A Comparative Analysis of Outcomes in Primary Myelodysplastic Syndrome (MDS) and Therapy-Related MDS Reveals Two Subgroups with Differing Risk Profiles: Implications for the Application of a Prognostic Classification.
Authors: Alvares Caroline , Ashley Sue , Saso Radovan , Patel Gita , Qureshi Amrana , Potter Michael , Ethell Mark , Treleaven Jennifer , Dearden Claire , Morgan Gareth 
Published: April 2020

Abstract
Myelodysplastic syndrome is a heterogenous clonal disorder stemming from an insult at the progenitor cell level. The development of an International Prognostic Scoring System (IPSS) based on bone marrow blast percentage, degree of cytopenia and karyotype has allowed the widespread application of the IPSS to guide therapy in patients with MDS. To date, there are no reports distinguishing primary MDS from therapy related MDS (t-MDS) in terms of outcomes within a treatment algorithm. We performed a comparative analysis of patients with primary MDS and t-MDS, to ascertain whether both groups have similar risk profiles and outcomes within a defined treatment protocol. Between 1995 and 2005, 95 patients were diagnosed with MDS at our centre with an average follow-up of 6 years. In total, 50 patients presented in a de novo setting of which 41 received intensive therapy and 9 patients received non-intensive treatment. Of the 45 patients diagnosed with t-MDS, 25 received intensive treatment and 20 patients were managed non-intensively. Therapeutic decisions were based on ECOG performance status and cytogenetic risk group. Demographic analysis of primary and t-MDS patients showed no significant differences when comparing age, sex, degree of presentation cytopenia, or median IPSS score (IPSS 2.0 for primary MDS and 1.5 for t-MDS, p=0.4). In the primary MDS group, 32 patients had an IPSS of ≥1.5 (INT-2/high risk MDS) compared to 27 patients in the t-MDS group. There were 18 patients with primary MDS and 18 patients with t-MDS in the INT-1/low risk category (IPSS ≤1.0). Cytogenetic analysis of primary MDS and t-MDS patients showed a greater frequency of complex karyotypes and chromosome 7 abnormalities in t-MDS patients. A normal karyotype was commoner in the primary group (19:6 patients respectively). The median overall survival (OS) was 25 months for primary MDS patients and 16 months for the t-MDS group (p=0.1). On multivariate analysis, WBC and blast percentage were independent predictors of OS in primary MDS patients (p&lt;0.001, p=0.02). Using a WBC cut-off of 4.0, the median survival was 46 months if WBC &lt;4.0 and 11 months if WBC ≥ 4.0 (p=0.003). IPSS score was not a significant prognostic parameter for this group. In t-MDS patients, Hb, platelets and IPSS score were all independent predictors of OS (p=0.05, p=0.04, p=0.009). WBC was not significant. This group had a median survival of 21 months if IPSS ≤1.0 and 10 months if IPSS &gt;1.0, p=0.02). Remission rates were higher in primary MDS (86%) compared to t-MDS patients (68%) within the intensively treated arm (81% versus 39% for whole group, respectively). However, this did not translate into a better relapse free survival for primary MDS patients (p=0.9). Univariate analysis using binary logistic regression did not identify any factors that predicted response in the primary group. Age was a significant predictive factor for likelihood of response in the t-MDS group (p=0.008). These findings suggest that prognostic systems may need to be refined in MDS for patients presenting with de novo or therapy related disease. Adjustment for performance status may additionally contribute to risk based therapeutic protocols. According to our results, primary MDS may be more chemosensitive than t-MDS but if responses are obtained in t-MDS patients, they are maintained at a similar rate to primary MDS.