Low dose weekly HMA-venetoclax dosing is associated with greater cost-effective efficacy than standard dosing in AML/MDS: Real-world evidence

Abstract Introduction Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in elderly patients unfit for intensive chemotherapy have substantial clinical and economic challenges. While hypomethylating agents (HMA) plus venetoclax (Ven) improve outcomes over HMAs alone, the combination at standard-dose (SD) frequently causes severe myelosuppression, leading to toxicities and hospitalizations. Recent studies suggest that a metronomic low-dose (MLD) regimen of decitabine plus Ven yields comparable efficacy with fewer toxicities. This study aims to evaluate economic outcomes and days spent in the hospital of MLD versus SD HMA/Ven using real-world cohorts at Montefiore Einstein Comprehensive Cancer Center (MECCC). Methods At MECCC, we analyzed both prospective and retrospective cohorts of myeloid malignancies (MDS, AML, chronic myelomonocytic leukemia) ineligible for intensive chemotherapy, grouping them into SD HMA/Ven (azacitidine 75 mg/m² for 5–7 days or decitabine 20 mg/m² for 5 days plus Ven 400 mg daily for 14–28 days per 28-day cycle) or MLD HMA/Ven (subcutaneous decitabine 0.2 mg/kg weekly plus Ven 400 mg weekly). Using patient-level data, we constructed a Markov model, with three exclusive health states “on treatment”, “off treatment” and “death”. Transition probabilities between different health states were calculated using the TreeAge Pro software. Overall survival was assessed by Kaplan–Meier analysis and parametric fits for overall survival and event-free survival were modeled with log-normal distributions chosen by Akaike Information Criterion. Model costs (calculated in 2024 USD) were obtained from the Centers for Medicare and Medicaid Services, Physician Fee Schedule and published literature. Utilities for progression-free and progressive disease states were referenced from prior studies. All analyses were calculated from a US third-party payer perspective. To determine cost effectiveness, total costs and quality-adjusted life years (QALY) were estimated and the incremental cost-effectiveness ratio (ICER) was calculated as the difference in cost divided by the difference in QALYs between the MLD and SD arms, with results compared against a willingness-to-pay (WTP) threshold of $150,000 per QALY. Probabilistic (10,000 Monte Carlo simulations) and one-way sensitivity analyses were used to assess robustness of the model. Additionally, longitudinal absolute neutrophil count (ANC) data and hospitalization events were extracted via a HIPAA-compliant tool. Hospitalization rates were modeled with negative binomial regression adjusting for treatment duration, age, Charlson Comorbidity Index and ECOG Performance Status. Results Between November 2018 and January 2024, 68 patients with myeloid malignancies were treated at MECCC with HMA/Ven therapies. In the MLD cohort (n = 31; median age 73 years, range 52–87), there were 21 AML, 8 MDS, and 2 chronic myelomonocytic leukemia cases. The SD cohort (n = 37; median age 69 years, range 30–94) comprised 33 AML and 4 MDS patients. Overall survival was comparable between the two cohorts (p = 0.066). Monthly treatment costs were substantially lower for MLD ($5,269 vs. $19,875). Lifetime healthcare costs were $244,223 for MLD versus $299,038 for SD, with QALYs of 13.17 versus 4.86, yielding an ICER of –$6,598 per QALY, indicating dominance of MLD regimen. All 10,000 Monte Carlo simulations in probabilistic sensitivity analysis remained below the $150,000/QALY WTP threshold. One-way sensitivity analyses identified terminal care cost, supportive care cost, and SD discontinuation probability as the main influential parameters. Longitudinal ANC analysis showed longer follow-up in MLD (median 147.5 vs. 75.5 days; p<0.001), lower neutropenia burden (time with normal ANC: 35.5% vs. 19.4%, p=0.036; time in grade 4 neutropenia: 22.4% vs. 46.5%, p<0.001), and faster ANC recovery (over 50% achieving ANC >1.5×10⁹/L by day 76 vs. never reached in SD). Hospitalization data revealed fewer days hospitalized per 100 treatment days with MLD (4.5 days vs. 8.5 days) and a 39% lower adjusted hospitalization risk (incidence rate ratio 0.61; 95% CI 0.38–0.98; p=0.042). Conclusion MLD HMA/Ven combination appears more cost-effective compared to SD and is associated with less neutropenia, fewer hospitalizations and lower overall costs. These findings support broader evaluation of MLD regimens in prospective, randomized trials and highlight the potential to optimize patient care and reduce healthcare burden.