A Phase II Clinical Trial Of Lenalidomide and Prednisone In Low and Intermediate-1 IPSS Risk, Non-Del (5q) MDS Patients

Anemia remains the most common management challenge for patients (pts) with lower risk MDS (Low and int-1 International prognostic Scoring System (IPSS) groups). Lenalidomide (LEN) is the treatment of choice for lower risk MDS pts with chromosome 5 deletion (del5q) where 67% of pts on MDS-003 study became red blood cell transfusion independence (RBC-TI). The MDS-002 study reported 26% RBC TI rate in non-del5q MDS pts. Strategies to optimize LEN responses in non-del5q include identifying predictive biomarkers or combination strategies to potentiate erythropoietin receptor signaling.

Dexamethasone increases the proliferation of immature erythroid progenitors and in vitro increases erythroid progenitor sensitivity to LEN by enhancing erythropoietin (EPO)-transcriptional response and colony forming capacity (BL Ebert, un-published data).

We hypothesize that combination treatment with LEN and prednisone will yield a higher erythroid response rate in patients with non-del (5q) lower risk MDS compared to the historical clinical trial experience with LEN monotherapy (MT).

The study was an investigator initiated two- step phase II design. In the first step 25 eligible patients were to be registered. If fewer than 4 of these 25 achieved erythroid hematological response (HI-E), then the study will be terminated early with the conclusion that the regimen does not warrant further investigation. Key eligibility criteria included confirmed MDS diagnosis, low or int-1 IPSS, RBC transfusion-dependent anemia defined as having received ≥4 transfusions of RBCs for Hgb ≤ 9.0 g/dl within 56 days or symptomatic anemia (Hgb ≤ 9.0 g/dl), erythroid stimulating agents failure or endogenous serum epo > 500 mU/ml., absolute neutrophil count (ANC) ≥ 500 /mm≥, platelet count ≥ 50,000 /mm≥, and creatinine Clearance ≥ 30 mL/min. The planned dose of LEN for subjects with a baseline CrCl >60ml/min was 10 mg/day. Prednisone dose was 30 mg po daily cycle 1 tapered by 10 mg after each cycle to 5 mg po every other day for responders beyond cycle 6. The primary objective was best response (HI-E) by IWG 2006 criteria within 24 weeks.

Twenty five pts were enrolled. Baseline characteristics are summarized in table-1. The HI-E rate was 20% (5/25), and 22% (5/23) of evaluable patients. All responders became RBC TI (5 out of 23). The median time to response was 57 days. The median duration of response was 80 days (95% CI 69-91). Three out of 5 responders did not have hypomethylating agent (HMA) while 14 out of 20 non-responders received prior HMA. No patient transformed to acute myeloid leukemia. At a median follow up of 25 months the median OS was not reached (2 deaths).

The most common adverse events deemed related to study drug (>10% of pts) included, neutropenia 54%, thrombocytopenia 40%, anemia 32%, diarrhea 27%, myalgia 20%, edema 24%, rash 20%, infection 12%, fever 12%, and fatigue 12%. Grade III/IV events included anemia (n=8), neutropenia (n=4), thrombocytopenia (n=3), and Cerebrovascular event (n=1). The most common causes for study discontinuation were no response (10 pts), loss of response (4pts), infection (4pts) and rash (4pts).

Combination treatment with LEN and prednisone did not yield a higher erythroid response rate in patients with non-del (5q) lower risk MDS compared to the historical LEN MT. HI-E rates are less in pts who received HMA compared to MDS-002 study. Toxicity profile was similar to LEN (MT).

Komrokji:Celgene: Research Funding, Speakers Bureau. Off Label Use: use of lenalidomide in non del 5q. Lancet:Celgene: Research Funding. List:Celgene: Research Funding.