Treatment of Lower Risk MDS with Del 5q with Lenalidomide (LEN): Results of the French ATU Program.

LEN is particularly effective on anemia of lower risk MDS with del 5q (List et al, NEJM, 2006). A compassionate program (ATU) of LEN in low and int 1 risk MDS with del 5q and transfusion dependence was opened by the French health agency between Jan and Sept 2007.

Patients (pts) received 10 mg of LEN/day, 3 weeks on, 1 week off. Response was assessed after 8, 16, 32, and 48 weeks according to IWG 2006 criteria. After the first months of the program, G-CSF use was recommended in case of grade 3-4 neutropenia in order to avoid dose reduction.

95 pts from 35 centers were enrolled. Median age was 73 [42–92], M/F 25/70, median interval from diagnosis to LEN was 29 months (range 1–234). Median follow-up after inclusion was 16 months. At inclusion (WHO classification), 41 pts had del 5q syndrome, 8 RA, 9 RARS, 2 RCMD-RS, 10 RCMD, 1 CMML and 24 RAEB-1. IPSS was low in 29/95 (31%) and int-1 in 66/95 (69%). Del 5q was isolated, with 1 additional and > 1 additional abn in 75/95 (79%), 13/95 (14%), and 6/95 (6%) pts respectively (resp). 62 pts had previously received an erythropoietic stimulating agent (ESA). Median transfusion requirement was 4 units/2 months and platelet count < 100G/L and ANC < 1G/L present in 9.5% and 12.6%, resp.

62/95 pts (65%) achieved erythroid response, including 60 (63%) transfusion independence (TI). Median time to TI was 16 weeks. TI was achieved in 49/75 (65%), 7/13 (54%) and 4/6 (67%) pts with isolated del 5q, del 5q+1abn, del5q + >1abn, resp (p=0.5). Complete, partial and no cytogenetic response were observed in 20%, 40%, 40% pts resp. TI rate was not significantly influenced by concomitant G-CSF (n=25) vs no G-CSF (72% vs 60%, p=0,34), previous ESA vs no ESA (61 vs 73%, p=0.13), interval from diagnosis<2 years vs >2 years (69 vs 59%, p=0.5) or IPSS low vs Int-1 (52% vs 66.7%, p=0.36) but there was a trend for higher TI rate in pts with baseline platelets >100 G/l vs <100 G/l (68.4% vs 33%, p=0.06). Median daily dose of LEN during the first 16 weeks was 7.5 mg (2.5–10).

During the first 8 weeks, Grade III-IV neutropenia and thrombocytopenia were seen in 62% and 25% of cases, leading to dose reduction in 55% of the pts. 7 pts had early discontinuation of LEN due to non hematological side effects in 4 (diarrhea, thrombosis and skin reaction), patient decision in 1 and cytopenias in 2 pts. 8 pts developed deep venous thrombosis (DVT) after a median of 16 weeks (range 8–90) of LEN. 7 of them were females, 6 had achieved TI, none of them had experienced thrombocytopenia at week 8 and only 1 grade 3 thrombocytopenia at week 16. In pts who achieved TI and had reached Hb levels >13 g/dl, 5/31 (16%) developed DVT, compared to 1/29 (3%) with maximum Hb level <13 g/dl (p=0.1).

2 pts died from sepsis while having grade 4 neutropenia (in spite of G-CSF in 1 case) and 1 pt, died from CNS bleeding while having grade 4 thrombocytopenia. All 3 pts had pancytopenia at onset of LEN. Non hematological Grade 3-4 side effects were Quincke's oedema (n=1) and rash (n=1).

10 (16%) pts who achieved TI relapsed after a median time of 15 months (10–22). Median response duration was not reached.

With a median follow up of 16 months since LEN onset, 6 pts (6.3%) had progressed to AML 7–15 months (median 10) after LEN onset, and 12–149 months (median 25) after diagnosis. In those pts, whose median age was 71 (62–82), 2 had achieved TI, 4 (66%) had RAEB-1, 2 had isolated del 5q, and 4 had del 5q+1 abn), 2 had IPSS low and 4 int-1. At AML progression, 2/3 evaluable pt had persistant del 5q without new abn and 1 had an isolated t(1;3) without 5q deletion, that was already present at onset of LEN.

13 pts died during follow up, including 4 of those who had achieved TI. OS at 16 months was 86%, 95% and 66% in the whole cohort, in pts who achieved TI and in non responders, respectively (p=0.0005).

In a historical cohort of 37 lower risk MDS with del 5q treated before the LEN era, and included in GFM trials using ESA, with a median follow-up of 51 months since diagnosis (4–233), 7 pts (19%) had progressed to AML, 12–54 months (median 35) after diagnosis.

Our results confirm the high rate of TI achieved with LEN in lower risk MDS with del 5q with acceptable toxicity . Cytopenias should however be closely monitored during the first weeks of treatment, and our results also suggest that achieving Hb level> 13g (especially in females) may increase the risk of DVT. Finally, the rate of AML did not appear to be higher than in lower risk MDS with del 5q treated in the pre LEN era, although continued follow up remains necessary.

Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.