Low dose lenalidomide versus placebo in non-transfusion dependent patients with low risk, del(5q) myelodysplastic syndromes (SintraREV): a randomised, double-blind, phase 3 trial.

BACKGROUND

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.

METHODS

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.

FINDINGS

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.

INTERPRETATION

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.

FUNDING

Bristol Myers Squibb.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests MD-C reports receiving consulting fees from BMS, Novartis, Blueprint Medicines, GlaxoSmithKline, Agios Pharmaceuticals, Hemavan, Syros Pharmaceuticals, Keros Therapeutics, and Curis; honoraria for lectures, presentations, speaking bureaus, manuscript writing, or educational events from BMS, Novartis, and Keros Therapeutics. RCJ reports receiving support for attending meetings or travel from Novartis, AbbVie, and AstraZeneca and her participation on a data safety monitoring board or an advisory board for AstraZeneca and Novartis. J-ÁH-R reports grants or contracts from Janssen and Sanofi; consulting fees from Janssen, AbbVie, AstraZeneca, BeiGene, Lilly, and Menarini Stemline; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Roche, AbbVie, BeiGene, BMS and Celgene, Amgen, Takeda, AstraZeneca, Sanofi, and Lilly; support for attending meetings or travel from Janssen, AbbVie, Amgen, AstraZeneca, BeiGene, and Novartis; participating on a data safety monitoring board or an advisory Board for Janssen, Roche, AbbVie, BeiGene, BMS and Celgene, Amgen, Takeda, AstraZeneca, Sanofi and Lilly. JB reports receiving payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from BMS and Celgene; support for attending meetings or travel from BMS and Celgene; and participation on an advisory board for BMS and Celgene. UP reports grants or contracts from Amgen paid to GWT-TUD and the University of Leipzig; grants or contracts from Janssen paid to GWT-TUD; consulting fees from BMS, Novartis, AbbVie, Geron, and Curis; and support for attending meetings or travel from BMS. KSG reports grants or contracts from BMS; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from BMS and AbbVie; participation on a data safety monitoring board or an advisory board for BMS, AbbVie, and Jazz Pharmaceuticals. All other authors declare no competing interests.