Patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy usually receive azacitidine or decitabine with venetoclax. The hypomethylating agent (HMA) component needs repeated visits for injections or infusions, and monitoring, transfusions, and complications add more. Time spent in care is now treated as a cost of therapy, often called time toxicity.
A real-world analysis of patients receiving parenteral HMAs with venetoclax measured this burden, and the phase I/II ASCERTAIN-V trial evaluated an all-oral alternative: oral decitabine-cedazuridine plus venetoclax, approved by the US FDA earlier this year (Zeidan et al., 2026; Roboz et al., 2026). Oral HMA formulations are now being developed across several myeloid malignancies. The two studies address complementary questions and can’t show how oral and injectable treatment differ in healthcare utilization, survival, or quality of life.
The Time Demands of HMA-Venetoclax Treatment
The phase III VIALE-A trial showed improved overall survival with azacitidine plus venetoclax over azacitidine alone. Azacitidine is generally given over seven days of a 28-day cycle and intravenous decitabine over five days, venetoclax is oral.
Visits are most frequent early, when patients need close monitoring for cytopenias, infections, and response, and transfusions and hospitalization may follow. These demands often continue after remission until disease progression or unacceptable toxicity, though schedules may be modified to allow hematologic recovery. For older patients with comorbidities, repeated appointments also create transportation difficulties, caregiver demands, and interruptions to daily life. This time toxicity captures a practical aspect of therapy.
Real-World Study: Healthcare Utilization in 737 Patients
Amer Zeidan and colleagues conducted a retrospective cohort study in the Humana Healthcare Research Database, which holds medical and pharmacy claims from patients across the United States, predominantly Medicare Advantage beneficiaries.
Population: 737 adults with newly diagnosed AML who started parenteral azacitidine or decitabine with venetoclax between October 2020 and June 2024.
Characteristics: median age 76 years, about 70% on azacitidine, more than one-third with prior myelodysplastic syndromes.
Follow-up: median eight months.
Encounters were classified as inpatient admission, emergency department visit, outpatient treatment administration, transfusion support, or other outpatient care, with each calendar day counted once by the most intensive encounter. Time outside acute or cancer-related care was the proportion of days without a qualifying encounter. It doesn’t show whether patients were at home or how they felt.
Results: Nearly 12 Days per Month in Healthcare
Patients averaged 11.9 healthcare days per month, 8.2 outpatient and 3.4 inpatient. About 3.2 outpatient days were HMA administration and about one was transfusion support. The rest were other AML-related and non-AML care.
Injections and infusions therefore made up a meaningful share, but most visit days came from other parts of disease management, so removing parenteral administration would reduce clinic attendance without removing the need for monitoring, transfusions, or hospitalization. In the first six months, patients averaged 12.9 days per month.
Time Outside Cancer-Related Care
Patients spent about 65% of follow-up outside acute or cancer-related care. The share rose from about 50% in the first month to nearly 70% by month six, largely with fewer HMA administration and inpatient days. Patients who died or lost insurance eligibility dropped out of later monthly estimates, so the rise can’t be interpreted entirely as clinical improvement. The analysis had no data on fatigue, physical function, or quality of life, and time away from facilities isn’t necessarily time spent feeling well.
Azacitidine Versus Decitabine
Utilization was similar despite different schedules: 12.0 days per month with azacitidine and 11.8 with decitabine. The difference in schedule length was small next to hospitalizations, transfusions, and other outpatient care. Treatment wasn’t randomized, so this doesn’t show equivalent patient experience or outcomes.
Treatment Persistence
Median time to discontinuation or death was 5.2 months counting all administered cycles, and 2.8 months counting only cycles that met predefined criteria for HMA administration and venetoclax supply. After remission, venetoclax duration and HMA schedules are often adjusted to limit cytopenias, so a cycle outside the criteria may reflect appropriate management.
The claims data couldn’t show response, toxicity, or progression, and lacked molecular risk, remission status, measurable residual disease, and physician-assessed adverse events. The findings describe delivery in routine practice, not the reasons for individual discontinuations.
Oral Hypomethylating Agents
The time demands give a rationale for oral alternatives. Oral decitabine is extensively degraded before absorption, which limits systemic exposure. Cedazuridine, a cytidine deaminase inhibitor, blocks this degradation, so oral decitabine reaches exposure comparable to intravenous administration.
Oral decitabine-cedazuridine (INQOVI, Taiho Oncology) was first approved in the United States for myelodysplastic syndromes and chronic myelomonocytic leukemia. Pairing it with venetoclax, already oral, could remove routine HMA injection or infusion visits while keeping the principle of combining an HMA with BCL-2 inhibition.
Other formulations are in development, and each formulation’s role depends on evidence specific to its disease and setting:
- Oral decitabine-cedazuridine (INQOVI): studied with venetoclax in newly diagnosed AML.
- Oral azacitidine-cedazuridine (ASTX030): in the phase III AZTOUND trial in myelodysplastic syndromes and chronic myelomonocytic leukemia, which has met its primary pharmacokinetic endpoint.
- Oral azacitidine (ONUREG): approved as maintenance after intensive induction in selected AML patients.
ASCERTAIN-V: An All-Oral Regimen in Newly Diagnosed AML
ASCERTAIN-V, published in The New England Journal of Medicine in June 2026, was a multicenter, open-label, nonrandomized trial; enrolled 189 patients across three development phases at 34 centers in the United States, Canada, and Spain. Patients had newly diagnosed AML and were at least 75 years old or had comorbidities precluding intensive induction chemotherapy. They received oral decitabine-cedazuridine on days 1-5 of a 28-day cycle with oral venetoclax. Schedules were modified during development to address prolonged myelosuppression.
Remission and Survival
In the pivotal phase IIb cohort of 101 patients, 47% achieved complete remission, meeting the prespecified primary efficacy criterion, and 63% achieved complete remission or complete remission with incomplete hematologic recovery.
Median overall survival was 15.5 months at a median follow-up of 11.2 months, and an estimated 75% of patients in complete remission had an ongoing response at 12 months. Pharmacokinetic analyses found no clinically relevant interaction between decitabine-cedazuridine and venetoclax. These results establish clinical activity in patients ineligible for intensive chemotherapy.
Myelosuppression and Schedule Adjustments
In the phase IIb cohort, grade 3 or higher anemia occurred in 30%, neutropenia in 26%, and febrile neutropenia in 25%. In earlier phases, prolonged venetoclax exposure delayed hematologic recovery and led some patients to discontinue. Investigators then introduced more flexible dosing after marrow blast clearance, shortening venetoclax and decitabine-cedazuridine and timing the next cycle by early marrow assessment.
Mean venetoclax administration fell from 23.9 days in cycle 1 to 17.5 days by cycle 3, and serious adverse events and febrile neutropenia became less frequent in later cycles among patients continuing therapy. The nonrandomized design can’t show how much of this came from dosing changes. Patients still needed close monitoring and supportive care, including attention to venetoclax interactions with azole antifungals.
FDA Approval
On May 13, 2026, the FDA approved oral decitabine-cedazuridine with venetoclax for adults with newly diagnosed AML who are 75 years or older or have comorbidities precluding intensive induction chemotherapy. The decision rested on ASCERTAIN-V, with the regulatory assessment emphasizing complete remission and remission duration, and made this the first FDA-approved all-oral regimen for this population.
ASCERTAIN-V didn’t prospectively measure healthcare utilization or patient-reported quality of life, and didn’t compare oral with parenteral administration. Since only part of the burden comes from administration visits, this gap matters.
Measuring the Patient Experience
AML trials have emphasized remission, survival, and adverse events, which remain essential but say little about time in care. An oral regimen may reduce scheduled appointments, but its effect on total utilization will depend on cytopenias, infections, transfusion needs, disease control, adherence, and access to monitoring. Fewer administration visits don’t mean fewer complications or lighter follow-up.
Prospective studies could measure healthcare visit days, hospital-free days, time outside cancer-related care, treatment satisfaction, and caregiver burden alongside efficacy. Patient-reported measures are especially needed. For older patients on prolonged lower-intensity therapy, keeping disease control while spending less time in facilities is a clinically relevant goal.
References
- Zeidan AM, Zhao R, Voegel A, et al. Time burden and treatment patterns of patients with newly diagnosed acute myeloid leukemia receiving parenteral hypomethylating agents in combination with venetoclax. Leukemia & Lymphoma. Published October 28, 2026. DOI: 10.1080/10428194.2026.2726604.
- Roboz GJ, Zeidan AM, Mannis GN, et al. All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia. New England Journal of Medicine. 2026;394:2107–2116. DOI: 10.1056/NEJMoa2510223.
