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Background Given rapid innovation in advanced therapies for moderately to severely active ulcerative colitis (UC), we investigated their comparative efficacy and safety during induction and maintenance through network meta-analysis. Methods Using Bayesian methods, endpoints of clinical remission and clinical response per Full Mayo score, and endoscopic improvement were assessed in bio-naive and -exposed populations. Safety was assessed in overall populations by all adverse events (AEs), serious AEs, discontinuation due to AEs, and serious infections. Phase 3 randomized controlled trials were identified via systematic literature review, including the following advanced therapies: infliximab, adalimumab, vedolizumab, golimumab, tofacitinib, ustekinumab, filgotinib, ozanimod, and upadacitinib. Random effects models were used to address between-study heterogeneity. Intent-to-treat (ITT) efficacy rates were calculated by adjusting maintenance outcomes by likelihood of induction response. Results Out of 48 trials identified, 23 were included. Across all outcomes and regardless of prior biologic exposure, ITT efficacy rates were highest for upadacitinib, owing to its highest ranking for all efficacy outcomes in induction and for all but clinical remission during maintenance among bio-naive induction responders. For all advanced therapies versus placebo, there were no significant differences in serious AEs or serious infections across therapies. For all AEs, golimumab had higher odds versus placebo during maintenance; for discontinuation due to AEs, upadacitinib had lower odds versus placebo during induction, while ustekinumab and vedolizumab had lower odds versus placebo during maintenance. Conclusions Upadacitinib may be the most efficacious therapy for moderately to severely active UC based on ITT analyses, with similar safety across advanced therapies.

Cost-effectiveness data on chimeric antigen receptor (CAR) T cell therapies for relapsed/refractory large B cell lymphoma (R/R LBCL), accounting for inpatient/outpatient site of care (site), are sparse.This payer model compares lifetime costs/benefits for CAR T cell-treated (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tisagenlecleucel [tisa-cel]) patients with R/R LBCL in the USA. Three-month post-infusion costs were derived from unit costs and real-world all-payer (RW) site-specific utilization data for 1175 patients with diffuse R/R LBCL (CAR T cell therapy October 2017-September 2020). Therapy- and site-specific grade 3+ cytokine release syndrome (CRS) and neurologic event (NE) incidences were imputed from published trials. Lifetime quality-adjusted life-years (QALYs) and long-term costs were calculated from therapy-specific overall and progression-free survival data, adjusted for differences in trial populations. The base case used 17% outpatient site (RW) for all therapies. ZUMA-1 trial cohorts 1/2 informed other axi-cel base case inputs; ZUMA-1 cohorts 4/6 data (updated safety management) supported scenario analyses.Base case total costs for axi-cel exceeded liso-cel ($637 K versus $621 K) and tisa-cel ($631 K versus $577 K) costs. Three-month post-infusion costs were $57 K to $59 K across all therapies. Total QALYs for axi-cel also exceeded those for liso-cel (7.7 versus 5.9) and tisa-cel (7.2 versus 5.0) with incremental costs per QALY gained of $9 K versus liso-cel and $25 K versus tisa-cel. Base case incremental net monetary benefit was $255 K (95% confidence interval (CI) $181-326 K) for axi-cel versus liso-cel, and $280 K (95% CI $200-353 K) versus tisa-cel. Longer survival with axi-cel conferred higher lifetime costs. In all scenarios (e.g., varied outpatient proportions, CRS/NE incidence), axi-cel was cost-effective versus both comparators at a maximum willingness-to-pay of under $26 K/QALY as a result of axi-cel's higher incremental survival gains and quality-of-life.Axi-cel is a cost-effective CAR T cell therapy for patients with R/R LBCL compared to tisa-cel and liso-cel. Site of care does not impact the cost-effectiveness of CAR T cell therapy.

Aim: Evaluate the relative efficacy of oral versus injectable azacitidine (AZA) maintenance therapy in acute myeloid leukemia (AML) after complete remission. Materials & methods: Systematic literature review identified QUAZAR AML-001, HOVON 97 AML, UK NCRI AML16 and QoLESS-AZA-AMLE (sensitivity analysis) trials. Network meta-analysis and matching-adjusted indirect comparisons assessed survival outcomes. Results: In the network meta-analysis, combining the HOVON 97 and UK NCRI trials, oral AZA (QUAZAR) was associated with significantly improved overall survival (OS) versus injectable AZA (hazard ratio: 0.744; 95% credible interval: 0.557–0.998). After matching-adjusted indirect comparisons, to address differences in patient characteristics across trials, OS improvements were maintained with oral versus injectable AZA (hazard ratio: 0.753; credible interval: 0.563–0.998). Conclusion: In AML, maintenance therapy with oral AZA was associated with improved OS versus injectable AZA.

Background Patients with treatment-resistant major depressive disorder (TRD) have limited treatment options. We developed an early stage cost-effectiveness model of TRD to explore the potential value of a hypothetical monotherapy relative to the standard of care (SOC). The relative impacts of the monotherapy's three differentiating features over SOC are explored: efficacy advantage, tolerability advantage, and price premium. Methods We adapted an existing economic model of TRD to evaluate the cost-effectiveness of a hypothetical monotherapy for TRD with a 25% efficacy advantage, a 10% tolerability advantage, and a 50% price premium over SOC (selective serotonin reuptake inhibitor plus atypical antipsychotics [SSRI + AAP]). The model is a hybrid of a decision tree that captures patients' outcomes after an 8-week acute treatment phase and a Markov model that simulates patients' depression course through a 10-month maintenance phase. Sensitivity (deterministic and probabilistic) and scenario analyses were conducted to characterize the relative impacts of the monotherapy's three differentiating features over SOC. Results Over the 12-month time horizon, the hypothetical monotherapy is shown to dominate SOC; it generates lower costs and higher quality-adjusted life years in comparison to SSRI + AAP. Sensitivity and scenario analyses showed that this dominance depends largely on the monotherapy's efficacy and tolerability advantages over SOC. Specifically, a monotherapy with ≥ 12% efficacy or ≥70% tolerability advantage (and a 50% price premium) will always be superior to SSRI + AAP. Between these two extremes, most profiles, nonetheless, generate incremental cost-utility ratios for the monotherapy, which fall below common payer willingness-to-pay thresholds. Conclusion Our adaptation of an existing economic model of TRD provides a flexible platform for researchers to evaluate the efficacy/tolerability improvements required for a successful new TRD product and for decision-makers to assess the cost-effectiveness impact of uncertainties inherent in early stage product development in TRD.

Introduction: For medically fit patients with AML, intensive chemotherapy (IC) is used to induce complete remission (CR). Following CR, some patients may be considered for curative-intent hematopoietic stem cell transplantation. For others, the aim of treatment is to prevent relapse, which usually occurs within 1 year from CR. Post CR, treatment may include consolidation therapy, consisting of chemotherapy given soon after CR is achieved. In addition, maintenance therapy with intravenous (IV) or subcutaneous (SC) injection of AZA has shown evidence of statistically significant improvement in unadjusted time to relapse, though not in unadjusted overall survival (OS), vs placebo (PBO) in randomized controlled trials (RCTs) (Wei. 2019). In the QUAZAR AML-001 trial, maintenance with CC-486, an oral hypomethylating agent, resulted in significant improvements in unadjusted time to relapse and OS vs PBO (Wei et al. 2019). No head-to-head trials have compared CC-486 with AZA. Objective: To assess the relative efficacy of CC-486 compared with AZA. Methods: A systematic literature review was conducted to identify RCTs assessing AML maintenance therapy with AZA, for comparison with CC-486. Bayesian network meta-analysis (NMA) compared endpoints of CC-486 and AZA. Hazard ratios (HR), 95% credible intervals (CrI), and surface under the cumulative ranking curve (SUCRA) values were calculated. The impact of differences in potential treatment-effect-modifying characteristics between populations in the NMA was explored using anchored matching-adjusted indirect comparison (MAIC). The NMA was repeated using CC-486 vs PBO efficacy from the MAIC, to satisfy the assumption of clinical similarity necessary in NMA (Hoaglin et al. 2011). Results: Four RCTs evaluating OS outcomes that could be compared were identified: QUAZAR AML-001 (CC-486) (Wei et al. 2019), HOVON 97 AML (SC AZA) (Huls et al. 2019), UK NCRI AML16 (SC AZA) (Burnett et al. 2015), and QoLESS-AZA-MLE (SC and IV AZA, included in sensitivity analysis) (Oliva et al. 2019). Other efficacy and safety endpoints were not analyzed owing to lack of comparable data among the 4 identified RCTs. Results of the NMA indicated CC-486 was associated with statistically significant improvement in OS vs SC AZA (HR 0.744; CrI 0.557, 0.998); SC AZA was not statistically different from PBO (HR 0.926; CrI 0.771, 1.120). SUCRA values associated CC-486 with the best OS (98.8%). In a sensitivity analysis, CC-486 was associated with statistically significant improvement in OS vs SC or IV AZA (HR 0.741; CrI 0.556, 0.992). In the MAIC, a structured process was used to evaluate the need for adjustment due to differences in trial populations in the NMA. Populations for each trial were compared (Table). Per methodological guidance (Phillippo et al. 2016), the MAIC sought to adjust characteristics with evidence of (a) treatment-effect-modifying status on the scale of parameters entering the NMA and (b) substantial imbalance across populations. Using the QUAZAR individual patient data, univariate analyses were conducted to determine prognostic and effect-modifying status of variables (Table). For each SC AZA trial, a multivariate Cox model was estimated, including all significant prognostic variables reported, and effect modifiers that remained significant when controlling for prognostic variables and improved model fit. Among variables reported for UK NCRI, no effect modifiers enhanced the multivariate model; for HOVON, treatment interactions with age > 81 years (the oldest age in HOVON) and absolute neutrophil count (ANC) did. MAIC was therefore conducted by re-weighting QUAZAR patients to match means/shares of the HOVON patients, adjusting for mean age, % aged > 81 years, % poor cytogenetic risk, and mean ANC. Effective sample size was 411 (−13% vs N = 472 in QUAZAR). Frequency-weighted, unadjusted (including only a treatment covariate) Cox regression was conducted. After adjusting for effect-modifying differences, the OS improvement of CC-486 vs PBO observed in QUAZAR was maintained in the HOVON population. Incorporating the adjusted HR from the MAIC in the NMA, CC-486 continued to be associated with statistically significant improvement in OS vs SC AZA (HR 0.753; CrI 0.563, 0.998). Conclusion: Maintenance CC-486 appears to significantly improve OS compared with SC AZA for patients with AML who have achieved CR after IC, based on a systematic analysis of RCT outcomes. Disclosures Tabah: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Huggar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Karyopharm Therapeutics: Current equity holder in publicly-traded company; FibroGen: Current equity holder in publicly-traded company. Wang:Medicus Economics: Current Employment; Bristol Myers Squibb: Research Funding. Johnson:Medicus Economics: Current Employment; BMS: Research Funding. Copher:Bristol Myers Squibb: Current Employment. O'Connell:Bristol-Myers Squibb: Consultancy; Other biopharmaceutical manufacturers: Consultancy; Medicus Economics, LLC: Current Employment. Leblanc:AbbVie, Agios, Amgen, AstraZeneca, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Helsinn, Heron, Otsuka, Medtronic, Pfizer, Seattle Genetics, Welvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; American Cancer Society, BMS, Duke University, NINR/NIH, Jazz Pharmaceuticals, Seattle Genetics: Research Funding; UpToDate: Patents & Royalties: Royalties; Agios, AbbVie, and Bristol Myers Squibb/Celgene: Speakers Bureau; AstraZeneca: Research Funding.

Venous thromboembolism (VTE), comprised of deep vein thrombosis (DVT) and pulmonary embolism (PE), is commonly treated with a low-molecular-weight heparin such as enoxaparin plus a vitamin K antagonist (VKA) to prevent recurrence. Administration of enoxaparin + VKA is hampered by complexities of laboratory monitoring and frequent dose adjustments. Rivaroxaban, an orally administered anticoagulant, has been compared with enoxaparin + VKA in the EINSTEIN trials. The objective was to evaluate the cost-effectiveness of rivaroxaban compared with enoxaparin + VKA as anticoagulation treatment for acute, symptomatic, objectively-confirmed DVT or PE.A Markov model was built to evaluate the costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios associated with rivaroxaban compared to enoxaparin + VKA in adult patients treated for acute DVT or PE. All patients entered the model in the 'on-treatment' state upon commencement of oral rivaroxaban or enoxaparin + VKA for 3, 6, or 12 months. Transition probabilities were obtained from the EINSTEIN trials during treatment and published literature after treatment. A 3-month cycle length, US payer perspective ($2012), 5-year time horizon and a 3% annual discount rate were used.Treatment with rivaroxaban cost $2,448 per-patient less and was associated with 0.0058 more QALYs compared with enoxaparin + VKA, making it a dominant economic strategy. Upon one-way sensitivity analysis, the model's results were sensitive to the reduction in index VTE hospitalization length-of-stay associated with rivaroxaban compared with enoxaparin + VKA. At a willingness-to-pay threshold of $50,000/QALY, probabilistic sensitivity analysis showed rivaroxaban to be cost-effective compared with enoxaparin + VKA approximately 76% of the time.The model did not account for the benefits associated with an oral and minimally invasive administration of rivaroxaban. 'Real-world' applicability is limited because data from the EINSTEIN trials were used in the model. Also, resource utilization and costs were based on the US healthcare system.Rivaroxaban is a cost-effective option for anticoagulation treatment of acute VTE patients.

This study estimated the average lifetime costs of patients with chronic lymphocytic leukemia (CLL) relative to similar patients without cancer. An analysis of the Medicare 5% database (1999-2007) was conducted. Each patient with CLL was matched up to three patients without cancer based on year of birth, gender, race and state. Average total lifetime costs were estimated using the Kaplan-Meier sample average estimator and stratified by treatments. For patients who died, average monthly costs during continuing and terminal phases were compared between cohorts. A total of 7463 patients with CLL and 22 331 matched controls were identified (mean age: 76 years; proportion of women: 49%). The mean observation period was 39.4 months for patients with CLL and 45.9 months for matched controls. Patients with CLL incurred average costs of $87,151 compared to $47 642 for matched controls (p0.001). Among common CLL treatments, average costs per patient were $5140 for rituximab and $953 for radiation therapy. Compared to matched controls, patients with CLL had significantly higher monthly costs during the continuing and terminal phases. This study showed that average lifetime costs to Medicare were $87,151 for patients with CLL compared to $47,642 for matched controls without cancer, for a significant difference of $39,509.

Background: Adalimumab is indicated for the treatment of moderately to severely active Crohn's disease (CD). A systematic analysis of risks and benefits of adalimumab versus traditional non-biologic therapies for patients refractory to non-biologic therapy is lacking. Methods: A base-case analysis compared expected benefits of adalimumab therapy with a 12-week stopping rule for non-responders versus non-biologic therapies using data from clinical trials (CHARM, CLASSIC I). Adverse events (AEs) recorded in clinical trials (CHARM, CLASSIC I, CLASSIC II, GAIN, open-label extensions) were compiled. Sensitivity analyses incorporated all observed benefits of adalimumab and placebo (CHARM, CLASSIC I, GAIN) and observed AEs from a systematic literature review of non-biologic therapies (MEDLINE search of randomized trials 1990–2007). Distributional information from maintenance clinical trial observations and benefit model predictions were used in a probabilistic simulation. Incremental net benefits were estimated based on utility estimates from the literature. Results: Average time in remission (i.e., CDAI

OBJECTIVE To assess the effectiveness, safety, and treatment patterns of anti-angiogenic agents in metastatic renal cell carcinoma (mRCC) in tertiary clinical practice settings. PATIENTS AND METHODS We retrospectively reviewed the medical records in two tertiary oncology centres in the USA for all patients treated while off clinical trials from April 2003 to June 2008 who met the entry criteria and received one or more prescriptions for sunitinib or sorafenib, or one or more intravenous administrations of bevacizumab (off-label) as first-line anti-angiogenic treatment. The objective response rate (ORR) reviewed by independent physicians, adverse events (AEs), and treatment modifications were assessed. RESULTS Among 144 patients receiving sunitinib (57), sorafenib (62) and bevacizumab (25), the median treatment duration was 10.5, 8.1 and 7.9 months, and the ORR was 37%, 9% and 13%, respectively. The ORR was lower for patients with metastases to bone, brain, lungs or lymph nodes. Common AEs (all grades) for sunitinib were fatigue (53%), diarrhoea (37%); for sorafenib, diarrhoea (50%), fatigue (40%); for bevacizumab, fatigue (40%), nausea (24%). In all, 34 (60%), 51 (82%) and 20 (80%) patients receiving sunitinib, sorafenib and bevacizumab, respectively, discontinued treatment; 10 (18%), 11 (18%) and four (16%) discontinued due to AEs; 21%, 40% and 12% had a dose interruption, and 30%, 35% and 0% had a dose reduction. CONCLUSIONS Currently available anti-angiogenic agents had considerable effectiveness in clinical practice. However, the response rates appeared to be low in certain subgroups, but sample sizes were small. Patients had significant rates of AEs, many of which led to treatment modifications. The findings from this retrospective study suggest that there is a need for better-tolerated therapies for mRCC.

The valuation of drugs for rare diseases is an important and complex issue. Some have questioned whether treatments for rare diseases can be accurately assessed through traditional cost-effectiveness analysis.1 Coyle and others2 propose a method for economic evaluation of novel treatments for rare diseases in the article titled “Opportunity Cost of Funding Drugs for Rare Diseases: The Cost-Effectiveness of Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.” We were intrigued by the authors’ conclusions, as we modeled the benefits of eculizumab treatment in the same disease for the manufacturer last year in a submission to policy makers and estimated highly different results. To be clear, we developed this health economic model as paid consultants for Alexion (Alexion did not pay us to write this letter). As we were unable to obtain the model from the authors, we set out to validate the model ourselves based on two presented estimates that could be used for validation: 11.88 life-years for eculizumab and 10.75 life-years for standard of care (SOC) over 40 years discounted at 5% per year.2(p7) We created a simple validation model (Figure 1), assuming a constant hazard of mortality and a homogeneous patient population, to assess the implied undiscounted survival curves. Upper and lower confidence intervals were constructed using the estimated incremental discounted life-years presented in Table 2 of Coyle and others.2(p7) Figure 1 Actual eculizumab survival from Hillmen and others3 and Kelly and others4 and implied survival curves in validation model based on Coyle and others’2 results. We then reviewed actual event data on survival, including the open-label extension studies described by Hillmen and others3 comprising 195 paroxysmal nocturnal hemoglobinuria (PNH) patients over 66 months. Hillmen and others3(p68) reported that “patient survival at 36 months was 97.6% [95% confidence interval (CI): 93.7%–99.1%], which was sustained out to 66 months.” The Leeds cohort is the longest cohort study for PNH patients of which we are aware. The most recent published results are by Kelly and others,4 who included 79 PNH patients treated up to 8 years. Kelly and others4(p6788) reported that “the 5-year survival rate for the patients treated with eculizumab [was] 95.5% (95% CI: 87.6%–98.5%).” We plotted these survival values relative to those predicted by the model we made that replicated Coyle and others’2 model (Figure 1). Our estimates of the Coyle model predictions are well outside the confidence intervals of these other studies. Hillmen and others5(p1254) reported median survival for SOC-treated patients as 10 years; our estimates of the Coyle model predictions for SOC are 62.6% at 10 years. As the Coyle model consists of 47 distinct health states and at least 34 parameters affecting the transitional probabilities, the ratio of states (and parameters) to patients in the eculizumab clinical trials suggests that many transitional probabilities used in the model are likely dependent on the experience of just a few patients, at best. It is unclear where PNH-specific data for the SOC treated patients would come from, given the near absence of clinical trials evaluating SOC. The parameters for age and gender, important for modeling mortality over 40 years, do not appear in the manuscript or supplemental material. One parameter listed is “Relative rate of thrombosis from taking warfarin as a primary prophylaxis v. not taking warfarin,” which was sourced from an analysis of patients with stage 4 metastatic breast cancer.2,6 In fact, many sources are not from studies of patients with PNH. The article omits key PNH and eculizumab studies, such as Hillmen and others3 and Kelly and others,4 from the analysis. Coyle and others2(p2) introduce opportunity costs as a necessary consideration for reimbursement decisions, as they represent “the benefits foregone by adopting one intervention over another.” For their opportunity cost argument to be relevant, available resources (i.e., the health care budget) need to be constrained, such that adopting one intervention eliminates the possibility of adopting another (e.g., through increased taxes). However, this is an open issue. The authors reject consideration of a budget impact model for eculizumab in PNH,2(p11) implying that an avalanche of similar product approvals would become problematic (i.e., “the accumulated impact of similar such decisions will not be negligible”). This reasoning is insufficient, as no evidence is presented on the likely accumulated costs and no argument is made on the threshold where the budget impact justifies rejecting life-saving treatments. Rare diseases like PNH are generally recognized by health economists and policy makers to be a challenging area for the application of standard health economic assessments. Many experts believe that the application of traditional health economic modeling to orphan drugs can have a discriminatory impact on patients with rare diseases.7 A first step to advance this argument would be to work carefully to build models that make the best use of actual data for the rare disease drugs at issue and then diligently, and transparently, validate them. We question whether the authors have demonstrated that modeling an ultra-orphan disease is feasible, and we caution readers to carefully consider the assumptions made before drawing conclusions from their results.

Safety and treatment patterns of sunitinib and sorafenib in metastatic renal cell carcinoma (mRCC) had been previously reported using retrospective chart review of patients treated in US tertiary centers. Because practice patterns may vary between hospital- and office-based settings, this study examined safety and treatment patterns of these agents in US community oncology clinics. Medical records were retrospectively reviewed for 250 patients with mRCC treated at 18 community oncology clinics. Eligible patients were ≥18 years old and received ≥1 prescription for sunitinib (n = 131) or sorafenib (n = 119) as first-line anti-angiogenic treatment. Rates of adverse events (AEs) and treatment modifications were analyzed; reasons for treatment modifications were examined. Median duration of first-line sunitinib and sorafenib treatment was 5.9 and 5.5 months, respectively. Among patients treated with sunitinib and sorafenib, 86% (30%) and 87% (28%), respectively, experienced ≥1 all-grade (grade 3/4) AE. The most common AEs were fatigue/weakness in sunitinib (all-grade: 42%; grade 3/4: 5%) and skin rash in sorafenib (all-grade: 35%; grade 3/4: 6%). Sixty-two and 64% of patients treated with sunitinib and sorafenib, respectively, had ≥1 treatment modification due to AEs. Recorded AE rates in patients with mRCC treated with angiogenesis inhibitors in community practice tended to be lower than in tertiary centers, possibly due to shorter treatment duration. Rates of treatment modifications due to AEs tended to be higher in community practice. This study provides evidence from an office-based setting of unmet need for agents that may provide improved tolerability in mRCC.

BACKGROUND: Patients with myelodysplastic syndrome (MDS) or severe anemia requiring repeated red blood cell (RBC) transfusions risk developing transfusional iron overload, which can reduce survival. Iron chelation therapy (ICT) has been shown to improve survival and quality of life in patients; however, ICT utilization in clinical practices is not well understood. STUDY DESIGN AND METHODS: Medical records of patients diagnosed with MDS or severe anemia at least 6 months before data extraction, aged at least 21 years at diagnosis, and who received at least one RBC transfusion were reviewed. ICT eligibility was defined as at least 20 units of RBCs transfused or at least two serum ferritin levels exceeding 1000 µg/L. Study endpoint was ICT treatment rate among ICT-eligible patients with lower-risk MDS (International Prognostic Scoring System [low or intermediate-1]; World Health Organization [refractory anemia {RA}, refractory anemia with ringed sideroblasts {RARS}, refractory cytopenia with multilineage dysplasia {RCMD}, refractory cytopenia with multilineage dysplasia and ringed sideroblasts, or 5q]; French-American-British [RA/RARS]). RESULTS: Among 78 ICT-eligible patients with lower-risk MDS, 32 (41%) received ICT. At ICT initiation, treated patients received on average 13.3 transfusions (27.6 units) and mean first post-ICT initiation serum ferritin was twice the MDS Foundation recommendation at 1949 µg/L. Median overall survival for all ICT-eligible patients was significantly longer for those ICT-treated patients than untreated patients (8.7 years vs. 4.7 years, log-rank p = 0.02; multivariate hazard ratio 0.372, p = 0.03). CONCLUSION: This study finds only 41% of ICT-eligible patients with lower-risk MDS received ICT in clinical practice, and treatment was initiated later than recommended. Receipt of ICT was associated with significantly longer survival.

Objective To describe the use of a generalizable stochastic-simulation model of the treatment of neuropathic pain associated with peripheral neuropathies. Methods We developed a model to simulate treatment outcomes in a hypothetical cohort of patients with peripheral neuropathies. Each patient was randomly assigned an average pretreatment daily pain score (on a 0–10 scale), based on an assumed distribution of mean pretreatment pain scores in the cohort. Patients were randomly assigned daily pain scores, based on their pretreatment average and an assumed distribution of daily pain scores around this mean. Treatment outcomes were then simulated using the expected mean change (vs. baseline) in pain scores. Model outcomes include the expected increase in days with no or mild pain (score ⩽3), days with ⩾30% and ⩾50% reductions in pain intensity, and days with 2- and 3-point absolute reductions in pain intensity. To illustrate its use, the model was estimated over a 12-week period using data from a recent clinical trial of a new antiepileptic (pregabalin). Results Treatment over 12 weeks (84 days) was projected to result in 26 (±0.4) (mean [±SE]) additional (vs. no treatment) days with no or mild pain, 33 (±0.5) days with a ⩾30% reduction in pain intensity, 28 (±0.4) days with ⩾50% reduction in pain intensity, and 34 (±0.5) and 30 (±0.5) days with ⩾2-point and ⩾3-point absolute reductions in pain intensity. Conclusions When combined with data on health-state utilities and treatment costs, this new analytical tool can provide a foundation for formal cost-effectiveness evaluations of interventions for painful peripheral neuropathies.

Abstract 2563 Background: Results from the phase 3 VISTA trial demonstrated that bortezomib (Velcade®) plus melphalan and prednisone (VMP) has superior efficacy to MP alone in patients with newly diagnosed multiple myeloma (MM) ineligible for ASCT. In a similar patient population, the three-arm phase 3 MM-015 trial compared lenalidomide (Revlimid®) plus MP with or without continuous lenalidomide maintenance treatment after cycle 9 (MPR-R vs MPR) with MP alone. There was no difference in progression-free (PFS) or overall survival (OS) between patients who received MPR or MP during the 9-cycle induction period; MPR-R was associated with superior PFS vs MP during the R maintenance period. To assess the value of R in combination with MP followed by R maintenance therapy we indirectly estimated the incremental cost-effectiveness of VMP vs MPR-R as therapy for MM patients ineligible for ASCT. Methods: An Excel-based Markov model from the US payer's perspective was developed. Simulations were performed for hypothetical cohorts of newly diagnosed MM patients ineligible for ASCT with an average age of 70 years at treatment initiation. The model includes seven health states representing periods of treatment response (stable disease/minimal response, partial response, and complete response), treatment-free interval/maintenance treatment, progressive disease, second-line treatment, and death. Monthly transition probabilities were estimated from patient-level data for VISTA for VMP and MP (data cut-off June 15 2007; San Miguel et al NEJM 2008) and published results for MM-015 for MPR-R (data cut-off April 15 2009; Palumbo et al ASH 2009). As previously reported (Wang et al ASH 2009), costs included per-protocol drug and medical costs, treatment-related adverse event costs, second-line treatment costs, and resource utilization during the treatment-free interval and progressive disease; all costs were adjusted to 2010 US dollars. State-specific utility estimates were derived from patient-level EQ-5D data from the VISTA trial using US-specific weights. Health outcomes (as indicators of the effectiveness of therapy) were expressed in life years (LYs) and quality-adjusted LYs (QALYs). Costs and health outcomes were discounted at 3%. Incremental cost-effectiveness ratios (ICERs) were calculated for VMP vs MPR-R over a lifetime horizon (20 years). In the base case, the MPR-R vs MP hazard ratio (HR) for PFS was set to 0.499 and that for OS was set to 1, due to a lack of survival benefit with MPR-R vs MP observed in MM-015. One-way sensitivity analyses were conducted by running the model with upper and lower values of key parameters to assess the general robustness of model findings and identify key drivers. Results: Model base case results for the incremental cost-effectiveness of VMP relative to MPR-R are shown in the Table. Estimated OS was 4.187 years with VMP vs 3.409 years with MPR-R over a lifetime horizon. Lifetime direct medical costs were $119,102 with VMP vs $241,247 with MPR-R; the lifetime cost of R maintenance was $107,047. Thus, VMP appears associated with reduced costs and better outcomes vs MPR-R; VMP costs approximately 50% less than MPR-R and seems to provide slightly more QALYs (0.567) on average. One-way sensitivity analyses supported the general robustness of model findings and identified the MPR-R vs MP HR for OS as a key driver; only when this HR was set to ≤0.25 did MPR-R become cost-effective vs VMP at $100,000 per QALY. Conclusions: In newly diagnosed MM patients ineligible for ASCT, VMP appears to be associated with lower costs and better health outcomes vs MPR-R. From a cost-effectiveness perspective, R maintenance therapy therefore seems to have little benefit in this patient population. The current comparison was based on published results for MPR-R from MM-015 after a median follow-up of 9.4 months (vs 16.3 months for VMP vs MP in VISTA), at which time no survival benefit was observed for MPR-R vs MP. If longer follow-up in MM-015 indicates a survival benefit for MPR-R vs MP, a re-estimation of the incremental cost-effectiveness of VMP vs MPR-R using the present Markov model would be warranted; however, updated data (Palumbo et al EHA 2010) show no significant difference in OS between the MPR-R and MP arms at a median follow-up of 21 months. Disclosure: Wang: Millennium Pharmaceuticals: Consultancy, Research Funding. Huang:Millennium Pharmaceuticals, Inc: Employment. Ba-Mancini:Millennium Pharmaceuticals, Inc.: Employment. Shi:Millennium Pharmaceuticals, Inc: Employment. Chen:Millennium Pharmaceuticals: Consultancy, Research Funding. Korves:Millennium Pharmaceuticals, Inc: Research Funding. Dhawan:Johnson & Johnson: Employment, Equity Ownership. Cakana:Johnson & Johnson: Employment, Equity Ownership. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Duh:Millennium Pharmaceuticals, Inc: Consultancy, Research Funding.

Abstract 2477 Poster Board II-454 Background: Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world, comprising over one-third of all new leukemia cases. Alemtuzumab is a humanized monoclonal antibody targeted to lymphocytes through the CD52 receptor that has been demonstrated to reduce the amount of malignant lymphocytes in patients with CLL. Alemtuzumab is, however, associated with various adverse events (AEs) including cytopenia, infections, and cardiac dysfunction. The current study aimed to quantify the incremental cost to Medicare of treating CLL patients with alemtuzumab. Methods: An analysis of patients' electronic health insurance claims records (1999-2007) from the Medicare 5% national sample was conducted. Patients with continuous enrollment for 3 or more months prior to their first observed claim with a CLL diagnosis, no more than two malignancies (by ICD-9 diagnostic codes associated with claims), and 1 or more claim for alemtuzumab were included in the analysis. Patients who had HMO coverage under Medicare were excluded from the analysis to ensure data completeness. A pre-post design was used to quantify the incremental costs associated with alemtuzumab by calculating health care costs within 6 months after alemtuzumab initiation relative to the 6-month period before alemtuzumab initiation. Mean monthly (per-patient per-month, PPPM) costs were calculated and were grouped by sites of care, service type, tests and procedures, treatment and drugs, and by AEs. To estimate the costs of AEs, claims with ICD-9 diagnostic codes for the AE of interest were grouped and mean PPPM costs were calculated for those groups. These groups were not mutually exclusive: claims could be associated with more than one diagnostic code. Statistical comparisons between the pre- and post-treatment periods were based on paired Student t-tests. Results: A total of 81 CLL patients treated with alemtuzumab formed the study population. The mean age (SD) was 75.2 (7.5) years and females represented 38.3% of the cohort. Patients were observed for an average of 50 months and mean time between the first observed CLL diagnosis and initiation of alemtuzumab treatment was 36 months. After alemtuzumab initiation, mean total healthcare costs increased from $4,272 to $10,385 PPPM (cost difference: $6,113, P Conclusions: Amongst a cohort of Medicare fee-for-service patients with CLL, alemtuzumab was associated with a significant increase in healthcare costs in the 6 months after initiation of therapy of which the costs of alemtuzumab, oncology services, cytopenias, infections, and cardiac dysfunctions were large components. Disclosures: Lafeuille: Groupe d'analyse: Employment; GlaxoSmithKline: Research Funding. Vekeman:Groupe d'analyse: Employment; GlaxoSmithKline: Research Funding. Kerrigan:GlaxoSmithKline: Employment. Wang:Analysis Group: Employment; GlaxoSmithKline: Research Funding. Duh:GlaxoSmithKline: Research Funding; Analysis Group: Employment.

Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (5 years (5 years (800 mg (5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

Abstract 1379 Poster Board I-401 Background: Data from the phase III VISTA trial demonstrated superiority in terms of clinical effectiveness of bortezomib (Velcadë) plus melphalan and prednisone (VMP) relative to melphalan and prednisone alone (MP) in the initial treatment of patients with multiple myeloma (MM). The aim of this study was to utilize data from the VISTA study and published literature to compare lifetime health outcomes and the cost-effectiveness of these regimens as induction therapy for MM patients ineligible for autologous stem cell transplantation (ASCT). An indirect comparison of VMP versus thalidomide plus MP (MPT) was also conducted using published results from the IFM 99-06 clinical trial for MPT (Facon et al, Lancet 2007). The goal of this study and the derived model was to assess the relative costs and outcomes from these two trials, recognizing the limitations imposed by using data derived from independent studies. Methods: A Markov model from the US payer's perspective was developed. Simulations were performed for hypothetical cohorts of newly diagnosed MM patients with an average age of 70 years at treatment initiation and who were not eligible for ASCT. The model includes seven health states representing periods of treatment response (stable disease/minimal response, partial response, or complete response), treatment-free interval, progressive disease, second-line treatment and death. Monthly transition probabilities were estimated from patient-level VISTA trial data for VMP and MP (with a data cut-off of June 15, 2007), and from the published phase lll IFM 99-06 trial for MPT. Costs included per-protocol drug and medical costs, treatment-related adverse events, second-line treatment, and resource utilization during treatment-free interval and progressive disease. Unit costs of medications and resources were obtained from published literature. All costs were adjusted to 2009 US dollars. State-specific utility estimates were derived from patient-level EQ-5D data from the VISTA trial using US-specific weights. Health outcomes were expressed in life-years (LYs) and quality-adjusted life-years (QALYs). Both cost and health outcomes were discounted at 3%. Incremental cost-effectiveness ratios (ICERs) were calculated for VMP versus MP, and VMP versus MPT, over a lifetime horizon (approximated by 20 years). One-way sensitivity analyses were conducted by running the model with upper and lower values of key parameters to assess the general robustness of model findings and identify key drivers. Results: Model base case results for the incremental cost-effectiveness of VMP relative to MP and MPT are shown in the Table. Comparison of the model's overall survival (OS) projections with the observed differences indicates a conservative approximation of the treatment differences for VMP. The estimated OS was 4.187 years with VMP versus 2.864 years with MP and versus 4.140 years with MPT over a lifetime horizon. Lifetime direct medical costs range from $57,864 for MP to $129,902 for MPT. The cost per LY and QALY gained with VMP compared with MP is $40,051 and $56,109, respectively. VMP is dominant (cost saving and better outcomes) compared with MPT, costing 17.7% less and providing slightly more QALYs on average. One-way sensitivity analyses suggest general robustness of model findings and the key drivers include VMP/MP hazard ratio from second-line treatment to death, and the MPT/MP hazard ratio for treatment discontinuation. Conclusions: In newly diagnosed MM patients ineligible for ASCT, VMP is projected to improve long-term health outcomes, offering a substantial survival benefit compared with MP. The incremental cost-effectiveness of VMP versus MP is within the generally accepted cost-effectiveness range of $50,000 to $100,000 per QALY, suggesting that VMP is cost-effective compared with MP in the United States. Within this cost-effectiveness model, compared with MPT, VMP is dominant, yielding lower costs and better health outcomes. Disclosures: Wang: Milllennium: Research Funding. Huang: Milllennium: Employment, Equity Ownership. Shi: Millennium Pharmaceuticals, Inc.: Employment. Duh: Milllennium: Consultancy, Research Funding. Chen: Milllennium: Research Funding. Chang: Milllennium: Research Funding. Korves: Milllennium: Research Funding. Dhawan: Johnson and Johnson Research Pharmaceuticals: Employment. Cakana: Johnson & Johnson: Employment, Equity Ownership. van de Velde: Johnson & Johnson: Employment, Equity Ownership. Esseltine: Milllennium: Employment, Equity Ownership. Garrison: Milllennium: Consultancy.

Background: Induction therapy for multiple myeloma (MM) patients who are eligible for autologous stem cell transplant (ASCT) has evolved with the introduction of novel agents, such as bortezomib (VELCADE®, Vel) and thalidomide (THALOMID®, Thal). Phase 3 trial data show the clinical effectiveness of front-line bortezomib-based therapies, but little is known about the comparative economic benefit of bortezomib-based regimens in newly diagnosed MM in the transplant setting. Here we report a pharmacoeconomic analysis of the IFM 2005-01, GIMEMA MMY-3006, and the Myeloma-Autogreffe Group (MAG) phase 3 trials, comparing the relative costs of Vel–dexamethasone (Vel/Dex), vincristine–doxorubicin–dexamethasone (VAD), Vel–Thal–Dex (VTD), and Thal–Dex (TD). Methods: Expanding on a previous budget impact model of bortezomib treatment for relapsed MM (Fullerton et al. Blood2007: Abstract 3324), an Excel-based model was developed to calculate the cost of therapy for MM patients eligible for ASCT, including costs incurred during induction therapy and single or double transplant. Per IFM 2005-01 protocol design, we assumed that patients who achieved at least very good partial response (≥VGPR) after their first transplant did not need a second transplant; the GIMEMA and MAG trials were based on a similar tandem transplant protocol. Costs were evaluated from a health system perspective and included: induction therapy costs (drugs, medical care, adverse events [AEs], and prophylaxis treatment), cost of the first ASCT, and cost of the second ASCT if required. Drug costs were calculated based on 2008 Average Wholesale Price and applied to trial regimens. Medical care costs were based on the Medicare physician fee schedule and assumptions drawn from National Comprehensive Cancer Network (NCCN) MM treatment guidelines. AE costs (grade ≥3 AEs reported in at least two studies) were estimated using available incidence data and reported as per-event costs or annual costs depending on the data source. The unit cost of a transplant ($139,220) was calculated based on data from 1,917 MM patients treated at >120 centers in the OptumHealth database. Results: In IFM 2005-01, estimated mean per-patient treatment costs from start of induction to completion of second transplant (if required) were lower for patients receiving Vel/Dex induction ($201,793) versus VAD ($217,526), due to better post-induction response with Vel/Dex. More patients achieved post-transplant ≥VGPR with Vel/Dex than with VAD (72% vs 52%), and therefore did not require a second transplant. Similarly, in GIMEMA MMY-3006, post-induction and posttransplant ≥VGPR achieved with VTD induction was greater than that achieved with TD (post-induction: 60% vs 27% and post-transplant: 77% vs 54%), thereby reducing the need for a second transplant among patients receiving VTD induction therapy. Consequently, estimated mean treatment costs were lower for patients receiving VTD induction ($200,093) versus TD ($218,886). Estimated mean treatment costs for patients receiving VD induction in IFM 2005-01 ($201,793) and VTD induction in GIMEMA MMY-3006 ($200,093) were both lower than those for patients receiving TD induction in the MAG phase 3 trial ($239,851). Conclusions: In summary, the model showed that total costs were lower for patients receiving bortezomib-based induction compared with TD induction in both the GIMEMA MMY-3006 and MAG trials. These health economic analyses also suggest that bortezomib-based induction results in lower mean per-patient treatment costs when compared with VAD or TD induction, primarily due to better response post-first ASCT. Table: Cost Summaries of ASCT Trials Induction costs VD (IFM) VTD (GIMEMA) TD (MAG) Drugs $15,940 $24,273 $16,596 Medical care $4,147 $3,578 $1,019 Adverse events $2,948 $1000 $5,610 Total induction costs (per patient) $23,035 $28,852 $23,225 Transplant costs 1st ASCT $139,220 $139,220 $139,220 2nd ASCT $39,538 $32,021 $77,406 Total transplant costs (per patient) $178,758 $171,241 $216,626 TOTAL costs $201,793 $200,093 $239,851