PCN73 Cost-Effectiveness Analysis of Arsenic Trioxide for the Treatment of Patients with Acute Promyelocytic Leukemia in the US Tallman M1, Lo-Coco F2, Barnes G3, Kruse M4, Wildner R4, Martin M5, Mueller U6, Tang B3, Pathak A3, Weinstein MC7 1Memorial Sloan Kettering Cancer Center, New York City, NY, USA, 2University Tor Vergata, Rome, Italy, 3Teva Pharmaceutical, Frazer, PA, USA, 4Optum, Waltham, MA, USA, 5Mapi, Uxbridge, UK 6Teva Pharmaceutical, Ulm, Germany, 7Harvard School of Public Health, Boston, MA, USA Background Methods (cont.) . Acute promyelocytic leukemia (APL) is a distinct subtype of acute Table 3. Treatment costs considered in the model myeloid leukemia (AML)1 with ~1,000 -1,500 new cases in the US Treatment phase Treatment Arm per year Stable Disease (1st- ATRA + AraC + ATO +ATRA AIDA – Arsenic trioxide (ATO) is currently licensed for the treatment of line) Chemo APL for patients who are refractory to, or have relapsed from Direct medical costs previous treatment with all-trans retinoic acid (ATRA) and • Induction $20,503 $20,503 $20,503 anthracycline-based chemotherapy • Consolidation $778 $778 $778 . Current 1st-line treatment in the US (NCCN)1: • Maintenance N/A $40 $40 – ATO+ATRA: Drug costs . Induction with ATO+ATRA • Total drug costs . Consolidation with ATO+ATRA per treatment $61,797 $13,146 $38,008 – AIDA arm . Induction with ATRA+idarubicin Table 4 . Adverse events costs considered in the model . Consolidation with ATRA+idarubicin+mitoxantrone Treatment Phase Adverse Event Event Cost – ATRA+AraC+Chemo: Neutropenia $0 . Induction with ATRA+cytarabine (AraC)+daunorubicin Thrombocytopenia $0 Induction . Consolidation with ATRA+daunorubicin Hepatic toxicity $0 . Overall, studies indicate that ATO is a possible 1st-line alternative Fever of Unknown Origin $0 option for APL2 Neutropenia $8,734 Thrombocytopenia $1,376 Consolidation Objective Hepatic toxicity $6,382 . To estimate the cost-effectiveness of ATO in 1st-line in the treatment Fever of Unknown Origin $8,734 6 years post-induction of APL using the third-party perspective in the US Late secondary leukemia $25,220 remission AE costs incurred during the induction phase were reimbursed under Methods the induction DRG Target Population Results . Based on the clinical trial populations: patients are 45 years old at Figure 4. Base case results model entry based on median age of APL patients at first diagnosis.3 Totals Incremental ICERs Comparators Regimen QALY QALY Cost LYs Cost LYs $/LY $/QALY .See Figure 1 below for choice of therapy s s Time Horizon ATRA + .55 years until patients reach 100 years of age or have died AraC + $96,940 8.57 6.71 ------Ref Ref Model Structure Chemo .A four-state Markov (“state-transition”) model was developed based on AIDA $101,396 10.09 8.13 $4,457 1.52 1.43 $2,933 $3,122 ATO + the natural history and outcomes of APL using a 1 month cycle length $136,170 17.79 14.33 $34,773 7.71 6.19 $4,512 $5,614 (Figure 2) ATRA .All patients begin in the “stable disease” health state and stay in this Sensitivity Analyses state while receiving their initial therapy until they experience a disease . A large number of deterministic sensitivity analyses (DSA) were carried event or die out including regimen costs, medical costs, AE probability, AE costs, efficacy (i.e., transition probabilities) and shown as Tornado diagrams Figure 1. Choice of therapy (See Figures 3 and 4). ATO + ATRA M Figure 3. Tornado diagram ATO vs AIDA

1st-line APL patients (low to intermediate risk) ATRA + AraC + Chemo To Markov states, Drug Cost of ATO Consolidation (1st Line) ($6,621-$11,035); BC: $8,828 M Figure 3 Completed/Off-Treatment Cost ($133-$222); BC: $177 Drug Cost of AIDA Maintenance (1st Line) ($1,169-$701); BC: $935 AIDA Cost of Neutropenia - Consolidation ($10,917-$6,550); BC: $8,734 M Drug Cost of AIDA Consolidation (1st Line) ($4,309-$2,586); BC: $3,447

Probability of Neutropenia - Consolidation 2nd Cycle (AIDA) (0.95-0.57); BC: 0.76 Figure 2. Markov Bubble Diagram Stable Disease Cost - Consolidation (ATO) ($583-$972); BC: $778

Stable Disease Cost - Consolidation (AIDA) ($972-$583); BC: $778

Probability of Neutropenia - Consolidation (AIDA) (0.4375-0.2625); BC: 0.35

Cost of Fever of Unknown Origin - Consolidation ($10,917-$6,550); BC: $8,734

$2,327 $3,327 $4,327 $5,327 $6,327 $7,327 $8,327 Figure 4. Tornado diagram ATO vs. ATRA + AraC + Chemo

Mortality . Age-specific mortality rates for the US population4 were used to Probabilistic sensitivity analysis estimate the probability of dying for all other causes Using the Markov cohort-model, a second-order PSA with 1,000 samples Transition probabilities (EFS (event-free survival) and OS) (see was conducted Table 1) . At a threshold of $9,000 per QALY, the probability of ATO being cost- . Monthly probabilities of experiencing an event were estimated from effective was 83% Lo-Coco 20135 for the AIDA and ATO + ATRA treatment arms. . At a threshold of $14,000 per QALY, the probability of ATO being cost- . ATRA + AraC + Chemo arm used results from Powell 20106 effective was 100% Adverse event rates Conclusions . Adverse event rates were obtained from published sources: . ATO + ATRA - Lo-Coco 20135 . Arsenic Trioxide provides excellent clinical results, with . AIDA - Lo-Coco 20135 improvements in quality of life and survival . ATRA + AraC + Chemo - Powel l 20126 . Arsenic Trioxide is cost-effective with a base-case ICER Costs of $5,614 compared to AIDA in the 1st-line setting . Costs of the treatment regimens were estimated using the standard . Versus the AIDA regimen, the ATO regimen wholesale acquisition costs (WAC) in the US.7 displayed a ~75% increase in QALYs with a . Costs for ATO + ATRA or AIDA were based on the roughly 35% increase in costs treatment regimen as outlined in Lo-Coco 20135 . For the ATRA+AraC+Chemo arm, the analysis was . Arsenic Trioxide is cost-effective with a base-case ICER st performed using the costs from Powell 20106 of $5,148 compared to ATRA + AraC + Chemo in 1 -line . Calibration was used (Microsoft Excel Solver ) to . Versus ATRA + AraC + Chemo regimen, the ensure that the deviation between the observed data ATO regimen has more than double the QALYs, (clinical trials) and predicted data (model-produced with an only 40% increase in costs. outcomes) is minimized . Extensive deterministic and probabilistic sensitivity . See Tables 3 and 4 analyses show that ATO is 100% cost-effective at . Utilities (see Table 2) willingness-to-pay thresholds of $14,000 and higher Table 1. Clinical Transition Probabilities . Overall the shorter and better-tolerated regimen of Parameter Treatment Arm ATO+ATRA is a highly cost-effective strategy compared to AIDA ATRA + AraC + Transition Probabilities, ATO + ATRA ATRA+Ara-C+chemotherapy or AIDA in the treatment of 5 (Lo-Coco Chemo monthly (1st-line) (Lo-Coco 2013 ) 5 6 newly diagnosed low-to-intermediate risk APL patients 2013 ) (Powell 2010 ) st References Probability of a 1 event 0.00084 0.00202 0.00530 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. 3-1-2013. Probability of disease 8-9-2013 0.00058 0.00444 0.00510 2. 6.National Horizon Scanning Centre. Arsenic trioxide (Trisenox) for acute promyelocytic leukaemia - first line therapy. death from stable disease Birmingham, England: University of Birmingham, 2007 3. Lo-Coco F, Avvisati G, Vignetti M et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by Table 2. Utilities risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 2010;116(17):3171-3179. Model Parameter Value Data Sources 4. Wilmoth, J, Shkolnikov, V, and Barbieri, M. The Human Mortality Database. 2014. http://www.mortality.org/. Accessed: 2014 5. Lo-Coco F, Avvisati G, Vignetti M et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med Background UK utility values Varies by age Szende 20148 2013;369(2):111-121. 9 6. Powell BL, Moser B, Stock W et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic Background US utility values Varies by age Hanmer 2006 leukemia: North American Leukemia Intergroup Study C9710. Blood 2010;116(19):3751-3757. st 10 7. Optum. EncoderPro. 2014. https://www.encoderpro.com/epro/. Accessed: 12-1-2014 Progression-free state: 1 -line treatment 0.78 Woods 2012 8. Szende A, Janssen B, Cabases J, Ramos Goñi JM. Self-Reported Population Health: An International Perspective Based on nd 11 EQ-5D. Springer; 2014. Progression-free state: 2 -line treatment 0.65 Ferguson 2008 9. Hanmer J, Lawrence WF, Anderson JP, Kaplan RM, Fryback DG. Report of nationally representative values for the Progression state: 2nd-line treatment 0.47 Ferguson 200811 noninstitutionalized US adult population for 7 health-related quality-of-life scores. Medical Decision Making 2006;26(4):391-400. 10. Woods B, Hawkins N, Dunlop W, O'Toole A, Bramham-Jones S. Bendamustine versus chlorambucil for the first-line treatment Death 0 Assumption of chronic lymphocytic leukemia in England and Wales: a cost-utility analysis. Value Health 2012;15(5):759-770. 11. Ferguson, J., Tolley, K., Gilmour, F, and Priaulx, J. Health state preference study mapping the changes over the course of the disease process in chronic lymphocytic leukemia. 11-8-2008.

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