Should Immunosuppressive Therapy (IST) Be Used More Often In Lower Risk MDS?

Erythropoiesis stimulating agents (ESA) or lenalidomide (in case of del 5q) are the usual first line treatments of anemia of low/int-1 IPSS (lower) risk MDS. After their failure, IST with ATG+/−CsA is among the approaches considered, with 30 to 50% erythroid response (Sloand, JCO 2008; Lim, Leukemia 2007, and others), including durable red cell transfusion independence (RBC-TI). In multivariate analysis, predictors of response to IST in MDS include low/Int-1IPSS (especially int-1 without excess blasts due to presence, in addition of anemia, of thrombocytopenia or intermediate (int) karyotype) and, depending on studies, age ≤60 y and HLA DR-15 positivity. Pts with those good prognostic factors were however overrepresented in several MDS series treated with IST and analysis of the first 400 pts included in the European LeukemiaNet lower risk MDS registry found only 2 pts treated with IST (De Witte, personal communication). We reviewed the characteristics and outcome of MDS pts treated with IST in our centre and assessed the frequency of low/int-1 MDS pts potentially candidates to IST, based on published prognostic factors, in the Groupe Francophone des Myélodysplasies (GFM) patient database.

From Jan 2004 to Feb 2010, we treated in our center 12 MDS by IST. From mid 2003 to end of 2008, 1311 MDS pts with IPSS scoring, were entered into the GFM registry. We computed in this registry the frequency of pt subsets potentially good candidates to IST based on age, having anemia with low/int-1 IPSS, or int-1 with <5% marrow blasts (i.e due to associated thrombocytopenia or int karyotype). HLA DR-15 typing was not available in that registry.

The 12 pts treated with IST included 8M/4F. Median age was 63.5 y, (range 47–78, 50% pts older than 65 y). WHO classification was RA =3, RCMD =7, RAEB1 =2; cytogenetics normal /-Y =10; +8 =1; failed =1 pts). IPSS was Int-2 in 1, Int-1 in 10 and ND in 1 pt. All pts were RBC transfusion dependent and 11/12 also had platelets ≤50G/L. Pts received ATG (n=7) or ATG+CsA (n=5). Five (42%) pts, all with RA or RCMD, were responders at 6 months, according to IWG 2006 criteria (4 RBC-TI including 3 CR and one HI-E+ HI-P) and 7 were non-responders (NR). 4/6 DR-15 positive pts responded versus 1/5 DR-15 negative pts.Three of the 6 pts aged >65 y responded. With a median follow-up of 21.5 months (6-68), erythroid response was ongoing after 17, 21, 44, 47 and 62 months, respectively. Three NR pts died at 11, 16 and 18 months (one Int-2 pt with RAEB and +8, from AML progression, and 2 pts from marrow failure). In the GFM database, pts with transfusion dependent anemia and IPSS low or int-1, and IPSS int-1 with <5% marrow blasts (i.e with associated thrombocytopenia or int karyotype) represented respectively 20 and 5.5% of the total pt number considering only pts aged <60 y, 22 and 6.5% considering pts <65 y, and 24 and 6.5 % considering pts <70 y.

We confirm that durable erythroid responses to IST can be obtained in selected int-1 MDS patients, including in some pts aged >65 y. In the GFM data base of # 1300 pts, and based on published prognostic factors, the proportion of potential candidates to IST was very low if the age limit chosen was < 60y, and only slightly increased if the age limit was set to 65 or 70 years. Use of low-dose alentuzumab (Sloand, ASH 2009, abstr n°116), which appears to have less immediate toxicity than ATG (and therefore can be envisaged more easily above 60–65 years) may possibly extend the number of lower risk MDS that may benefit from IST.

Off Label Use: ATG ciclosporine.