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

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 neutropenia	46.8/ 27.3	39.7 /17.6
Antibiotics for fever at home	6.9	7
Hospitalization for febrile neutropenia	0.5	2.7
RBC transfusions	5	5.4
Gr 3 Thrombopenia	20	16
Platelets transfusion	8.6	7.9
Interval between courses > 35 days	26.1	18.4
Median time interval between courses	31 d	28 d
Courses with doses reductions	9.6	21.6

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 N	DFS median mo	P VALUE	1y DFS %	2y DFS %
All patients	56	65	7.9		41.5	12.3
Age ≥ 70	58.3	28	8.6 vs 7.7		46.4	17.9
WBC ≥ 3.3 G/L	48.1	26	7.0 vs12.4		23.1	11.5
Previous MDS	51.9	27	13.8 vs 6.4	.05	51.9	22.2
MDS only	68.4	13	16.8 vs 6.4	.008	69.2	30.8
Previous cancer	54	20	7.5  vs 7.9		35	5
Cancer only	80	8	12.4  vs 7.75		50	12.5
Poor cytogenetic	53	44	5.1 vs 15.3	.04	29.5	6.8
Complex caryotype	49.2	32	4.8 vs 12.9	.012	25	9.4
Monosomal caryotype	50	27	4.6 vs 12.9	.002	18.5	7.4
Chromosome 5 abnormality	52.5	32	5 vs 13.8	.002	18.8	6.3
Chromosome 7 abnormality	54.5	24	3.6 vs 12	.001	20.8	4.2
3q	55.6	5	10.4 vs 7.7		40	0
17p deletion	48.5	16	5.0 vs 10.5		25	12.5
MLL	80	4	3.4 vs 8.4		25	0
poor cytogenetic + MDS	42.9	9	7.7 vs 7.9		44.4	22
poor cytogenetic + cancer	46.7	7	4.8 vs 7.9		28.9	0
poor cytogenetic + cancer + MDS	71.4	5	3.4 vs 8.4		20	0
cancer + MDS	0	0	-		-	-
Poor cytogenetic only rev aza	57.5	23	6.3 vs 12.9	.055	21.7	4.3
Poor cytogenetic only SA2	55	43	6.4		30.2	20.9

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.