Early Treatment of Anemia of Lower Risk MDS by Erythropoiesis-Stimulating Agents (ESAs): A Report On 112 Cases.

ESAs are frequently effective in anemia of lower risk MDS, and at least 2 groups have shown that ESAs did not increase the risk of AML progression while possibly improving overall survival (OS) in those patients (pts) (Blood 2008:111: 574-582, JCO 2008, 26: 3607-13). Although responses to ESAs are generally transient and most pts ultimately require RBC transfusions, ESAs are increasingly used before RBC transfusion requirement, and we evaluated this attitude in our GFM experience. Patients : In a cohort of 403 MDS patients (pts) treated with ESAs either in GFM clinical trials or according to GFM therapeutic guidelines (www.gfmgroup.org)(Blood 2008:111: 574-582), 112 pts had de novo low or int-1 IPSS MDS with Hb<10g/dl, serum EPO<500UI/l, no del 5q and had never been transfused.

Median age of the 112 pts was 75y (range 47-91), including 21 RA, 22 RAEB-1, 34 RARS, 19 RCMD, and 16 RCMD-RS. Karyotype was favorable (n=80), intermediate (n=15), missing (n=17, but those pts had isolated anemia and no excess of blasts), IPSS was low (n=39), int-1 (n=56). Median Hb level at onset of ESA was 9.2g/dl (range 8.0-10). Median endogenous EPO level was 51UI/l (10-397 UI/l). Pts received: epoietin alfa 16%, epoietin beta 27%, darbepoeitin 31%, GCSF was added in 16% pts. 70 (63%) pts had erythroid response at 12 weeks (IWG 2006 criteria). After a median follow-up of 29 months, 36 (51%) of them were still responders while 34 (49%) had relapsed after a median duration of response of 28.2 months (range 3-74). In univariate analysis (IWG 2006 criteria), EPO level =<100 U/l (72% response versus 30% with EPO> 100 U/l, p=0.0003) and interval from diagnosis to onset of ESA < 6 months (76% response, versus 46% if the interval was >=6 months, p=0.0005), were associated with higher response rate. In multivariate analysis, interval from diagnosis to onset of ESA <6 months (p=0.01), Hb level >=9g/dl (p=0.04) and serum EPO =<100UI/l (p=0.02), predicted better response to ESA. Allocating one point to each of those 3 parameters resulted in a score where pts could be dichotomized as follows: serum EPO =<100 UI/l: 1 point/ serum EPO>100 UI/l: 0 point; / interval diagnosis- onset of ESA<6 months: 1 point/ >=6 months: 0 point/ Hb level >=9g/dl: 1 point/ <9 g/dl: 0 point. By summing up each category points, a score of 0, 1, 2, or 3 was obtained with a corresponding response rate of 0%, 30, 67% and 89% respectively. Onset of ESA within 6 months of diagnosis was associated with a median response duration of 30 months, vs 20 months in pts who started ESA>= 6 months after diagnosis (p=0.07) In multivariate analysis, shorter time between diagnosis and onset of ESA (p=0.009), lower serum EPO level (p=0.04) and RCMD-RS (compared to other WHO subtypes) (p=0.03) were associated with longer response to ESA. Median interval from diagnosis to first RBC transfusion requirement was 80 months in pts with onset of ESA within 6 months of diagnosis and 35 months in patients who started ESA later (p =0.007), a somewhat unexpected finding because more rapidly evolving anemia may be for many physicians an incentive for earlier onset of ESA. Freedom from AML-progression (FFP) at 5 years was significantly higher in responders (90%) than in non-responders (61%) (p=0.006). Median overall survival (OS) from onset of ESA was 73.5 months in responders and 42.7 months in non-responders (p=0.14). FFP and OS did not differ according to onset of ESA within 6 months or >=6 months from diagnosis.

ESA onset within 6 months of diagnosis, in lower risk MDS with Hb<10g/dl not requiring RBC transfusions and with serum EPO level <500U/l, was associated with higher response rates and a trend for more prolonged responses, supporting a benefit of early onset of ESA to avoid the consequences of anemia. Our study could also suggest that early introduction of ESA can delay the need for RBC transfusions during disease evolution, hypothetically by slowing the disease course, but randomized studies are required to document this point.

Rose:Novartis: Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.