first diagnosis of ATTRwt-CM or prescription of tafamidis, then followed until last activity or death. Of these, 209 patients were prescribed tafamidis during follow-up, 167 (80%) within 1 month, 98% by 6 months, and 100% by 9 months. Median time from index to tafamidis prescription, calculated using the Kaplan-Meier method, was 5.8 months (95% confidence interval [CI] 2.4-not evaluable). RESULTS: Factors associated with tafamidis prescription in a multivariable Cox proportional hazards regression (hazard ratio [95% CI]) included age ≥ 65 years (2.1 [1.07-4.05]), male sex (1.6 [1.07-2.28]), having heart failure/cardiomyopathy (2.4 [1.54-3.82]), and having had technetium-99m pyrophosphate myocardial scintigraphy (1.7 [1.28-2.28]). CONCLUSIONS: The clinical characteristics of patients with ATTRwt-CM who were prescribed tafamidis in the real world were broadly comparable with those who took part in ATTR-ACT. Further studies are needed to evaluate hereditary and ATTRwt-CM patient populations in the real world and assess the long-term outcomes associated with disease management pathways. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT01994889.

Thrombopoietin receptor agonist discontinuation rates and reasons among patients with immune thrombocytopenia: a study of administrative claims linked with medical chart review.

Administrative claims provide a rich data source for retrospective studies of real-world clinical practice, yet some important data may be inconsistent or unavailable. This study explored factors influencing discontinuation of thrombopoietin receptor agonists (TPO-RAs) among patients with immune thrombocytopenia (ITP), by adding medical chart abstraction for additional details. Adult (≥ 18 years) patients with continuous commercial or Medicare Advantage with Part D health insurance coverage were included. Inclusion criteria were ≥ 1 claim for eltrombopag or romiplostim and ≥ 2 diagnoses of ITP between December 31, 2017, and January 1, 2020. Providers were asked to provide access to medical charts for abstraction. The analyses included only patients who discontinued TPO-RA and described patient characteristics, treatment patterns, platelet values, and reasons for discontinuation. Among 207 ITP patients treated with a TPO-RA, 137 (66%) discontinued treatment during the observation period. The mean TPO-RA treatment duration was 185 days. Mean platelet count at the time of discontinuation was 197 × 109/L. The most common reason for discontinuation was improvement of the patient's condition (42%). Other reasons included worsening of ITP/lack of response (12%), adverse events (12%), and cost-related or social reasons (23%). No reason was reported for 10%. Notably 26% of patients who discontinued remained off all ITP therapy for the remainder of the study, with a mean treatment-free period of 262 days. These results emphasize that some patients with ITP are able to discontinue TPO-RA therapy and achieve durable treatment-free periods.

Baseline characteristics and secondary medication adherence among Medicare patients diagnosed with transthyretin amyloid cardiomyopathy and/or receiving tafamidis prescriptions: A retrospective analysis of a Medicare cohort.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed, life-threatening condition that mostly affects older persons. In May 2019, regulatory approval of tafamidis provided the first pharmacologic treatment of ATTR-CM. In the pivotal phase 3 Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), 97.2% of patients were classified as adherent (defined as taking ≥ 80% of scheduled doses). Given its recent approval, there is limited real-world evidence examining patient adherence to tafamidis. OBJECTIVE: To evaluate adherence patterns, demographics, and clinical characteristics of patients in the United States receiving tafamidis prescriptions through Medicare. Secondarily, we aimed to evaluate concomitant medications filled by this patient population. METHODS: We conducted a retrospective cohort study of US Medicare claims data, limited by the Health Insurance Portability and Accountability Act of 1996, in adult patients with an adjudicated pharmacy claim for tafamidis (tafamidis free acid 61-mg capsule once daily or tafamidis meglumine four 20-mg capsules once daily) between May 1, 2019, and June 30, 2021. Gaps in therapy were measured using day gaps between prescription refills and continuous measure of medication gaps. Implementation adherence was assessed through modified medication possession ratio (MPRm), medication refill adherence (MRA), and proportion of days covered (PDC). Patients were grouped based on Medicare coverage. Patients were analyzed by subgroups based on age and at the zip code level, via distressed communities index quartiles and rural-urban tiers. RESULTS: A total of 3,558 patients who received a prescription fill of a tafamidis formulation were identified using Medicare Fee-for-Service (FFS) and Medicare Advantage (MA) claims data from May 1, 2019, to June 30, 2021. The characteristics of this patient population were consistent with published literature, as 98.6% were older than 65 years, 53.4% were between 75 years and 84 years, and 81.5% were male. In the patient population receiving tafamidis refills, adherence was high across all 3 measures, with mean MPRm greater than 90% and mean MRA greater than 80%, across all age groups. Mean PDC adherence rates were 79% or more across all age groups. Concomitant medications were generally indicated for heart failure and thrombosis. Among monotherapy groups with similar demographic makeup, adherence was significantly higher among users of tafamidis free acid vs tafamidis meglumine (P < 0.0001 across all mean adherence measures). CONCLUSIONS: Our results demonstrate that real-world adherence to tafamidis in the Medicare population is high, regardless of age, zip code-level socioeconomic quartile, or geography. Adherence was higher among patients receiving tafamidis free acid, suggesting that the enhanced convenience of a single capsule once daily may positively contribute to adherence among patients with ATTR-CM. DISCLOSURES: Darrin Benjumea is an employee of Genesis Research who has been contracted by Pfizer, Inc., for involvement in this study. Andrew Peterson is an employee of University of the Sciences who has been contracted by Pfizer, Inc., for involvement in this study. Zach Bredl is an employee of Care Journey who has been contracted by Pfizer, Inc., for involvement in this study. Anuja Roy, Nick Marchant, Jose Alvir, Rahul Bhambri, Jason Kemner, and Bhash Parasuraman are employees of Pfizer, Inc., and own stock and/or stock options. This study was supported by Pfizer, Inc.

Baseline Characteristics and Secondary Medication Adherence Patterns Among Patients Receiving Tafamidis Prescriptions: A Retrospective Analysis Using a National Specialty Pharmacy Dispensing Database.

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a serious, underrecognized condition, which leads to heart failure and early mortality if left untreated. Until recently, heart transplantation was the only treatment for ATTR-CM. Regulatory approval of tafamidis transformed treatment for patients. In the phase 3 Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), which established the safety and efficacy of tafamidis, medication adherence was high with 97.2% of patients taking ≥80% of scheduled doses. Evidence of real-world adherence to cardiology drugs demonstrates low adherence and suboptimal outcomes; however, real-world adherence to tafamidis has not been investigated. The main objective of this study was to describe adherence patterns of patients filling tafamidis in the Symphony Health database. Methods: This retrospective analysis of the Symphony Health Solutions claims database used secondary adherence measures, including modified medication possession ratio (MPRm), days between fills adherence rate, and compliance rate, to assess adherence patterns of 2020 patients filling tafamidis free acid 61-mg capsules or tafamidis meglumine 4x20-mg capsules from June 1, 2019 to August 31, 2020. Results: Patients receiving a tafamidis formulation had characteristics consistent with the expected patient population; 71.6% were aged 75-84 years, 83.2% were male, and the highest proportion resided in the Northeast region (30.5%) of the United States. Adherence for tafamidis was high, as 75% to 100% of the patients across subgroups met or exceeded the commonly defined adherence threshold of 80%. Median number of refills ordered and received was six refills per patient. Most patients received refills with no gap (n=1633) or a gap <30 days (n=1267/1317 patients). Adherence was high across follow-up time, sex, and age subgroups. Adherence varied by geographic region, with the Northeast being significantly higher than the Midwest (mean MPRm 94.41% vs 88.21%, p=0.0007). Conclusion: These results provide evidence that real-world adherence to tafamidis in patients with ATTR-CM is high.

Temporal Trends in Diagnostic Testing Patterns for Wild-Type Transthyretin Amyloid Cardiomyopathy in the Medicare Fee-for-Service Population.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is frequently misdiagnosed or diagnosed late in the disease course. ATTRwt-CM can be diagnosed invasively through tissue biopsy, but current diagnostic recommendations indicate technetium-99m pyrophosphate (99mTc-PYP) bone scintigraphy is an acceptable noninvasive alternative. The relative use of these confirmatory diagnostic tests in routine clinical practice is unknown. A retrospective observational study assessed temporal trends in biopsy and 99mTc-PYP scintigraphy and differences in patient characteristics using in/outpatient claims data from the US Medicare fee-for-service database. Claims prevalence for biopsy alone (≥1 claim for cardiac/extracardiac biopsy), imaging alone (≥1 claim for 99mTc-PYP scintigraphy), and both tests and patient demographic, geographic, and clinical characteristics were examined. Of patients (n = 1226) receiving an ATTRwt-CM diagnostic code, 29%, 47%, and 24% were diagnosed by biopsy alone, 99mTc-PYP scintigraphy alone, and both tests, respectively. Patients with claims for 99mTc-PYP scintigraphy alone were older than those with claims for biopsy alone (79.9 vs 76.5; p <0.001). Fewer patients in the southern United States and more patients in the northeastern United States had claims for 99mTc-PYP scintigraphy alone than biopsy alone (p <0.001). There was a temporal trend toward more claims for 99mTc-PYP scintigraphy alone (odds ratio 1.21; p <0.001) and both tests (odds ratio 1.10; p = 0.008) versus biopsy alone. From 2017 to 2019, claims increased for 99mTc-PYP scintigraphy alone. In conclusion, these data suggest a growing preference for the noninvasive imaging technique, which has high sensitivity/specificity, usability, and accessibility and may help facilitate earlier disease diagnosis. United States regional differences in the use of 99mTc-PYP scintigraphy highlight the need for education initiatives.

Tapering and Discontinuation of Thrombopoietin Receptor Agonist Therapy in Patients with Immune Thrombocytopenia: Results from a Modified Delphi Panel.

BACKGROUND: Recent evidence suggests that in patients with immune thrombocytopenia (ITP) with a stable response on thrombopoietin receptor agonists, treatment may be tapered and/or discontinued. OBJECTIVES: The objective of this study was to provide a guide for tapering and discontinuation of TPO-RA therapy in patients with ITP, based on hematologist survey results, existing evidence, and expert consensus. PATIENTS/METHODS: UK hematologists completed a survey to characterize self-reported practice patterns related to TPO-RA tapering and discontinuation in patients with ITP. Using a modified Delphi panel approach, ITP experts developed consensus statements regarding the use of TPO-RA tapering and discontinuation. RESULTS: Survey respondents estimated that 30-34% of their patients were suitable for tapering or discontinuation and that 29-35% of these patients required treatment re-initiation after an average treatment-free interval of 86-106 days. No clear predictors of patient suitability or response to tapering or discontinuation were identified. The ITP expert consensus was that approximately 30% of patients are eligible for tapering and discontinuation, which may be considered after 6-12 months for patients demonstrating an adequate treatment response (platelet count >50,000/µL at ≥75% of assessments in the preceding 6 months). Treatment re-initiation may be considered if the platelet count decreases or if the patient becomes symptomatic. Individual differences need to be taken into account when considering TPO-RA tapering or discontinuation. CONCLUSIONS: Tapering and discontinuation of TPO-RA therapy may be considered for certain patients with ITP. Further study is needed to better predict patients likely to achieve sustained off-treatment responses after tapering and discontinuation.

The Cost-effectiveness of Eltrombopag for the Treatment of Immune Thrombocytopenia in the United States.

PURPOSE: Eltrombopag was evaluated as a second-line treatment for adult chronic immune thrombocytopenia (ITP) in the 2006 Phase III RAISE (Eltrombopag for Management of Chronic Immune Thrombocytopenia) randomized, placebo-controlled trial. More than 80% of patients reached satisfactory platelet counts within 2 weeks. However, the economic value of eltrombopag as a second-line treatment for ITP remains to be formally assessed. This study aimed to estimate the cost-effectiveness of treating ITP with a comparable thrombopoietin receptor agonist (eltrombopag vs romiplostim). METHODS: A Markov model was implemented over a lifetime time horizon to estimate the benefits and costs of each treatment. The model featured 3 health states based on current guidelines: (1) on treatment; (2) treatment failure/discontinuation; and (3) mortality. In line with therapeutic goals in ITP, model patients could experience 3 events: no bleeding, mild/moderate bleeding, or severe bleeding. Data on eltrombopag use were obtained from an open-label extension of previous Phase II/III trials, including RAISE. Romiplostim data were obtained from Phase III trials and an extension study. Lifetime overall survival was extrapolated by using treatment-specific mortality rates derived from severe bleeding and natural mortality rates. The costs of drugs, routine care, bleeding episodes, adverse events, and mortality were represented in the model. FINDINGS: Eltrombopag-treated patients gained 17.58 life years and 14.68 quality-adjusted life years, whereas romiplostim-treated patients gained 17.52 life years and 14.67 quality-adjusted life years. The total lifetime cost of eltrombopag treatment was estimated at $1.58 million versus $2.13 million for romiplostim. Sensitivity analyses supported base case findings. Deterministic sensitivity analysis predicted the greatest sensitivity to the rates of severe bleeding, discontinuation, and natural mortality. Probabilistic sensitivity analysis showed that eltrombopag would be an efficient use of resources at a $50,000 threshold in 52.8% of cases. In all probabilistic iterations, the total cost of eltrombopag treatment was lower than with romiplostim, primarily because of lower drug costs. IMPLICATIONS: Clinical data were applied in an economic analysis, and eltrombopag exhibited economic dominance compared with romiplostim, driven largely by the reduced costs of primary therapy. This model was limited by a lack of specific patient-level data and robust data on the duration of secondary therapy, as well as by the fact that utilization values are likely conservative estimates for routine care use.

Real-world evidence on clinical outcomes in immune thrombocytopenia treated with thrombopoietin receptor agonists.

Aim: Eltrombopag and romiplostim are US FDA approved for treatment of immune thrombocytopenia in patients with insufficient response to other treatments. Clinical or real-world data comparing outcomes of the two drugs are limited. Methods: This retrospective cross-sectional study sought information on bleeding-related episodes (BREs), adverse events (AEs) and other outcomes of eltrombopag or romiplostim treatment in immune thrombocytopenia. Results: Patients receiving eltrombopag experienced significantly reduced BREs, severe BREs, rescue medication use and platelet transfusions. Diarrhea and headache were significantly less frequent in patients receiving eltrombopag; other AEs occurred equally in both groups. Conclusion: There may be a potential advantage for the use of eltrombopag versus romiplostim in the practice settings studied, based on rates of BREs and AEs and rescue medication utilization.

Burden of illness among patients with severe aplastic anemia who have had insufficient response to immunosuppressive therapy: a multicenter retrospective chart review study.

This study assessed treatment patterns and healthcare resource utilization (HRU) of patients with severe aplastic anemia (SAA) with insufficient response to immunosuppressive therapy (IST). A retrospective chart review was conducted at Dana-Farber Cancer Institute (DFCI), United States, and Hôpital Saint-Louis (HSL), France. Eligible patients were ≥ 18 years old, diagnosed with acquired SAA between January 1, 2006, and July 31, 2016, had insufficient response to IST, and had ≥ 12 months of follow-up post-diagnosis. Overall survival (OS) was estimated using the Kaplan-Meier method. Among the 40 patients, mean age at diagnosis was 44 years and 53% were women. Median follow-up time after SAA diagnosis was 48.3 months. Ninety-five percent of patients received antithymocyte globulin (ATG) as primary therapy prior to hematopoietic stem cell transplant (HSCT). Most common secondary SAA therapies prior to HSCT were eltrombopag (28%) and androgens (15%). Seventy-five percent of patients received HSCT. Prior to HSCT, patients received an average of 2.7 red blood cell (RBC) and 3.3 platelet transfusions per month; patients had 0.9 hospitalizations, 0.4 emergency room visits, and 12.8 office visits per year. Five-year OS was 75%, with infection as the primary cause of death. Additionally, this study provides information on the subgroup of patients receiving eltrombopag which was the most common secondary therapy. This study quantified transfusion and HRU burden associated with SAA and demonstrated high 5-year survival in a recently treated cohort.

Budget Impact Of Eltrombopag As First-Line Treatment For Severe Aplastic Anemia In The United States.

BACKGROUND: Severe aplastic anemia (SAA) is a rare autoimmune condition resulting in low blood cell counts across lineages. Immunosuppressive therapy (IST) has demonstrated low response, toxicity, and risk of transformation. In a Phase I/II trial, the addition of eltrombopag to first-line IST increased response rates relative to an IST-only historical cohort. METHODS: A model was developed to estimate the budget impact of treating SAA with eltrombopag-based therapy from a US private healthcare system perspective. A simulated cohort of newly diagnosed SAA patients based on the total US population received 6 months of IST ± eltrombopag and were followed for 1 year, with mutually exclusive patient cohorts entering in years 1, 2, and 3. The model assessed the budget impact of first-year treatment for each cohort without considering subsequent years. At 6 months, responders in either arm received maintenance therapy (low-dose cyclosporine), and non-responders received 6 months of second-line eltrombopag monotherapy. Costs considered included first-line, maintenance, and second-line therapy, administration, routine care, mortality, and adverse events (AEs). All cost data were reported in 2018 US dollars. RESULTS: The annual incidence of aplastic anemia was 0.000234%, with 83.8% of cases assumed to be SAA. Based on trial data, 94% of patients receiving eltrombopag and IST responded versus 66% of patients receiving IST, with a 0.3% reduction in the annual risk of mortality for the eltrombopag + IST group. Use of first-line eltrombopag in a model SAA population based on the total US population increased overall costs by $50 million over 3 years. First-line drug costs accounted for an increase of $69 million, while improved response produced $19 million in secondary therapy cost savings. Sensitivity analyses confirmed the robustness of the analysis. CONCLUSION: High response rates combined with reduced rescue medication use and mortality in patients treated with eltrombopag and IST mediated higher medication costs.

Changes in health-related quality of life with long-term eltrombopag treatment in adults with persistent/chronic immune thrombocytopenia: Findings from the EXTEND study.

Patients with persistent/chronic immune thrombocytopenia (cITP) have low platelet counts, increased risk of bleeding and bruising, and often suffer from reduced health-related quality of life (HRQoL). cITP treatments may either improve HRQoL by increasing platelet counts or decrease it because of side effects. The open-label EXTEND study (June 2006 to July 2015) evaluated long-term safety, tolerability, and efficacy of eltrombopag (an oral thrombopoietin-receptor-agonist) in adults with cITP who completed a previous eltrombopag ITP trial. The final results of EXTEND were published and used to assess changes in patient-reported HRQoL over time and association between HRQoL and platelet response. Four validated HRQoL instruments were administered: SF-36v2 including physical component summary (PCS) and Mental Component Summary; Motivation and Energy Inventory Short Form (MEI-SF); Fatigue Subscale of FACIT (FACIT-Fatigue); and FACT-Thrombocytopenia Subscale Six-Item Extract (FACT-Th6). For the 302 patients enrolled, median duration of eltrombopag treatment was 2.37 years. All 4 HRQoL instruments demonstrated positive mean changes from baseline over time adjusted for patient baseline characteristics and rescue therapy use, and had positive association with platelet response (platelet count ≥30 × 109 /L; ≥50 × 109 /L; and ≥50 × 109 /L and >2 times baseline). Improvements from baseline started within 3 months and persisted through 5 years of treatment for FACIT-Fatigue and FACT-Th6 (P <.05 for nearly all time points); through 2.5 years for SF-36v2 PCS and less consistently for the MEI-SF. In conclusion, in addition to eltrombopag increasing platelet counts and reducing bleeding/bruising, it also alleviated fatigue, concerns about bleeding and bruising, and improved physical function in many patients, especially responders.

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-consequence model comparing eltrombopag and romiplostim in pediatric patients with chronic immune thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is an auto-immune disorder characterized by enhanced platelet destruction and, subsequently, the potential for increased bleeding. Thrombopoietin receptor (TPO-R) agonists have recently emerged as promising therapies for ITP patients who are refractory to other treatments. While eltrombopag (EPAG) is the only TPO-R agonist US Food and Drug Administration approved for use in pediatric patients, romiplostin (ROMI) has been used in Phase III clinical studies. METHODS: A cost-consequence model (CCM) was developed to evaluate the costs of EPAG, ROMI, and watch-and-rescue (W&R) in relation to their respective treatment outcomes in previously-treated pediatric chronic ITP (cITP) over a 26-week time horizon. The costs of drugs, administration, routine care, rescue medications, adverse events, and mortality were included. Data on platelet count response rate, bleeding events, and adverse events were derived from all relevant identified Phase III-registered clinical trials, health outcomes were compared via indirect treatment comparison. RESULTS: The overall estimated cost of EPAG per patient was US$66,550, compared to US$101,056 for ROMI and US$32,720 for W&R. EPAG's lower cost compared to ROMI was largely due to lower drug costs (US$62,202 vs US$84,396), administration costs (US$0 vs US$1,955), and significantly lower costs due to severe bleeding (US$354 vs US$10,191). When assessing cost per severe bleeding event avoided, EPAG was dominant over ROMI (less expensive and more effective). EPAG was again dominant over ROMI when assessing the cost per responder and per bleeding event (any grade). Sensitivity analysis was consistent with the base case findings. CONCLUSION: EPAG was the preferred TPO-R agonist to treat cITP when indirectly compared to ROMI, largely driven by its favorable severe bleeding outcomes and lower drug and administration costs.

A decision framework for treating chronic immune thrombocytopenia with thrombopoietin receptor agonists.

Aim: Eltrombopag and romiplostim are comparable second-line therapies in chronic immune thrombocytopenia. Treatment decisions are made in different contexts. A framework was created to outline decision pathways for physicians and payers. Materials & methods: The costs of drugs, administration, routine care, bleeding, other adverse events and mortality were included in the year-long calculation of total costs from a US private payer perspective. Treatment parameters and outcome data were obtained from relevant clinical trials. Results: The total cost per year, per patient of eltrombopag was US$51,000 versus US$76,000 for romiplostim. Drug costs and costs associated with bleeding-related events were the main drivers of cost difference. Conclusion: This framework facilitates decision-making in the management of chronic immune thrombocytopenia with eltrombopag and romiplostim.

Patient-reported outcomes of multiple myeloma patients treated with panobinostat after ≥2 lines of therapy based on the international phase 3, randomized, double-blind, placebo-controlled PANORAMA-1 trial.

The phase 3 PANORAMA-1 trial led to regulatory approvals of panobinostat (PAN) in combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of multiple myeloma after ≥2 prior regimens, including BTZ and an immunomodulatory drug. Patient-reported outcomes (PROs) were assessed in PANORAMA-1, with data available for 73 patients in the PAN + BTZ + DEX arm and 74 patients in the placebo (PBO) + BTZ + DEX arm. Per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), global health status/quality of life (QoL) scores initially declined with PAN + BTZ + DEX during the first 24 weeks before approaching baseline scores and remaining steady during the next 24 weeks, with no difference between arms at Week 48. The EORTC QLQ-Myeloma module (EORTC QLQ-MY20) demonstrated initial improvements and subsequent stabilization of disease symptom scores in both arms and initial worsening and subsequent improvement of side effects of treatment scores, with the initial worsening more pronounced and recovery less pronounced with PAN + BTZ + DEX. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scores remained relatively stable and similar between the arms. Overall, these PRO findings support the addition of PAN to the BTZ+DEX regimen as an efficacious treatment option, with limited symptomatology and impact on patients' QoL. The reported results are based on a descriptive analysis of the data. No formal statistical tests have been performed.

Treatment-free interval as a metric of patient experience and a health outcome of value for advanced multiple myeloma: the case for the histone deacetylase inhibitor panobinostat, a next-generation novel agent.

BACKGROUND: Patients with relapsed or relapsed/refractory multiple myeloma (RRMM) face poor treatment options by the time third-line therapy is required, despite advances in overall survival in recent years. Treatment free interval (TFI) and opportunities to maintain quality of life (QoL) have been cited as additional measures of efficacy that can be utilized in personalized treatment decisions. METHODS: The clinical health outcomes data from PANORAMA-1, the pivotal phase-3 trial comparing panobinostat-bortezomib-dexamethasone (PAN-BTZ-DEX) with placebo (PBO)-BTZ-DEX in RRMM patients treated with 1 to 3 prior regimens, retrospectively assessed TFI as a health outcome measure and metric of patient treatment experience relevant to the RRMM population. RESULTS: PAN-BTZ-DEX shows promise for prolonged TFI (mean TFI, 7.49 months; 95% CI, 6.02 to 8.71) compared to PBO-BTZ-DEX (mean TFI, 3.86 months; 95% CI, 3.08 to 4.60) for heavily pre-treated advanced RRMM patients), due to the short duration of therapy and extended progression free-survival. Further, QoL during the TFI was similar to baseline. CONCLUSIONS: PAN-BTZ-DEX provides a treatment regimen with prolonged TFI benefits previously not available for RRMM patients. TFI has not been traditionally measured in clinical trials, but should be assessed in prospective data collection given its value to payers, providers, and patients.

Value of transfusion independence in severe aplastic anemia from patients' perspectives - a discrete choice experiment.

BACKGROUND: Aplastic anemia is a rare, serious blood disorder due to bone marrow failure to produce blood cells. Transfusions are used to reduce risk of bleeding, infection and relieve anemia symptoms. In severe patients, transfusions may be required more than once/week. It is unclear from the patient perspective the impact that transfusions have on quality of life. This study aimed to elicit patient preferences for attributes associated with severe aplastic anemia (SAA) treatment, including transfusion independence. METHODS: An online discrete choice experiment (DCE) was conducted among patients with SAA who experienced insufficient response to immunosuppressive therapy and transfusion dependence for ≥3 months in the past 2 years. Recruitment occurred through the Aplastic Anemia and Myelodysplastic Syndromes International Foundation and referrals from clinical sites in the US and France. Respondents chose between hypothetical treatment pairs characterized by a common set of attributes: transfusions frequency, fatigue, risk of infection, and risk of serious bleeding. Conditional logit model with effects coding was used to estimate part-worth utilities for different attribute levels and the relative importance of each attribute. Predicted utility scores for transfusion frequency levels were reported. RESULTS: Thirty patients completed the survey. Most were age ≥ 40 years (73.3%), female (70.0%), and from the US (86.7%). 33.3% underwent bone marrow transplant; 36.7% received iron chelation therapy. Patients largely agreed that transfusion independence would result in less burden on time and costs, greater control and quality of life, less fatigue (86.7% noted each) and less scheduling around medical appointments (83.3%). The DCE found highest relative importance for risk of bleeding (0.30), followed by risk of infection (0.28), fatigue (0.23), and frequency of transfusions (0.20). More frequent transfusions resulted in lower utility, particularly when increasing monthly transfusions frequency from 4 (0.57) to 8 (0.35). CONCLUSIONS: Our study showed that higher utility was associated with fewer transfusions in SAA patients with insufficient response to immunosuppressive therapy. While risk of bleeding, risk of infection, and fatigue were more important for patient treatment preferences, frequency of transfusions was also important.

Panobinostat Plus Bortezomib Versus Lenalidomide in Patients with Relapsed and/or Refractory Multiple Myeloma: A Matching-Adjusted Indirect Treatment Comparison of Survival Outcomes using Patient-level Data.

BACKGROUND: In the UK, the standard of care for patients with multiple myeloma who received ≥2 prior treatments is lenalidomide plus dexamethasone (LEN + DEX) and pomalidomide plus DEX (POM + DEX) (in Wales only). Recently, panobinostat plus bortezomib and DEX (PAN + BTZ + DEX) was licensed in this setting. The current study assessed the progression-free survival (PFS) and overall survival (OS) outcomes with PAN + BTZ + DEX versus LEN + DEX (primary comparator) and POM + DEX (exploratory comparator). METHODS: Since an anchor-based indirect treatment comparison was not feasible, the matching-adjusted indirect treatment comparison approach was used. To compare the survival outcomes, patient-level data were generated for the comparators utilizing published Kaplan-Meier survival estimates. The use of approximated patient-level data and matched data for PAN + BTZ + DEX allowed the use of Cox proportional hazards models and the assessment of the proportional hazards assumption. In cases where there was evidence that the proportional hazards assumption was violated, time-dependent hazard ratios (HRs) were estimated. Median and mean values for PFS and OS were predicted. RESULTS: For both PFS and OS, the proportional hazards assumption was not satisfied, therefore time-dependent HRs were estimated. Using time-dependent HRs, the mean PFS was estimated to be 11.83 months for PAN + BTZ + DEX and 10.96 months for LEN + DEX. The corresponding mean OS estimates were 30.73 and 27.76 months, respectively. Comparisons with POM + DEX were affected by large uncertainty and did not allow making robust inferences. CONCLUSIONS: To our knowledge, this is the first study that combined matching-adjusted indirect treatment comparison with time-dependent HRs to address changing patterns in the HR. The results suggest that treatment with PAN + BTZ + DEX and LEN + DEX are associated with similar mean PFS and OS in the third-line treatment setting of multiple myeloma.

Estimating the Economic Impact of Adding Panobinostat to a U.S. Formulary for Relapsed and/or Refractory Multiple Myeloma: A Budget Impact and Cost-Benefit Model.

BACKGROUND: Multiple myeloma is an incurable B-cell malignancy with a natural history that involves alternating periods of remission and subsequent relapse. For relapsed and/or refractory multiple myeloma (RRMM), the typical patient currently receives more lines of therapy than has been feasible in the past, translating into longer progression-free survival (PFS). Consequently, cost issues have become more prominent because patients may be offered newer and more expensive therapies during a more prolonged overall treatment course. OBJECTIVE: To estimate the economic impact of adding panobinostat to a U.S. health plan formulary as a treatment option with bortezomib and dexamethasone for patients with RRMM previously treated with a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), using a budget impact and cost-benefit model. METHODS: Total costs of commonly used salvage therapy regimens were combined with market share data and population prevalence estimates of RRMM to yield the total cost of treatment, from the perspective of a U.S. third-party payer (commercial or Medicare) with a time horizon of 1 year. Comparator treatment regimens included bortezomib-dexamethasone, lenalidomide-dexamethasone, lenalidomide-bortezomib-dexamethasone, carfilzomib monotherapy, carfilzomib-lenalidomide-dexamethasone, and pomalidomide-dexamethasone. Costs (2015 U.S. dollars) included drug costs for oral oncology agents, medical and administration costs for injectable oncology agents, costs of adverse event (AE) prophylaxis and monitoring, and costs of grade 3/4 AEs. RESULTS: In a hypothetical health plan with 1 million members, the annual number of RRMM patients with previous PI and IMiD treatments was estimated at 16 and 118 for a commercial and Medicare plan, respectively. Introduction of panobinostat as part of the panobinostat-bortezomib-dexamethasone regimen was not expected to result in a substantial budget impact to either commercial or Medicare plans, with an incremental cost < $0.01 per member per month. Panobinostat-bortezomib-dexamethasone had a low cost per treated patient per month without progression, owing to the minimal increase in expenditure over existing bortezomib-based regimens and long median PFS, compared with median duration of treatment. CONCLUSIONS: Adding panobinostat to a plan formulary as a treatment option is expected to be cost neutral (and potentially cost saving in the context of new and more expensive treatment regimens). With a low cost per month without progression, panobinostat-bortezomib-dexamethasone represents good value for the money. DISCLOSURES: Funding for this study was sponsored by Novartis, East Hanover, New Jersey. Bloudek and Kish are employees of Xcenda, a consulting company contracted by Novartis to conduct this analysis. Roy, Globe, and Kuriakose are employees of Novartis. Siegel is on the advisory boards and speaker's bureau of Celgene, Onyx/Amgen, Millennium/Takeda, and Novartis and is on the advisory boards of Merck. Jagannath is a consultant to Sanofi, Bristol-Meyers Squibb, and Celgene. Orloski is a contractor to Xcenda and provided medical writing support, which was funded by Novartis. Study design and concept were contributed by Bloudek, Roy, and Kish, assisted by Globe. Bloukek took the lead in data collection, along with Kish, and data interpretation was performed by Siegal, Jagannath, Globe, and Kuriakose. The manuscript was written primarily by Orloski, along with Roy and Kish, and revised by Roy, along with Siegal, Jagannath, Globe, Orloski, and Kuriakose.

Real-world treatment patterns and associated progression-free survival in relapsed/refractory multiple myeloma among US community oncology practices.

BACKGROUND: Evidence supporting optimal treatment sequencing in relapsed/refractory multiple myeloma (RRMM) patients requiring multiple therapy lines is lacking. METHODS: Using retrospective chart data, this study describes real-world RRMM treatment patterns and related progression-free survival (PFS) in US community oncology clinics. RESULTS: Bortezomib ± a non-immunomodulatory drug (IMiD), lenalidomide ± a non-proteasome inhibitor (PI), bortezomib + an IMiD were the most commonly used regimens in early lines of therapy. Median PFS was similar in 1(st) (11.1 months) and 2(nd) line (10.5) and decreased in lines 3 through 5 (3(rd): 7.9; 4(th): 7.2, 5(th): 5.4). Longest PFS (12.5 months) in first line was with bortezomib + ImiD; longest PFS in second line was with lenalidomide ± a non-PI was (13.2 months). CONCLUSIONS: Re-treatment with bortezomib was common; novel agents were reserved for later therapy lines. Overall, the observed PFS associated with real-world treatment sequences were shorter than those reported in clinical trials.