---
title: "Economic and Organizational Analysis of Hypomethylating Agents in AML Treatments"
id: "plos-one-20-economic-and-organizational-impact-of-oral-versus-intravenous-and-subcutaneous"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-20-economic-and-organizational-impact-of-oral-versus-intravenous-and-subcutaneous"
content_type: "clinical_feed_article"
specialty: "Hematology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358426"
published_at: "2026-09-22T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Economic and Organizational Analysis of Hypomethylating Agents in AML Treatments
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-20-economic-and-organizational-impact-of-oral-versus-intravenous-and-subcutaneous
- **Specialty:** [Hematology](https://medichelpline.com/clinical-feed/hematology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358426)
- **Published At:** 2026-09-22T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Study evaluates economic impact of **hypomethylating agents** administered orally, intravenously, and subcutaneously in **acute myeloid leukemia** (AML) patients not suitable for intensive chemotherapy. - Focus is on the **Spanish National Health System**, highlighting the need for cost-effective treatments. - Oral decitabine/cedazuridine (DEC-C) showed significantly lower costs (€1,306) compared to intravenous (€9,998) and subcutaneous (€12,177) methods. - Key savings from reductions in hospitalization, transport, and infection risk associated with oral administration. - Oral therapies enhanced patient convenience and may alleviate resource strain on healthcare systems, emphasizing integration into treatment pathways.
## Clinical Analysis & Structured Key Points
Economic and organizational impact of oral versus intravenous and subcutaneous administration of hypomethylating agents in patients with acute myeloid leukemia not eligible for intensive chemotherapy in Spain | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Reader Comments Figures Figures Abstract Acute myeloid leukemia (AML) primarily affects older adults, many of whom are unsuitable for intensive chemotherapy. Hypomethylating agents (HMA) -intravenous (IV) decitabine and subcutaneous (SC) azacitidine- are standard therapeutic options but require frequent hospital visits and substantial healthcare resource use. Oral decitabine/cedazuridine (DEC-C) offers a therapeutically equivalent alternative that may reduce hospital resource burden and improve patient convenience. This study estimated and compared the economic and organizational impact of IV, SC, and oral HMA administration in AML patients unfit for standard intensive chemotherapy, from the perspective of the Spanish National Health System. A micro‑costing model quantified direct non‑pharmacological costs associated solely with the administration route across five domains: drug preparation and administration, treatment‑related hospitalizations, medical transportation, catheter management, and infections. Resource use was derived from a survey of 30 healthcare professionals across 16 hospitals and valued using official tariffs. Costs were calculated separately for induction and subsequent cycles; drug acquisition costs were excluded. Non‑pharmacological costs per patient were €9,998 for IV decitabine, €12,177 for SC azacitidine, and €1,306 for oral DEC‑C, representing cost reductions of 87% and 89% for oral therapy versus IV and SC, respectively. Savings were driven mainly by reductions in hospitalization (58–61%), transport (13–22%), infections (9%–12%), administration‑related activities (11–12%) and the avoidance of catheter-related costs. Oral therapy also markedly reduced resource utilization, including 40–50 fewer hours of healthcare professional time, 8–9 fewer inpatient days, and 4–8 fewer ambulance transfers per patient. Catheter use decreased by 33%, and infection risk declined by 87% versus IV and 54% versus SC. Oral administration substantially reduces direct non‑drug costs and frees hospital capacity, offering meaningful organizational efficiencies and contributing to the sustainability of AML care within a resource‑constrained health system. These findings reinforce the value of integrating oral HMAs into clinical pathways. Citation: Lloret Avellá M, Carmo M, Paladio Duran N, Blancher Parcerisa P (2026) Economic and organizational impact of oral versus intravenous and subcutaneous administration of hypomethylating agents in patients with acute myeloid leukemia not eligible for intensive chemotherapy in Spain. PLoS One 21(9): e0358426. https://doi.org/10.1371/journal.pone.0358426 Editor: Daniel Thomas, Stanford University, UNITED STATES OF AMERICA Received: March 12, 2026; Accepted: August 27, 2026; Published: September 22, 2026 Copyright: © 2026 Lloret Avellá et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the manuscript and its Supporting Information files. Funding: This study was funded by Otsuka. Funders were involved in study conceptualization, review of the manuscript and decision to publish. Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Maria Lloret and Mafalda Carmo are employees of IQVIA. Nuria Paladio and Pere Blancher are employees of Otsuka. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Introduction Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by clonal proliferation of myeloid precursors and impaired hematopoiesis, leading to bone marrow failure and systemic complications [ 1 ]. The median age at diagnosis is approximately 68 years, and the disease predominantly affects older adults, many of whom present with comorbidities that render them unfit for intensive chemotherapy regimens [ 2 – 4 ]. In Spain, AML incidence continues to rise, reflecting demographic trends and improved diagnostic capabilities, thereby amplifying the need for treatment strategies that are clinically effective while minimizing hospital resource demands, respecting patients’ preferences and promoting at home treatment [ 5 – 8 ]. For patients deemed unsuitable for standard intensive chemotherapy, hypomethylating agents (HMA) like decitabine and azacitidine – constitute the foundation of frontline therapy [ 3 , 9 ]. While these agents confer meaningful clinical benefits, traditional intravenous (IV) and subcutaneous (SC) administration require frequent visits over consecutive days, prolonged chair occupancy, and substantial involvement of nursing, pharmacy, and medical staff [ 10 , 11 ]. These factors contribute to increased operational costs, strain on infusion capacity, and heightened infection risk, particularly in immunocompromised patients [ 12 ]. Oral formulations of HMA have emerged as a promising solution to these challenges. Oral decitabine is co‑formulated with cedazuridine, a cytidine deaminase inhibitor (DEC‑C), that increases systemic decitabine exposure through inhibition of cytidine deaminase–mediated first‑pass metabolism in the gut and liver [ 13 ]. Clinical trials have confirmed the non-inferiority of oral DEC-C in terms of efficacy and safety in patients with newly diagnosed AML who are ineligible for standard intensive chemotherapy (SIC) [ 14 ]. Beyond clinical equivalence, oral administration offers practical advantages, including reduced reliance on infusion infrastructure, lower staffing needs, and fewer hospital accesses [ 3 , 5 ]. These benefits align with broader healthcare objectives of improving efficiency, reducing costs, and enhancing patient autonomy and use of home-based care [ 5 ]. Existing studies in solid tumors demonstrate substantial reductions in infusion time and non‑drug costs when shifting from IV to SC delivery [ 10 , 11 , 15 ], but the incremental advantages of oral therapy in hematologic malignancies have not been fully quantified. The present study addresses this evidence gap by evaluating the direct non‑pharmacological costs and resource utilization associated with oral DEC-C versus IV decitabine and SC azacitidine in AML patients unfit for SIC in Spain. By incorporating healthcare professional time, hospitalization needs, catheter‑related procedures, infection risk, and transport requirements, this evaluation offers a comprehensive assessment of how administration route influences the economic and organizational sustainability of AML care. Materials and methods Study design and perspective This study was designed as a cross-sectional micro-costing analysis conducted from the perspective of the Spanish National Health System. This analysis used a bottom-up approach, whereby individual resource components were identified, measured, assessed, and subsequently aggregated to estimate total costs. The primary objective of this approach was to isolate and quantify the economic and organizational impact associated with the mode of administration of HMAs (oral versus IV and SC) in patients with AML who were considered unfit for SIC, rather than comparing pharmacological alternatives. Accordingly, drug acquisition costs were excluded, and clinical equivalence in terms of efficacy and safety was assumed based on available evidence. This methodological approach allows a focused assessment of administration-driven resource use within the Spanish National Health System. The analysis covered a full treatment course and used a deterministic Excel‑based model that encoded all parameters, assumptions and intermediate calculations. Because the analytic horizon was less than one year, no discounting was applied. Analytic framework and model structure The methodological framework was adapted from Di Costanzo et al., with modifications to reflect Spanish hospital operations and resource use patterns [ 16 ]. A bottom‑up micro‑costing approach was implemented, estimating costs across five administration‑driven domains: (i) drug preparation, dispensation and administration; (ii) treatment‑related hospitalizations; (iii) medical transportation for dosing‑day visits; (iv) catheter implantation, follow‑up and complication management; and (v) infection incidence and management. In this study, treatment‑related hospitalizations refer specifically to inpatient admissions required to complete multi‑day treatment administration, rather than admissions driven by disease progression or toxicity. Resource use was estimated per cycle and stratified into induction (cycle 1) and consolidation (cycles 2–6), with route‑specific aggregation reflecting typical Spanish practice: five cycles for IV decitabine and oral DEC‑C, aligned with the median number of treatment cycles received by patients in the pivotal oral DEC‑C clinical trial, and six for SC azacitidine, in alignment with PETHEMA recommendations on response timing for SC azacitidine [ 14 , 17 ]. Data sources The model integrated two types of data: 1) primary data, collected through a structured survey targeting healthcare professionals (HCP) directly involved in HMA delivery and supportive care in AML patients; 2) secondary data from Spanish hospital tariffs for unit costs. Together, these inputs determined route‑specific resource use per cycle and allowed estimation of whole‑treatment costs for each modality. Primary data were obtained through a structured survey conducted between March and May 2025–30 healthcare professionals across 16 hospitals in Spain. The sample included equal numbers of hematologists, nurses, and hospital pharmacists. Respondents were required to have direct responsibility for prescribing, preparing, dispensing, or administering HMAs. Respondents reported cycle-specific estimates of treatment workflows, professional time requirements, catheter-related procedures, hospitalization patterns, ambulance use, and infection management pathways. Narrative descriptions of workflows were collected to contextualize quantitative inputs and validate internal consistency. Follow-up calls were conducted to reconcile discrepancies. These items informed the domain‑specific resource quantities used in the model, which were subsequently monetized using unit costs derived from official Spanish hospital tariffs and the eSalud database for consumables, staff time, bed-days, and transport [ 18 , 19 ]. All unit costs are expressed in euros (€) at 2024 values and can be consulted in S1 Table . Assumptions and attribution rules Model assumptions were defined a priori to isolate the effect of administration route. Cycle length was fixed at 28 days across routes; dosing‑day counts, and route‑specific cycle totals reflected Spanish practice and served only to structure aggregation of resources. For catheter use, only the subset of IV‑treated patients requiring central access for drug delivery was attributed to the administration route; catheter use in SC or oral cohorts, when present, was considered background to transfusion or other supportive‑care needs. Infection incidence was apportioned to hospital access, catheter exposure and patient‑related etiologies according to the survey and was managed in ambulatory or inpatient settings consistent with national practice. Oral administration was modeled as requiring minimal observation and no infusion chair occupancy. Hospitalization probabilities were assumed to be highest in induction and lower thereafter for all routes, according to data from the survey and consistent with published data [ 20 ]. These attribution rules were designed to ensure that differences in costs and operational burden across routes reflect administration‑driven mechanisms rather than underlying clinical heterogeneity. Sensitivity and scenario analyses To assess the robustness of the base-case results to parameter uncertainty and structural assumptions, three complementary analyses were conducted. First, a one-way deterministic sensitivity analysis (OWSA) individually varied 23 model parameters across plausible ranges while holding all other inputs at their base-case values. Ranges were derived from a prespecified hierarchy: empirical survey percentiles where available, ± 20% for tariff-sourced unit costs, ± 50% for cost items with documented regional heterogeneity, and analyst-proposed bounds for parameters lacking cycle-level survey data. The twelve most influential parameters and their tested ranges are reported in S4 Table . Second, a probabilistic sensitivity analysis (PSA) was conducted using second-order Monte Carlo simulation with 10,000 iterations. Twenty-two uncertain parameters were simultaneously sampled from parametric distributions: Beta distributions for probabilities and proportions, calibrated to survey-derived means and standard deviations using the method of moments where feasible, and Gamma distributions for cost inputs and staff salaries. Convergence was assessed by monitoring the running mean at progressive iteration milestones ( S5 Table ). Third, thirteen structural scenario analyses evaluated the impact of alternative clinical and methodological assumptions on the incremental non-drug cost ( S6 Table ). Scenarios addressed: (i) equalization of administration-related infection rates across routes; (ii) equalization of hospitalization probabilities, including scenarios in which all routes were assigned IV, SC, or population-weighted hospitalization rates; (iii) variation in catheter-use attribution and treatment duration; and (iv) a maximum conservative stress test combining the most unfavorable assumptions simultaneously. Drug acquisition costs were excluded from all uncertainty analyses, consistent with the base-case study design. Results are reported in Supporting Information ( S4 – S6 Tables ). Ethics statement This study used aggregated, non-identifiable information from healthcare professionals and publicly available tariffs; no patient-level data were collected, and no ethical approval was required. Where applicable, institutional approvals for survey activities were obtained. Moreover, the study was performed according to the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) practices. Results Model input parameters Table 1 summarizes the parameterization used to quantify route‑dependent resource use. All administration pathways followed a 28‑day cycle structure. Route‑specific treatment days were 5 for oral and IV and 7 for SC, with whole‑course cycle totals of 5 (IV, oral) and 6 (SC). Days with drug preparation/dispensing – used as a proxy for hospital access – were highest for SC (7) and IV (5), and lowest for oral (1). Hospitalizations for treatment administration probabilities, derived from the HCP survey, were parameterized separately for induction (cycle 1: IV 50%, SC 40%, oral 20%) and consolidation (cycles 2 + : IV 30%, SC 20%, oral 10%). HCP reported that most patients received HMA through SC route (73%), followed by IV (20%) and oral (7%). The probability of having a central venous catheter was higher for patients on IV treatment (77%) than for those on SC (44%) or oral (23%) alternatives. For the model, we assumed that the difference in catheter use between SC users – who account for most of AML unfit patients – and the IV ones (33%) could be attributed to the IV administration route. HCP reported that 44% of patients developed a moderate or severe infection during treatment, of which 21% from the catheter (9% weighted incidence), 35% from visits to the hospital (16% weighted incidence), 22% related to other pathologies, and 22% from other causes. In the model, infection risk was decomposed into catheter‑related and hospital‑access–related components, scaled by route‑specific visit frequency and use of catheter attributable to the administration route. Over the full course, weighted treatment‑related infection risks were IV 25%, SC 22%, and oral 3%. Download: PNG larger image TIFF original image Table 1. Model input parameters. https://doi.org/10.1371/journal.pone.0358426.t001 Healthcare professionals time Table 2 summarizes the total minutes dedicated by HCP for activities related to catheter management and drug preparation, dispensing and/or administration, and the respective estimated cost. The detailed time reported by HCP in the survey per sub-activity and segregated by HCP type is presented in S2 and S3 Tables . Download: PNG larger image TIFF original image Table 2. Healthcare professionals’ time and cost per activity, patient and cycle. https://doi.org/10.1371/journal.pone.0358426.t002 Whole-treatment non-drug costs Across the entire treatment course, non‑drug direct costs per patient were €9,998 for IV, €12,177 for SC, and €1,306 for oral administration ( Table 3 ). These totals were composed of drug administration costs of €957, €1,323, and €23 respectively; treatment‑related hospitalization of €6,042, €6,966, and €711; ambulance transport of €1,521, €2,808, and €418; infection management of €1,220, €1,080, and €154; and catheter management attributable to IV route of €257. In cycle 1, non‑drug totals were €2,564 (IV), €2,781 (SC), and €831 (oral). Hospitalization dominates parenteral costs in cycle 1 because of higher admission shares and multi‑day dosing. For cycles 2 + , per‑cycle non‑drug totals were €1,858 (IV), €1,879 (SC), and €119 (oral), reflecting persistent multi‑day dosing for parenteral delivery and minimal on‑site needs for oral dispensation. Download: PNG larger image TIFF original image Table 3. Estimated cost per patient per administration modality, type of cost and cycle. https://doi.org/10.1371/journal.pone.0358426.t003 Operational and organizational outcomes Route‑attributable professional minutes required for drug administration were lower for oral therapy as shown in Table 4 . Over the full course, IV and SC administration required approximately 2,476 and 3,040 minutes per patient, respectively, compared with 62 minutes for oral DEC‑C. When catheter‑management time was included, IV rose by roughly 248 minutes to a combined 2,724 minutes, whereas SC and oral remained essentially unchanged. Treatment‑related inpatient days were approximately nine for IV and ten for SC, compared with about one day under the oral route. Infection‑related hospital days added roughly two to three days for parenteral routes and were near zero for oral therapy, yielding about eleven to twelve total route‑attributable hospital days for IV/SC and one day for oral. Ambulance transports followed the dose‑day structure and admission patterns: when aggregated over the entire treatment course and expressed per patient, the model estimated a mean of approximately five round‑trip ambulance transports for IV therapy, nine for SC therapy, and between one and one point four for oral therapy, reflecting the substantially lower need for facility‑based administration with oral treatment. Download: PNG larger image TIFF original image Table 4. Operational resource use per patient (whole treatment course). https://doi.org/10.1371/journal.pone.0358426.t004 Sensitivity and scenario analyses Full results of the sensitivity and scenario analyses are presented in Supporting Information ( S4 – S6 Tables ). Oral DEC‑C remained less costly than both IV decitabine and SC azacitidine in all 46 one-way parameter variations tested in the one-way deterministic sensitivity analysis ( S4 Table ). The m
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