Evolution of iron overload in patients with low-risk myelodysplastic syndrome: iron chelation therapy and organ complications

Abstract

This study aimed to evaluate the evolution of iron overload, assessed by serum ferritin (SF), in transfusion-dependent lower risk patients with myelodysplastic syndrome (MDS), as well as to describe the occurrence of organ complications, and to analyze its relationship with iron chelation therapy. This observational retrospective study was conducted from March 2010 to March 2011 in 47 Spanish hospitals. A total of 263 patients with lower risk MDS (International Prognostic Scoring System [IPSS] low/intermediate-1 risk or Spanish Prognostic Index [SPI] 0-1 risk), transfusion-dependent, and who had received ≥10 packed red blood cells (PRBC) were included. At MDS diagnosis, patients received a mean of 2.8 ± 3.9 PRBC/month, and 8.7% of patients showed SF ≥1000 μg/L. Over the course of the disease, patients received a mean of 83.4 ± 83.3 PRBC, and 36.1% of patients presented SF ≥2500 μg/L. Cardiac, hepatic, endocrine, or arthropathy complications appeared/worsened in 20.2, 11.4, 9.9, and 3.8% of patients, respectively. According to investigator, iron overload was a main cause of hepatic (70.0%) and endocrine (26.9%) complications. A total of 96 (36.5%) patients received iron chelation therapy for ≥6 months, being deferasirox the most frequent first chelation treatment (71.9%). Chelation-treated patients showed longer overall survival (p < 0.001), leukemia-free survival (p = 0.007), and cardiac event-free survival (p = 0.017) than non-chelated patients. In multivariable analyses, age (p = 0.011), IPSS (p < 0.001), and chelation treatment (p = 0.015) were predictors for overall survival; IPSS (p = 0.014) and transfusion frequency (p = 0.001) for leukemia-free survival; and chelation treatment (p = 0.040) and Sorror comorbidity index (p = 0.039) for cardiac event-free survival. In conclusion, these results confirm the potential survival benefit of iron chelation therapy and provide additional evidence on the deleterious effect of iron overload in lower risk MDS patients.

Potential anti-leukemic activity of iron chelation after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia

“…[13] In myelodysplastic syndromes, different studies have suggested that iron-chelating agents may increase survival rates and reduce the risk of development into AML, although the molecular mechanism involved has not yet been elucidated and could involve a reduction in the production of free radicals, DNA damage and effect on mTOR and NFkB pathways. [14,15] In conclusion, we confirmed in this well-defined homogenous population of AML patients, the negative impact of high ferritin level before allo-HSCT on different outcomes. Moreover, our study has shown that iron-chelating agents in addition to their effect on normalizing ferritin levels after allo-HSCT and lowering toxic labile plasma iron, they have a significant impact on the incidence of relapse following allo-HSCT and could be implicated in apoptosis of erythroid precursors and DNA damage associated with malignant transformation.…”

Iron overload in myelodysplastic syndromes (MDS)

“…However, the differences were not statistically significant. The IRON2 study from Spain, which found significantly longer overall survival and leukemia-free survival in chelated patients with lower risk MDS, also demonstrated significantly longer event-free survival regarding cardiac complications [40]. As already alluded to, iron overload may not only be related to cardiomyopathy but also to atherosclerosis.…”

“…List et al [27] Low/lnt-1 15% (n = 173) 15% (n = 52) 22% (n = 77) Gattermann et al [28] Low/lnt-1 21.5% (n = 247) 22% (r = 50) 13% (n = 100) Nolte et al [29] Low/lnt-1 11% (n = 50) NR NR Angelucci et al [30] Low/lnt-1 Transfusion independence in 15.5% (n = 152) Table 2 Clinical studies showing that iron chelation improves survival in patients with lower risk MDS [32][33][34][35][36][37][38][39][40].…”

Updated recommendations on the management of gastrointestinal disturbances during iron chelation therapy with Deferasirox in transfusion dependent patients with myelodysplastic syndrome – Emphasis on optimized dosing schedules and new formulations

“…Consequently, several retrospective and observational studies have suggested a beneficial influence of iron chelation on mortality and morbidity in MDS patients with transfusional IO [17][18][19][20][21][22][23][24].…”

“…Recently, several retrospective but also some prospective studies have indicated, that transfusion dependent patients with MDS might benefit from consequent iron chelation with regard to morbidity and mortality [17][18][19][20][21][22][23][24]. However, gastrointestinal adverse events leading to reduced quality of life in these patients are associated with low treatment adherence and are considered as a major obstacle in achieving consequent and effective iron chelation with DFX.…”