Venetoclax Combo Extends Life in Bulgarian AML Patients but at a Steep Price, Real-World Model Finds

Acute myeloid leukemia is among the most feared diagnoses in medicine, and for older patients who cannot tolerate intensive chemotherapy, the options have long been grim. Azacitidine monotherapy, the historical standard for this fragile population, achieves remission in fewer than a third of patients over 65, with survival often falling below one year. The arrival of venetoclax, a targeted BCL-2 inhibitor combined with azacitidine, changed the therapeutic landscape, dramatically improving response rates and survival in clinical trials. But a drug that works is not automatically a drug a health system can afford, and a new exploratory economic evaluation from Bulgaria now puts hard numbers on that tension, revealing a combination therapy that delivers real gains in life and quality of life at a cost that dwarfs the country’s willingness-to-pay thresholds.

The study, published in the journal Pharmacia, is notable for what it did not use: the polished, idealized data of randomized clinical trials. Instead, researchers built their model on local real-world evidence drawn from 69 Bulgarian patients treated at the Specialized Hospital for Active Treatment of Hematological Diseases. Forty-nine patients received venetoclax plus azacitidine in a prospective cohort followed from 2022 to 2024, after venetoclax entered the national reimbursement lists, while 20 patients treated with azacitidine alone between 2018 and 2022 served as the comparator. By anchoring the azacitidine cohort in the pre-venetoclax era, the investigators deliberately avoided calendar-related bias, ensuring that both groups were treated within comparable modern clinical contexts.

All patients had newly diagnosed acute myeloid leukemia and were deemed ineligible for intensive chemotherapy for concrete clinical reasons: age of 75 or older, significant pulmonary or cardiac disease, liver cirrhosis, active resistant infection, poor functional status, kidney failure, or similar conditions. This is precisely the population in which treatment decisions carry the highest stakes and the least margin for error, and in which the balance between extending life and preserving its quality becomes most delicate.

Methodologically, the team constructed a one-year state-occupancy model with monthly cycles, dividing each patient’s trajectory into three mutually exclusive states: event-free survival, progressed or relapsed disease, and death. Rather than a full Markov transition model, which would have demanded stronger assumptions than the sparse progression data could justify, the researchers used a partitioned-survival-style approach in which monthly state proportions were derived directly from observed overall survival and reconstructed event-free survival. Progressed disease occupancy was calculated as the difference between the two survival curves, and death as one minus overall survival, with internal consistency checks ensuring that event-free survival never exceeded overall survival and that no state ever turned negative.

Quality of life entered the model through monthly patient responses to the EORTC quality-of-life questionnaire, mapped onto utility values using a published regression algorithm. Event-free patients carried a mean utility of 0.75, while those in progressed or relapsed disease averaged 0.63. Costs were tallied from the perspective of the Bulgarian National Health Insurance Fund and included drug acquisition, hospitalization, monitoring, diagnostic investigations, and supportive and palliative care, all priced at 2024 list prices and converted to euros at the fixed national exchange rate. Venetoclax acquisition alone cost roughly €9,760 per month, while azacitidine monotherapy ran about €2,802 monthly.

The base-case results were stark. Total yearly costs reached €99,532.86 per patient on the combination versus €44,344.09 on azacitidine alone, an incremental cost of €55,188.77. Against that expenditure, the combination delivered 0.51 quality-adjusted life-years versus 0.32, and 0.68 life-years versus 0.45, yielding incremental gains of 0.19 QALYs and 0.23 life-years. The resulting cost-effectiveness ratios were €289,309.59 per QALY gained and €235,736.28 per life-year gained, both far above Bulgaria’s accepted threshold of roughly €54,815, which corresponds to three times gross domestic product per capita.

Probabilistic sensitivity analysis using Monte Carlo simulation underscored how fragile the value proposition is at current prices. Only 4.4 percent of simulated cost-per-QALY estimates fell below the national threshold, and for cost per life-year gained the figure was 6.7 percent. The analysis suggested that the combination would only become acceptably cost-effective at a willingness-to-pay threshold of around €300,000, equivalent to more than twelve times GDP per capita, with results plateauing near €400,000. The model also faithfully captured the darker side of the therapy: some patients experienced severe adverse events during induction, and in certain simulations the combination produced negative quality-adjusted or even negative life-year gains, reflecting early treatment-related mortality.

One-way sensitivity analyses revealed that the results were most sensitive to the effectiveness of the combination itself. If venetoclax plus azacitidine delivered 30 percent lower QALYs or life-years than assumed, the cost per QALY soared past €1.5 million and the cost per life-year beyond €1.9 million. Yet the dispersion of probabilistic results clustered tightly around the base case for survival outcomes, suggesting that the survival benefit itself was relatively consistent, even as quality-of-life impacts varied more widely across patients.

Perhaps the most intriguing finding is how closely the Bulgarian real-world result mirrors trial-based economics from wealthier countries. The exploratory cost-utility ratio of roughly €289,000 per QALY aligns remarkably well with a United States estimate of $260,343 per QALY, lending incidental validation to the quality-of-life mapping algorithm the Bulgarian team employed. Meanwhile, first-year survival in the local cohort was numerically higher on the combination, and event-free survival was significantly better, indicating improved disease control even within a single year of follow-up. The authors contrast this with a real-world study in older, frailer patients where the combination was poorly tolerated, noting that their cohort’s median age of 71, close to Bulgarian life expectancy, may partly explain the difference.

The researchers are careful to frame their work as hypothesis-generating rather than reimbursement-grade. The sample of 69 patients is small, progression ascertainment was incomplete, the one-year horizon misses longer-term survival and late costs, and no external validation against larger multicenter datasets was yet possible. Longer time horizons in other analyses have pushed cost-effectiveness ratios down dramatically, to figures as low as $74,141 per life-year gained, suggesting that the true value of the combination may be substantially better than a one-year snapshot can capture. Still, the study delivers something Bulgaria has lacked: a transparent, locally grounded account of what this breakthrough therapy actually costs and delivers within its own health system. As venetoclax and similar targeted agents spread across Central and Eastern Europe, models like this one will become essential instruments for deciding which medical miracles a national payer can realistically afford, and at what price the arithmetic of hope must ultimately be settled.

Subject of Research: Cost-effectiveness of venetoclax plus azacitidine versus azacitidine monotherapy in Bulgarian patients with acute myeloid leukemia ineligible for intensive chemotherapy

Article Title: Exploratory cost-utility and cost-effectiveness analysis of venetoclax plus azacitidine vs. azacitidine monotherapy in Bulgarian patients with AML ineligible for intensive chemotherapy: a real-world-data-influenced state-occupancy model

Article References: Donchev, M., Davidkova, Y., Tachkov, K., & Petrova, G. (2026). Exploratory cost-utility and cost-effectiveness analysis of venetoclax plus azacitidine vs. azacitidine monotherapy in Bulgarian patients with AML ineligible for intensive chemotherapy: a real-world-data-influenced state-occupancy model. Pharmacia, 73, Article e197277. https://doi.org/10.3897/pharmacia.73.e197277

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e197277

Keywords: acute myeloid leukemia, venetoclax, azacitidine, cost-effectiveness, cost-utility analysis, QALY, real-world data, state-occupancy model, Bulgaria, health economics, pharmacoeconomics, National Health Insurance Fund