Phase 3 Study of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent (TD) Low Risk Del(5q) MDS Patients with Del(5q) — Preliminary Blinded Analysis of the European Sintra-REV Trial

Background: Lenalidomide (LEN) is a reference treatment in IPSS low and in1 (lower) risk MDS patients with isolated de(5q) (MDS-del(5q)) and RBC - TD. Most low risk MDS-del(5q) patients with anemia and independent of transfusions develop TD or need of treatment for symptomatic anemia very early after diagnosis (median time to transfusion/treatment of 20 months, López Cadenas et al abstract 3180 ASH, 2016). LEN directly targets the del(5q) clone improving anemia, quality of life and survival in this subset of patients. Limited data also suggest a role of LEN in non-TD patients with del(5q) (Oliva et al Cancer Med 2015). However no prospective randomized study of LEN has been performed in this group of patients.

Material: The Sintra-Rev clinical trial is a phase III European multicenter study, in low-risk MDS-del(5q) patients, with anemia (Hb<12g/dL) without TD. Patients were randomized in a double-blind design to LEN (5mg/day) vs placebo (2:1 randomization) for 2 years of treatment and 2y of FU. The primary endpoint was the time to TD, the secondary endpoints included erythroid and cytogenetic response (HI-E -IWG 2006 criteria-; minor HI-ER was defined as Hb increase 1 to 1.5 g/dL), overall survival (OS), event free survival (EFS), time to AML and mutational analysis (TP53 and other myeloid genes). Preliminary blinded results of efficacy of the entire cohort after 12 weeks of treatment are reported.

Results: Main clinical characteristics of the 58 patients included are summarized in Table 1: 81% were females, median age was 72 years (37-89), median Hb at inclusion 9.8 g/dL(7.1 - 11.7) g/dL and most patients (86%) had isolated del(5q) cytogenetic abnormality. Three patients were excluded due to screening failures and 58 were finally included in the trial. Seven patients discontinued before 12 weeks: Three developed disease progression (defined as TD), two withdrew consent, one due to changes in patient's status and it was not specified in the remaining patient. Therefore, fifty-four patients were finally evaluable for efficacy and 58 for safety at w12. HI-E was observed in 20/54 patients (37%), minor HI-ER in 6/54 (11%), stable disease in 25/54 (46%) and TD (transfusion dependency) in 3 (6%). In the 26 patients achieving HI-E or minor HI-E, the median Hb level rise was 2.2 g/dL (range 1-4.4) and median Hb level was 12.5 g/dL (9.8-14.2). Cytogenetic response (CyR) was available in 41/54 patients: complete in 16 (30%), partial in 9 (17%), no CyR in 16 (30%) and no available in 13 (23%) patients.

54 patients developed adverse events (AE) in the first 12w, most of them hematological and probably related to the treatment. Hematological toxicity occurred in 74% of patients (neutropenia or thrombocytopenia) and only one third was grade 3/4 (neutropenia 35% or thrombocytopenia 3%). Non-hematological adverse events potentially related to the investigational drug were described in 19 patients (35%) but only 2/19 (11%) were grade 3. Nine serious AE were reported in 7 patients: congestive heart failure (2), vestibular neuritis, polyarthritis, arterial hypertensive crisis, carpal arthritis, respiratory infection, chronic obstructive pulmonary disease exacerbation and blurred vision. Only the last one (blurred vision) was potentially related with the study drug

Conclusions: In this preliminary and blinded analysis we confirm a high rate of erythroid and cytogenetic responses early (w12) after study treatment with an adequate safety profile. Unblinded data will be presented at the meeting.

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