Robin Marie, D'Aveni Maud, Stamatoullas Aspasia, Raffoux Emmanuel, Chevallier Patrice, Garnier Alice, Mediavilla Clémence, Carre Martin, Himberlin Chantal, Sébert Marie, Ravinet Aurélie, Desseaux Kristell, Labussière Hélène, Alani Mustafa, Rubio Marie-Thérèse, Huynh Anne, Adès Lionel, de Latour Régis Peffault, Paul Franciane, Chermat Fatiha, Petit Raphael, Mokeddem Chama, Charbonnier Amandine, Thépot Sylvain, Chevret Sylvie, Fenaux Pierre
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.
Lancet Haematol. 2025 Sep;12(9):e705-e716. doi: 10.1016/S2352-3026(25)00172-3. Epub 2025 Aug 7.
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.
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.
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.
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.
Taiho Oncology and Astex Pharmaceuticals.
在急性髓系白血病和骨髓增生异常综合征的造血干细胞移植（HSCT）后，使用去甲基化药物联合供体淋巴细胞输注作为维持治疗可能会降低复发风险。我们旨在评估口服地西他滨和西扎珠单抗（ASTX727）作为移植后复发风险极高的急性髓系白血病或骨髓增生异常综合征患者异基因HSCT后维持治疗的活性和安全性。
我们在法国的12个中心进行了一项多中心、单臂、2期研究（GFM-DACORAL-DLI）。我们纳入了年龄在18-70岁之间、东部肿瘤协作组体能状态为0-2、无HSCT禁忌证且疾病风险极高（根据修订的骨髓增生异常综合征国际预后评分系统预后差或极差、根据2017年欧洲白血病网分类急性髓系白血病风险不良；遗传学不利；以及骨髓增生异常综合征或骨髓增殖性肿瘤后急性髓系白血病，或完全缓解后不到2年复发）的患者。患者在移植前5-45天入组。从HSCT后第40天开始，以递增剂量口服ASTX727（100 mg西扎珠单抗加35 mg地西他滨，从每个周期1天开始，增加到3天），最多10个周期。当患者在第4周期后无禁忌证时，建议进行供体淋巴细胞输注。主要终点是HSCT后1年的无病生存率，在首批28例接受ASTX727治疗的入组患者中进行评估。在所有接受至少一个疗程ASTX727治疗的参与者中评估安全性。本研究已在ClinicalTrials.gov注册（NCT04857645）；入组已完成，但随访仍在进行中。
在2021年9月28日至2023年3月1日期间，59例患者接受筛查，51例患者接受了异基因HSCT（中位年龄62.0岁[IQR 56.5-65.0]；22例[43%]为女性，29例[57%]为男性）。34例患者接受了ASTX727维持治疗；其中7例接受了至少一次供体淋巴细胞输注。14例（41%）患者完成了10个周期。中位随访时间为12.6个月（IQR 10.3-14.3）。在首批28例接受ASTX727治疗的入组患者中，HSCT后一年的无病生存率为70.4%（95%CI 55.1-89.9）。最常见的3级或更严重不良事件是血液学事件，34例患者中有25例（74%）发生（21例[62%]为中性粒细胞减少，8例[24%]为血小板减少，4例[12%]为贫血）。34例患者中有14例（41%）发生严重不良事件，其中8例为血液学事件，3例为胃肠道事件。发生了1例与治疗相关的死亡，原因是血小板减少。
ASTX727可能是移植后复发风险极高的急性髓系白血病或骨髓增生异常综合征患者HSCT后的一种潜在治疗选择。有必要进一步研究以确定这种治疗方法的疗效和安全性。
大鹏肿瘤公司和阿斯泰克制药公司。
