BACKGROUND : Treatment-free remission in chronic myeloid leukaemia-ie, achievement of a sustained deep molecular response leading to discontinuation of BCR-ABL1 tyrosine kinase inhibitor (TKI) therapy-has become a potential aim of therapy. Highly priced second-generation TKIs might offer deep molecular response status more quickly and for more patients than imatinib; however, with the availability and lower cost of generic imatinib, the value of second-generation TKIs as frontline therapy for this particular treatment endpoint remains unknown. We aimed to assess the potential value of second-generation TKIs used as frontline therapy in patients with chronic myeloid leukaemia in chronic phase in relation to the probability of achieving sustained deep molecular responses compared with generic imatinib, and the associated cost of each modality. METHODS : We used a decision analytic model to consider the value of different TKI approaches from the payer's perspective. The proportion of patients achieving sustained deep molecular response after 5 years of treatment in chronic phase was estimated at 26% with imatinib and 44% with second-generation TKIs. We also modelled more favourable scenarios of the proportion of patients achieving such response with second-generation TKIs at 66%, 88%, and a near-perfect response of 99%. For each scenario, we examined the impact of the combination of health utilities for chronic-phase chronic myeloid leukaemia (base case 0·89, range 0-1) and the annual cost of second-generation TKIs (base case US$152 814 [ie, the price of nilotinib in the USA], range 0-240 000) on the cost-effectiveness of second-generation TKIs compared with generic imatinib. We used different price scenarios for generic imatinib in the USA (average price $35 000 per year; lowest price $4400 per year), Europe ($4000 per year), and developing countries ($2100 per year). We calculated incremental cost-effectiveness ratios (ICERs) and assessed cost-effectiveness by considering two societal willingness-to-pay thresholds: $50 000 per quality-adjusted life-year (QALY) in all markets and $200 000 per QALY in the USA. RESULTS : In the base case, we obtained an ICER of $22 765 208, meaning that second-generation TKIs as frontline therapy to achieve sustained deep molecular response was not cost-effective under either of the societal willingness-to-pay thresholds. In our sensitivity analyses, none of the explored scenarios showed potential treatment value for use of second-generation TKIs at the current prices in the USA or at the price of $30 000-40 000 per year elsewhere. For example, considering a scenario in the USA using second-generation TKIs versus imatinib (annual price $4400 per year) with the potential benefit in favour of second-generation TKI (willingness to pay $200 000 per QALY, 66% of patients achieving sustained deep molecular response, and health utility of the chronic phase of 0·1), the cost of second-generation TKIs would need to be less than $25 000 per year to be a cost-effective option. Under the same conditions in developing nations, with a price of generic imatinib of $2100 per year and a willingness to pay of $50 000 per QALY, the annual price of second-generation TKIs should not exceed $10 000 per year of therapy. CONCLUSIONS : Considering the current prices of second-generation TKIs and of generic imatinib under different pricing scenarios in the USA, Europe, and developing countries, second-generation TKIs at current prices do not offer good value as frontline therapy in chronic myeloid leukaemia in order to achieve sustained deep molecular response and treatment-free remission. BACKGROUND : National Cancer Institute.