Hedwig M. Blommestein

Systematic Literature Review and Network Meta-Analysis of Treatment Outcomes in Relapsed and/or Refractory Multiple Myeloma

Purpose Since 2000, many new treatment options have become available for relapsed and/or refractory multiple myeloma (R/R MM) after a long period in which dexamethasone and melphalan had been the standard treatment. Direct comparisons of these novel treatments, however, are lacking. This makes it extremely difficult to evaluate the relative added value of each new treatment. Our aim was to synthesize all efficacy evidence, enabling a comparison of all current treatments for R/R MM. Methods We performed a systematic literature review to identify all publicly available phase III randomized controlled trial evidence. We searched Embase, MEDLINE, MEDLINE In-Process, Cochrane Central Register of Controlled Clinical Trials, and the Web site www.ClinicalTrials.gov . In addition, two trials presented at two international hematology congresses (ie, ASCO 2016 and European Hematology Association 2016) were added to include the most recent evidence. In total, 17 randomized controlled trials were identified, including 18 treatment options. The evidence was synthesized using a conventional network meta-analysis. To include all treatments within one network, two treatment options were combined: (1) bortezomib monotherapy and bortezomib plus dexamethasone, and (2) thalidomide monotherapy and thalidomide plus dexamethasone. Results The combination of daratumumab, lenalidomide, and dexamethasone was identified as the best treatment. It was most favorable in terms of (1) hazard ratio for progression-free survival (0.13; 95% credible interval, 0.09 to 0.19), and (2) probability of being best (99% of the simulations). This treatment combination reduced the risk of progression or death by 87% versus dexamethasone, 81% versus bortezomib plus dexamethasone, and 63% versus lenalidomide plus dexamethasone. Conclusion Our network meta-analysis provides a complete overview of the relative efficacy of all available treatments for R/R MM. Until additional data from randomized studies are available, on the basis of this analysis, the combination of daratumumab, lenalidomide, and dexamethasone seems to be the best treatment option.

The costs of initial treatment for patients with acute myeloid leukemia in the Netherlands.

The aim of this study was to calculate the costs of the current initial treatment of acute myeloid leukemia. Resource use was collected for 202 patients who started with intensive chemotherapy in 2008 or 2009. The costs of the first induction course were significantly higher than the costs of the second induction course. Allogeneic transplantation from a matched unrelated donor was significantly more expensive than the other consolidation treatments. In-hospital stay was the major cost driver in the treatment of AML. Research regarding possibilities of achieving the same or better health outcome with lower costs is warranted.

A cost‐effectiveness analysis of real‐world treatment for elderly patients with multiple myeloma using a full disease model

To study the impact of novel treatments for elderly (≥66 yr) patients with multiple myeloma (MM) in daily practice by comparing real‐world effects [overall survival (OS) and quality‐adjusted life years (QALYs)] and costs over time. Also, we calculate cost‐effectiveness of treatment sequences commonly prescribed to predict effects and costs if patients had received a different treatment sequence.

A Practical Guide for Using Registry Data to Inform Decisions About the Cost Effectiveness of New Cancer Drugs: Lessons Learned from the PHAROS Registry

Decision makers increasingly request evidence on the real-world cost effectiveness of a new treatment. There is, however, a lack of practical guidance on how to conduct an economic evaluation based on registry data and how this evidence can be used in actual decision making. This paper explains the required steps on how to perform a sound economic evaluation using examples from an economic evaluation conducted with real-world data from the Dutch Population based HAematological Registry for Observational Studies. There are three main issues related to using registry data: confounding by indication, missing data, and insufficient numbers of (comparable) patients. If encountered, it is crucial to accurately deal with these issues to maximize the internal validity and generalizability of the outcomes and their value to decision makers. Multivariate regression modeling, propensity score matching, and data synthesis are well-established methods to deal with confounding. Multiple imputation methods should be used in cases where data are missing at random. Furthermore, it is important to base the incremental cost-effectiveness ratio of a new treatment compared with its alternative on comparable groups of (matched) patients, even if matching results in a small analytical population. Unmatched real-world data provide insights into the costs and effects of a treatment in a real-world setting. Decision makers should realize that real-world evidence provides extremely valuable and relevant policy information, but needs to be assessed differently compared with evidence derived from a randomized clinical trial.

Cost-effectiveness of rituximab as maintenance treatment for relapsed follicular lymphoma: results of a population-based study.

On the basis of two population‐based registries, our study aims to calculate the real‐world cost‐effectiveness of rituximab maintenance compared with observation in relapsed or refractory follicular lymphoma patients who responded to second‐line chemotherapy.

Cost-effectiveness of obinutuzumab for chronic lymphocytic leukaemia in The Netherlands

BACKGROUND Obinutuzumab combined with chlorambucil (GClb) has shown to be superior to rituximab combined with chlorambucil (RClb) and chlorambucil (Clb) in newly diagnosed patients with chronic lymphocytic leukaemia (CLL). This study evaluates the cost-effectiveness per life-year and quality-adjusted life-year (QALY) of GClb compared to RClb, Clb, and ofatumumab plus chlorambucil (OClb) in The Netherlands. METHODS A Markov model was developed to assess the cost-effectiveness of GClb, RClb, Clb and other treatments in the United Kingdom. A country adaptation was made to estimate the cost-effectiveness of these therapies in The Netherlands using Dutch unit costs and Dutch data sources for background mortality and post-progression survival. RESULTS An incremental gain of 1.06 and 0.64 QALYs was estimated for GClb compared to Clb and RClb respectively, at additional costs of €23,208 and €7254 per patient. Corresponding incremental cost-effectiveness ratios (ICERs) were €21,823 and €11,344 per QALY. Indirect treatment comparisons showed an incremental gain varying from 0.44 to 0.77 QALYs for GClb compared to OClb and additional costs varying from €7041 to €5028 per patient. The ICER varied from €6556 to €16,180 per QALY. Sensitivity analyses showed the robustness of the results. CONCLUSION GClb appeared to be a cost-effective treatment strategy compared to RClb, OClb and Clb.

Potential health gains for patients with metastatic renal cell carcinoma in daily clinical practice: A real-world cost-effectiveness analysis of sequential first- and second-line treatments

Introduction Randomised controlled trials have shown that targeted therapies like sunitinib are effective in metastatic renal cell carcinoma (mRCC). Little is known about the current use of these therapies, and their associated costs and effects in daily clinical practice. We estimated the real-world cost-effectiveness of different treatment strategies comprising one or more sequentially administered drugs. Methods Analyses were performed using patient-level data from a Dutch population-based registry including patients diagnosed with primary mRCC from January 2008 to December 2010 (i.e., treated between 2008 and 2013). The full disease course of these patients was estimated using a patient-level simulation model based on regression analyses of the registry data. A healthcare sector perspective was adopted; total costs included healthcare costs related to mRCC. Cost-effectiveness was expressed in cost per life-year and cost per quality-adjusted life-year (QALY) gained. Probabilistic sensitivity analysis was conducted to estimate the overall uncertainty surrounding cost-effectiveness. Results In current daily practice, 54% (336/621) of all patients was treated with targeted therapies. Most patients (84%; 282/336) received sunitinib as first-line therapy. Of the patients receiving first-line therapy, 30% (101/336) also received second-line therapy; the majority was treated with everolimus (40%, 40/101) or sorafenib (28%, 28/101). Current treatment practice (including patients not receiving targeted therapy) led to 0.807 QALYs; mean costs were €58,912. This resulted in an additional €105,011 per QALY gained compared to not using targeted therapy at all. Forty-six percent of all patients received no targeted therapy; of these patients, 24% (69/285) was eligible for sunitinib. If these patients were treated with first-line sunitinib, mean QALYs would improve by 0.062–0.076 (where the range reflects the choice of second-line therapy). This improvement is completely driven by the health gain seen amongst patients eligible to receive sunitinib but did not receive it, who gain 0.558–0.684 QALYs from sunitinib. Since additional costs would be €7,072–9,913, incremental costs per QALY gained are €93,107–111,972 compared to current practice. Discussion Health can be gained if more treatment-eligible patients receive targeted therapies. Moreover, it will be just as cost-effective to treat these patients with sunitinib as current treatment practice.

Microcosting Study of Rituximab Subcutaneous Injection Versus Intravenous Infusion

PURPOSE The goal of this study is to identify and compare all direct costs of intravenous and subcutaneous rituximab given to patients with diffuse large B-cell lymphoma in the Netherlands. METHODS Using a prospective, observational, bottom-up microcosting study, we collected primary data on the direct medical costs of the preparation, administration, and acquisition of rituximab. Drug costs and costs of drug wastage, labor costs, material costs, and outpatient costs were identified using standardized forms, structured using prices from official pricelists, and compared for the intravenous and subcutaneous forms of rituximab. FINDINGS Measurements were taken on 53 rituximab administrations (33 intravenous and 20 subcutaneous) and on 13 rituximab preparation (7 intravenous and 6 subcutaneous). The mean total costs were €2176.77 for the intravenous infusion and €1911.09 for the subcutaneous injection. The estimated difference of €265.17 (95% CI, €231.99-`€298.35) per administration was mainly attributable to differences in time spent in the chemotherapy unit, related outpatient costs, drug wastage, and drug costs. IMPLICATIONS Rituximab administered in the form of subcutaneous injection is less costly than its intravenous form. With their equal effectiveness taken into account, subcutaneous rituximab administration can result in significant savings when transferred to the total diffuse large B-cell lymphoma population in the Netherlands.

Policymaker, Please Consider Your Needs Carefully: Does Outcomes Research in Relapsed or Refractory Multiple Myeloma Reduce Policymaker Uncertainty Regarding Value for Money of Bortezomib?

INTRODUCTION Dutch policy regulations require outcomes research for the assessment of appropriate drug use and cost-effectiveness after 4 years of temporary reimbursement. We investigated whether outcomes research reduced policymaker uncertainty regarding the question whether the costs are worth public funding. METHODS Our cohort study included 139 patients with relapsed/refractory multiple myeloma who were treated outside of a clinical study; 72 received bortezomib and 67 did not receive bortezomib. Detailed data were retrospectively collected from medical records in 38% of Dutch hospitals. RESULTS All patients received second-line treatment; 65%, 40%, and 14%, received three, four, or five or more lines of therapy. Neither a specific treatment sequence nor an appropriate comparator could be identified because of large variation in regimes. Kaplan-Meier curves showed an increased overall survival (mean [median] 29.5 [33.2] vs. 28.0 [21.6] months) for patients treated with bortezomib (Wilcoxon P = 0.01). Total mean costs were €81,626 (range €17,793-€229,783) and €52,760 (range €748-€179,571) for patients receiving bortezomib and patients not receiving bortezomib, respectively. Patients treated with bortezomib, however, were not comparable to other patients despite attempts to correct for confounding. Therefore, it was impossible to develop a feasible model to obtain a valid incremental cost-effectiveness estimate. CONCLUSIONS It was possible to develop evidence on bortezomibs use, effects, and costs in everyday practice. Much uncertainty, however, remained regarding its cost-effectiveness. Policymakers should carefully consider whether outcomes research sufficiently decreases uncertainty or whether other options (e.g., finance- and/or outcomes-based risk-sharing arrangements) are more appropriate to ensure sufficient value for money of expensive drugs.

Second-line treatment for acute graft-versus-host disease with mesenchymal stromal cells: A decision model

No standard second‐line treatment exists for acute graft‐versus‐host disease steroid‐refractory (SR‐aGvHD), and long‐term outcomes remain poor. Mesenchymal stromal cells (MSCs) have been evaluated as treatment, but no disease model (DM) exists that integrates and extrapolates currently available evidence. The aim of this study was to develop such a DM to describe the natural history of SR‐aGvHD and to predict long‐term outcomes.