first report of drug-induced esophagitis by deferasirox

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CASE REPORT First report of drug-induced esophagitis by deferasirox Takeshi Yoshikawa Takeshi Hara Hiroshi Araki Hisashi Tsurumi Masami Oyama Hisataka Moriwaki Received: 18 June 2011 / Revised: 13 March 2012 / Accepted: 14 March 2012 / Published online: 1 May 2012 Ó The Japanese Society of Hematology 2012 Abstract Deferasirox is a new oral iron chelator used to treat transfusional iron overload. We describe a case of a 79-year-old man with myelodysplastic syndrome (MDS) who developed esophagitis induced by deferasirox. He repeatedly received multiple red blood cell transfusions after a diagnosis of MDS. Two years after starting red blood cell transfusions, he was diagnosed with iron overload, and was then started on deferasirox at 1 g/day with about 400 ml of water. He was admitted to our institution because he was unable to swallow his own saliva 1 month after starting deferasirox. Esophagogastroendoscopy revealed white- coated mucosa covering the entire esophagus. A component analysis of biopsy specimens using high-performance liquid chromatography identified deferasirox. Symptoms resolved within about 2 weeks after discontinuing deferasirox, and repeated endoscopy showed marked improvement of esophagitis after 1 month. Re-administration of deferasirox was not attempted. Unfortunately, the patient died due to pneumonia 6 months after administration of deferasirox was started. This is the first report of drug-induced esophagitis associated with deferasirox. Keywords Drug-induced esophagitis Á Deferasirox Introduction Iron overload due to red blood cell transfusions represents an important problem around the world for patients with thalassemia, myelodysplastic syndrome (MDS), or severe aplastic anemia. Desferrioxamine has been available as an iron-chelating agent since the early 1960s, resulting in increased survival for these patients [1]. In addition, two oral iron chelators have been developed. Deferiprone was approved for use in India in 1995 and in Europe in 1999 [2], while deferasirox was approved in the United States in 2005 and in Japan in 2008. Deferasirox is thus the only oral iron chelator available in these two countries [2]. The main adverse events of deferasirox in the initial clinical trials were transient gastrointestinal complaints [3, 4], but no reports have described esophagitis. We report herein a case of drug-induced esophagitis in a patient treated with deferasirox for MDS. Case report A 79-year-old man was diagnosed with refractory cytopenia with unilineage dysplasia (RCUD) and subsequently received multiple red blood cell transfusions at another institution. A total of 48 U of red blood cell transfusions were administered, the serum ferritin level was 1480 lg/L, and a diagnosis of iron overload was made. He was then started on deferasirox at 1 g/day with about 400 ml of water 2 years after starting red blood cell transfusions. Progres- sion of anemia led to general fatigue, resulting in admission to our institution 1 month after starting deferasirox. Repeat bone marrow aspiration showed MDS, and the serum fer- ritin level was 1606 lg/L. On presentation, he was unable to swallow his own saliva. Laboratory studies showed T. Yoshikawa Á M. Oyama Department of Internal Medicine, Kisogawa Municipal Hospital, Aichi, Japan T. Hara Á H. Araki Á H. Tsurumi (&) Á H. Moriwaki First Department of Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan e-mail: [email protected] 123 Int J Hematol (2012) 95:689–691 DOI 10.1007/s12185-012-1060-7

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Page 1: First report of drug-induced esophagitis by deferasirox

CASE REPORT

First report of drug-induced esophagitis by deferasirox

Takeshi Yoshikawa • Takeshi Hara •

Hiroshi Araki • Hisashi Tsurumi • Masami Oyama •

Hisataka Moriwaki

Received: 18 June 2011 / Revised: 13 March 2012 / Accepted: 14 March 2012 / Published online: 1 May 2012

� The Japanese Society of Hematology 2012

Abstract Deferasirox is a new oral iron chelator used to

treat transfusional iron overload. We describe a case of a

79-year-old man with myelodysplastic syndrome (MDS)

who developed esophagitis induced by deferasirox. He

repeatedly received multiple red blood cell transfusions after

a diagnosis of MDS. Two years after starting red blood cell

transfusions, he was diagnosed with iron overload, and was

then started on deferasirox at 1 g/day with about 400 ml of

water. He was admitted to our institution because he was

unable to swallow his own saliva 1 month after starting

deferasirox. Esophagogastroendoscopy revealed white-

coated mucosa covering the entire esophagus. A component

analysis of biopsy specimens using high-performance liquid

chromatography identified deferasirox. Symptoms resolved

within about 2 weeks after discontinuing deferasirox, and

repeated endoscopy showed marked improvement of

esophagitis after 1 month. Re-administration of deferasirox

was not attempted. Unfortunately, the patient died due to

pneumonia 6 months after administration of deferasirox was

started. This is the first report of drug-induced esophagitis

associated with deferasirox.

Keywords Drug-induced esophagitis � Deferasirox

Introduction

Iron overload due to red blood cell transfusions represents

an important problem around the world for patients with

thalassemia, myelodysplastic syndrome (MDS), or severe

aplastic anemia. Desferrioxamine has been available as an

iron-chelating agent since the early 1960s, resulting in

increased survival for these patients [1]. In addition, two

oral iron chelators have been developed. Deferiprone was

approved for use in India in 1995 and in Europe in 1999

[2], while deferasirox was approved in the United States in

2005 and in Japan in 2008. Deferasirox is thus the only oral

iron chelator available in these two countries [2]. The main

adverse events of deferasirox in the initial clinical trials

were transient gastrointestinal complaints [3, 4], but no

reports have described esophagitis. We report herein a case

of drug-induced esophagitis in a patient treated with

deferasirox for MDS.

Case report

A 79-year-old man was diagnosed with refractory cytopenia

with unilineage dysplasia (RCUD) and subsequently

received multiple red blood cell transfusions at another

institution. A total of 48 U of red blood cell transfusions

were administered, the serum ferritin level was 1480 lg/L,

and a diagnosis of iron overload was made. He was then

started on deferasirox at 1 g/day with about 400 ml of water

2 years after starting red blood cell transfusions. Progres-

sion of anemia led to general fatigue, resulting in admission

to our institution 1 month after starting deferasirox. Repeat

bone marrow aspiration showed MDS, and the serum fer-

ritin level was 1606 lg/L. On presentation, he was unable to

swallow his own saliva. Laboratory studies showed

T. Yoshikawa � M. Oyama

Department of Internal Medicine,

Kisogawa Municipal Hospital, Aichi, Japan

T. Hara � H. Araki � H. Tsurumi (&) � H. Moriwaki

First Department of Internal Medicine,

Gifu University Graduate School of Medicine,

1-1 Yanagido, Gifu 501-1194, Japan

e-mail: [email protected]

123

Int J Hematol (2012) 95:689–691

DOI 10.1007/s12185-012-1060-7

Page 2: First report of drug-induced esophagitis by deferasirox

leukocytosis (31400/mm3) and an elevated C-reactive pro-

tein (4.8 mg/dL), while b-D glucan was within the normal

range. Liver and kidney functions were normal. Negative

results were obtained for bacterial cultures of a blood

sample obtained on admission. Esophagogastroendoscopy

revealed white-coated mucosa covering the entire esopha-

gus (Fig. 1), with no abnormal findings in the stomach.

Standard histological and microbiological investigations

showed no evidence of esophageal candidiasis. A compo-

nent analysis of biopsy specimens using high-performance

liquid chromatography identified the presence of deferasi-

rox (Fig. 2). A diagnosis of deferasirox-induced esophagitis

was therefore made. Deferasirox was discontinued, and

nearly all symptoms resolved within 2 weeks. No other

treatment was required for esophagitis. Repeat endoscopy

performed 1 month later showed marked improvement of

the esophagitis. Re-administration of deferasirox was not

attempted. Unfortunately, the patient died due to pneumo-

nia 6 months after administration of deferasirox was

started.

Discussion

Causes of esophagitis include reflux esophagitis, infectious

microbes such as Candida albicans, and drug-induced

esophagitis. Candida species are the most common cause

of esophagitis and, after the oropharynx, the esophagus is

the most common site of gastrointestinal candidiasis. The

prevalence of esophageal candidiasis has increased mainly

because of the high frequency of this complication in

AIDS. Approximately 10–15 % of patients with AIDS will

suffer from this disorder during their lifetime [5, 6],

although a reliable diagnosis can only be made based on

histological evidence of tissue invasion in biopsy material.

The etiology of drug-induced esophagitis includes

impaired motility of the esophagus by pharmaceuticals or

Fig. 1 Endoscopic image of the esophagus on admission. White-

coated mucosa is apparent throughout the esophagus on gastrointes-

tinal endoscopy

Fig. 2 High-pressure liquid chromatogram of esophageal biopsy specimens. Positive control (deferosirax) is shown in the left panel, and the

sample is shown in the right panel

690 T. Yoshikawa et al.

123

Page 3: First report of drug-induced esophagitis by deferasirox

corrosive esophagitis from alkaline or acidic drugs. Injury

to the esophageal mucosa caused by drugs passing through

the esophagus is a rare but well-known clinical condition,

as recognized by terms such as ‘‘pill-esophagitis’’ [7].

Esophageal mucosal injury caused by reflux of gastric

contents is a common condition. Much less common is

esophagitis from injurious agents passing down the

esophagus, seen most typically in cases after the ingestion

(usually accidental) of a caustic alkali. The potential of

medications such as quinidine, potassium, and tetracycline

derivatives to cause esophagitis or discrete ulcers has

recently been recognized. This effect usually results from

prolonged contact of the drug with the esophageal mucosa

and the ability of the drug to alter local conditions, such as

the production of acidic conditions by tetracycline. How-

ever, adverse effects of deferasirox involving the esopha-

gus occurred in only a small number of patients in the

initial clinical trials [3, 4]. We hypothesized that prolonged

direct contact of deferasirox with the mucosa caused

esophagitis. The present patient was elderly and tended to

sleep for longer periods. We suspected that such factors

contributed to esophagitis. We directed the patient to take

deferasirox with more water, but this did not prevent

esophagitis. Bed-ridden elderly patients require particular

attention in terms of the risk of such adverse effects.

Treatment for deferasirox-induced esophagitis is very

important. In this patient, no drugs were used to treat the

esophagitis; in fact, discontinuation of deferasirox was

sufficient. Stopping the drug might be enough for this type

of esophagitis, and no other treatment may be required.

In summary, this is the first report of deferasirox-

induced esophagitis. Knowledge of the potential for drug-

induced esophagitis is important, as the incidence of MDS

is increasing, and MDS patients are living longer. The use

of iron-chelating agents is thus also likely to increase.

Deferasirox-induced esophagitis must be considered as a

potential complication in elderly patients.

Conflict of interest None.

References

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haematological diseases. Br J Hematol. 2007;138:407–21.

2. Kontoghiorghes GJ. Deferasirox: uncertain future following renal

failure fatalities, agranulocytosis and other toxicities. Expert Opin

Drug Saf. 2007;6:235–9.

3. Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu

L, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral

iron chelator, in patients with beta-thalassemia. Blood.

2006;107:3455–62.

4. Stumpf JL. Deferasirox. Am J Health Syst Pharm. 2007;64:

606–16.

5. Moore RD, Chaisson RE. Natural history of opportunistic disease

in an HIV-infected urban clinical cohort. Ann Intern Med.

1996;124:633–42.

6. Dupont B, Denning DW, Marriot D, Sugar A, Viviani MA,

Sirisanthana T. Mycosis in AIDS. J Med Vet Mycol. 1994;32

(suppl):65–7.

7. Castell DO. ‘‘Pill esophagitis’’—the case of alendronate. N Engl J

Med. 1996;335:1058–9.

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