Cost-Effectiveness of Liposomal Cytarabine-Daunorubicin (CPX-351) Compared to Conventional Cytarabine-Daunorubicin Chemotherapy in Acute Myeloid Leukemia
Authors: Bewersdorf Jan Philipp , Goshua George , Patel Kishan K , Shallis Rory M. , Podoltsev Nikolai , Huntington Scott F. , Zeidan Amer M. 
Published: November 2021

Abstract
Introduction: A randomized phase III trial demonstrated improved overall survival (OS) and event-free survival (EFS) for older patients diagnosed with therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC) treated with a liposomal formulation of daunorubicin-cytarabine (CPX-351) when compared with 7+3 induction and consolidation therapy, a previous standard of care. Based on those results, CPX-351 was approved in 2017 in the United States (US) for adults with newly diagnosed t-AML and AML-MRC irrespective of age. However, the health economic implications of CPX-351 from a US payer perspective are not well-characterized.
Methods: We constructed a partitioned survival analysis based on the data from the original phase III trial (Lancet et al. JCO 2018) and subsequent updates (Lancet et al. Lancet Haematology 2021) and post-hoc analyses from the landmark trial (Villa et al. JME 2019). Newly diagnosed AML patients at a median age of 68 years entered the model with active AML and received either CPX-351 or 7+3 induction and consolidation therapy followed by allogeneic hematopoietic cell transplant (allo-HCT) for some patients. Parametric survival distributions were fitted using patient-level data recreated from the Kaplan-Meier curves and at-risk tables for EFS and OS for both study arms. Log-logistic distributions demonstrated the best fit and were chosen for this model. Frequency and setting (inpatient vs outpatient) of re-induction and consolidation therapy were used as outlined in the original study. Costs and practice patterns of salvage therapy, receipt of allo-HCT, supportive care, and incidence of complications were derived from the original trial or published literature (Table). If available, costs for the Medicare population rather than commercially insured patients were used. For the CPX-351 arm, the maximum new technology add-on payment granted by the Centers for Medicare & Medicaid Services for fiscal year 2020 was added to the costs of inpatient induction and consolidation therapy in the 7+3 arm. Costs were adjusted for inflation to 2020 US dollars using the personal consumption expenditure health index. Previously published utilities were used and measured in quality-adjusted life years (QALYs). Costs and utilities were discounted by 3% annually (range 3-5% in one-way sensitivity analysis) and modelled over a 10-year time horizon. Model outputs were used to calculate the incremental cost-effectiveness ratio (ICER) for CPX-351 over 7+3. A willingness-to-pay (WTP) threshold of $150,000/QALY gained was used to determine cost-effectiveness. One-way sensitivity analyses were performed with utility values varied with a 10% range and all other variables across a 50% range. In probabilistic sensitivity analyses using 10,000 Monte Carlo simulations, beta distributions were used to describe probabilities and utilities, while gamma distributions were used for costs.
Results: CPX-351 and 7+3 were associated with lifetime costs of $371,482 and $256,415, respectively, for an incremental cost of $115,066 with CPX-351. CPX-351 resulted in an incremental gain of 0.49 QALYs compared to 7+3 (CPX-351: 1.11 QALYs vs 7+3: 0.62 QALYs) resulting in an ICER of $231,563/QALY gained in the base case analysis. In one-way sensitivity analyses our model was most sensitive to the probability of receiving allo-HCT in either arm (Figure). In threshold analyses, a reduction of the CPX-351 add-on charge in the inpatient setting by 70.4% (from $47,353 to $14,004) would lower the ICER below the WTP threshold of $150,000/QALY. Probabilistic sensitivity analysis yielded a median ICER of $222,894 (95% credible interval: $142,863 - $313,289) with 7+3 favored in 96.4% of 10,000 iterations at a WTP threshold of $150,000.
Conclusion: Use of CPX-351 under the current pricing model is unlikely to be cost-effective for most older patients with t-AML/AML-MRC who resemble those enrolled in the clinical trial. A reduction by 70.4% for the CPX-351 add-on charge in the inpatient setting would be necessary to lower the ICER below the conventional WTP threshold of $150,000/QALY. Higher rates of allo-HCT and outpatient consolidation with CPX-351 did not lead to gains in clinical utility or cost reductions substantial enough to make CPX-351 cost-effective. The implications of a potential outpatient administration of CPX-351 induction on its cost-effectiveness require additional studies.
Figure 1 Figure 1.

Disclosures
Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Podoltsev: PharmaEssentia: Honoraria; Blueprint Medicines: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; CTI BioPharma: Honoraria; Bristol-Myers Squib: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Huntington: Bayer: Honoraria; Thyme Inc: Consultancy; Servier: Consultancy; Novartis: Consultancy; SeaGen: Consultancy; AstraZeneca: Consultancy, Honoraria; Genentech: Consultancy; TG Therapeutics: Research Funding; Flatiron Health Inc.: Consultancy; DTRM Biopharm: Research Funding; AbbVie: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Zeidan: Astex: Research Funding; Amgen: Consultancy, Research Funding; Epizyme: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Aprea: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Consultancy; Jasper: Consultancy; Astellas: Consultancy; Genentech: Consultancy; Geron: Other: Clinical Trial Committees; Agios: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; BioCryst: Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; BeyondSpring: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; ADC Therapeutics: Research Funding; Jazz: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding.