Should every Patient with MDS get Iron Chelation – Probably Yes

Kanjaksha Ghosh1 and Kinjalka Ghosh2

1 Surat Raktadan Kendra & research Centre, Gujrat , India
2 Clinical Biochemistry, KEM Hospital & Seth GS Medical College Mumbai, India

Corresponding author: Kanjaksha Ghosh MD FRCP FRCPath. Surat Raktadan Kendra & research Centre, Udhna Magdalla Road Surat 395002, Gujrat , India. E-mail: kanjakshaghosh@hotmail.com

Published: September 1, 2017
Received: July 5, 2017
ccepted: July 21 , 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017055 DOI 10.4084/MJHID.2017.055
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Dear Editor,

We read with interest the review article on iron chelation therapy in MDS patients[1] in one of the recent issue of the journal. A recently similar article has also been published suggesting that iron chelation may be helpful in high-risk transfusion dependent MDS patients too.[2] The effect of iron chelation therapy in low-risk MDS patient is reasonably well established as it improves not only the quality of life but also the survival as shown in Dusseldorf MDS registry study.[3] In high-risk MDS iron chelation therapy was usually not considered because of short survival, and, because of some of the complications of chelation, likely in patients with hepatic dysfunction with short survival, it was found to be not worth pursuing. However, since some of the current drugs used for the purpose, e.g., decitabine & azacitidine based therapy, have improved the survival of high-risk MDS patients, so consideration of iron chelation therapy becomes apparent also in these cases. However, this brings us to an important question, i.e., Should all MDS patients even with minor iron overload with serum ferritin above 500 ng/ml. receive iron chelation therapy, particularly when efficient oral iron chelator is now available? To support this idea Angelucci et al.[1] have in the paper under discussion made significant observations. Our knowledge and experience on iron chelation mainly emerge from our therapeutic practice of using the same for transfusion dependent thalassemia patients. Here iron deposition happens in bulk and chelation tends to remove the iron from this bulk relatively inert as well as the extremely active labile and non transferring bound free iron pool generating active, reactive oxygen species (ROS). ROS is capable of mutagenesis by inducing double stranded DNA break.[4] This mutagenesis can theoretically help in the progression of a relatively benign form of MDS to an aggressive one. Though this has not been directly proven it was shown that patients with higher transfusion requirement and iron overload also tend to evolve rapidly into leukemia.[5]
It may be argued that patients with severe prognosis require more red cell transfusions and then develop higher iron overload and having a rapid evolution of MDS to more aggressive form naturally require more transfusions, and thus, the evolution to leukemia has nothing to do with iron overload. On the other hand, it may also be argued that marked iron load, associated with a higher labile iron pool being toxic to red cell progenitors[6,7] and by causing direct red cell membrane damage,[8] induces more frequent red cell transfusion and then more iron overload.
This iron overload brings about genomic instability,[4,8,9] mitochondrial damage and mutation in mitochondrial genome,[10,11] and by producing an unbalanced immune system, leads to rapid progression of MDS[12] to accelerated phase of leukemogenesis. If our second argument and Angelucci et al.[1] argument are correct the iron accumulation even in a minimal amount in crucial cellular compartments without necessarily producing massive iron overload could be damaging and mutagenic. Thus, every patient with MDS and even minimal iron overload should get adequate iron chelation and efforts needs to be made to see whether such intervention alters the natural history of the disease.

References   

  1. Angelucci E, Urru SA, Pilo F, Piperno A. Myelodysplastic Syndromes and Iron Chelation Therapy. Mediterr J Hematol Infect Dis. 2017 Mar 1;9:e2017021. https://doi.org/10.4084/mjhid.2017.021            
  2. Musto P, Maurillo L, Simeon V, Poloni A, Finelli C, Balleari E, Ricco A, Rivellini F, Cortelezzi A, Tarantini G, Villani O, Mansueto G, Milella MR, Scapicchio D, Marziano G, Breccia M, Niscola P, Sanna A, Clissa C, Voso MT, Fenu S, Venditti A, Santini V, Angelucci E, Levis A. Iron-chelating therapy with deferasirox in transfusion-dependent, higher risk myelodysplastic syndromes: a retrospective, multicentre study. Br. J. Haematol. 2017.177:741-750       .
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