Journal Article Ahead of print 1 citation
PubMed: 40784355 DOI: 10.1016/S2352-3026(25)00172-3
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.
Lancet Haematol
Authors: Marie Robin, Maud D'Aveni, Aspasia Stamatoullas, Emmanuel Raffoux, Patrice Chevallier, Alice Garnier, Clémence Mediavilla, Martin Carre, Chantal Himberlin, Marie Sébert, Aurélie Ravinet, Kristell Desseaux, Hélène Labussière, Mustafa Alani, Marie-Thérèse Rubio, Anne Huynh, Lionel Adès, Régis Peffault de Latour, Franciane Paul, Fatiha Chermat, Raphael Petit, Chama Mokeddem, Amandine Charbonnier, Sylvain Thépot, Sylvie Chevret, Pierre Fenaux
Affiliations
- Service d'Hématologie-Greffe, Hôpital Saint-Louis, APHP, Université de Paris Cité, Paris, France.
- Service d'Hématologie Adulte, Université de Lorraine, CHRU Nancy, Nancy, France.
- Département d'Hématologie, Centre Henri Becquerel, Rouen, France.
- Service d'Hématologue Adulte, Hôpital Saint-Louis, APHP, Université de Paris Cité, Paris, France.
- Service Hématologie Clinique, CHU Hôtel Dieu, Nantes, France.
- Service des Maladies du Sang, CHU de Haut-Lévêque, Bordeaux, France.
- Service d'Hématologie Clinique, CHU de Grenoble-Alpes, Grenoble, France.
- Service d'Hématologie, CHU de Reims, Reims, France.
- Service d'Hématologie-Sénior, Hôpital Saint-Louis, APHP, Université de Paris Cité, Paris Saint-Louis Leukaemia Institute, Paris, France.
- Service d'Hématologie Clinique et de Thérapie Cellulaire, CHU Estaing, Clermont-Ferrand, France.
- Service de Biostatistique et Informatique Médicale, Hôpital Saint-Louis, APHP, Université de Paris Cité, Paris, France.
- Hématologie, Centre Hospitalier Lyon-Sud, Lyon, France.
- Service d'Hématologie, Greffe de Cellules Souches Hématopoïétiques, CHU/IUCT Oncopole, Toulouse, France.
- Service d'Hématologie-Greffe, Hôpital Saint-Louis, APHP, Université de Paris Cité, Paris, France.
- Service d'hématologie clinique, Hôpital Saint Eloi, Montpellier, France.
- Groupe Français des Myélodysplasies (GFM) Hôpital Saint-Louis, APHP, Paris, France.
- Service des Maladies du Sang, CHU d'Angers, Angers, France; Fédération Hôpital-Universitaire FFHU-GOAL (Grand Ouest Against Leukaemia), France.
- Service Hématologie Clinique et Thérapie Cellulaire, CHU d'Amiens Picardie - Site Sud, Amiens, France.
Abstract
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.
MeSH
Cells, Myelodysplastic Syndromes, Disease-Free Survival, Safety, Microscopy, Electron, Scanning Transmission, Lymphocytes, Decitabine, Stem Cells, Contraindications, Maintenance, Drug-Related Side Effects And Adverse Reactions, Therapeutics, Cell Transplantation, Stem Cell Transplantation, Transplantation, Thrombocytopenia