Prognostic Impact of Rare Single Abnormalities in Myelodysplastic Syndromes

Introduction: Since its implementation in 2012, the IPSS-R (Greenberg et al., 2012), defines the latest standard in risk stratification of patients with Myelodysplastic Syndromes (MDS). However, the prognostic impact of rare abnormalities remains unclear as yet because the number of these aberrations was too low to allow a valid statistical analysis. Hence, rare abnormalities were coalesced in one group in the IPSS and IPSS-R and, due to the unknown prognosis of these abnormalities, classified as prognostically intermediate. The main goal of the study presented here was to analyse the type, frequency and prognosis of rare single abnormalities in a large cohort of patients with primary, untreated MDS and integrate them in the existing IPSS-R in order to refine its predictive power.

Methods: The data set analyzed was derived from the IPSS-R database and extended by additional data  from European centers. In total, 7245 patients with primary, untreated MDS were included. Of these, we identified 410 (6%) pts. with rare single abnormalities. An aberration was defined as rare when it occurred in less than 10 patients in the cytogenetic scoring system that was the basis for the IPSS-R (Schanz et al., 2012). Additionally, further cytogenetic abnormalities not considered in this score were detected. A specific cytogenetic subgroup was defined as having at least n=5 cases with the same abnormality. Survival analyses was performed in cytogenetic subgroups with a minimum number of n=10 exclusively. The participating centers (in numerical order) were: Spain (n=110; 26.8%), MD Anderson Cancer Center (69; 16.8%), Düsseldorf (44; 10.8%), IMRAW (41; 10.0%), France (32; 7.8%), Pavia (21; 5.1%), Vienna (19; 4.6%), Japan (13; 3.2%), Vienna Medical University (12; 2.9%) Italy (11; 2.7%), Cleveland (10; 2.4%), Dundee (9; 2.2%), Brazil (8; 2.0%), Netherlands (5; 1.2%), Czech (2, 0.5%), Freiburg (1; 0.2%), Innsbruck (1; 0.2%), Sweden (1; 0.2%), and Russia (1; 0.2%). The median overall- (OS) and AML-free survival (AFS) was calculated for any specific cytogenetic subgroup.

Results: Rare single abnormalities detected were: der(1;7)(n=24; 5.9%), partial or total monosomy 13 (22; 5.4%), partial or total monosomy 9 (22; 5.4%), +21 (20; 4.9%), +mar (14; 3.4%), del(3p) (12; 2.9%), total or partial monosomy 21 (11; 2.7%), total or partial monosomy X (11; 2.7%), total or partial monosomy 18 (10; 2.4%), +1/+1q (10; 2.4%), del(17p) (9; 2.2%), total or partial monosomy 14 (9; 2.2%), total or partial monosomy 16 (9; 2.2%), total or partial monosomy 6 (9; 2.2%), total or partial monosomy 1 (8; 2.0%), t(11q23;varia) (7; 1.7%), total or partial monosomy 19 (6; 1.5%), +11/+11q (6; 1.5%), +13 (6; 1.5%), +14 (6; 1.5%), del(5p) (5; 1.2%), total or partial monosomy 2 (5; 1.2%), +15 (5; 1.2%) and +X (5; 1.2%) The remaining 159 patients (38.7%) showed very rare abnormalities occurring in less than 5 patients each. The median overall survival as well as the AML-free survival in each category will be presented in detail. Furthermore, a multivariate model including all relevant confounders and a  proposal to integrate these abnormalities in the cytogenetic module of the IPSS-R will be suggested.

Conclusions: In order to overcome the problem of their extremely low frequency, knowledge about rare single abnormalities in MDS can only be gained by large, international cooperative projects. The present study was performed to identify and comprehensively analyze rare abnormalities occurring in MDS, uninfluenced by therapy or additional abnormalities. The results will lead to a further refinement of the cytogenetic prognostic classification in patients with MDS.

The study was supported by a grant from the European Leukemia Net (ELN)