LETTER TO THE EDITOR

Iron chelation therapy for a case of transfusion-independentMDS-RARS with significant iron overload

Haruhiko Ohashi • Kayo Arita • Yasuhiro Suzuki •

Akihiro Tomita • Tomoki Naoe • Ai Hattori •

Yasuaki Tatsumi • Koichi Kato • Hirokazu Nagai

Received: 22 October 2012 / Revised: 21 November 2012 / Accepted: 21 November 2012 / Published online: 4 December 2012

� The Japanese Society of Hematology 2012

A 60-year-old man was referred to our institution for

evaluation of anemia. He had not received medical exam-

ination or treatment for years and had no family history of

hematological disorders. He used a moderate amount of

alcohol daily (75–100 g ethanol per day) for more than a

decade. Laboratory examination at the first visit showed

white blood cells, 2,900/mm3 (71 % neutrophils, 20 %

lymphocytes, 6 % monocytes, 3 % eosinophils, 1 %

basophils); hemoglobin concentration, 7.6 g/dl; platelet

count, 301,000/mm3, MCV, 106 fl; MCH, 36.2 pg; MCHC,

34.2 %; reticulocyte count, 3.4 %; AST, 60 IU/l; ALT,

84 IU/l; LDH, 225 IU/l; direct bilirubin, 0.15 mg/dl; indi-

rect bilirubin, 2.31 mg/dl; C-reactive protein 0.31 mg/dl;

serum iron, 232 lg/dl; UIBC, 16 lg/dl; ferritin, 3,278 ng/

ml; and haptoglobin, 16 mg/dl. Serum concentrations of

vitamins B6 and B12 and of folic acid were normal, and

HBs antigen, HBs antibody, and HCV antibody were

negative. Bone marrow (BM) examination revealed hy-

percellular marrow (245,000/mm3) dominated by erythro-

blasts with megaloblastic changes. Myeloblasts included

1 % nucleated cells, and there was no apparent myeloid or

megakaryocytic dysplasia. On iron staining, most erythro-

blasts were ringed sideroblasts (Fig. 1a). Chromosomal

analysis found normal male karyotype.

A tentative diagnosis of refractory anemia with ringed

sideroblasts subtype of myelodysplastic syndrome (MDS-

RARS) was made. Metenolone acetate (10 mg/day) was

initiated, but hemoglobin levels did not improve (Fig. 1b).

The possibility of X-linked sideroblastic anemia (XLSA), a

congenital disorder that is occasionally diagnosed later in life

[1], was considered, and pyridoxal phosphate hydrate

(90 mg/day) was administered orally, but was ineffective

(Fig. 1b). In addition to very high serum ferritin (3.278 ng/

ml) and elevated serum transferrin saturation (93.5 %), mild

hepatic dysfunction (AST 60 IU/l, ALT 84 IU/l) and mild

hepatosplenomegaly with markedly high density of the liver

on CT was observed at presentation (Fig. 1c). Thus, this

patient was considered to have iron overload (IO), despite the

fact that he had never been transfused, was negative for HCV

infection, and had no signs of chronic inflammation. Neither

glucose intolerance nor decreased cardiac function was

observed. After 1 year from the first visit, despite significant

reduction of alcohol intake, serum ferritin levels remained

high, and the abnormalities in liver function remained

unchanged (Fig. 1b). Considering the possibility that sus-

tained IO in the liver may lead to hepatic cirrhosis and/or

hepatocellular carcinoma [2], we initiated administration of

an oral iron chelating agent (deferasirox 1,000 mg/day).

Serum ferritin decreased steadily, falling to less than 500 ng/

ml in 19 months (Fig. 1b). AST and ALT also normalized,

and the density of the liver on CT decreased from 100 to

70 HU. No hematological improvement was observed,

either in the peripheral blood (PB) or in the BM.

Thus, the clinical picture of this patient consisted of an

unusual combination of sideroblastic anemia and clinically

H. Ohashi � H. Nagai

Division of Hematology, National Hospital Organization Nagoya

Medical Center, Nagoya, Japan

H. Ohashi (&) � K. Arita � H. Nagai

Clinical Research Center, National Hospital Organization

Nagoya Medical Center, 4-1-1 Sannomaru,

Naka-ku, Nagoya, Japan

e-mail: hohashi@nnh.hosp.go.jp

Y. Suzuki � A. Tomita � T. Naoe

Department of Hematology and Oncology, Nagoya University

Graduate School of Medicine, Nagoya, Japan

A. Hattori � Y. Tatsumi � K. Kato

Department of Medicine, School of Pharmacy,

Aichi Gakuin University, Nagoya, Japan

123

Int J Hematol (2013) 97:151–153

DOI 10.1007/s12185-012-1230-7

relevant IO [3, 4]. The diagnosis of MDS-RARS seemed

reasonable, but exclusion of other diseases, such as RARS-

T[5] or XLSA, was not possible. Thus, after obtaining

written informed consent from the patient and approval by

the ethics review board of the institution, we performed

genetic analyses using genomic DNA from the PB cells.

The nucleotide sequences of all the exons of the TET2 and

ALAS-2 genes, exon 12 of the JAK2 gene, exon 10 of the

MPL gene, and exons 14–16 of the SF3B1 gene were

determined by direct sequencing. In exon 3 of the TET2

gene, and in exon 15 of the SF3B1 gene, previously

reported mutations were identified [6, 7]. Both mutations

appeared to be heterozygous in the granulocytes, but were

not detected in the T-lymphocytes (Fig. 1d, e). No variant

sequences were found in other genes. These results con-

firmed the diagnosis of MDS-RARS. Ineffective erythro-

poiesis is considered to be the main cause of anemia in

MDS, which may lead to iron accumulation through iron

redistribution to non-hematopoietic organs and down-reg-

ulation of hepcidin. Hemolysis is occasionally difficult to

separate from ineffective erythropoiesis clinically. In order

to clarify whether ineffective erythropoiesis and/or hemo-

lysis by MDS-RARS was solely responsible for IO in this

patient [8], we performed mutational analysis of hemo-

chromatosis-associated genes, for which mutations have

been described in Japanese patients [9]. All exons of five

genes (HFE, HJV, HAMP, TFR2, SLC40A1) were

sequenced, but no mutation was found.

0

1000

2000

3000

4000

5000

0

5

10

15

20

25

30

35

40

45

1 2 3 4 5 6 7 8 9 10 11 12 13

A C D

E

B

Granulocytes

Granulocytes

T-lymphocytes

T-lymphocytes

2009/8 2010/8 2011/8 2012/8

WBC (x102 /µl)

Hb (g/dl)

Plt (x104 /µl)

ALT (x10-1 IU/l)

Ferritin (ng/ml)

M.A. P.P.H.Deferasirox

Fig. 1 a Iron staining of the bone marrow aspiration smear taken at

presentation. Most of the erythroblasts have perinuclear blue dots and

are judged to be ringed sideroblasts. b Clinical course of the patient.

After initiation of iron chelating therapy, serum ferritin and ALT

decreased steadily, while hemoglobin concentration stayed

unchanged. MA metanolone acetate, PPH pyridoxal phosphate

hydrate. c Abdominal CT scan at presentation. The density of the

liver is significantly higher than that of other organs. d Sequence of

exon 3 of the TET2 gene. An insertion of guanine, which should lead

to a frame shift and truncation of the protein (C1271X), is observed in

the granulocyte (above), while the sequence is wild-type in the

T-lymphocytes (below). Arrow indicates the inserted nucleotide and

the overlapping sequences. e Sequence of exon 15 of the SF3B1 gene.

An A to G transition (indicated by an arrow), which should lead to an

amino acid change (K700E), is present in the granulocyte (above) but

not in the T-lymphocytes (below)

152 H. Ohashi et al.

123

Diagnosis of MDS without an excess of blasts and with

normal karyotypes can be difficult. Even in patients with

ringed sideroblasts in the BM, the hallmark of RARS, the

possibility of hereditary or environmental factor-related

conditions remains to be excluded. In our case, identifica-

tion of acquired mutations of TET2 and SF3B1 genes

confirmed the diagnosis of MDS-RARS. In addition, the

fact that all of the hemochromatosis-associated genes we

examined were wild-type suggest that ineffective erythro-

poiesis and/or hemolysis due to MDS-RARS may be the

sole cause of IO in this patient. Oral iron chelating agents

are widely prescribed for patients with transfusion-depen-

dent MDS and IO, among whom episodic cases of hema-

tological improvement have been reported [10]. In the

present case, clinical IO improved with iron chelation

therapy, but the anemia remained unchanged.

Acknowledgments This work was supported in part by the

Research Committee for Idiopathic Hematopoietic Disorders of the

Japanese Ministry of Health, Labor, and Welfare and the National

Hospital Organization Research Fund.

Conflicts of interest The authors declare no conflicts of interest.

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