Lenalidomide (LEN) in INT 2 and High Risk MDS with DEL 5q. Interim Results of a Phase II Trial by the GFM.

Background: LEN is now considered a reference (and possibly “targeted “) treatment in IPSS low and int 1 risk MDS with del 5q. Int 2 and high risk MDS with del 5q (with excess of blasts and /or additional cytogenetic abn,) has poor prognosis with limited therapeutic options. Apart from small n° of case reports, results of LEN in those pts are unknown.

Methods: We performed a phase I-II study of LEN (10 mg /d x21d q 28 d, increased to 15mg/d after 2 cycles, in the absence of response and DLT) in MDS with del 5q and high or int 2 IPSS (including RAEB-T) . Dose reductions were made in case of NCI CTCAE grade >2 toxicity or, for hematological toxicity, grade 4 (ANC<0.5 G/l or plts <25 G/l). Addition of G-CSF was recommended if ANC< 1 G/l before and during treatment. Response (IWG 2006 criteria) was evaluated after 2 and 4 cycles

Results: Between Nov 2006 and July 2007, 49 pts from 9 centres were included. 30 of them, included > 8 weeks before first interim analysis (1 July 2007), are analyzed here: 15 F, 15 M, median age 68 (range 35–85). 4 pts had received previous chemotherapy (2 LD AraC, 2 anthr-AraC). 2 pts had RA, 6 RAEB-1, 12 RAEB-2, 10 RAEB-T. 19 pts were IPSS high and 11 were int 2. Del 5q was isolated, with 1 additional and > 1 additional abn in 4, 8 and 18 pts respectively (resp) (in the last group, median n° of additional abn was 5, range 2–22). All pts had transfusion dependent anemia. Plts were < 100G/l in 16 pts (5 required plt transfusions) and ANC <1.5G/l in 28 pts. Median number of days of LEN received was 34 (range 14–126) . Dose reduction to 5 mg/d or 5mg / 2d was required in 11 pts and 1 pt resp, due to thrombocytopenia (n=9) neutropenia (n=2), rash (n=1). 1 pt stopped LEN after 2 weeks, for unrelated disorder without evidence of progression, and was excluded from analysis. 6 of the 29 evaluable pts (21%), had response (2 CR, 2 PR, 2 HI-E.) 3 (10%) pts died during the first course, from sepsis (2), cardiac failure (1) and the remaining 20 pts progressed within the 2 first cycles All responses were observed after 2 cycles. 2 and 3 of the responders achieved complete and partial cytogenetic response, resp. Duration of CR, PR, and HI-E was 5+ and 4 mos, 5+ and 4+ mos, 2+ and 2 mos, resp. CR or PR was achieved in 4 / 12 pts (33%) with isolated del 5q or with single additional abn vs 0/17 pts with >1 additional abn ; 3/19 pts (16%) with <20% blasts vs 1/10 with >20% blasts; and 4/14 (29%) with initial plts> 100G/l, vs 0/15 pts with lower plts. 18 pts were alive and 11pts had died after 6 to 210 days (median 80) from early death (n= 3, as seen above) or progression (n=8). Non fatal SAEs were sepsis (10), cardiac failure (2), CNS bleeding (1) thrombosis (1 ischemic colitis, 1 pulmonary embolism). Hospitalization was required in 28/29 pts during treatment. Median number of RBC and Plt transfusions during each cycle was 4 and 1.5 resp. 4 pts (all responding) remained on study.

Conclusion LEN as single agent, at the dose used, yielded significant responses in high and int 2 MDS with del 5q in the absence of cytogenetic complexity and of thrombocytopenia, while other patients generally progressed rapidly. Significant myelosuppression, requiring hospitalisation in almost all cases, was observed. Higher LEN doses, and/or combination to cytoreductive or hypomethylating agents, may improve results.