Cost-effectiveness of continuous vs. treatment-free remission strategies in chronic myeloid leukemia: a Markov modeling study from a single center in Bulgaria

Introduction : Chronic myelogenous leukemia (CML) is a malignant disease of the pluripotent hematopoietic stem cell, characterized by the presence of the BCR-ABL1 fusion gene, resulting from a balanced translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11)], known as the Philadelphia (Ph) chromosome. CML is an acquired disease of the hematopoietic stem cell, common to myelo- and lymphopoiesis, characterized by the uncontrolled proliferation of granulopoiesis—current status and goals. The introduction of targeted therapy with tyrosine kinase inhibitors (TKIs) for this rare, life-threatening disease has turned it into a chronic disease that can be controlled in over 90% of cases. Second-generation TKIs (nilotinib, dasatinib, and bosutinib) have an advantage over imatinib (first-generation) in terms of the frequency and speed of achieving cytogenetic and molecular responses in CML. However, they cause more severe adverse effects and are much more expensive than imatinib, especially when compared with the prices of several already registered generic products of imatinib and dasatinib. On the other hand, the constantly increasing costs of diagnosis, treatment, and monitoring of the response of CML to different therapeutic strategies require periodic pharmacoeconomic analyses of the cost-effectiveness, cost-benefit, and cost-utility types to assess which therapeutic strategies are cost-effective for a given period and in the long term, including due to changes in the annual costs of treatment when cheaper generic products for some strategies appear on the pharmaceutical market, with a view to their use in therapeutic practice. In addition, over the past decade, patients with CML who have achieved a stable deep molecular response for at least 2–3 years have been enrolled in large-scale clinical trials evaluating treatment-free remission (TFR). The present study aims to analyze and estimate savings from a portion of the costs of drug therapy under different strategies that include patients in remission in the so-called treatment-free phase of first- and second-line therapy for chronic-phase CML (CML-CP). The research perspective is that of the payer—the National Health Insurance Fund (NHIF)—and the cost research horizon is 20 one-year cycles. Methods : A diagram of a general Markov model of CML disease, including the three disease phases and possible transitions among health states, including death, was developed. Two alternative pharmacoeconomic Markov chain models were also developed. One is a model of the diagnosis and continuous treatment of CML-CP in the first and second lines of CML-CP treatment until the end of the patients’ lives, i.e., a standard model without the TFR phase, and the second is an extended model with the TFR1 and TFR2 phases included, i.e., with the inclusion of the TFR phase in both lines of CML-CP. The transition probabilities between states were extracted from real clinical data, with missing annual values imputed using the median. The analysis was conducted over 20 years. Both costs and health effects were discounted by 3% per year, in accordance with established pharmacoeconomic practices. Costs are based on annualized drug therapy costs for each treatment line. Health effects are measured in quality-adjusted life years (QALYs), assuming a utility value of 0.92 for all living health states, as reported in the literature. Transition to the TFR phase is defined as achieving a deep molecular response (MR4.5 log or MR5 log) after first- or second-line therapy. The duration of stay in the TFR phase is 5–7 years, assuming 50% of patients return to their respective treatment lines.