Maintenance Therapy With Alternating Azacytidine and Lenalidomide Cycles In Elderly (≥ 60) Fit Patients (Pts) With Poor Prognosis AML In First Complete Remission (CR) After Lia Induction. A Phase II Multicentric Goelams Trial

The prognosis of poor risk AML in elderly pts justifies either supportive care only or investigational studies without obvious benefit of post-remission chemotherapies. A phase I study has demonstrated that the combination of azacitidine and lenalidomide is well-tolerated in AML with efficacy superior to that of single-agent therapy in higher-risk MDS (Sekeres JCO2010). The GOELAMS group investigated the efficacy of 12 maintenance cycles alternating monthly azacitidine (sc 75 mg/m²/d1-7) and lenalidomide (10mg/d1-21) every 28 days for pts in CR and compared the results to previous SA2002 and BGMT95 prospective trials which shared the same LIA induction followed by chemotherapy-based maintenance.

Between 3/2011 and 2/2013, 117 pts from 27 centers (median age 69 yrs; 60-80, 9 pts ≥ 75) with previously untreated poor prognosis AML were included. Risk factors allowing inclusion were either: i) centrally reviewed (IL) poor risk cytogenetics (n=83) defined as complex karyotype (≥3 abnormalities), monosomal karyotype, t(6;9), del or – 5 or 7, and EVI1 or MLL rearrangement except for t(9;11); ii) preceding MDS (n=52) or iii) secondary leukemia occurring after previous cancer (n=37). Median WBC was 2.9 G/L (0.5-160), 19 pts had WBC > 30 G/L. Induction chemotherapy included lomustine 200 mg/m² po d1, Idarabucine 8 mg/m²/d (d1-5), cytarabine 100mg/m²/d CI (d1-7) and G-CSF (d15 to recovery).

At the end of induction, CR (excluding CRp) was achieved in 56% (65 pts), 9% died from infection (n=6), cerebral hemorrhage (n=1) or multiorgan failure (n=4) and 35% (41pts) failed to achieve CR. Despite a trend towards a higher CR rate in pts without previous MDS (59% vs 48% CR), CR was not related to any of the risk factors studied. Median follow-up for survivors is 16 months (3-25). Monthly alternating azacitidine-lenalidomide maintenance therapy was started in 65 pts. Except for 1 pt who died during cycle1 of lenalidomide without any obvious explanation, tolerance was good. Median nadir of neutrophils and platelets was 1 and 96 G/L respectively. Grade 3/4 adverse events occurred in 6% of cycles and were due to infection, haemorrhage, hepatitis or fatigue (3%, 1%, 0.5%, 0.5% of cycles respectively). Median CR duration was 4.5 mo (1-23) and 40 pts relapsed. Allogeneic SCT with non myelo-ablative preparative regimen was performed in 4 pts less than 70 years in CR1: 1 is alive in relapse, 2 died of GVH and 1 is in continuous CR. Pts achieving CR had a median OS of 13 mo (95% CI 7.3-18.6), 54% being alive at 1 year and 15% at 2y. In refractory pts, the median OS was 7 mo (95% CI 2.8-11.2) with 32% alive at 1 year (P = 0.0001). OS and DFS reported in the current trial and compared to historical controls are described below:

induction results are similar to those observed in the 128 poor risk cytogenetic pts of the previous SA2002/BGMT trials treated with the same LIA induction (CR 58%, early death 15%, failure 27%) but who received maintenance therapy with 6 mini-reinductions (Ida 10mg/m² d1, cytarabine 50 mg/m²x2/d d1-5) and 6MP-MTX for 2years. No significant survival benefit was observed compared to pts with poor risk cytogenetics treated with chemotherapy maintenance in our previous trials. However, pts included in this trial have probably an even worse prognostic than those included in the GOELAMSSA2/BGMT95 trial which excluded AML secondary to MDS and previous cancers. This type of alternating azacitidine/lenalidomide maintenance improves OS and DFS of pts without poor risk cytogenetics (median DFS not reached and 19 mo) and could be randomly compared with conventional chemotherapy maintenance in AML secondary to MDS or cancer but also in older pts with intermediate risk cytogenetics.