Oral Azacitidine Maintenance after Front-Line Treatment with Azacitidine and Venetoclax in Elderly AML Patients. Single Center Experience
Authors: Gardeney Helene , Torregrosa Jose , Brechet Maud , Moya Niels , Dindinaud Elodie , Basle Caroline , Raimbault Anna , Gallego Hernanz Maria Pilar 
Published: December 2024

BACKGROUND
The combination of VENETOCLAX and AZACITIDINE (AZA-VEN) has resulted in an increase in the duration of first remission (CR1) in many older patients with newly diagnosed acute myeloid leukemia (AML). However, it came at the cost of increased toxicity. Thus, it can be challenging to maintain it over months of treatment due to adverse events (AEs). Meanwhile, prevention of AML relapse is an important goal, as it is known that the longer the duration of CR1 is, the better the survival is. So, there is an unmet need for de-escalation and a maintenance strategy after AZA-VEN induction treatment to sustain therapeutic activity while lowering toxicity.
METHODS
We conducted a retrospective study in our institution (Poitiers' University Hospital) of using oral azacitidine (ONUREG®), as maintenance therapy in patients with AML in first remission after frontline treatment with AZA-VEN.
Patients included were 65 years old or older, not candidates for hematopoietic stem-cell transplantation or intensive chemotherapy, and in first cytologic response with (CR) or without (CRi) complete blood count recovery after a minimum of 6 cycles of AZA-VEN. Patients started ONUREG® at 300mg daily for 14 days over a 28-day cycle.
The primary endpoint was the duration of the first complete remission.
Secondary endpoints included progression-free survival, overall survival, and tolerance.
RESULTS
A total of 14 patients were included. The median age was 75.5 years older (range 59 to 87). Noticeably, 6 patients (42.8%) had an adverse prognostic according to 2022 ELN score, and on a molecular level, 4 (33%) patients were NPM1 mutated, and 6 (42.8%) patients presented an R140 IDH2 mutation. The median number of AZA-VEN cycles before ONUREG® was 8 (range, 6 to 20), and 5 (35.7%) patients had a CRi at the start of ONUREG®.
After a median follow-up of 24.5 months (95%CI 20.1-NA), the median duration of the first complete remission was 16 (95%CI 15.4-NA) months (to note, no medullary evaluation was systematically performed to assess AZA-VEN response but was mandatory before switching to ONUREG® maintenance to ensure CR1). Median overall survival was not reached from the time of diagnosis (only one patient relapsed and died rapidly). At the bone marrow assessment performed after a minimum of 3 cycles of ONUREG® (or sooner at clinician appreciation), 11 (91%) patients were still in cytologic response. Moreover, only 1 patient (8%) has developed a clonal selection at 3 months of molecular revaluation (measured by NGS).
Two of three patients still reliant on transfusion during AZA-VEN treatment acquired transfusion independence after starting ONUREG® maintenance after two and three cycles, respectively.
The most common grade 3 and 4 adverse events (AEs) were neutropenia (in 33% of patients), thrombopenia (in 42 %), and gastrointestinal events (in 0.8 %). Dose adjustments were necessary for 5 (40%) patients and consisted mainly of a dose reduction to 200 mg a day in 14 days over a 28-day cycle, which permitted the resolution or reduction of AEs to a grade 1. No febrile neutropenia or hospitalization related to ONUREG® treatment was noticed.
At data cutoff, only one patient had discontinued ONUREG® maintenance due to progression.
CONCLUSIONS
ONUREG® maintenance therapy seems effective and well tolerated after AZA-VEN in older AML patients. Once obtained, the cytologic response does not seem to be impacted by switching to ONUREG® maintenance. As expected, side effects were mainly gastrointestinal and neutropenia, both easily manageable. This approach can improve the quality of life for patients, with fewer hospital visits and no life-threatening events.