Introduction: The 1st generation tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of chronic myelogenous leukemia (CML). The 2nd generation TKIs (2G-TKI), dasatinib and nilotinib, further improved the outcomes among CML patients. Which of the 2G-TKIs is effective for an individual patient depends, among other factors, on genetic mutations that the patient may have. The National Comprehensive Cancer Network (NCCN) guidelines provide recommendations for management of cytogenetic/hematologic resistance to TKIs. The objective of this study was to assess potential economic consequences of limiting access to therapies, while taking into account frequencies of the genetic mutations that make patients insensitive to 2G-TKIs.

Methods: A decision analytics economic model was developed to examine clinical and economic outcomes among patients treated with 2G-TKIs from a US payer perspective. The model was based on a hypothetical cohort of 1,000 CML patients, who are treated with dasatinib or nilotinib following treatment failure with imatinib. BCR-ABL1 genetic mutation frequencies among the patients and impact of mutations on treatment responses to 2G-TKIs were obtained from published literature. Clinical outcomes were estimated after 12 months of treatment and included complete hematologic response (CHR) and major cytogenetic response (MCyR). The annual total TKI drug costs (2014 Wholesale Acquisition Costs) per CHR and MyCR were estimated. Three hypothetical TKI access scenarios were compared: 1) open access to both 2G-TKIs; 2) access to 2G-TKIs restricted to dasatinib only (DASA-Only); and 3) access to 2G-TKIs restricted to nilotinib only (NILO-Only).

Results: The model showed that among the hypothetical cohort of 1,000 TKI treated CML patients, the percentage of patients with CHR was greatest in the open access (92.6%), followed by DASA-Only (88.2%) and NILO-Only (66.7%). Similarly, the percentage of CML patients with MCyR was greatest in the open access (56.4%), followed by DASA-Only (53.4%) and NILO-Only (46.9%). These findings were primarily due to the incidence of mutations with insensitivity or resistance to dasatinib (12.4%) and to nilotinib (19.1%) (Table). Compared to the TKI costs per CHR in open access ($120,706/CHR), the costs were 5% higher ($126,753/CHR) in DASA-Only, and,40.8% higher ($169,990/CHR) in NILO-Only. Likewise, compared to the TKI costs per MCyR in open access ($198,284/MCyR), the cost were a 5.5% higher ($209,259/MCyR) in DASA-Only, and,21.8% higher ($241,515/MCyR) in NILO-Only.

Conclusions: Open access to TKIs in a managed care setting is important in order to enable clinicians to choose the most appropriate TKI treatment for a CML patient. Open access to both 2G-TKIs is likely associated with greater rates of positive clinical outcomes, including CHR and MCyR, and lower costs compared to restricted access.

Table.

BCR-ABL1 Mutation Frequencies Among CML Patients

Mutation NamePercentage of Patients with Mutation Mutation Class for 2G-TKI Response*
DasatinibNilotinib
T315I 3.3 D D 
M351T 7.3 A A 
G250E 5.3 A A 
F359V 4.3 A C 
M244V 5.0 A A 
Y253H 3.0 A C 
E255K 3.1 B C 
H396R 3.3 A A 
F317L 2.7 C A 
E355G 2.3 A A 
Q252H 1.7 B B 
E255V 1.6 B C 
E459K 1.6 A A 
F486S 1.5 A A 
L248V 1.2 A A 
D276G 1.2 A A 
E279K 1.2 A A 
Y253F 0.7 A B 
F359C 0.7 A C 
F359I 0.7 A B 
*Class A: mutation may confer same response as normal genotype to 2G-TKI. Class B: mutation may confer intermediate insensitivity/resistance to the 2G-TKI. Class C: mutation may confer substantial insensitivity/resistance to the 2G-TKI. Class D: mutation may confer non-response to the 2G-TKI. 
Mutation NamePercentage of Patients with Mutation Mutation Class for 2G-TKI Response*
DasatinibNilotinib
T315I 3.3 D D 
M351T 7.3 A A 
G250E 5.3 A A 
F359V 4.3 A C 
M244V 5.0 A A 
Y253H 3.0 A C 
E255K 3.1 B C 
H396R 3.3 A A 
F317L 2.7 C A 
E355G 2.3 A A 
Q252H 1.7 B B 
E255V 1.6 B C 
E459K 1.6 A A 
F486S 1.5 A A 
L248V 1.2 A A 
D276G 1.2 A A 
E279K 1.2 A A 
Y253F 0.7 A B 
F359C 0.7 A C 
F359I 0.7 A B 
*Class A: mutation may confer same response as normal genotype to 2G-TKI. Class B: mutation may confer intermediate insensitivity/resistance to the 2G-TKI. Class C: mutation may confer substantial insensitivity/resistance to the 2G-TKI. Class D: mutation may confer non-response to the 2G-TKI. 
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Disclosures

Jabbour:Ariad, Novartis, BMS, Pfizer, and Teva : Consultancy. Dinara:Bristol-Myers Squibb: Employment, Equity Ownership. Melissa:Bristol-Myers Squibb: Consultancy, Research Funding. Jay:Bristol-Myers Squibb: Consultancy, Research Funding.

Topics:
economics, leukemia, myelocytic, chronic, mutation, protein-tyrosine kinase inhibitor, dasatinib, nilotinib, imatinib mesylate, treatment outcome, treatment failure, national comprehensive cancer network

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2014 by The American Society of Hematology
2014
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