Labile plasma iron levels predict survival in patients with lower-risk myelodysplastic syndromes

Louise de Swart, Chloé Reiniers, Timothy Bagguley, Corine van Marrewijk, David Bowen, Eva Hellström-Lindberg, Aurelia Tatic, Argiris Symeonidis, Gerwin Huls, Jaroslav Cermak, Arjan A van de Loosdrecht, Hege Garelius, Dominic Culligan, Mac Macheta, Michail Spanoudakis, Panagiotis Panagiotidis, Marta Krejci, Nicole Blijlevens, Saskia Langemeijer, Jackie Droste, Dorine W Swinkels, Alex Smith, Theo de Witte, EUMDS Steering Committee, Louise de Swart, Chloé Reiniers, Timothy Bagguley, Corine van Marrewijk, David Bowen, Eva Hellström-Lindberg, Aurelia Tatic, Argiris Symeonidis, Gerwin Huls, Jaroslav Cermak, Arjan A van de Loosdrecht, Hege Garelius, Dominic Culligan, Mac Macheta, Michail Spanoudakis, Panagiotis Panagiotidis, Marta Krejci, Nicole Blijlevens, Saskia Langemeijer, Jackie Droste, Dorine W Swinkels, Alex Smith, Theo de Witte, EUMDS Steering Committee

Abstract

Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients. clinicaltrials.gov Identifier: 00600860.

Trial registration: ClinicalTrials.gov NCT00600860.

Copyright© 2018 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
LPI and NTBI correlated to TSAT and ferritin in different patient groups. (A) Relation between LPI and TSAT. (B) Relation between NTBI and TSAT. (C) Relation between LPI and ferritin. (D) Relation between NTBI and ferritin. Each dot represents one sample (median: 5 samples/patient). RS: ring sideroblastic; TI: transfusion-independent; TD: transfusion-dependent.
Figure 2
Figure 2
Survival according to LPI (A) or NTBI (B) and transfusion status. LPI, NTBI and transfusion status were analyzed as time dependent factors, implicating that patients may switch groups over time according to the LPI/NTBI and transfusion status at each specific time point. LLOD: lower limit of detection; TI: transfusion-independent; TD: transfusion-dependent; LPI: labile plasma iron; NTBI: non-transferrin bound iron.
Figure 3
Figure 3
Flow diagram of patients treated with transfusions and erythropoietin stimulating agents (ESAs). In total, 10 patients became transfusion-independent after starting ESA treatment
Figure 4.
Figure 4.
Proposed pathogenesis of iron toxicity in lower-risk MDS: the impact of ineffective erythropoiesis (A) and of transfusions (B). Ineffective erythropoiesis, especially in RS MDS, results in increased bone marrow production of GDF15 and possibly twisted gastrulation 1 and erythroferrone. These factors inhibit hepcidin production by the hepatocytes. Low hepcidin levels increase iron absorption from intestinal mucosa and increase iron release from the macrophages. Eventually, this may lead to toxic levels of NTBI and LPI, causing damage in solid organs, the immune system and the marrow. During transfusions hepcidin levels increase, despite higher GDF15 levels, leading to lower iron absorption in the gut. However, transfusions cause massive iron loading of RES-macrophages leading to elevated, circulating stored iron levels and toxic iron species - despite elevated hepcidin levels - and subsequent toxicities. Figure adapted from ML Cuijpers, et al. RS: ring sideroblastic; GDF15: growth differentiation factor 15; TWSG1: twisted gastrulation 1; LPI: labile plasma iron; NTBI: non-transferrin bound iron; sTFR: soluble transferrin receptor; RES: reticuloendothelial system; TSAT: transferrin saturations; EPO: erythropoietin.

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