A Phase I-II Study Of The Efficacy and Safety Of Lenalidomide (LEN) Combined To Azacitidine (AZA) In Higher Risk MDS and AML With Del 5q – A Study By The Groupe Francophone Des Myelodysplasies (GFM)

Higher risk MDS and AML with del(5q) carry very poor prognosis, but show some response to AZA and LEN as single agents (Adès et al. Blood 2009, Itzykson, Blood, 2010). The combination of LEN and AZA has been tested in non-del 5q MDS patients with encouraging results and limited toxicity (Sekeres, Blood 2012). Sequential combination of AZA and LEN has also shown to be feasible and potentially effective in higher-risk MDS with del(5q) in a phase I study (Platzbecker et al, Leukemia 2013 ). In this phase I-II trial, we combined escalating doses of LEN to AZA in higher risk MDS and AML with del(5q).

Patients aged 18 or more, with IPSS int-2 or high MDS, CMML with WBC < 13,000/mm3 and marrow blasts > 10% and AML (20-30% marrow blasts) with 5q deletion with or without additional cytogenetic abnormalities could be included provided they had not previously received LEN or AZA. Patients should also have contra indication to intensive chemotherapy (IC), precluding inclusion in a GFM competing trial combining IC and LEN in higher risk MDS and AML with del 5q (results of that trial are also submitted to ASH 2013). In the present trial, patients received AZA (75 mg/m2 x5days, every 28 days) combined to escalating doses of LEN (5 mg/d x14 days in cohort 1, 5 mg/d x21 days in cohort 2 and 10 mg/d x21 days in cohort 3). For patients in hematological CR, PR , HI or marrow CR (MDS) and CR or PR (AML) after cycle 2 or 4, treatment was to be continued at the same schedule unless unacceptable toxicity or overt progression occurred. The main endpoint was response assessed after 2-4 cycles (IWG 2006 criteria). Median [IQR] are reported unless specified.

35 patients were enrolled in the study, including 15, 10 and 10 patients in cohort 1 (LEN 5mg/d x14d), 2 (LEN 5mg/d x21d) and 3 (LEN 10mg/d x21d) respectively. 18 were males and the median age was 68.9 (62.7-73). According to WHO classification, 1 patient had CMML, 7 RAEB1, 15 RAEB2 and 11 AML (with 20 to 30% marrow blasts). PS was 0, 1, 2 in 31%, 40%, 29% patients respectively. However, as said above, patients included in this trial were considered unfit for IC due to their age and/or comorbidities including cardiovascular events in 23 patients (still active in 19 at inclusion), pulmonary events in 7 (still active in 5), and neurological events in 6 pts. Del(5q) was isolated in only 2 pts, and 33 pts (94%) had del (5q) and at least 2 additional abnormalities. Baseline platelet count was 50 G/L (25-74), baseline Hb level was 9.15 (8.60-9.80), and baseline ANC was 1 G/l (0.545-1.66), including 38% patients with less than 0.8 G/L. IPSS was int-2 in 27% patients and high in 73% patients.

With a median follow-up of 3.5 months, 98 cycles were administered (median 2 /patient, including 4 patients who received 6 or more cycles). In the three cohorts, the median number of cycles received was 2, 2 and 2 respectively.

15 (43%) patients discontinued treatment before the second cycle, due to early death (n=10), adverse events (n=2), progression (n=2), or CNS hemorrhage (n=1). They were all considered as non responders (primary endpoint). Of the 35 pts, 4 (11%) achieved CR and 2 (5.5 %) marrow CR after 2 cycles. After 4 cycles, The 2 marrow CR converted into CR and one additional patient achieved stable disease with HI leading to an overall response rate (ORR) of 7 (20%). The ORR was 13% in cohort 1, 10% in cohort 2, and 30% in cohort 3 (p=0.53). 4/6 complete responders achieved cytogenetic response, including 1 complete (CCyR) and 3 partial. The 6 CR included one of the 2 patients with isolated del(5q), who also obtained CCyR, and 5 of the 33 (15%) patients with complex karyotype. One year OS was 39%.

Regarding toxicity, 31 SAEs (grade 3-4) were reported in 19 patients, including 1 cardiovascular event, 6 pulmonary infection, 5 gut events, 3 neurological events. No difference in grade >2 toxicity was seen in the 3 cohorts (10, 10, and 11 events, respectively).

In this elderly population of higher risk MDS or AML considered unfit for intensive chemotherapy , and with del 5q that was part of a complex karyotype in almost all cases , the combination of AZA with escalated doses of LEN was associated with early discontinuation (<4 cycles) in 43% of the patients, mostly due to progression or toxicity, and only 20 % response (including 17% CR). The fact that 15% of patients with del 5q and complex karyotype achieved CR, with cytogenetic response in several cases, may however be encouraging.

Off Label Use: LEN in higher risk MDS. Fenaux:CELGENE: Research Funding.