Post-transplant oral decitabine and cedazuridine maintenance in high-risk acute myeloid leukemia or myelodysplastic syndrome

Introduction

Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the primary curative treatment for patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The ability of allo-HSCT to harness graft-versus-leukemia (GVL) effects can potentially overcome disease resistance associated with adverse cytogenetics and molecular risk features (1-5). Despite recent advances in transplant conditioning therapy, careful donor selection, and supportive care, relapse remains the primary cause of post-transplant failure, affecting 40–80% of high-risk patients (6). Post-allo-HSCT relapses are associated with adverse prognosis, limited salvage therapies, and poor survival, emphasizing the need for better maintenance strategies to reduce the risk of relapse (6).

Hypomethylating agents (HMAs) such as azacitidine and decitabine have transformed the treatment paradigm in myeloid malignancies outside of transplantation (7), but their efficacy in preventing post-transplant relapses remains uncertain. Recent research focuses on developing oral formulations and combination approaches to enhance feasibility, adherence, and effectiveness (8). The GFM-DACORAL-DLI trial shows crucial improvement, evaluating oral decitabine and cedazuridine (ASTX727) as maintenance therapy following allo-HSCT in patients with very high-risk AML or MDS (9).

Role of maintenance therapy after allo-HSCT

Post-allo-HSCT relapses are influenced by various factors, including minimal residual disease, adverse cytogenetic or molecular profiles, inadequate GVL effect, and immune reconstitution (10). Over recent years, post-transplant maintenance has been limited to targeted therapies for specific subgroups, such as FLT3 inhibitors in FLT3-mutated AML, or clinical trials involving HMAs (11).

HMAs may help prevent relapses following transplant by inducing hypomethylation, reactivating tumor suppressor genes, and regulating the immune system to potentiate GVL effect while reducing graft-versus-host disease (GVHD). These actions could suppress residual disease and promote a favorable immune balance (12). However, studies, including those with azacitidine, have not consistently shown relapse prevention, possibly due to limited drug exposure or tolerability post-transplant (13).

Oral HMAs, particularly the decitabine-cedazuridine, improve pharmacokinetics and patient convenience (9). Cedazuridine increases the plasma concentration of decitabine by inhibiting cytidine deaminase, an enzyme responsible for decitabine breakdown, making oral dosing comparable to intravenous treatment and facilitating outpatient treatment (14).

The GFM-DACORAL-DLI study: design and primary findings

The GFM-DACORAL-DLI trial was a phase 2, single-arm study across 12 centers in France for adults aged 18–70 with very high-risk AML or MDS who had received allo-HSCT (9). Eligibility was based on adverse European LeukemiaNet (ELN) risk for AML or poor/very poor IPSS-R Revised International Prognostic Scoring System risk for MDS. Participants received oral decitabine/cedazuridine (ASTX727) starting at 40 days post-transplant with escalating doses of 100 mg cedazuridine plus 35 mg decitabine (1–3 days per cycle) for up to 10 cycles. Donor lymphocyte infusion (DLI) could be given after cycle four according to protocol criteria. DLIs were administered using an escalating dose approach, such as 5×10⁶, 1×10⁷, 5×10⁷, and 1×10⁸ CD3⁺ cells/kg for human leukocyte antigen (HLA)-matched donors, with lower starting doses for mismatched donors, and were given only after immunosuppression withdrawal, which was usually tapered starting around day 120 post-transplant in the absence of GVHD (9). GVHD prophylaxis in the trial consisted primarily of ciclosporin and mycophenolate mofetil combined with either anti-thymocyte globulin (73% of patients) or post-transplant cyclophosphamide (27%). Cyclosporin was administered from day −14 until approximately day 120 post-transplant, while mycophenolate mofetil was given from day +1 to day +45 (9).

The primary outcome of the study was 1-year disease-free survival (DFS) post-HSCT, with maintenance therapy.

Among 51 transplanted patients, 34 met the study criteria and initiated ASTX727 at a median of 53 days post-transplant. Of these, 14 patients (41%) completed all 10 planned cycles. Post-transplant DLI was administered in 7 patients (9). The primary endpoint was achieved among the first 28 treated patients; the estimated 1-year DFS rate was 70.4% [95% confidence interval (CI): 55.1–89.9%], significantly higher than the null hypothesis of 12%, reflecting positive results in this high-risk group. In post-hoc analysis including all 34 treated patients, the 1-year DFS was 75.8% (62.5–91.1%). Overall, among all 51 patients regardless of ASTX727 treatment, the 1-year DFS was 62.1% (50.0–77.1%) compared to 33% (17.3–62.6%) at 2 years (9).

From a safety perspective, ASTX727 was associated with expected hematologic toxicity: grade ≥3 events predominantly comprised neutropenia and thrombocytopenia, with one treatment-related death due to thrombocytopenia. Non-hematologic toxicity was generally manageable, and serious adverse events occurred in 41% of patients treated (9).

The above findings support the feasibility of oral decitabine/cedazuridine maintenance in a very high-risk patient with MDS or AML following allo-HSCT, with promising early disease control (9).

Discussion

The GFM-DACORAL-DLI study targets a key unmet need: developing efficacious and tolerable maintenance therapy to minimize post-allo-HSCT relapse in patients with very high-risk AML/MDS. The approximately 70% 1-year DFS reported in the treated cohort compares favorably to historical data, where high relapse rates and poor survival impose persistent therapeutic challenges (9). While this single-arm study does not provide the same level of evidence as a randomized trial, it does emphasize an essential improvement over historical outcome.

Oral decitabine/cedazuridine improves feasibility and patient adherence compared to intravenous or subcutaneous formulation of HMAs, which present greater practical complexities in administration (15).

HMAs may potentially augment the GVL effect while mitigating GVHD, although there is no definitive immunologic data from this trial. Previous studies showed that HMAs can expand the population of regulatory T-cell and increase the function of CD8⁺ T cell (16,17).

The study design included optional DLI (9), which may synergize with epigenetic therapy to potentiate antileukemic immunity, while it could also potentiate the risk of GVHD. Although GVHD events were reported in the overall treated cohort, the study did not include a subgroup analysis of GVHD specifically after DLI, which limits the ability to assess the relationship between DLI administration and GVHD risk (9). Since maintenance therapy could begin as early as day 40 post-transplant, some patients were likely still receiving immunosuppressive therapy, which may impact GVL effect and the interaction between HMA and DLI.

Like other post-transplant maintenance therapies, it is paramount to balance efficacy with potential adverse effects. Hematologic toxicity from ASTX727 was anticipated during the initial post-transplant phase; however, careful monitoring with dose adjustments allowed patients to complete treatment (9). Future research is required to optimize dosing, timing, and supportive care to improve tolerability.

Previous randomized maintenance trials in an unselected cohort of patients with AML/MDS in post-transplant settings have been negative for agents like azacitidine, highlighting the difficulty of preventing relapse in diverse population cohorts (13). By contrast, decitabine has shown signs of reducing relapse in some prospective studies, especially among younger, healthier patients (18). Similarly, the GFM-DACORAL-DLI study showed feasibility and activity in an older, very high-risk population, albeit with limitations inherent to single-arm designs (9).

The findings of the GFM-DACORAL-DLI study should also be considered within the broader context of the literature evaluating HMAs as post-allo-HSCT maintenance therapy. A recent meta-analysis on HMA maintenance after allo-HSCT highlighted that HMAs might reduce relapse risk without significantly increasing non-relapse mortality, while there is still substantial heterogeneity among studies (19). Additionally, a randomized phase II trial showed that low-dose decitabine maintenance after allo-HSCT notably improved relapse-free survival compared to observation in patients with high-risk AML (20). More recently, next-generation HMAs such as guadecitabine have been studied in the post-transplant setting, with early studies showing feasibility and promising signals for relapse prevention (21). Overall, these findings highlight the continued interest in epigenetic maintenance strategies and indicate the necessity for larger randomized trials to better define their role after allo-HSCT.

Limitations and unmet needs

The trial’s non-randomized, single-arm design limits definitive conclusions about efficacy when compared with historical data. Selection bias is particularly significant because only patients who experienced early post-transplant recovery without active GVHD or infection were eligible to initiate ASTX727 (9). These patients may inherently have a better prognosis than those who could not begin treatment maintenance. This study, therefore, could potentially introduce immortal time bias although Simon-Makuch analyses were used to account for treatment initiation over time: some residual bias may remain.

A significant limitation is the relatively small number of patients who ultimately started maintenance treatment, because only 34 of 51 transplanted patients met the eligibility criteria.

Furthermore, only approximately 41% of patients completed all planned cycles (9), highlighting the real-world difficulty of providing extended maintenance early after transplant and emphasizing the importance of strategies that optimize exposure while minimizing toxicity.

Importantly, standardized assessment of measurable residual disease (MRD) was limited in the trial (9), precluding detailed evaluation of how maintenance therapy affects subclinical disease dynamics. Future trials should integrate sensitive MRD monitoring to identify patients most likely to benefit and potentially tailor treatment duration.

The impact of concomitant DLI on outcomes is still uncertain due to the small sample size (9). Future randomized studies that compare ASTX727 maintenance with and without DLI, or against observation alone, would help clarify its independent role.

Ultimately, extended follow-up is necessary to determine whether the early DFS benefit translates into lasting survival gains, particularly given the observed decline in survival during the second year (9).

Conclusions

Overall, the GFM-DACORAL-DLI trial presents preliminary data indicating that oral maintenance therapy combining decitabine and cedazuridine, with optional DLI, can be delivered effectively following allo-HSCT in patients with very high-risk AML and MDS (9). One-year DFS has exceeded historical benchmarks, indicating tremendous potential for further evaluation. This post-allo-HSCT maintenance approach shows promise as an improved maintenance strategy to prevent relapses following transplant, especially in patients with adverse cytogenetic and molecular risk factors who are otherwise associated with poor prognosis. Future randomized phase 3 trials are essential to confirm its clinical efficacy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0137/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0137/coif). F.R. reports honoraria from Amgen, Pfizer, Astellas Pharma, Celgene, Agios, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb, Takeda, Jazz Pharmaceuticals, Novartis, Syros Pharmaceuticals, and Taiho Pharmaceutical, outside the submitted work; and consulting or advisory role in Amgen, Astellas Pharma, Celgene, Jazz Pharmaceuticals, Agios, AbbVie/Genentech, Bristol Myers Squibb, AstraZeneca, Taiho Oncology, Syros Pharmaceuticals, and Certara Inc., outside the submitted work. No funding was received for this manuscript. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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