Safety and Long-Term Efficacy of Maintenance Therapy with Alternating Azacytidine (AZA) and Lenalidomide (Len) 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
Authors: Hunault Mathilde , Maillard Nathalie , Tanguy-Schmidt Aline , Himberlin Chantal , Choufi Bachra , Bonmati Caroline , Couturier Marie Anne , Deconinck Eric , Marolleau Jean Pierre , Orsini-Piocelle Frédérique , Delaunay Jacques , Tavernier Emmanuelle , Récher Christian , Lissandre Severine , Ojeda-Uribe Mario , Sanhes Laurence , Sutton Laurent , Banos Anne , Lioure Bruno , Bernard Marc , Bouscary Didier , Saad Alain , Rouille Valérie , Guardiola Philippe , Luquet Isabelle , Bene Marie C , Dreyfus Francois , Cahn Jean-Yves , Pigneux Arnaud , Ifrah Norbert 
Published: October 2019

Abstract
In elderly pts, the prognosis of AML associated with poor risk cytogenetics or secondary to either MDS or previous cancer is so bad that only supportive care or investigational studies are usually recommended. Fit patients may achieve CR after conventional induction, but early relapse appears to be nearly inescapable whatever classical consolidation or maintenance therapy is used. Therefore, the GOELAMS investigated the impact of a maintenance using two agents mainly used in MDS, ie AZA and Len.
Between March 2011 and February 2013, 117 pts from 27 centers (median age 69 yrs; 60-80) with previously untreated poor prognosis AML were included. Poor Risk factors were either preceding MDS (n=52), previous cancer (n=37) or centrally reviewed (IL) poor risk cytogenetics (n=83) defined as complex karyotype (≥3 abnormalities, n=65), monosomal karyotypes (n=54), del or - 5 (n=61) or 7 (n=44), 3q abnormality (n=9) or MLL rearrangement except for t(9;11) (n=5). Median WBC was 2.9 G/L (0.5-160), 7 pts had WBC ≥ 30 G/L. Induction chemotherapy included Lomustine 200 mg/m² po d1, Idarubicine 8 mg/m²/d (d1-5), Cytarabine 100mg/m²/d CI (d1-7). Patients in CR received 12 maintenance cycles alternating every 28 days AZA (sc 75 mg/m²/d1-7) and Len (10mg/d1-21), which started if PMN and platelets were >1 G/L and 100 G/L respectively. After d42, subsequent cycles were reduced to 50 mg/m²/d and 5 mg/d. GCSF was allowed in case of PMN < 0.5 G/L after 7 days or febrile neutropenia. At the end of induction, CR was achieved in 56% (65 pts) without any predictive factor, 9% died from infection (n=6), cerebral hemorrhage (n=1) or MOF (n=4) and 35% (41pts including 5 CRp) failed to achieve CR. The 12 planned maintenance courses could be given to 21 pts (32%) (median: 6). Few toxicities were observed. AZA courses were slightly more toxic than Len courses (table 1). Table 1.AZA courses %Len courses %Gr 3/4 neutropenia46.8/ 27.339.7 /17.6Antibiotics for fever at home6.97Hospitalization for febrile neutropenia0.52.7RBC transfusions55.4Gr 3 Thrombopenia2016Platelets transfusion8.67.9Interval between courses > 35 days26.118.4Median time interval between courses31 d28 dCourses with doses reductions9.621.6
Maintenance courses were interrupted because of relapse (n= 34, 77%), alloSCT (n=4 %), count error (n=1 %) or toxicities (n =5, 11%) occurring after Len (depression, vascular purpura and pseudomembranous diarrhea, sudden death, all during cycle 1) or after Aza (atrial fibrillation and cardiac dysfunction). Twenty Gr3/4 AE were reported among 441 cycles (0.56%/courses). Median follow-up for survivors was 38 mo (26-47). Median OS was 10 mo, with 21% 2y OS. Median CR duration was 7 mo (1-30). Impact of prognostic factors on DFS is shown table 2. Within poor risk factors, Cytogenetic abnormalities appeared as even poorer than previous MDS or cancer. Table 2.CR %CR NDFS median moP VALUE1y DFS %2y DFS %All patients56657.941.512.3Age ≥ 7058.3288.6 vs 7.746.417.9WBC ≥ 3.3 G/L48.1267.0 vs12.423.111.5Previous MDS51.92713.8 vs 6.4.0551.922.2MDS only68.41316.8 vs 6.4.00869.230.8Previous cancer54207.5 vs 7.9355Cancer only80812.4 vs 7.755012.5Poor cytogenetic53445.1 vs 15.3.0429.56.8Complex caryotype49.2324.8 vs 12.9.012259.4Monosomal caryotype50274.6 vs 12.9.00218.57.4Chromosome 5 abnormality52.5325 vs 13.8.00218.86.3Chromosome 7 abnormality54.5243.6 vs 12.00120.84.23q55.6510.4 vs 7.740017p deletion48.5165.0 vs 10.52512.5MLL8043.4 vs 8.4250poor cytogenetic + MDS42.997.7 vs 7.944.422poor cytogenetic + cancer46.774.8 vs 7.928.90poor cytogenetic + cancer + MDS71.453.4 vs 8.4200cancer + MDS00---Poor cytogenetic only rev aza57.5236.3 vs 12.9.05521.74.3Poor cytogenetic only SA255436.430.220.9
In the previous GOELAMS SA2 trial, 78 pts with poor risk cytogenetics without secondary leukemia received the same LIA induction followed in CR by maintenance therapy with 6 mini-reinductions (Ida 10mg/m² d1, cytarabine 50 mg/m²x2/d d1-5) and 6MP-MTX for 2years. In the present study, the DFS of the group of pts with poor risk cytogenetics without previous cancer or MDS is very similar.
This alternating azacitidine/lenalidomide maintenance improved DFS and OS of pts without poor risk cytogenetics (median 15.7 and 24 mo). In this setting, it could be randomly compared to conventional chemotherapy maintenance.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.