Cost-Effectiveness Analysis (CEA) of Sequential Treatment with Tyrosine Kinase Inhibitors (TKIs) for Chronic Myelogenous Leukemia (CML)
Authors: Whalen John , Stillman Ipek , Ambavane Apoorva , Felber Eugene , Makenbaeva Dinara , Bolinder Bjorn 
Published: October 2019

Abstract
Background: Imatinib has been approved for treatment of newly diagnosed CML since 2001. For patients failing imatinib, other treatment options such as dasatinib, nilotinib, bosutinib, and high-dose imatinib are recommended. Previous economic analyses assumed that patients are treated until progression, despite guidelines recommending changing treatments for non-responders. The objective was to perform a CEA of sequential treatment with 2nd line TKIs, from a commercial payer perspective in the United States (US).
Methods: A Markov-cohort model was used to simulate lifetime treatment costs and health outcomes (discounted 3.0% per annum) for patients resistant or intolerant to 1st line imatinib. It compared six treatment sequences, starting from 2nd line (shown in the results table). The model included five health states: chronic phase 2nd line TKI, chronic phase 3rd line TKI, chronic phase no TKI, post-progression, and death. After 12 months of TKI treatment, patients without a major molecular or complete cytogenetic response (MMR or CCyR) moved to the next line of therapy (per NCCN guidelines). Patients could also move to the next treatment line if they lost MMR or CCyR, or discontinued due to drug-related toxicity. Data for response achievement, risks of progression, death, adverse events, and discontinuation were primarily based on data in published trials. Due to the lack of head-to-head studies for dasatinib vs. nilotinib in 2nd line, and a lack of time-to-response data for all three 2nd line treatments, MMR and CCyR rates were interpolated from available data points in 2nd line, while dasatinib and nilotinib rates were assumed to be equal in 3rd line. Dasatinib and imatinib progression, loss of response, and survival rates for 2nd line responders were assumed equal, due to data limitations. In each health state, patients accrued drug costs, resource use (related to monitoring, AE management, and disease management) costs and quality-adjusted life years (QALYs). Resource use, cost, and utility estimates were based on FDA labels, RedBook, Medicare and AHRQ Healthcare Cost Utilization Project data, and published economic analyses. Multi-way uncertainty analyses evaluated key contributors to uncertainty in the results, by testing various assumptions for probabilities of discontinuation, response, loss of response, progression, and survival.
Results: The model predicts that 2nd line dasatinib provides increased survival (ΔLYs = ~0.4-2.6 years) and QALYs (ΔQALYs = ~0.4-2.8 years) in all patient groups when compared with 2nd line high-dose imatinib or nilotinib sequences. Also, 2nd line dasatinib was more costly (ΔLifetime Costs = ~$65,000 - $225,000) than high-dose imatinib and nilotinib, primarily due to longer survival and corresponding longer time on TKI treatment. In ±20% univariate sensitivity analyses, the model was most sensitive to 2nd line progression and survival estimates.
Conclusions: This analysis suggests that dasatinib may be associated with increased life expectancy and quality of life when compared with high dose imatinib or nilotinib, among patients who are resistant or intolerant to 1st line imatinib, primarily based on higher cytogenetic response rates observed in studies of dasatinib. Other studies have shown improved quality of life for responders, and landmark analyses have shown improved survival for patients achieving cytogenetic response, but head-to-head clinical studies of sequential use of dasatinib and nilotinib are needed to confirm the model result. Based on the threshold of $150,000/QALY, dasatinib can be considered cost-effective in the US.
Results Table: Sequence # Sequence 1 Sequence 2 Sequence 3 Sequence 4 Sequence 5 Sequence 6 1st line (not modeled – assumes 1st line imatinib for all sequences) 2nd line DAS NIL HDI DAS NIL HDI 3rd line NIL DAS NIL BOS BOS DAS Imatinib-resistant population LYs 7 6.5 4.5 7.3 6.8 4.5 QALYs 5.9 5.4 3.6 6.2 5.7 3.6 Lifetime Cost $497,391 $431,346 $270,308 $496,897 $431,084 $270,051 ICERs: DAS followed by NIL vs. NIL followed by DAS - $129,139 DAS followed by NIL vs. HDI followed by NIL - $96,356 Imatinib-intolerant population LYs 7.8 7.1 -- 8.1 7.4 -- QALYs 6.7 6.0 -- 7.0 6.3 -- Lifetime Cost $599,270 $509,456 -- $598,766 $509,174 -- ICERs: DAS followed by NIL vs. NIL followed by DAS - $125,800
BOS=bosutinib; DAS=dasatinib; HDI= high-dose imatinib; NIL=nilotinib; ICER=incremental cost-effectiveness ratio

Disclosures
Whalen: Evidera, Inc.: Consultancy, Employment; Bristol-Myers Squibb: Research Funding. Stillman:Evidera, Inc.: Consultancy, Employment; Bristol-Myers Squibb: Research Funding. Ambavane:Evidera, Inc.: Consultancy, Employment; Bristol-Myers Squibb: Research Funding. Felber:Bristol-Myers Squibb: Employment, Equity Ownership. Makenbaeva:Bristol-Myers Squibb: Employment, Equity Ownership. Bolinder:Bristol-Myers Squibb: Employment, Equity Ownership.