The Effect of Transfusion Dependency and Secondary Iron Overload on Survival of Patients with Myelodysplastic Syndrome.
Authors: Malcovati Luca , Della Porta Matteo G. , Pascutto Cristiana , Invernizzi Rosangela , Passamonti Francesco , Arcaini Luca , Maffioli Margherita , Rumi Elisa , Travaglino Erica , Bernasconi Paolo , Lazzarino Mario , Cazzola Mario 
Published: April 2020

Abstract
According to evidence- and consensus-based practice guidelines (Haematologica2002;87:1286–306), red cell transfusion is the therapy of choice for the majority of patients with myelodysplastic syndrome (MDS) and symptomatic anemia. Previous studies have shown that widespread organ dysfunction can result from transfusion iron overload developing in non-thalassemic adults (Schafer et al, N Engl J Med1981;304:319–24; Cazzola et al, Blood1988;71:305–12). In this study, we evaluated the effect of transfusion dependency and secondary iron overload on survival of MDS patients classified according to WHO criteria. Four hundred and sixty-seven consecutive patients with a diagnosis of de novo MDS made at the IRCCS Policlinico San Matteo, University of Pavia Medical School, Pavia, Italy, between 1992 and 2002 were retrospectively evaluated and reclassified according to the WHO criteria. The effects that developing transfusion dependency or secondary iron overload had on survival were evaluated by applying Cox proportional hazards regression with time-dependent covariates. Transfusion-dependent patients had a significantly shorter overall survival (OS) and leukemia-free survival (LFS) than did patients who did not become transfusion-dependent (HR=2.16, P&lt;.001 and HR=2.02, P&lt;.001, respectively). Transfusion burden, calculated as the number of transfusions per month, was found to have a significant effect on both OS (HR=1.35, P&lt;.001) and LFS (HR=1.75, P&lt;.001). These effects were maintained after accounting for cytogenetics. We then assessed the survival of transfusion-dependent and non-transfused patients considering non-leukemic death as an end-point. In the first 50 months of follow-up transfusion-dependent patients had a significantly worse survival than those who did not require transfusions (HR=1.98, P=.01). Cardiac failure was significantly more frequent in transfusion-dependent patients (P=.01). Focusing the analysis on WHO subgroups, transfusion requirement affected both the OS and LFS of patients with RA, RARS or MDS with del(5q) (HR=1.54, P&lt;.001 and HR=1.44, P=.05, respectively), and of those with RCMD or RCMD-RS (HR=1.87, P=.04 and HR=1.54, P=.02, respectively), while it showed no effect on the survival of RAEB patients. Finally, we evaluated the prognostic value of patients with MDS developing iron overload during their follow-up. The development of secondary iron overload significantly affected survival (P&lt;.001) with a HR of 1.36 for every 500 ng/mL increase in serum ferritin. The effect of iron overload was maintained after adjusting for transfusion burden (HR=1.30, P=.003). With respect to WHO subgroups, the effect of secondary iron overload was still present in patients with RA/RARS (HR=1.51, P&lt;.001), while it was not significant in those with RCMD/RCMD-RS (HR=1.34, P=.20). In conclusion, these findings show that the development of transfusion dependency significantly worsens the survival of MDS patients. Although this poor prognosis partly reflects the severity of bone marrow failure, our observations also suggest that development of secondary iron overload per se can worsen survival of transfusion-dependent patients. These individuals may therefore considerably benefit from therapeutic approaches aimed at reducing transfusion needs and/or at preventing secondary iron overload.