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In the U.K. Medical Research Council Myeloma IX trial (mmix), zoledronic acid 4 mg once every 3&ndash, 4 weeks, compared with clodronate 1600 mg daily, reduced the incidence of skeletal related events (sres), increased progression-free survival (pfs), and prolonged overall survival (os) in 1970 patients with newly-diagnosed multiple myeloma. The incidence of confirmed osteonecrosis of the jaw was higher with zoledronic acid than with clodronate. The objective of the present study was to evaluate, based on the findings in mmix, the cost-effectiveness of zoledronic acid compared with clodronate in patients with newly-diagnosed multiple myeloma. An economic model was used to project pfs, os, the incidence of sres and adverse events, and expected lifetime health care costs for patients with newly diagnosed multiple myeloma who are alternatively assumed to receive zoledronic acid or clodronate. The incremental cost-effectiveness ratio (icer) of zoledronic acid compared with clodronate was calculated as the ratio of the difference in cost to the difference in quality-adjusted life years (qalys). Model inputs were based on results of mmix and published sources. Results were generated under different assumptions regarding the beneficial effects of zoledronic acid on os beyond 5 years after treatment initiation. Assuming lifetime treatment effects of zoledronic acid, treatment with zoledronic acid (compared with clodronate) increased qalys by 0.27 at an additional cost of CA$13,407, yielding an icer of CA$49,829 per qaly gained. If the threshold icer is CA$100,000 per qaly, the estimated probability that zoledronic acid is cost-effective is 80%. Assuming that the benefits of zoledronic acid on pfs and os diminish over 5 years beginning at the end of year 5, the icer is CAN$63,027 per qaly gained. If the benefits of zoledronic acid on pfs and os are assumed to persist for 5 years only, the icer is CAN$76,948 per qaly gained. Compared with clodronate, zoledronic acid represents a cost-effective treatment alternative in patients with multiple myeloma.

Glycophorin A is a protein with an abundant glycosylation (60% carbohydrate by weight), and studies have suggested that resistance of target cells to natural killing may be correlated with the level of glycophorin A expression. To assess the role of glycophorin A and of its carbohydrates in sensitivity to lysis by natural killer (NK) cells, the glycoprotein was inserted into the membrane of K562 target cells using electropulsation. Peripheral blood lymphocytes were used as effector cells. When glycophorin A was inserted into the membrane, the level of resistance to NK cell attack increased with the number of glycophorin A molecules electroinserted. The resistance to lysis was not due to a defect in target cell-effector cell binding. Electroassociation of glycophorin A did not cause a decrease in the expression of either "positive signals" for NK cells (such as CD71, CD15, and CD32 antigens) or cellular adhesion molecules (CD18, CD29, CD54, and CD58). Furthermore, electroinsertion of glycophorin A did not trigger any "negative signals," such as class I HLA antigen expression. Finally, it was shown that the sialic acid and O-linked oligosaccharides of glycophorin A did not play any role in its effect against NK cells. Conversely, the unique N-linked oligosaccharide was shown to be essential for resistance to occur.

Background Recent clinical trial data have demonstrated that 3 years (yrs) of adjuvant imatinib therapy for patients with surgically resected GIST leads to a significant improvement in recurrence free survival & overall survival vs. 1 yr of therapy. The objective of this study is to assess cost-effectiveness of treating with 3 yrs vs. 1 yr of adjuvant imatinib in Canada from a payer's perspective. Methods A Markov model was developed to predict GIST recurrence, treatment (txt) costs, & quality-adjusted survival over a lifetime horizon. Patients transitioned between 3 health states: free of GIST recurrence, GIST recurrence, & death. Monthly recurrence & mortality rates for 3 yr & 1 yr imatinib were derived from SSGXVIII/AIO clinical trial. The 5 yr recurrence rate observed in the trial was extrapolated for the remaining duration of the model horizon. First recurrence after active txt was treated with imatinib 400 mg daily and recurrence during active txt was treated with 800mg daily. For subsequent disease progression, patients were treated with imatinib 800mg, sunitinib or best supportive care. After 5 years, txt specific mortality rate was applied for patients with recurrence. Costs & utilities were derived from published literature. Expected costs & quality-adjusted life years (QALYs) were estimated for each txt strategy. Costs & QALYs were discounted at 5% per yr. Extensive sensitivity analyses were conducted. Results Patients on 3 yrs of imatinib had higher QALYs (7.70 vs 6.54) vs. 1yr of imatinib. Total lifetime cost per patient was $182,000 with 3 yrs vs. $134,500 for 1 yr of imatinib therapy. Incremental cost effectiveness ratio of 3 yrs of imatinib vs 1 yr of imatinib was $40,877/QALY. Model results were sensitive to rate of GIST recurrence beyond 5 yrs. At a threshold of $100,000 or $50,000/QALY, 3yr imatinib therapy was cost-effective in 100% of simulations vs. 1 yr of imatinib. Conclusions Model results suggest that treating patients with 3 yrs of imatinib is cost-effective vs. 1 yr of imatinib below the commonly used threshold in Canada. Both clinical & economic results suggest treating surgically resected GIST patients with 3 yrs of imatinib would result in improved quality-adjusted & overall survival. Disclosure A. Parthan: Study was sponsored by Novartis and I have consulting relationship with Novartis. M. Sanon: The study was sponsored by Novartis and I had consultancy relationship with Novartis at the time of the study. J. Coombs: Employed at Novartis and holds Stock for Novartis. K. El Ouagari: employed at Novartis and owns stocks for Novartis

Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G + T arm. The primary efficacy endpoint was a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Summary PFS outcome has previously been reported; more detailed PFS as well as the initial overall survival (OS) data are presented. Results 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer prognostic factors (older age, poorer performance status, reduced albumin) were associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G + T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G + T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 and 59% G + T340. Conclusions The combination of G plus TH-302 improved the efficacy of G. A TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. Disclosure All authors have declared no conflicts of interest.

Background: Deferasirox (Exjade®) is a recently approved once-daily oral chelator that has been shown to produce reductions in liver iron concentrations and serum ferritin similar to those with infusional deferoxamine (Desferal®), in patients with β-thalassemia major or sickle cell disease (SCD) and chronic iron overload from blood transfusions. The objective of this study was to estimate the cost of deferoxamine administration in Canada and evaluate the cost-effectiveness of deferasirox versus deferoxamine for chronic iron overload from blood transfusions from the Ontario provincial healthcare system. Methods: Cost of chelation therapy with deferoxamine was estimated from five major treatment centers in Canada. Costs comprised the material used and the time spent by hospital pharmacists in preparing deferoxamine infusions. Cost-effectiveness of the new oral iron chelator, deferasirox, which could replace deferoxamine, was estimated using a Markov model. The model estimates and compares the total lifetime costs and quality-adjusted life years (QALYs) related to the use of deferasirox or deferoxamine in patients with β-thalassemia major at risk of chronic iron overload from blood transfusions. Dosages of deferasirox and deferoxamine used in the model were those that have been shown to be similarly effective in such patients. Compliance with deferoxamine was based on analyses of health-insurance claims data from transfusion-dependent thalassemia patients. Probabilities of complications of iron overload and death by compliance with chelation were estimated from published studies. Because data on compliance with deferasirox in typical clinical practice are unavailable, we used published data on compliance with the oral chelator deferiprone versus deferoxamine. Costs of deferasirox, deferoxamine, and drugs used in the treatment of complications of iron overload were based on publicly available data sources. Utilities were based on a study of patient preferences for oral versus infusional chelation therapy, as well as published literature and assumption. Future costs and QALYs were discounted at 5% annually. Costs were adjusted to 2004 Canadian dollars. Results: Cost of yearly infusion therapy in Canada was estimated at $6,000 per patient, excluding deferoxamine drug cost. Cost-effectiveness of deferasirox compared to deferoxamine was estimated at $45,054 per QALY gained resulting mainly from a gain in 2.9 QALYs obtained at an expected lifetime cost of $130,058 per patient. Cost-effectiveness is sensitive to the estimated costs of deferoxamine and infusional therapy, as well as the quality of life benefit associated with oral versus infusional therapy, and is more favorable in younger patients. Conclusion: In patients with transfusion-dependent β-thalassemia, the cost-effectiveness of deferasirox versus deferoxamine is within the range generally considered acceptable in Canada.

14660 Background: Canadian guidelines recommend zoledronic acid (ZA) (4 mg every 3 weeks) in patients with hormone HRPC and asymptomatic or minimally symptomatic bone metastases to reduce skeletal-related events (SRE). However, IV pamidronate (90 mg every 3 weeks) (PA) is also routinely used in this setting in spite of no significant improvement in occurrence of SRE or pain compared to NT. Objectives: To assess the cost effectiveness of ZA, PA, or no bisphosphonate therapy (NT) in the management of prostate cancer patients with bone metastases in Canada. Methods: A literature-based decision analytic model was developed to estimate the incremental cost and quality-adjusted life years (QALY) associated with the 3 treatment options. The model included assumptions about SREs, mortality, drug and administration costs, cost of SREs, reduced quality of life due to SRE and bone pain, and therapy duration. Sensitivity analyses considered several scenarios in which various assumptions were used regarding treatment efficacy and QALY gains due to pain relief and SRE prevention. All costs were expressed in Canadian dollars (2004). Results: The cumulative number of SREs over a patient’s remaining lifetime (1.9 years) was estimated at 2.69 for PA and NT patients and 1.76 for ZA. Total discounted costs were $11,918 for NT, $17,593 for PA, and $19,312 for ZA. Compared with patients receiving NT or PA, quality-adjusted survival increased by 0.094 (range depending on scenario considered: 0.072 to 0.106) QALY per patient for those on ZA compared to PA or NT. Compared to NT, ZA resulted in a cost per QALY gained of $78,366 (range: $50,717 to $101,831). Compared to PA, ZA resulted in a cost per QALY gained of $18,343 (range: $2917 to $23,835) per QALY gained. PA was more expensive than NT but did not improve patient-related outcomes. Conclusions: For HRPC patients with bone metastasis, zoledronic acid appears to be the only clinically valuable and economically acceptable option in Canada with a cost effectiveness likely better than previously reported. No significant financial relationships to disclose.