Department of Hematology, Hospital Universitario de Salamanca, Salamanca, Spain; IBSAL, Instituto de investigación Biomédica de Salamanca, Salamanca, Spain.
Department of Hematology, Hospital Universitario de Salamanca, Salamanca, Spain; IBSAL, Instituto de investigación Biomédica de Salamanca, Salamanca, Spain.
Lancet Haematol. 2024 Sep;11(9):e659-e670. doi: 10.1016/S2352-3026(24)00142-X. Epub 2024 Jul 18.
Lenalidomide is the standard of care for patients who are transfusion dependent with chromosome 5q deletion (del[5q]) myelodysplastic syndromes. In the SintraREV trial, we aimed to investigate whether an early intervention of low lenalidomide doses for 2 years could delay transfusion dependency in patients with anaemia who were not transfusion dependent.
This randomised, double-blind, phase 3 trial, was conducted at 22 sites (University Hospitals) in Spain, France, and Germany. Eligible patients were aged 18 years or older diagnosed with low-risk or intermediate-1-risk del(5q) myelodysplastic syndromes with non-transfusion-dependent anaemia (according to the IPSS), were erythropoietin-stimulating agents naive, and had an ECOG performance status of 2 or less. Patients were randomly assigned (2:1) by means of a telephone system to receive lenalidomide 5 mg daily in 28-day cycles versus placebo for 2 years. The primary endpoint was time to transfusion dependency based on blinded independent central review. Analysis were by intent-to-treat (ITT) and evaluable population. Safety analyses included all participants who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT01243476) and EudraCT (2009-013619-36) and is complete.
Between Feb 15, 2010, and Feb 21, 2018, 61 patients were randomly assigned to receive lenalidomide (n=40; two did not receive treatment) or placebo (n=21). The median age was 72·2 (IQR 65·4-81·9) years, 50 (82%) patients were female, and 11 (18%) were male. The median follow-up time was 60·6 (IQR 32·1-73·9) months. Regarding primary endpoint, median time to transfusion dependency was not reached (95% CI not applicable) in the lenalidomide group versus 11·6 months (95% CI 0·00-30·11) in the placebo group (p=0·0027). Lenalidomide significantly reduced the risk of transfusion dependency by 69·8% (hazard ratio 0·302, 95% CI 0·132-0·692; p=0·0046). The most frequent treatment-related adverse event was neutropenia, occurring in 24 (63%) of 38 patients in the lenalidomide group (grade 3 and 4 in 17 [45%] patients and one [3%], respectively) and in four (19%) of 21 patients in the placebo group (grade 3 in one [5%] patient). Thrombocytopenia was detected in seven (18%) of 38 patients receiving lenalidomide (grade 3 in two [5%] patients). Regarding the non-haematological toxicity, skin disorders (rash nine [23%] of 38 patients) were the most frequently described toxicities among patients receiving lenalidomide, being grade 3 in one (3%) of 38 patients. 19 serious adverse events were reported in 13 patients, 18 in the lenalidomide group and one in the placebo group, five of which were potentially related to the study drug. No treatment-related deaths were identified.
An early approach with low doses of lenalidomide across two years delays the time to transfusion dependency and improves the rate and quality of the responses, with a manageable safety profile in patients who are non-transfusion dependent with del(5q) low-risk myelodysplastic syndromes.
Bristol Myers Squibb.
来那度胺是染色体 5q 缺失（del[5q]）骨髓增生异常综合征伴输血依赖患者的标准治疗方法。在 SintraREV 试验中，我们旨在研究低剂量来那度胺的早期干预是否可以延迟未输血依赖的贫血患者的输血依赖时间。
这是一项在西班牙、法国和德国的 22 家医院（大学医院）进行的随机、双盲、III 期试验。符合条件的患者年龄在 18 岁或以上，诊断为低危或中危-1 风险的 del(5q)骨髓增生异常综合征，非输血依赖型贫血（根据 IPSS），对红细胞生成素刺激剂无反应，ECOG 表现状态为 2 或更低。患者通过电话系统随机分配（2:1）接受来那度胺 5mg 每日，28 天为一个周期，与安慰剂治疗 2 年。主要终点是根据盲法独立中央审查的输血依赖时间。分析按意向治疗（ITT）和可评价人群进行。安全性分析包括至少接受一次治疗的所有参与者。该试验在 ClinicalTrials.gov（NCT01243476）和 EudraCT（2009-013619-36）上注册，并已完成。
在 2010 年 2 月 15 日至 2018 年 2 月 21 日期间，61 名患者被随机分配接受来那度胺（n=40；2 名未接受治疗）或安慰剂（n=21）。中位年龄为 72.2（IQR 65.4-81.9）岁，50 名患者（82%）为女性，11 名（18%）为男性。中位随访时间为 60.6（IQR 32.1-73.9）个月。关于主要终点，来那度胺组未达到输血依赖时间中位数（95%CI 不适用），而安慰剂组为 11.6 个月（95%CI 0.00-30.11）（p=0.0027）。来那度胺显著降低输血依赖风险 69.8%（风险比 0.302，95%CI 0.132-0.692；p=0.0046）。最常见的治疗相关不良事件是中性粒细胞减少症，发生在来那度胺组的 38 名患者中的 24 名（45%）和安慰剂组的 21 名患者中的 4 名（19%）（分别为 3 级和 4 级和 1 级，3%）。血小板减少症发生在接受来那度胺治疗的 38 名患者中的 7 名（18%）（2 级）。关于非血液学毒性，皮肤疾病（皮疹 38 名患者中有 9 名[23%]）是接受来那度胺治疗的患者中最常描述的毒性，其中 1 名（3%）患者为 3 级。在 13 名患者中报告了 19 例严重不良事件，其中来那度胺组 18 例，安慰剂组 1 例，其中 5 例可能与研究药物有关。未发现与治疗相关的死亡。
低剂量来那度胺早期治疗两年可延迟输血依赖时间，并提高低危 del(5q)骨髓增生异常综合征非输血依赖患者的反应率和质量，安全性可管理。
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