Prognosis of MDS Subtypes RARS, RCMD and RCMD-RS Does Not Differ by Cytomorphologic Criteria but Cytogenetics Allows to Delineate a Subgroup with Inferior Clinical Course,

In 2008 the WHO classification combined the former categories RCMD (refractory cytopenia with multilineage dysplasia) and RCMD-RS (with ring sideroblasts ≥15%) thus not separating according to ring sideroblasts anymore in MDS with multilineage dysplasia, while the category refractory anemia with ring sideroblasts (RARS) was maintained separately. One aim of this study was to evaluate whether or not a separation with respect to ring sideroblasts is reasonable. Study Design: To investigate the clinical impact and genetic background of these MDS subtypes, we studied outcomes, cytogenetics, and molecular genetics in 1082 de novo MDS pts (153 RARS, 606 RCMD, 323 RCMD with ring sideroblasts ≥15% termed “RCMD-RS“): 703 m/379 f; median age, 73.1 yrs; 21.0–90.4 yrs. Cytogenetic risk groups were defined according to the International Prognostic Scoring System (IPSS; Greenberg et al., 1997). Results: Sex ratio (male preponderance in all subtypes; male/female ratio 1.9 in the whole cohort) did not differ significantly between the 3 MDS subgroups. Mean age (RARS: 71.8; RCMD: 70.1; RCMD-RS: 72.6 yrs) reached significant difference between RARS vs RCMD (p=0.020) and between RCMD vs RCMD-RS (p=0.004). Mean WBC count differed between all subgroups (RARS: 6.1; RCMD: 4.4; RCMD-RS: 5.3×10(9)/l; RARS vs RCMD p<0.001; RARS vs RCMD-RS p=0.039; RCMD vs RCMD-RS p<0.001) whereas mean platelet count (RARS: 232; RCMD: 144; RCMD-RS: 218 × 10(9)/l) and Hb level (RARS: 96; RCMD: 105; RCMD-RS: 98 g/l) differed between RARS vs RCMD and RCMD vs RCMD-RS (all p-values <0.001). IPSS categories were available in 854/1082 pts as follows: 514 pts (60.2%) low-risk, 312 (36.5%) intermediate-1, and only 28 (3.3%) intermediate-2 risk (no pt was assigned to high risk IPSS). Cytogenetics was available in all 1082 pts: The majority (918/1082; 84.4%) had good karyotypes (KTs) according to IPSS mainly due to high rates of normal KTs (821/1082, 75.9%); 112 pts had intermediate (10.4%); and only 52 (4.8%) had poor KTs. In detail, good KTs were equally distributed in RARS: 123/153; 80.4%; in RCMD: 530/606; 87.5%; and in RCMD-RS: 265/323; 82.0%. 3-yr overall survival (OS) rates did not differ significantly between the three MDS subtypes (RARS: 78.1%; RCMD: 86.7%; RCMD-RS: 80.6%). Also when entities with ≥15% ring sideroblasts (RARS + RCMD-RS) were compared to RCMD (<15% ring sideroblasts), 3-yr OS rate was similar (80.0% vs 86.7%; n.s.). Further, multilineage dysplasia per se did not impact on 3-yr OS rate (RCMD + RCMD-RS: 83.8% vs 78.1% in RARS; n.s.). In contrast, 3-year OS rate was better in good KTs compared to intermediate or poor KTs (91.4% vs 60.0% vs 29.3%; p<0.001) in the total cohort. Also in the different MDS subtypes, good karyotypes showed better 3-year OS rate than intermediate/poor karyotypes (p-values for comparison of cytogenetic risk groups: RARS: p<0.001; RCMD: p=0.032; RCMD-RS: p=0.007). In subcohorts genes were analysed and were found to be mutated only with low frequencies: RUNX1 mut: 14/213 (6.6%), NRAS mut: 1/283 (0.4%), MLL -PTD: 4/294 (1.4%), FLT3 -ITD: 0/285. This underlines the low risk profile of the cohort. In univariable analysis, good + intermediate vs poor KTs (p<0.001), aberrant vs normal KT (p<0.001), age (p=0.080), and Hb level (both continuous; p=0.007) had a significant impact on OS, while WBC count, platelets, and percentage of ring sideroblasts (all as continuous variables) were not significant. In multivariable analysis, IPSS cytogenetic risk groups (p=0.005) and Hb (p=0.008) only remained significant. Conclusions: As investigated here in 1082 pts, RARS, RCMD, and RCMD-RS all show high rates of good karyotypes as defined by IPSS and show similar clinical outcomes which clearly supports to skip the RCMD-RS category as done by the WHO in 2008. The karyotype and Hb level were the only independent prognostically relevant parameters in multivariable analysis. However, >80% of patients show a good risk cytogenetic profile making prognostication according to karyotype relevant only in a small subset of patients. To overcome this shortcoming only an increasing panel of new molecular markers in MDS can pave future investigations which presently becomes available by the advanced sequencing techniques. After diagnosed by morphology and cytogenetics especially molecular genetic information may therefore guide treatment in the near future for this low risk subgroup of MDS patients as investigated here.

Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.