Oral azacitidine as maintenance therapy post allogeneic stem cell transplant in patients with myeloid malignancies

Abstract

Abstract Background: Despite improvements in overall survival (OS) after allogeneic stem cell transplant (alloSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), relapse rates remain up to 30-50% in high-risk patients. Data on outcomes of low dose parenteral azacitidine (AZA) maintenance after stem cell transplant (SCT) are conflicting. Oral AZA has been shown to prolong OS and relapse-free survival (RFS) in patients treated with intensive chemotherapy who are not eligible for SCT. We sought to investigate the tolerability and outcomes of patients treated with oral AZA as maintenance therapy in the post-SCT setting. Methods: We identified patients with myeloid disorders who received oral AZA as maintenance therapy after their first SCT. All patients were treated with daily oral azacitidine 200 or 300 mg for 14 days of a 28-day cycle, after engraftment was confirmed and once they were free of graft-versus-host disease (GVHD) or active infections. Measurable residual disease (MRD) was measured by multiparameter flow cytometry (sensitivity 10-4). OS and RFS were calculated from the date of SCT. Results: 11 patients were identified. The median age at diagnosis was 59 years (range 35-74). Nine patients were diagnosed with AML, one with MDS and one with mixed phenotype acute leukemia prior to SCT. At the time of SCT, eight patients were classified as newly diagnosed, and three had relapsed, refractory (R/R) disease. Per European Leukemia Network (ELN) 2022 guidelines, 7 (64%) patients had adverse risk disease, 2 (18%) patients had intermediate, and 2 (18%) patients had favorable risk disease. Four patients had complex cytogenetics, and 2 had TP53 mutations. In R/R patients, the median number of prior lines of treatment was 2.5 (range, 2-3). Initial induction therapies of patients were low-intensity venetoclax combinations in 6 (55%), intensive chemotherapy without venetoclax in 4 (36%), and hypomethylating agent-based therapy without venetoclax in 1 (9%). Pre-transplant MRD was undetectable in 6 (55%) patients: 75% of intensively treated and 43% of low-intensity-treated. Donor sources were matched unrelated in 7 (64%) patients and haploidentical in 4 (36%) patients. 1 (9%) patient had concurrent therapy, donor lymphocyte infusion, and 1 had concurrent venetoclax. The median time to starting oral AZA was 3 months (range, 2-25) post-SCT. Patients continued therapy for a median of 2.3 months (range, 0.03-25.2). At the time of data cut, none of the patients were still receiving oral AZA maintenance. The most frequent reason for discontinuation was gastrointestinal adverse events in 4 (36%) patients. Other reasons for discontinuation included cytopenias in one patient. Five (45%) patients discontinued therapy due to disease progression or MRD relapse while on oral AZA, while one patient remained disease-free during the course of maintenance therapy with negative MRD. Prior to starting oral AZA, 8 (73%) patients had undetectable MRD by flow cytometry. Of these patients, four were assessable for MRD after starting oral AZA. Four patients were not evaluable because of early treatment discontinuation and lack of response reassessment. Of the evaluable patients, 2 (50%) remained MRD negative and 2 (50%) became MRD positive. Three (27%) patients had positive MRD prior to starting oral AZA and they all remained positive while on therapy. Of the 5 pts who relapsed, 3 (60%) had positive MRD prior to starting oral AZA. At a median follow-up of 47 months (95%, 9-NE), median OS and RFS were 27.85 (95%, 11.73, NE) and 8.5 (95%, 3.4, NE), respectively. The 4-year OS and RFS rates were 33% (11%, 99%) and 20% (5.9%, 70%), respectively. Conclusion: Oral azacitidine is a feasible post-transplant maintenance therapy. Gastrointestinal side effects are common and require proactive management to maximize time on therapy. Larger sample sizes are required to define the role of oral azacitidine in the post-SCT maintenance setting.