Lenalidomide (LEN) Combined to Intensive Chemotherapy (IC) in AML and Higher Risk MDS with Del 5q. Interim Results of a Phase I/II Study.

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 et al. Hematologica 2000) and to azacytidine (AZA) (Itzykson, ASH 2008, abstr n° 2682). 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 (Blood, 2009, vol 113, 3947-52). 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 Daunorubicin (DNR) (45 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 (45mg/m2 d1), AraC (120 mg/m2/d d1-5) and LEN 10 mg/d d1-15, followed by maintenance LEN until progression. After the first cohort at this dosing level, escalation to DNR 60 mg/m2/d was planned in the absence of major dose limiting toxicity (DLT), while dose reduction to DNR 30mg/m2/d was planned in case of DLT. We report here results of the first cohort, at the reference date of Aug 1^st 2009.

Between Feb 2009 and June 2009, 18 patients from 9 centres were included, of whom 17 were evaluable (1 patient did not receive the treatment): 8 F, 9 M, median age 64 (range 30–79), 12 AML and 5 RAEB-2 (WHO classification). 16/17 patients had complex Karyotype (median number of 6 abnormalities (range 2-12) in addition to del 5q) and 1 AML had only one additional abnormality. 4 patients had received previous treatment (1 LD AraC alone, 2 AZA alone and 1 LEN followed by LD AraC and AZA), without response and 5 patients had therapy related disease. At inclusion, ECOG was 0 in 44%, 1 in 44% and 2 in 12%. Median baseline WBC, platelets and Hb level were 2.7 G/l (1.1-13.6), 28 G/l (11-135) and 9 g/dl (7.3-11.5). 2 patients had early discontinuation of LEN (d17 and d13) due to grade 3 increase in bilirubin in 1 patient and multiorgan failure related to sepsis in 1 patient. All 15 other patients received the entire induction course, without dose reduction of LEN or CT. 2 patients had early death (at d24 and d22) from multiorgan failure and fungal infection, respectively. Median duration of hospitalisation was 32 days (24-38). In responders, median time to ANC>1 G/l and platelet >50 G/l was 22 days (15-30) and 23 days (11-28), respectively. Median number of RBC and platelet units transfused in those patients was 8 (4-16) and 7 (2-12), respectively. 7 patients (41%) achieved CR, 1 achieved CRi (6%), 1 PR (6%) and 1 additional MDS patient restored normal PB count without marrow response, leading to an ORR of 10/17 (58%). Of the 8 patients who achieved hematological CR or CRi, 3 (with initially 4, 7 and 10 cytogenetic abnormalities, respectively) achieved cytogenetic CR, 3 cytogenetic PR and 2 had no significant cytogenetic response. All the pts who achieved CR could receive consolidation courses.

Intensive chemotherapy and LEN can be combined in higher risk MDS and AML with del 5q without leading to unexpected additive myelosuppression or to extra hematological DLT. 41%, 6% and 6% pts achived CR, CRi and PR respectively, in in population with limited response to other treatments. As DLT was not reached in this cohort, dose escalation is planned in the next pts. Updated results will be presented.

Off Label Use: lenalidomide is approved by FDA and EMEA only in the treatment of low risk MDS with 5q deletion. Fenaux:CELGENE: Research Funding.