Independent Impact of Iron Overload and Transfusion Dependency on Survival and Leukemic Evolution in Patients with Myelodysplastic Syndrome
Authors: Sanz Guillermo , Nomdedeu Benet , Such Esperanza , Bernal Teresa , Belkaid Mohamed , Ardanaz Ma Teresa , Marco Victor , Pedro Carme , Ramos Fernando , Cañizo Maria Consuelo del , Luño Elisa , Cobo Francesc , Carbonell Felix , Gomez Valle , Muñoz Juan A , Amigo Mari Luz , Bailen Alicia , Bonanad Santiago , Tormo Mar , Andreu Rafael , Arrizabalaga Beatriz , Arilla Maria J. , Bueno Javier , Requena Maria J. , Bargay Joan , Sanchez Joaquin , Senent Leonor , Arenillas Leonor , de Paz Raquel , Xicoy Blanca , Duarte Rafael , Cervera Jose 
Published: April 2020

Abstract
Transfusion dependency seems to have a major prognostic impact in patients with myelodysplastic syndrome (MDS) (Malcovati L et al. J Clin Oncol2007;25:3503). Preliminary data also suggest that the development of iron overload could influence outcome (Malcovati L et al. J Clin Oncol2005;23:7594 and Garcia-Manero G et al. Leukemia2008;22:538), but small numbers have precluded a meaningful analysis of the prognostic value of this characteristic. The main aim of this study was to evaluate the independent prognostic value of transfusion dependency (as defined in WHO-based Prognostic Scoring System [WPSS]) and iron overload (defined as serum ferritin level &gt;1,000 ng/mL) in a large series of 2,994 patients (median age, 74 yr) with de novo MDS according to FAB criteria (2,107 MDS according to WHO criteria). Complete transfusional history was available in 2,241 patients (835 transfusion dependent [TD] at diagnosis, 526 TD during follow-up, and 880 non-TD) and serum ferritin levels in 1,634. Karyotyping was successfully performed in 2,074 patients, who could then be classified by the International Prognostic Scoring System (IPSS) as low (861 patients), intermediate-1 (748), intermediate-2 (311), and high-risk (154). The numbers of patients in the five risk categories defined by the WPSS (available for 1,228 patients) were 257 (21%) in very low, 385 (31%) in low, 217 (18%) in intermediate, 271 (22%) in high, and 98 (8%) in very high, closely similar to those reported in the original WPSS series. Actuarial curves of overall survival (OS) and risk of evolution to acute myeloblastic leukemia (AML) were built by Kaplan-Meier method and differences between curves compared with log-rank tests. Multivariate analyses of OS and risk of evolution to AML were performed by Cox proportional hazards regression method, with development of transfusion dependency and iron overload entered as time-dependent covariates. Other variables included in the prognostic factor analyses were age, gender, hemoglobin level, absolute WBC, PMN, and platelet counts, proportion of blasts in blood and marrow, percentage of dysplastic features in the three different hematopoietic cell lines, cytogenetics according to IPSS cytogenetic risk subgroups, FAB and WHO classifications, ferritin, beta-2 microglobulin, erythropoietin, and LDH levels at diagnosis, and IPSS and WPSS risk categories. All the previous variables showed a statistically significant relationship with OS and/or AML risk on univariante analyses. Median OS for TD patients at diagnosis, TD patients during evolution, and non-TD patients was 19, 60, and 96 months, respectively (P&lt;.0001). Multivariate analyses in a set of 902 cases with complete data confirmed that development of iron overload (1st variable selected to enter the model; hazard ratio [HR], 52.4; P&lt;.0001) and transfusion dependency (2nd to enter; HR, 8.8; P&lt;.0001) were strongly associated with OS and added significant independent prognostic information to that afforded by the IPSS and WPSS scores or by other characteristics with universally recognized prognostic value. Further, multivariate analyses of AML transformation risk showed that iron overload (1st to enter; HR, 6.6; P&lt;.0001) and transfusion dependency (2nd to enter; HR, 3.5; P=.003) had also independent impact on that endpoint. These results demonstrate for the first time the independent prognostic value of development of iron overload on OS and AML risk in MDS, confirm the impact of transfusion dependency on those outcomes, and support that the inclusion of both variables in a new prognostic scoring system would add clinically relevant information. They also suggest that avoiding or reducing iron overload by an appropriate chelation therapy could improve OS and reduce the risk of AML transformation in MDS patients.