Oral therapies for unfit patients with acute myeloid leukemia

Since the VIALE‑A study, the combination of an HMA (azacitidine [AZA] or decitabine [DEC]) with the BCL2 inhibitor venetoclax (VEN) has been the standard AML therapy for older/unfit patients with AML [4]. The dual therapy resulted in a significant survival advantage compared to monotherapy (14.7 months vs. 9.6 months). Recently, the dose and the duration of VEN therapy (in the VIALE‑A study: 400 mg for 28 days) have been critically examined, as a shorter therapy regimen (7, 14, or 21 days) is associated with a comparable complete remission (CR) rate but has a more favorable side effect profile [5]. These data are from retrospective analyses. Prospective studies comparing this are currently underway and will provide clarity and could lead to optimization of the therapy in the future.

Long-term data from the VIALE‑A study (43.2 months median follow-up) showed a median OS of 14.7 months (95% confidence interval [CI]: 12.1–18.7) in the combination arm vs. 9.6 months (95% CI: 7.4–12.7) with placebo AZA [6].

Oral decitabine-cedazuridine (oDEC-C) has been approved by the European Medicines Agency (EMA) as monotherapy for newly diagnosed AML patients who do not qualify for standard induction chemotherapy. The phase 3 ASCERTAIN study showed that the total area under the curve (AUC) equivalence of decitabine administered orally over 5 days corresponds to the IV dose (90% CI between 80% and 125%; [7]).

In addition to the combination of VEN + HMA, glasdegib, a small molecule inhibitor of the hedgehog signaling pathway, is approved in combination with low-dose Ara‑C as first-line therapy. The BRIGHT AML 1003 study showed a significant OS benefit in patients receiving dual therapy (8.8 months vs. 4.9 months), but a significantly worse OS compared to the VIALE‑A study [8]. However, the phase 3 BRIGHT AML 1019 trial, where glasdegib was added to either cytarabine and daunorubicin (intensive therapy-eligible patients) or azacitidine (unfit patients), did not show any OS benefit [9]. Therefore, glasdegib no longer has a role in the first-line treatment of AML and is often listed as a therapy option with minor priority.

Before any therapy is started, molecular genetic testing must be performed and the results should be awaited. This information is important not only for the prognosis, but also for deciding on the first-line therapy: In summary, approximately 30% of patients have mutations relevant to therapy: (1) IDH1 inhibition in mIDH1 mut. (7–14%), (2) FLT3 inhibition (~20%; [10]).

In patients with an IDH1 R132 mutation, first-line therapy with the oral IDH1 inhibitor ivosidenib (IVO) in combination with an HMA can also be initiated. The phase 3 AGILE study investigated IVO in combination with AZA vs. AZA + placebo in newly diagnosed AML patients who are not eligible for intensive standard induction chemotherapy [11]. The primary endpoint was defined as event-free survival (including time from randomization until treatment failure, i.e., the patient did not have complete remission by week 24; relapse from remission; or death from any cause) and was achieved in significantly more patients with the dual therapy. The long-term OS data from the AGILE study were recently published (median follow-up of 28.6 months), with median OS in the IVO arm being 29.3 months compared to 7.9 months with placebo [12].

There is no direct randomized comparison between VEN + HMA vs. IVO + HMA in the first-line setting based on a prospective study. Retrospective analyses with real-world data showed that IVO + HMA therapy is superior to HMA therapy in terms of CR rate [13]. Olutasidenib is another IDH1 inhibitor that is approved in the United States, but not yet in Europe, for relapsed/refractory (r/r) AML with IDH1 mutation.

If VEN + HMA therapy fails and FLT3 mutation is present, gilteritinib (GIL) can be prescribed as monotherapy in the second-line setting. The second-generation FLT3 inhibitor led to significantly prolonged survival compared to salvage chemotherapy (9.3 vs. 5.6 months; [14]). In the first-line setting, combination therapy with GIL + AZA did not result in any survival benefit [15]; testing of the triple combination (VEN + AZA + GIL) regimen is currently the subject of studies. Initial data from phase 1/2 studies indicate high efficacy [16].

An overview of the currently available oral therapy options and the standard regimen is provided in Table 1.

Oral HMA therapies are available, but currently with restrictions for the group of unfit patients with AML: Oral azacitidine (oAZA) is indicated for maintenance therapy in adults with AML who have achieved CR or CR with incomplete blood count recovery after induction therapy with or without consolidation therapy and who are not eligible for hematopoietic stem cell transplantation (HSCT), including those who have opted against it [17]. It is important to note that the bioavailability of oAZA differs significantly from that of parenteral AZA. The cycle duration of this therapy (14 days) is correspondingly longer for the indicated indication.

At EHA and ASCO 2025, the first data on the fully oral combination therapy (oDEC-C + VEN; ASCERTAIN‑V study) were presented [18]. This phase 1/2 clinical trial was designed to optimize the safety and efficacy of DEC-C + VEN therapy in patients with newly diagnosed AML aged ≥ 75 years or with comorbidities that preclude intensive first-line induction therapy. The side effect profile, effectiveness, and survival rates are consistent with those of the previous combination. To date, EMA approval for this completely oral therapy option is still pending. A decisive factor in whether this therapy will become established will be whether it proves to be cost-effective. Not only the price of the therapy itself, but also the associated costs for the healthcare system and the hospital as a resource must be taken into account here. In a study by Italian colleagues comparing the non-drug healthcare costs between intravenous and oral decitabine in AML patients, the cost analysis favored the oral formulation [19]. It must be noted, however, that these authors used a central venous catheter as standard for patients receiving intravenous administration. In Austria, AZA is mostly used, which can be administered subcutaneously, thus eliminating the need for a central catheter. Overall, comparability between countries is difficult due to different healthcare systems. In addition, no precise analysis for the comparison of costs in Austria is available.

The oDEC‑C option essentially offers the possibility of a fully oral therapy, and studies are currently investigating its efficacy. In parallel to the oDEC‑C, an oral combination of AZA and cedazuridine (ASTX030) has been developed. The substance is still under investigation, and preliminary results have been promising: The pharmacokinetic equivalence to the scAZA formulation has been reached (100% bioavailability of oAZA if 20 mg cedazuridine has been added) and the safety profile was similar to what we know from the subcutaneous formulation [20].

In addition to dual combinations, triplet combinations are also being tested. The new class of menin inhibitors should also be mentioned, representing an emerging oral therapy option in the management of AML patients who carry KMT2Ar or NPM1m [21]. The phase 1/2 AUGMENT-001 study led to the approval of this drug for r/r AML patients by the US Food and Drug Administration (FDA), while authorization in Europe is still pending. The recently published efficacy results from the phase 2 part of this study revealed an ORR of 46.9% [22]. Considering this heavily pre-treated patient population (≥ 3 previous lines of therapy in 35.9%, previous VEN in 75%), this is a significant improvement for r/r AML patients carrying the respective mutational profile.

In summary, acute myeloid leukemia (AML) therapy in 2025 is already partly oral. In particular, oral decitabine-cedazuridine may enable a fully oral therapy regimen in the future. Further substances such as menin inhibitors, oral azacitidine etc. are under development. Ultimately, it is important to discuss the advantages and disadvantages of the treatment with the patient, as well the personal responsibility involved, in order to pursue the concept of patient-centered care while maintaining adherence and safety.