CC-486 plus venetoclax: another step toward oral AML therapy

In this issue of Blood Advances, Amaya et al¹ report a phase 1/1b study of an all-oral regimen with CC-486 and venetoclax (Ven) in acute myeloid leukemia (AML), continuing the evolution of AML therapy toward all-oral regimens.

The development of azacitidine plus Ven (Aza-Ven) represented a major advance for older adults and medically unfit patients with AML, a population historically associated with poor outcomes and limited treatment options. Before Ven-based therapy, patients ineligible for intensive induction chemotherapy were treated with hypomethylating agents (HMAs), low-dose cytarabine, or best supportive care. HMA monotherapy produced modest responses, and median overall survival (OS) was <1 year. These limitations highlighted the need for combinations capable of producing deep and durable remissions without the toxicity of conventional induction therapy.

The rationale for Ven in AML arose from recognition that AML blasts and leukemic stem cells (LSCs) frequently depend on antiapoptotic BCL-2 signaling for survival. Ven selectively inhibits BCL-2, promoting mitochondrial apoptosis. Although Ven monotherapy demonstrated proof-of-concept activity in relapsed or refractory AML, its single-agent activity was more limited, with significant variability based on prognostic factors.² Preclinical studies revealed that combining Ven with Aza produced complementary effects on mitochondrial apoptosis and LSC metabolism. Aza-Ven inhibits amino acid metabolism and oxidative phosphorylation in LSCs, providing a biologic rationale for its clinical efficacy.³ The randomized phase 3 VIALE-A trial established Aza-Ven as a standard frontline regimen for newly diagnosed AML in patients aged ≥75 years or with comorbidities precluding intensive induction. Compared with Aza alone, Aza-Ven increased the complete remission plus complete remission with incomplete count recovery (CR/CRi) rate from 28.3% to 66.4% and prolonged median OS from 9.6 to 14.7 months.⁴

The development of oral decitabine/cedazuridine provides an important precedent for incorporating oral HMA therapy into frontline Ven-based treatment. Prospective studies have demonstrated the activity of oral decitabine/cedazuridine plus Ven in older or medically unfit patients with AML. In May 2026, the US Food and Drug Administration approved the combination for adults with newly diagnosed AML who were at least 75 years old or had comorbidities precluding intensive induction, based on a single-arm study demonstrating an overall response rate (ORR) of 64% in the frontline cohort and durable responses.^5,6 These data support oral HMAs in frontline AML and not solely maintenance.

The CC-486 formulation of oral Aza is currently approved as a maintenance therapy in AML. The phase 3 QUAZAR AML-001 trial randomized 472 patients aged ≥55 years in first remission who were not candidates for transplantation at enrollment. Oral Aza maintenance significantly prolonged median OS from 14.8 months with placebo to 24.7 months and prolonged median relapse-free survival from 4.8 to 10.2 months.⁷ These findings established oral Aza maintenance for patients ineligible for transplantation in first remission.

The CC-486 formulation has a different pharmacokinetic and pharmacodynamic profile than standard subcutaneous or IV Aza, and the 2 are not directly interchangeable. An alternative oral formulation, Aza/cedazuridine, has demonstrated comparable total cycle Aza exposure area under the curve (AUC) to subcutaneous Aza in a recent phase 2 study, and the ongoing AZTOUND trial (ClinicalTrials.gov identifier: NCT04256317) is evaluating this formulation alone and in combination with Ven in participants with treatment-naive AML.^8,9

In this single-center phase 1/1b study, Amaya et al evaluate a fully oral regimen incorporating CC-486. Using an initial 3+3 design followed by cohort expansion, this study enrolled 35 patients considered unfit for intensive induction therapy, including 19 with relapsed or refractory AML and 16 newly diagnosed. In the dose-escalation phase, patients received CC-486 at either 200 or 300 mg on days 1 to 14 with standard-dose Ven. In the expansion phase, patients were treated with 300 mg CC-486 daily on days 1 to 14. Cycles were 42 days, with a 28-day treatment course followed by a 14-day window for count recovery.

The primary end point was ORR. Among patients with relapsed or refractory AML, the ORR was 32%, including complete remission in 3 patients (16%). The ORR was 63% for newly diagnosed patients, including 8 complete remissions (50%). Furthermore, 6 patients were successfully bridged to allogeneic transplantation: 2 in the newly diagnosed cohort and 4 with relapsed or refractory disease. Complete remission was also achieved in 4 of the 6 (67%) newly diagnosed patients with TP53-mutated AML, an encouraging observation in a population for whom effective treatment options remain limited. The authors noted that responses in the newly diagnosed cohort appeared broadly consistent with results from the VIALE-A study with respect to response rates, progression-free survival, OS, and minimal residual disease negativity. The results for patients with relapsed or refractory disease remained similar to standard Aza-Ven in this setting. Correlative analysis, including sequencing and metabolomics, appeared consistent with that of previous studies of traditional Aza-Ven and suggested that this regimen targets LSCs by disrupting complex II activity and oxidative phosphorylation, although this testing was performed on limited (n = 2) patient samples.

The regimen was generally well tolerated, without dose-limiting toxicities in either cohort. The adverse effect profile was overall similar to that of Ven and conventional Aza. The most common nonhematologic toxicity was nausea; however, this was largely mitigated with prophylactic oral ondansetron, and only 1 patient required dose reduction because of nausea. Hematologic toxicities during cycle 1 were neutropenia, anemia, thrombocytopenia, and febrile neutropenia. Cytopenias were less common beyond cycle 2, with only 3 patients requiring dose reductions due to cytopenias in subsequent cycles.

Importantly, long-term responders who remained on the study beyond 2 cycles required only once-monthly clinic visits, representing a significant reduction from the 5 to 7 monthly visits typically required for conventional Aza. Compliance was high, with only 1 reported missed dose on the protocol, supporting the practicality of a fully oral regimen.

These results should be interpreted in the context of the single-center design, small sample size, short median follow-up of ∼1.4 years, and limited number of heavily pretreated patients with relapsed or refractory disease. Nevertheless, this study supports continued prospective evaluation of oral CC-486-Ven, ideally in multicenter randomized trials. If confirmed, a fully oral CC-486-Ven regimen could represent an important next step in AML care by preserving therapeutic efficacy while reducing treatment burden, improving accessibility and quality of life and allowing more efficient allocation of health care resources.

Conflict-of-interest disclosure: M.K. is on the advisory boards of AbbVie, Dark Blue Therapeutics, Novartis, and Servier; receives consulting fees from AbbVie, AstraZeneca, Menarini/Stemline Therapeutics, Mitsubishi Tanabe Pharma American, and Servier; and reports research funding from AbbVie, Janssen, and Klondike Biopharma. K.S. declares no competing financial interests.