Oral Azacitidine Maintenance Therapy in Acute Myeloid Leukemia after Frontline Hypomethylating Agent and Venetoclax

Background:

Oral azacitidine (AZA) maintenance therapy is approved for adults with acute myeloid leukemia (AML) who achieve remission following intensive induction chemotherapy and who are not able to complete intensive curative therapy. There is no standard maintenance regimen for AML patients (pts) whose initial therapy is a hypomethylating agent (HMA) and venetoclax (VEN). HMA/VEN is commonly used in pts deemed ineligible for intensive chemotherapy due to age and/or comorbidities. Some pts experience cytopenias with long-term HMA/VEN and require regimen modifications. To date, there are no available reports of oral AZA maintenance after initial treatment with HMA/VEN.

Methods:

We reviewed charts at our institution over the time period from September 2020 through May 2024 for AML pts receiving frontline HMA/VEN followed by oral AZA maintenance. Follow-up cutoff date was May 31, 2024. Individuals were eligible if they: 1. had a diagnosis of AML; 2. underwent initial therapy with HMA/VEN; and 3. received oral AZA as maintenance therapy. The index date for follow-up and survival analyses was the date of oral AZA initiation. Descriptive statistics were used to summarize findings.

Results:

We identified 10 pts meeting inclusion criteria. Median age was 74.5 years (range, 67-85). Seven pts were male. According to 2022 European LeukemiaNet stratification, four (40%) were favorable risk, one (10%) intermediate risk, three (30%) adverse risk, and two (20%) unclassifiable due to incomplete diagnostic information. Five (50%) pts had known NPM1 mutations. Median length of frontline HMA/VEN therapy was five cycles (range, 2-11). Eight (80%) pts received intravenous (IV) or subcutaneous azacitidine as the initial HMA, and two (20%) received IV decitabine. Following shared decision making with providers, pts decided to pursue palliative maintenance therapy. Six (60%) pts were switched to oral AZA while in complete remission (CR), three (30%) in CR with incomplete count recovery (CRi), and one (10%) without having had a bone marrow examination to assess remission status. Seven (70%) pts were noted to have measurable residual disease present at the time of their transition to maintenance therapy.

All pts were started on oral AZA at 300 mg daily on days 1-14 of a 28-day cycle. Median duration of treatment with oral AZA was 8.7 months (range, 1.5 - 21.1), and median duration of follow-up was 20 months (range, 6.7 - 30.7). Median relapse-free survival (RFS) after index was 19.1 months (range, 3.6 - 30.7), and median overall survival (OS) was 20 months (range, 6.7 - 30.7). Doses were held or treatment was discontinued in some pts for side effects, hospitalization, or progression of disease. On oral AZA, six (60%) pts reported GI toxicity, including nausea, vomiting, and diarrhea. Due to GI toxicity, two (20%) pts required dose reductions to 200 mg daily on days 1-14. Five (50%) pts developed cytopenias requiring treatment interruption or dose reduction. One (10%) pt required dose reduction to 200 mg daily on days 1-14 due to cytopenias, while one (10%) pt had dosing decreased to 300 mg daily on days 1-7. Three (30%) pts had treatment discontinued due to cytopenias and two (20%) due to disease progression. Six (60%) pts experienced at least one hospitalization while on treatment with oral AZA, one for febrile neutropenia and bacteremia. Other hospitalizations were for pulmonary embolism, acute respiratory failure, decompensated liver cirrhosis, hip surgery, and ischemic bowel, all believed to unrelated to treatment with oral AZA. At data cutoff, five pts are living, four of whom remain in remission. One pt held therapy after 10.8 months following a CVA and has not resumed treatment in the setting of decreased functional status. Two pts remain on oral AZA, both of whom have been in remission for greater than one year. One pt was restarted on HMA/VEN after 6.6 months on oral AZA.

Conclusions:

Oral AZA can be used safely and effectively as maintenance therapy following frontline AML therapy with HMA/VEN. With median RFS and OS over one and a half years in this small cohort, there is evidence that pts can experience long-term benefit with good tolerability. Toxicity was generally mitigated with dose reductions and/or supportive medications. To the authors' knowledge, this is the first report of oral AZA maintenance therapy following treatment with HMA/VEN. Our findings show proof-of-principle and require investigation in a larger cohort.

Shah:Bristol Myers Squibb: Consultancy, Speakers Bureau; Incyte: Speakers Bureau. Chojecki:Morphosys: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Consultancy. Grunwald:GSK: Consultancy; Astellas Pharma: Consultancy; Blueprint Medicines: Consultancy; Bristol Myers Squibb: Consultancy; Cardinal Health: Consultancy; Daiichi Sankyo: Consultancy; Incyte Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; OncLive: Consultancy; Pfizer: Consultancy; Premier: Consultancy; Sanofi: Consultancy; Servier: Consultancy; Sobi: Consultancy; Ajax: Research Funding; Merck: Research Funding; Medtronic: Current holder of stock options in a privately-held company; Aptitude Health: Consultancy; Amgen: Consultancy; Genetech: Consultancy; Janssen: Research Funding.

Oral azacitidine was used off-label in the patient cohort presented in this project.