Hemochromatosis gene mutations may affect the survival of patients with myelodysplastic syndrome

Abstract

Conflict of interest statementThe authors declare that there are no conflicts of interest. AcknowledgementsThe authors would like to thank Wilma Miletić for help with manuscript preparation. 2 AbstractObjectives: The recent availability of potent oral iron chelators is renewing an interest in the assessment of the possible impact of HFE genetics in MDS.Methods: 36 newly diagnosed patients with MDS were studied for parameters of iron metabolism in addition to C282Y and H63D mutations of the HFE gene.Results: Mutations were present in 11 out of 36 patients (31%), which was not different from our general population and were equally distributed among MDS subtypes. Mutated patients had higher ferritin levels (p=0.039) and lower TIBC (p=0.018). Ferritin was found to be higher for the untransfused mutated patients (p=0.017), but not for transfusion-dependent patients in whom ferritin levels correlated significantly with the number of blood units received (p=0.04). There was no difference in the number of blood units received between the mutated and wild type patients. A new observation made was that the mutated patients had a lower overall survival (OS) in addition to a poorer leukemia free survival (LFS) (p=0.004 and p=0.003, respectively). Discussion:The HFE gene mutations are not more frequent in MDS patients. Iron overload in mutated patients was higher but there was no correlation found using supportive therapy for anaemia.The effect of mutations on survival could be mediated by changes in iron metabolism. Conclusion:The HFE gentopye may predict MDS prognosis and there is a need for further studies. It remains a challenging question if HFE mutated MDS patients should be considered for potent iron chelation therapy.

Management of cardiac hemochromatosis

“…Overexpression of the wild-type HFE gene in enterocytes and overexpression of the iron regulatory peptide hepcidin in the liver are other therapeutic approaches that could be investigated. The HFE genotype may affect the survival of patients with myelodysplastic syndrome, and studies need to be performed if these patients should be treated with potent iron chelation therapy [ 109 ].…”

A Systematic Literature Review of the Relationship between Serum Ferritin and Outcomes in Myelodysplastic Syndromes

“…Risk of bias assessed via the QUIPS tool indicated that studies were generally of good quality with low risk of bias. Baseline characteristics were inconsistently reported across five studies [15,16,21,25,34], and three studies were unclear in their information on variables in multivariate models [19,21,30]. Despite these minor gaps in information, studies consistently reported other elements (study attrition, prognostic factor, outcome measurement, and statistical discussion), resulting in a low risk of bias across the remaining categories (Supplementary Materials Table S3).…”

Could haemochromatosis (HFE) gene mutations affect response to iron chelation in myelodysplastic syndrome?

“…The authors reported that neither patients' characteristics (including baseline and follow‐up ferritin concentrations), nor mutations in any of the specific genes frequently mutated in myeloid malignancies showed significant associations with the occurrence of HI during ICT. We would like to point out that haemochromatosis ( HFE ) gene mutations, which affect significant proportion of MDS patients and increase the risk of iron accumulation in this context (De Souza et al , ; Lucijanic et al , ), were not assessed by Fabiani et al (2019).…”

“…Mutations show variable geographic distribution and affect up to one‐third of MDS patients when considering the two most frequent mutations (C282Y, H63D) (Lucijanic et al , ). Although considered not to be directly implicated in the pathobiology of MDS and not to significantly affect iron accumulation in the general population (Burt et al , ; Jackson et al , ; Rossi et al , ), heterozygosity for HFE gene mutations was shown to intensify iron overload (De Souza et al , ) and accelerate iron accumulation (Lucijanic et al , ) in transfusion‐independent MDS patients. Most interestingly, HFE ‐mutated patients seem to experience significantly shorter overall and leukaemia‐free survival (Lucijanic et al , ).…”

“…Although considered not to be directly implicated in the pathobiology of MDS and not to significantly affect iron accumulation in the general population (Burt et al , ; Jackson et al , ; Rossi et al , ), heterozygosity for HFE gene mutations was shown to intensify iron overload (De Souza et al , ) and accelerate iron accumulation (Lucijanic et al , ) in transfusion‐independent MDS patients. Most interestingly, HFE ‐mutated patients seem to experience significantly shorter overall and leukaemia‐free survival (Lucijanic et al , ). Therefore, the question emerges whether HFE ‐mutated MDS patients might require lower thresholds to start chelation therapy and/or more intensive chelation to achieve response, but these issues have not been sufficiently investigated at present.…”