Oral decitabine and cedazuridine maintenance after haematopoietic stem-cell transplantation in very high-risk acute myeloid leukaemia or myelodysplastic syndrome (GFM-DACORAL-DLI): a multicentre, single-arm, phase 2 trial.
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BACKGROUND: The combination of a hypomethylating agent with donor lymphocyte infusion as maintenance therapy after haematopoietic stem-cell transplantation (HSCT) in acute myeloid leukaemia and myelodysplastic syndrome might reduce the risk of relapse. We aimed to evaluate the activity and safety of oral decitabine and cedazuridine (ASTX727) as maintenance after allogeneic HSCT in patients with acute myeloid leukaemia or myelodysplastic syndrome at very high risk of relapse post-transplantation. METHODS: We conducted a multicentre, single-arm, phase 2 study (GFM-DACORAL-DLI) at 12 centres in France. We enrolled patients aged 18-70 years with an Eastern Cooperative Oncology Group performance status of 0-2, without contraindication for HSCT, and with very high-risk disease (poor or very poor prognosis according to the revised International Prognostic Scoring System for myelodysplastic syndrome, adverse risk according to the 2017 European LeukemiaNet classification for acute myeloid leukaemia; unfavourable genetics; and acute myeloid leukaemia post-myelodysplastic syndrome or post-myeloproliferative neoplasm, or relapsing less than 2 years after complete response). Patients were included 5-45 days before transplantation. ASTX727 was orally administered at escalating doses (100 mg cedazuridine plus 35 mg decitabine starting at 1 day per cycle and increasing to 3 days) from day 40 post-HSCT, up to ten cycles. Donor lymphocyte infusion was recommended when patients had no contraindication after cycle 4. The primary endpoint was disease-free survival at 1 year after HSCT, assessed in the first 28 enrolled patients treated with ASTX7277. Safety was assessed in all participants who received at least one course of ASTX727. This study was registered with ClinicalTrials.gov (NCT04857645); enrolment is complete but follow-up is ongoing. FINDINGS: Between Sept 28, 2021, and March 1, 2023, 59 patients were screened and 51 patients underwent allogeneic HSCT (median age 62·0 years [IQR 56·5-65·0]; 22 [43%] female, 29 [57%] male). 34 patients received maintenance treatment with ASTX727; seven of them received at least one donor lymphocyte infusion. 14 (41%) patients completed the ten cycles. Median follow-up was 12·6 months (IQR 10·3-14·3). Among the first 28 enrolled patients treated with ASTX727, disease-free survival at 1 year after HSCT was 70·4% (95% CI 55·1-89·9). The most frequent grade 3 or worse adverse events were haematological, occurring in 25 (74%) of 34 patients (21 [62%] neutropenia, eight [24%] thrombocytopenia, four [12%] anaemia). Serious adverse events occurred in 14 (41%) of 34 patients, and were haematological in eight patients and gastrointestinal in three patients. One treatment-related death, due to thrombocytopenia, occurred. INTERPRETATION: ASTX727 could be a potential treatment option after HSCT in patients with acute myeloid leukaemia or myelodysplastic syndrome at very high risk of relapse. Further investigation is warranted to establish the efficacy and safety of this therapeutic approach. FUNDING: Taiho Oncology and Astex Pharmaceuticals.