RBC Transfusion Independence and Safety Profile of Lenalidomide 5 or 10 mg in Pts with Low- or Int-1-Risk MDS with Del5q: Results From a Randomized Phase III Trial (MDS-004).

In a phase II study (MDS-003), lenalidomide (LEN) resulted in RBC transfusion-dependence (RBC-TI; ≥8 consecutive wks) in 67% of pts and complete cytogenetic response (CyR) in 45% of pts with RBC transfusion-dependent IPSS Low- or Int-1-risk MDS with del5q. The optimal LEN dose in these pts is unclear. This phase III study (MDS-004) compared the efficacy and safety of 2 LEN doses (5 and 10 mg) vs placebo (PBO).

In this multicenter, randomized, double-blind (DB) study, LEN naïve pts with RBC transfusion-dependent Low- or Int-1-risk MDS with del5q were randomized to receive LEN 5 mg on days 1–28 or LEN 10 mg on days 1–21, both of a 28-day cycle, or PBO. Erythroid response was assessed at 16 wks. Responders continued DB treatment for up to 52 wks, until erythroid relapse or disease progression. PBO and LEN 5 mg pts who did not respond by wk 16 were considered as treatment failures and received LEN 5 or 10 mg, respectively (resp), in an open-label (OL) extension phase. Pts who completed 52 wks of therapy could enter the OL phase at their current LEN dose. The primary end point was RBC-TI for ≥26 consecutive wks. Secondary end points included duration of TI, CyR (IWG 2000), progression to AML, and adverse events. Efficacy analyses used the modified intent-to-treat (mITT) population: pts with centrally-confirmed Low- or Int-1-risk MDS with del5q and documented RBC transfusion dependence who had received ≥1 dose of study drug.

Overall, 205 pts were randomized (LEN 5 mg, n=69; LEN 10 mg, n=69; PBO, n=67). The mITT population comprised: 138 pts (LEN 5 mg, n=46; LEN 10 mg, n=41; PBO, n=51); median age 69 y (range, 36–86 y); 76% female; 48% Low- and 52% Int-1-risk; and 75%, 16%, and 9% with isolated del5q, del5q + 1 abnormality, and del5q + ≥2 abnormalities, resp. Median time since diagnosis was 2.8, 2.5, and 2.4 y in LEN 5 mg, LEN 10 mg, and PBO groups, resp. Median baseline RBC transfusion requirement was 6 units/8 wks in each treatment group. Key efficacy results are reported in the Table. At 52 wks, significantly more LEN 5 mg (41%) or LEN 10 mg (56%) pts had achieved TI (≥26 consecutive wks) vs PBO (6%; both p<.001) (Table). Similar results were obtained using the IWG 2000 definition of TI (≥8 consecutive wks). RBC-TI was achieved at a median of 1 cycle of therapy (3.3 and 4.3 weeks, resp) for both LEN 5 and 10 mg. RBC-TI rate was not affected by age, gender, FAB classification, IPSS classification, time from diagnosis, cytogenetic complexity, baseline platelet counts, and number of cytopenias. CyR was reported in 17% and 41% of pts in LEN 5 and 10 mg groups, resp (p<.001 vs PBO for both), including complete CyR in 11% (LEN 5 mg; p<.01 vs PBO) and 24% of pts (LEN 10 mg; p<.001 vs PBO). None of the pts in the PBO group had CyR. In the safety population 4/69 (6%), 1/69 (1%), and 1/67 (2%) pts progressed to AML in the LEN 5 mg, LEN 10 mg, and PBO groups, resp; median time to AML progression from the first dose of study drug was 9.3, 5.9, and 3.1 months, resp. Grade 3-4 neutropenia was reported in 74%, 75%, and 15% of pts in the LEN 5 mg, LEN 10 mg, and PBO groups, resp, and thrombocytopenia in 33%, 41%, and 2% of pts, resp. DVT was reported in 1%, 6%, and 2% pts, resp. AEs leading to dose reduction were reported in 52% and 58% of LEN 5 and 10 mg pts, resp (none reported with PBO). These were due to neutropenia (28% vs 38%), thrombocytopenia (12% vs 23%), or febrile neutropenia (3% vs 0%) for LEN 5 and 10 mg, resp. Discontinuation due to AEs during the first 52 wks was reported in 16%, 9%, and 5% of pts in the LEN 5 mg, LEN 10 mg, and PBO groups, resp.

In this first randomized PBO-controlled study of LEN in pts with Low- or Int-1-risk MDS with del5q, both LEN 5 and 10 mg were generally well tolerated and achieved significant RBC-TI and CyR. LEN 10 mg was associated with better RBC-TI and CyR than LEN 5 mg, while maintaining a comparable safety profile. These data support the use of LEN 10 mg as a starting dose, with dose reductions or discontinuations if needed.

Fenaux:Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Epicept: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Merck: Honoraria, Research Funding. Giagounidis:Celgene: Consultancy; Novartis: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Selleslag:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Beyne-Rauzy:Celgene: Research Funding; Roche: Research Funding. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mittelman:Celgene: Clinical trials supported, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bio GAL: Equity Ownership, Patents & Royalties. Sanz:Celgene: Membership on an entity's Board of Directors or advisory committees. del Cañizo:Celgene: Membership on an entity's Board of Directors or advisory committees. Guerci-Bresler:Celgene: Consultancy. Schlegelberger:Celgene: Cytogenetic reference diagnostics. Kreipe:Celgene: Research Funding. Knight:Celgene: Employment, Equity Ownership. Francis:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment. Hellstrom-Lindberg:Celgene: Research Funding.