Can an All-Oral HMA Regimen Change Frontline Care in Unfit AML?

Just weeks after the FDA approved an all-oral regimen for newly diagnosed acute myeloid leukemia (AML), a panel of leukemia specialists met to discuss how it should be used. The question they took up was whether swapping an injectable hypomethylating agent (HMA) for a pill would make frontline therapy easier for older and unfit patients, or easier to get wrong.

That was the focus of a recent Frontline Forum held during the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. Hematologists from academic centers across the US reviewed the evolving landscape of lower-intensity therapy for patients who are ineligible for intensive chemotherapy, along with what it takes to deliver that therapy safely in inpatient, outpatient, and community settings.

The panel was led by Amer Zeidan, MBBS, MD, a professor of internal medicine and chief of the Division of Hematologic Malignancies at Yale Comprehensive Cancer Center in New Haven, Connecticut. He was joined by Marlise Luskin, MD, MSCE, an associate professor of medicine at Harvard Medical School, education director for the Adult Leukemia Program at Dana-Farber Cancer Institute, and associate program director of the Dana-Farber/Mass General Brigham Hematology/Oncology Fellowship Program in Boston, Massachusetts; Naval Daver, MD, professor, co-section head of AML, and director of the Leukemia Research Alliance Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston; Courtney DiNardo, MD, MSCE, a professor in the Department of Leukemia and Division of Cancer Medicine at MD Anderson; Nicholas J. Short, MD, an associate professor and associate program director in the Department of Leukemia at MD Anderson; Musa Yilmaz, MD, an associate professor in the Department of Leukemia and Division of Cancer Medicine at MD Anderson; Jorge Cortes, MD, chief of hematology in the Division of Hematology and Oncology at the University of Alabama at Birmingham (UAB) and deputy director of the O’Neal Comprehensive Cancer Center at UAB; Jamie L. Koprivnikar, MD, a hematologist-oncologist in the Division of Leukemia at John Theurer Cancer Center at Hackensack University Medical Center in New Jersey; and Michael R. Savona, MD, head of Hematology, Cellular Therapy, and Stem Cell Transplantation, Beverly and George Rawlings Director of Hematologic Malignancies Research, and a professor of medicine and cancer biology at Vanderbilt University Medical Center in Nashville, Tennessee.

Defining Intensive Chemotherapy Ineligibility

Zeidan opened by asking whether anyone uses a validated tool to decide who is fit for intensive induction. The answer around the table was no. Most clinicians still rely on what Zeidan called “the eyeball test.”

At MD Anderson, patients older than 60 years are generally steered toward lower-intensity combinations, except those with core binding factor AML, DiNardo explained. That is partly because the center’s intensive induction pairs chemotherapy with venetoclax (Venclexta), which can be harder on older patients than standard 7+3. Daver estimated that 60% to 70% of patients older than 60 years at MD Anderson receive lower-intensity combinations or triplets. However, he said those decisions remain individualized, with mutations such as RAS, PTPN11, NPM1, or core binding factor rearrangements sometimes tipping patients toward intensive chemotherapy.

“What’s evolved is this idea that if you get over 60 or 65 years of age, the vast majority of people who don’t have these activating mutations are getting hurt with chemotherapy,” Savona said. “You can do so well with these low-intensity regimens and now add other drugs to them and squeeze out a lot of benefit.”

Luskin framed the decision around the full treatment plan. For patients aged 60 to 65 years who are headed to transplant, she avoids intensive therapy that could erode performance status before they meet the transplant team. Short added that it took time for his group to stop inducing young, fit patients with TP53-mutated or complex karyotype disease. That shift came because outcomes were no better than with an HMA plus venetoclax as a bridge to transplant.

Several panelists warned that the trend toward lower-intensity therapy is already showing up in community practice, sometimes inappropriately. “We’re already getting referrals of people who are refractory to HMA [plus venetoclax] that never should’ve gotten [it],” DiNardo said. Cortes noted wide variation between institutions in how readily patients are labeled unfit.

The panel also anticipated that the phase 2 PARADIGM trial (NCT04801797), which Zeidan led, would accelerate HMA/venetoclax use in younger patients. Daver stressed that 60% of patients in that study went to transplant.¹ “If you do this in your community hospital without transplant, the outcomes will be very, very different,” he said.

Current Standard of Care

Zeidan noted that roughly 15 agents are now approved in AML. The most recent is oral decitabine/cedazuridine (DEC-C; Inqovi) in combination with venetoclax, approved by the FDA on May 13, 2026. The approval covers adults with newly diagnosed AML who are 75 years or older or who have comorbidities that preclude intensive induction.²

Under NCCN guidelines, azacitidine (Onureg) plus venetoclax is a preferred category 1 regimen for intensive chemotherapy–ineligible AML. Azacitidine plus ivosidenib (Tibsovo) holds the same status for IDH1-mutated disease.³ Zeidan observed that the guidelines list many other options, which matters chiefly because the listings support insurance approval.

VIALE-A

At a median follow-up of 43.2 months in the phase 3 VIALE-A trial (NCT02993523), the median overall survival (OS) was 14.7 months (95% CI, 11.9-18.7) with venetoclax plus azacitidine vs 9.6 months (95% CI, 7.4-12.7) with placebo plus azacitidine (HR, 0.58; 95% CI, 0.47-0.72; P <.001).⁴ Complete response (CR) rates were 38.8% (95% CI, 33.1%-44.7%) vs 17.9% (95% CI, 12.1%-25.2%), and CR/CR with incomplete hematologic recovery (CRi) rates were 66.8% (95% CI, 61.0%-72.2%) vs 29.0% (95% CI, 21.7%-37.1%), respectively. In the venetoclax arm, patients who achieved measurable residual disease (MRD) negativity had a median OS of 34.2 months (95% CI, 27.7-44.0) vs 18.7 months (95% CI, 12.9-23.5) for those who did not.

Zeidan noted that outcomes favored patients with IDH or NPM1 mutations, while those with TP53 or FLT3 alterations derived less benefit.

AGILE

In long-term follow-up of the phase 3 AGILE trial (NCT03173248), the median OS was 29.3 months (95% CI, 13.2-not reached [NR]) with ivosidenib plus azacitidine vs 7.9 months (95% CI, 4.1-11.3) with placebo plus azacitidine at a median follow-up of 28.6 months.⁵ The CR rates were 47% vs 15%, and the MRD negativity rate with the combination was 30.3%. DiNardo noted that MRD in AGILE was assessed by IDH1 digital droplet polymerase chain reaction rather than flow cytometry, so it cannot be compared directly with VIALE-A.

When Zeidan asked whether panelists would choose azacitidine plus ivosidenib over azacitidine plus venetoclax for a patient with an IDH1 mutation, Savona said he would, saving venetoclax for later. DiNardo said most centers at the table use a triplet instead, although she considers azacitidine plus ivosidenib the best doublet choice when community clinicians ask. Daver pointed to emerging retrospective data suggesting that patients who receive azacitidine plus ivosidenib first can often be salvaged with azacitidine plus venetoclax, whereas the reverse is less effective.

Luskin highlighted a practical advantage of the ivosidenib doublet. “There’s a little less art involved,” she said. “In terms of the community practices, in terms of when you should space out cycles, when you should dose reduce [venetoclax]… there’s less of that that needs to happen with azacitidine [plus ivosidenib].”

Real-World Data

Real-world analyses largely mirrored the trials, Zeidan explained. In the multicenter ARC Initiative, the median duration of response (DOR) was 11.0 months (95% CI, 8.8-15.2) among patients who were ineligible for intensive chemotherapy and received venetoclax.⁶ Most of these patients (75.9%) received venetoclax plus azacitidine, and 68.1% received antifungals in cycle 1. Granulocyte colony-stimulating factor was given to 44.8%, and 87.1% had a dose hold before the next cycle. None of these modifications compromised DOR. In an analysis of 331 patients in the COTA real-world database, the median real-world OS with first-line venetoclax-based therapy was 13.9 months.⁷

Koprivnikar said the survival figures matched her experience, but she flagged adherence as a growing concern. “Making sure that your patient can take their [venetoclax] religiously, but if they’re not taking their posaconazole [Noxafil], they’re underdosing by 75%,” she said. Zeidan agreed that missed antifungal doses go unnoticed even at large centers.

Savona described a less common practice: he withholds antifungal prophylaxis during the first cycle for patients with newly diagnosed AML to avoid uncertainty about how azoles affect venetoclax exposure. He cautioned that such nuances are hard to carry into community care. “This is the problem when you go to this all-oral thing, when we’re really not having the supervision and people feel comfortable,” he said.

The All-Oral Option: ASCERTAIN-V

The FDA approval of decitabine plus cedazuridine was based on the phase 1/2 ASCERTAIN-V trial (NCT04657081), in which 101 patients received DEC-C on days 1 to 5 plus venetoclax with a standard ramp-up to 400 mg daily.^8,9

At a median follow-up of 11.2 months, the CR rate was 46.5% (95% CI, 36.5%-56.7%), and the CR/CRi rate was 63.4% (95% CI, 53.2%-72.7%), with a median time to CR of 2.4 months. The median CR duration was NR, and 75.3% of responders remained in CR at 12 months. The median OS was 15.5 months (95% CI, 7.6-not estimable). The FDA’s independent review reported a CR rate of 41.6% (95% CI, 31.9%-51.8%).

Grade 3 or higher adverse effects (AEs) occurred in 98.0% of patients. The most common were febrile neutropenia (49.5%), anemia (38.6%), and neutropenia (35.6%). Mortality rates were 3.0% at 30 days and 9.9% at 60 days.

Zeidan characterized the regimen as broadly equivalent to azacitidine plus venetoclax in efficacy and safety. However, DiNardo noted that the trial’s 3 sequential cohorts told a story about management. “The phase 1A was when we were very rigorous about everyone [getting] 28 days [of treatment] and everyone [getting] the [end-of-cycle] marrow…and then it became more flexible as time went on,” she said. “Response rates [and] survival improved.”

Several panelists suggested the regimen may outperform its framing as a simple substitute. Daver noted that the population appeared enriched for higher-risk disease because centers were routing patients with targetable mutations to triplet trials. Savona said studies with cedazuridine have consistently shown survival above historical HMA expectations. Durability also drew attention. “The median DOR [on VIALE-A] was 17 or 18 months,” DiNardo said. “This is only at 12 months, but it sure looks like it’s going to beat that.”

Zeidan described his longest-treated patient on the trial: an 83-year-old woman who has remained in CR for nearly 3.5 years. She now takes 5 days of venetoclax and 2 days of DEC-C every 8 weeks.

That kind of de-escalation is essential, panelists stressed. “You have to dose reduce, and you have to dose reduce earlier than you would either standard [intravenous azacitidine] or decitabine,” DiNardo said. Daver added that prolonged myelosuppression with oral decitabine means cytopenias should not be attributed to venetoclax alone. Both cautioned about adding a third agent to an oral decitabine backbone.

Even so, Daver expects rapid adoption. “Already 70% have all moved to oral HMA-[venetoclax],” he said of frontline trials at MD Anderson. “For now, I think this is going to replace the [intravenous] HMA.”

Treatment Burden and Implementation

Zeidan presented an analysis showing that patients receiving injectable HMA-based therapy spend about 13 days per month in health care settings.¹⁰ He also shared a survey of patients with myelodysplastic syndromes that showed a preference for oral decitabine.¹¹ He framed the stakes in simple terms; with a median OS of about 15 months, 7 days of azacitidine each month consumes roughly a quarter of a patient’s remaining time.

Panelists agreed, however, that an oral regimen does not eliminate visits. “Clearly, they still need [to visit] twice a week at least [for] blood work,” Zeidan said, along with transfusion support, an early bone marrow assessment around day 21, and active venetoclax management. Luskin tells patients the oral regimen saves them daily infusion visits, but not the 2 to 3 visits per week for labs and transfusions.

Savona and Cortes expressed concern that the oral format could lead community practices to hold onto patients longer with less monitoring. “It gives the impression that it’s just easy and you can just give it, but they’re not being monitored,” Cortes said. “You just do the prescription and see [them] in a month.” DiNardo described a 45-year-old patient with NPM1- and RAS-mutated AML who developed tumor lysis syndrome requiring dialysis after starting HMA/venetoclax in the community.

Access in the inpatient setting is another barrier. “If you don’t have these in formulary, you cannot start oral [therapy] in the hospital,” Cortes said. He predicted many centers will give a first cycle of intravenous azacitidine plus venetoclax and then switch to the oral regimen. Luskin described doing exactly that for a patient admitted that week.

Key Takeaways

Asked for final thoughts, panelists returned to education and referral.

“HMA [plus venetoclax] is very quickly going to be the induction therapy of choice for all patients, whether we like it or not,” DiNardo said. “Making sure that we’re still communicating as best we can with the community oncologist, and helping to make sure that they are referring patients to transplant and using oral HMAs smartly, is going to be a big thing.”

Daver urged that every eligible patient receive a transplant consultation. “Even if you start in the community, do not forego the transplant,” he said. He also called for prescriptive, table-based guidance that advanced practice providers and nurses can follow.

Yilmaz highlighted the maintenance advantage for older patients who will not undergo transplant. “That’ll allow them to take an oral regimen like you [would take] a blood pressure pill,” he said. Luskin pointed to an underappreciated problem: incomplete records of which oral doses patients received when they arrive for second opinions.

“The regimen is great, and the approach is fantastic,” Cortes said, “But it is going to take a whole lot of re-education of the community because now it’s starting to feel like, ‘Oh, I could treat AML anywhere.’”

References

1. Fathi AT, Perl AE, Fell GG, et al. Azacitidine-venetoclax or induction chemotherapy for acute myeloid leukemia. N Engl J Med. 2026;395(9):845-858. doi:10.1056/NEJMoa2602804
2. FDA approves oral combination of decitabine and cedazuridine tablets with venetoclax for newly diagnosed acute myeloid leukemia. News release. FDA. May 13, 2026. Accessed October 5, 2026. https://tinyurl.com/mt9jcpw9
3. NCCN. Clinical Practice Guidelines in Oncology. Acute myeloid leukemia, version 5.2026. Accessed October 5, 2026. https://tinyurl.com/mva2ceu3
4. Pratz KW, Jonas BA, Pullarkat V, et al. Long-term follow-up of VIALE-A: venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol. 2024;99(4):615-624. doi:10.1002/ajh.27246
5. Montesinos P, Marchione DM, Recher C, et al. Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML. Blood Adv. 2025;9(20):5177-5189. doi:10.1182/bloodadvances.2025016399
6. Wolach O, Desai P, Chen EC, et al. Real-world patient management practices in responders to venetoclax for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2025;43(suppl 16):6527. doi:10.1200/JCO.2025.43.16_suppl.6527
7. Lachowiez CA, Barcellos A, Zettler CM, et al. Treatment patterns and real-world outcomes of molecular subgroups in patients with AML receiving frontline venetoclax-based therapy. JCO Oncol Pract. 2026;22(1):66-73. doi:10.1200/OP-24-00983
8. FDA approves oral combination of decitabine and cedazuridine tablets with venetoclax for newly diagnosed acute myeloid leukemia. News release. FDA. May 13, 2026. Accessed October 5, 2026. https://tinyurl.com/ykk7yhfz
9. Zeidan AM, Griffiths EA, Dinardo CD, et al. An all-oral regimen of decitabine-cedazuridine (DEC-C) plus venetoclax in patients with newly diagnosed AML ineligible for intensive induction chemotherapy: results from a phase 2 cohort of 101 patients. J Clin Oncol. 2025;43(suppl 16):6504. doi:10.1200/JCO.2025.43.16_suppl.6504
10. Zeidan AM, Wang Y, Yu R, Matusevich, Zhao R. Real-world characteristics, treatment modifications, and outcomes for patients with acute myeloid leukemia (AML) receiving hypomethylating agents (HMA) + venetoclax (VEN) as first-line treatment (1L). Blood. 2025;146(suppl 1):8176. doi:10.1182/blood-2025-8176
11. Zeidan AM, Perepezko K, Salimi T, Washington T, Epstein RS. Patients’ perspectives on oral decitabine/cedazuridine for the treatment of myelodysplastic syndromes/neoplasms. Ther Adv Hematol. 2024;15:20406207241257313. doi:10.1177/20406207241257313