A multiarm phase 1b study of personalized oral maintenance therapy with decitabine/cedazuridine (ASTX727) plus physician's choice of venetoclax, gilteritinib, enasidenib, or ivosidenib in Acute Myeloid Leukemia Free

Introduction: Patients (pts) with acute myeloid leukemia (AML) who achieve remission but are unable to undergo hematopoietic stem cell transplantation (SCT) or standard consolidation strategies are at high risk of relapse. Maintenance therapy consists of prolonged administration of lower intensity therapies with the goal of delaying/preventing relapse. Hypomethylating agents (HMAs) alone or in combination with the BCL-2 inhibitor venetoclax are effective maintenance strategies in AML (Wei 2020, Bazinet 2024). Multiple other oral molecularly-targeted agents are now available in AML (gilteritinib, ivosidenib, enasidenib).

Methods: This is a phase 1b study of ASTX727 (decitabine/cedazuridine) +/- physician's choice of a targeted agent (venetoclax, gilteritinib, enasidenib, or ivosidenib) as personalized fully oral maintenance therapy in AML. Pts ≥ 18 years with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) who were unable to complete standard therapy and not immediate candidates for SCT were eligible. Pts were required to have received at least 2 courses of intensive chemotherapy (intermediate to high-dose cytarabine-based) or 3 courses of low-intensity therapy (HMA or low-dose cytarabine-based) prior to enrollment. Other inclusion criteria were ECOG ≤ 3, neutrophils > 0.5 x 10⁹/L, and platelets > 50 x 10⁹/L. Treatment consisted of ASTX727 35/100 mg PO on D1-3 either alone (Arm A) or in combination with venetoclax 400 mg (azole adjusted) PO on D1-5 (Arm B), gilteritinib 120 mg PO on D1-28 (Arm C), enasidenib 100 mg PO on D1-28 (Arm D), or ivosidenib 500 mg PO on D1-28 (Arm E). Cycles were 28 days and continued for up to 24 courses. Each arm included a lead-in safety cohort using a 3+3 dose de-escalation design. The primary objective was safety/tolerability. Secondary objectives included relapse-free survival (RFS; starting from time of enrollment) and overall survival (OS). RFS and OS were censored at the time of SCT. This study is registered on ClinicalTrials.gov (NCT05010772).

Results: 35 pts have been enrolled (7 in Arm A, 25 in Arm B, 2 in Arm C, and 1 in Arm D). The median age was 66 years (range 26-83) and 18/35 (51%) were male. 4 (11%) pts had antecendent myelodysplastic syndrome (MDS) and 3 (9%) had therapy-related AML. ELN 2022 risk was favorable in 14 pts (40%), intermediate in 3 (9%), and adverse in 18 (51%). Complex cytogenetics were present in 3 (9%) pts and TP53 mutation in 1 pt (3%). Measurable residual disease (MRD) was detectable by flow cytometry in 9/34 (26%) pts at enrollment.

No dose-limiting toxicities (DLTs) were noted during cycle 1. The most common grade 3/4 adverse events were neutropenia (94%), leukopenia (94%), thrombocytopenia (71%), anemia (49%), hypertension (20%), and lung infection (20%). 13 (37%) pts experienced any grade 3/4 infection, including pneumonia in 7 (20%), neutropenic fever in 6 (17%), colitis in 2 (6%), Covid-19 in 2 (6%), and sepsis in 1 (3%). 1 (3%) death occurred on maintenance therapy (Arm B) due to pneumonia/sepsis. All other observed deaths occurred after relapse of AML or following transition to SCT.

The median follow-up time was 28.0 months (m) and the median number of cycles given was 5 (range 1-24). 6 (17%) pts proceeded to SCT and were censored at time of SCT. The median RFS was 24 m (2-yr 47%) for the full cohort, 24 m (2-yr 65%) in the pts who received intensive induction, and 22.4 m (2-yr 34%) in the pts who received low-intensity induction. The median RFS was 11.1 m (2-yr 21%) in Arm A, 24 m (2-yr 55%) in Arm B, and 10.5 m (2-yr 0%) in Arm C. Of the 9 pts who were MRD-positive at enrollment, 2 (22%) cleared their MRD while on maintenance. Compared to MRD-negative pts, those with MRD-positive disease at enrollment had significantly shorter RFS (median 6.6 m vs not reached; p=0.002).

The median OS was 30.7 m (2-yr 73%) for the full cohort, not reached (2-yr 100%) in the pts who had received intensive induction (n=18), and 30.5 m (2-yr 53%) in the pts who received low-intensity induction (n=17). The median OS was 36.3 m (2-yr 75%) in Arm A, 33.7 m (2-yr 70%) in Arm B, and 30.7 m (2-yr 100%) in Arm C.

Conclusions: Personalized fully oral maintenance therapy is feasible in AML. Myelosuppression and infections were the most common adverse events. Further enrollment and follow-up is needed to evaluate efficacy.