Lenalidomide (LEN) Combined to Intensive Chemotherapy (IC) In AML and Higher Risk MDS with Del 5q. Results of a Phase I/II Study of the Groupe Francophone Des Myelodysplasies (GFM)

Contrary to the “5q syndrome”, prognosis of MDS with del 5q with increased BM blast % and/or additional cytogenetic abnormalities (abn) and of AML with del 5q (isolated or complex) is poor. Furthermore, del 5q is present in 40–50% of higher risk MDS and AML with complex karyotype. Those patients respond poorly to IC with 20–30% CR, of short duration (Estey, Hematologica 2000) and to azacytidine (AZA) (Mufti, ASH 2009, abstr n° 1755). Lenalidomide (LEN) yields hematological but also frequently cytogenetic CR in lower risk MDS with del 5q. In a recent phase II study of LEN in higher risk MDS or AML with del 5q, 28% responded, some with cytogenetic responses, but with significant myelosuppression (Ades, Blood 2008). This prompted us to combine IC and REV in this patient population.

This still ongoing phase I/II study (Clinical trial.gov n° NCT00885508) combines induction DNR (45 mg/m2/d d1-3, escalated to 60 mg/m2/d d1-3) + AraC (200mg/m2/d d1-7) to LEN (10 mg/d d1-21)and G-CSF (from day 8 to end of aplasia) in IPSS int 2 or high MDS or AML with del 5q (isolated or not). Responders, ie CR, CRi or marrow CR according to AML criteria (Cheson JCO, 2003) receive 6 consolidation courses of DNR (45 mg/m2 d1), AraC (120 mg/m2/d×5) and LEN 10 mg/d d1-15, followed by maintenance LEN (14 days/month) until progression. After the first cohort at DNR 45 mg/m2/d d1-3 (n=31) proved safe, escalation to DNR 60 mg/m2/d during induction and consolidation courses was made (n=17).

Between Feb 2009 and April 2010, 48 pts from 11 centres were included: 22 Female, 26 Male, median age was 65 years (range 30–79), 36 (75%) AML and 12 (25%) RAEB-2 (WHO classification). 38/48 (79%) pts had complex Karyotype (median number of 6 abn (range 2–13) in addition to del 5q), 5 pts had isolated del 5q and 5 pts had del 5q+1 abn. 11 (23%) pts had therapy related disease. At inclusion, ECOG was 0 in 14 pts, 1 in 21 pts, 2 in 4 pts and 3 in 1 pt (8 missing data). Median baseline WBC, platelets and Hb level were 2.85 G/l (0.7-100), 45 G/l (11-213) and 8.7 g/dl (7.2-11.5) respectively (resp). 31 pts were included in the fist cohort (DNR 45 mg/m2) and 17 were included in the second cohort (DNR 60 mg). All but 7 pts received the planned schedule of LEN (21 days).

Overall, 5 pts had early death related to severe sepsis in 3, multiorgan failure in 1 and myocardial infarction in 1 pt. Median duration of hospitalisation during induction treatment was 30.5 days (range 19–43). In responders, median ti me to ANC>1G/l and platelet >50G/l was 23 days (range 1–36) and 22 days (range 9–38), 19 d and 19 d, 24d and 24d in the whole cohort, in DNR45 cohort and in DNR60 cohort resp (p=0.1). Median number of RBC and platelet units transfused during induction treatment was 9 (4-16) and 7 (3-21), resp.

24 pts (50%) achieved CR, 1 achieved CRi (2%), 1 PR (2%) and 3 pts (6%) normalized PB count without marrow response, leading to an ORR of 29/48 (60%). Of the 17 pts with hematological CR/CRi evaluable for cytogenetic response, 8 (Including 4 complex karyotype, 3 isolated del 5q and 1 del5q+1 abn) achieved cytogenetic CR, 5 cytogenetic PR and 4 had no cytogenetic response.

Eight of 12 (66%) MDS achieved CR/CRi compared to 17/36 (47%) AML (p=0.32). Four of 5 (80%), 4/5 (80%) and 17/38 (45%) pts with isolated del5q, del5q+1 abn and complex carytotype, resp, achieved CR/CRi (p=0.134). 17 of 31 (55%) pts in the DNR45 cohort achieved CR, vs 8/17 (47%) pts in the DNR60 cohort (p=0.76). Sex, ECOG status, Age, WBC count, Hb level, Platelet count had no effet on CR achievement. Among the 25 pts in CR, 14 relapsed and 2 died in CR (1 during consolidations and 1 after SCT). 1y DFS was 26.5% and significantly shorter in females (p=0.03) while other factors did not influence DFS. Estimated 2y OS was 30% and WHO diagnosis, Sex, Karyotype, and ECOG had no impact on OS.

Intensive chemotherapy (IC) and LEN can be combined in higher risk MDS and AML with del 5q without unexpected additive myelosuppression or extra hematological DLT. In this cohort of elderly pts with very poor cytogenetics, The CR rate was 50%, higher than generally reported with CT alone in similar pts. DFS remained however short, suggesting that induction or consolidation therapy should be improved. Based on the better efficacy of DNR 90 mg/m2/d (Lowenberg et al, and Fernandez H et al, NEJM, 2009) in the chemotherapy of elderly AML, and the adequate tolerance in our DNR 60 cohort, we will increase the DNR dose to 90 mg/m2/d in a next patient cohort.

Off Label Use: Lenalidomide in the treatment of AML and High risk MDS. Fenaux:CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.