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Update on Thalassemia Treatment in Taiwan, Including Bone Marrow

Transplantation, Chelation Therapy, and Cardiomyopathy Treatment Effects

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Update on Thalassemia Treatment in Taiwan, Including Bone Marrow

Transplantation, Chelation Therapy, and Cardiomyopathy Treatment
Effects
Ching-Tien Peng ab; Jeng-Sheng Chang a; Lin-Yen Wang c; Shyh-Shin Chiou d; Chih-Cheng Hsiao e;
Shih-Chung Wang f; Giun-Yi Hung g; Kang-Hsi Wu a
a
Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan b Department of
Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan c Department of Pediatrics,
Mackay Memorial Hospital, Taipei, Taiwan d Department of Pediatrics, Kaohsiung Medical University,
Kaohsiung, Taiwan e Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical
Center, Kaohsiung, Taiwan f Pediatric Hematology/Oncology, Changhua Christian Hospital,
Changhua, Taiwan g Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan

To cite this Article Peng, Ching-Tien, Chang, Jeng-Sheng, Wang, Lin-Yen, Chiou, Shyh-Shin, Hsiao, Chih-Cheng, Wang,
Shih-Chung, Hung, Giun-Yi and Wu, Kang-Hsi'Update on Thalassemia Treatment in Taiwan, Including Bone Marrow
Transplantation, Chelation Therapy, and Cardiomyopathy Treatment Effects', Hemoglobin, 33: 5, 304 — 311
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 Hemoglobin, 33(5):304–311, (2009)
Copyright © Informa UK Ltd.
ISSN: 0363-0269 print/1532-432X online
DOI: 10.1080/03630260903212969

PROCEEDINGS 17TH ICOC

Hemoglobin, Vol. 33, No. 5, August 2009: pp. 0–0
1532-432X
0363-0269
LHEM
Hemoglobin

Shenzhen, PR China, November 2007

UPDATE ON THALASSEMIA TREATMENT IN TAIWAN, INCLUDING

BONE MARROW TRANSPLANTATION, CHELATION THERAPY,
AND CARDIOMYOPATHY TREATMENT EFFECTS
Downloaded By: [China Medical University] At: 08:26 12 November 2009

Ching-Tien Peng,1,2 Jeng-Sheng Chang,1 Lin-Yen Wang,3 Shyh-Shin Chiou,4

Update
C.-T. Peng
on et
Thalassemia
al. Treatment in Taiwan

Chih-Cheng Hsiao,5 Shih-Chung Wang,6 Giun-Yi Hung,7 and Kang-Hsi Wu1

1
Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan
2
Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan
3
Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan
4
Department of Pediatrics, Kaohsiung Medical University, Kaohsiung, Taiwan
5
Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung
Medical Center, Kaohsiung, Taiwan
6
Pediatric Hematology/Oncology, Changhua Christian Hospital, Changhua, Taiwan
7
Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan

䡺 Over the past few decades, Taiwan has seen striking improvements in the life expectancy of its
400 registered b-thalassemia major (b-TM) patients due mainly to adequate transfusion regimens
and effective iron chelation therapy. Since 1995, Taiwanese citizens have enjoyed universal health
care through National Health Insurance (NIH), receiving comprehensive treatment at minimal
cost. In 1984, a national program for thalassemia prevention, control, and hematopoietic stem cell
transplantation (HSCT) was initiated. Recent data show 1- and 2-year event-free survival rates of
85 and 78%, respectively. Chelation agents like deferoxamine (DFO), deferiprone (L1) and defera-
sirox (DFRA) are available in Taiwan, and therapy is tailored to individuals based on drug avail-
ability and tissue distribution of iron load. Intensive chelation regimens combining L1 and DFO
are recommended in patients with cardiac complications, while DFRA has been found to be effective
in reducing serum ferritin, with acceptable side effects. Here, we report advances in thalassemia
treatment in Taiwan and suggest treatment guidelines.

Keywords Thalassemia, Iron chelator, Cardiomyopathy, Hematopoietic stem cell trans-

plantation (HSCT), Taiwan, Guideline

Presented at the 17th International Conference on Oral Chelation, Shenzhen, PR China, November
23–27, 2007.
Address correspondence to Dr. Kang-Hsi Wu, Department of Pediatrics, China Medical University
Hospital, 2 Yuh-Der Road, Taichung 404, Taiwan; Tel: +886-4-22052121, ext 2062; Fax: +886-4-22032798;
E-mail: d5284@mail.cmuh.org.tw

304
 Update on Thalassemia Treatment in Taiwan 305

INTRODUCTION
Taiwan’s a-thalassemia (a-thal) carrier rate is about 4% and that of
b-thal is about 2%. Currently there are 400 registered b-thal major (b-TM)
patients (1). Prior to 1976, few patients received adequate blood transfu-
sions and effective iron chelation was nonexistent. Untransfused patients
usually died in infancy or early childhood from anemia and infection; those
transfused regularly generally died from iron-induced cardiomyopathy.
From 1975 to 1994, the Taiwanese economy advanced markedly, spur-
ring advancement of thalassemia treatment centers and treatment quality.
Patients received better treatment protocols and experienced a far better
outcome. Introduction of the subcutaneous chelator deferoxamine (DFO)
in 1976 boosted survival rates, though deaths continued from iron overload
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toxicity, lack of compliance, or unaffordable drugs. In the few patients who

complied with DFO therapy, death nevertheless occurred due to cardiac
iron overload. In Taiwan, the first hematopoietic stem cell transplantation
(HSCT) was attempted in b-TM patients in 1984 resulting in a successful
“cure” (2). Nationwide prenatal screening began in 1993, after which the
birth rate of patients with b-TM fell to less than five patients per year.
In 1995, Taiwan introduced its National Health Insurance (NIH) system
of universal health care; since that time, patients with b-TM have been
eligible for comprehensive treatment [including blood transfusion, iron
chelation, close monitoring of physical development, medication, X-ray,
surgery, laboratory tests such as hemoglobin (Hb) electrophoresis, DNA
analysis for diagnosis and blood transfusions, HSCT, etc.). The oral iron
chelating agent deferiprone (L1) was first used in Taiwan in 1999, and its
use has gradually increased, particularly among patients with cardiac iron
loading. A second oral iron chelator, deferasirox (DFRA), was introduced
in clinical trials and was approved after a 1-year study in 2006. Identification
of cardiac siderosis has been made with T2-weighted magnetic resonance
imaging (MRI), prompting changes in and intensification of iron chelation
therapy. Taiwan has recently reached the HSCT international standard of
disease-free survival rate for thalassemia. Prevention of cardiac complica-
tions, early detection of cardiac problems, along with effective and safe
removal of iron from the heart, are key points in treatment. Here, we
present an update on our advances in the treatment of thalassemia patients
in Taiwan.

IRON CHELATION AND SIDEROSIS CARDIOMYOPATHY

TREATMENT
The past decade (January 1999 to the present time) has seen several
reports in the literature regarding treatment of thalassemia in Taiwan. Six
 306 C.-T. Peng et al.

reports of b-TM patients who received regular blood transfusions and vari-
ous types of chelation have compared the incidence of iron-induced cardiac
disease with the recovery rates for different treatment modalities. In partic-
ular, one report compared cardiac function in normal people and b-TM
patients (3); furthermore, another report showed a possible link between
glutathione S-transferase M1 (GSTM1) gene polymorphisms and cardiac
iron deposits in b-TM patients (4).
In our first prospective report (5), we had compared left ventricular
ejection fraction (LVEF) and cardiac iron levels as determined by T2-
weighted MRI over a 3-year period between a group of 13 b-TM patients
who were on DFO (50 mg/kg/day) for at least 5 days per week and 11 b-TM
patients who received L1 (75 mg/kg/day) orally every 8 hours. The study
demonstrated that L1, a small molecule that permeates all tissues, removed
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cardiac iron more efficiently and improved cardiac function to a greater

degree than DFO. Therefore, patients with lower signal intensity (SI) in T2-
weighted MRI taking L1 have options available, provided they undergo
careful follow-up. With respect to hepatic iron removal, the efficacy of L1
was at least equal to standard doses of DFO. We also reported on two b-TM
patients with severe heart failure whose condition reversed after intensive
combined therapy with both DFO and L1 (6), and have conducted five
other unpublished studies with similar responses. Available evidence
suggests combined therapy as the treatment of choice for patients with
established cardiac failure.
In another study, our group evaluated cardiac function using echocar-
diography to measure LV systolic, diastolic, and global functions to see if
nine b-TM patients with myocardial dysfunction could improve if chelation
therapy was switched from DFO to L1. We assessed these patients every 6
months for 9 years, and we again observed reversal of myocardial dysfunc-
tion, indicating a greater beneficial effect on the heart by L1 when
compared with DFO (7).
In a subsequent study, we enrolled 136 transfusion-dependent b-TM
patients from five medical centers in Taiwan (8) to determine if combina-
tion therapy was more effective in reducing iron burden, as gauged by
serum ferritin levels and SI of T2-weighted MRI, and improving heart func-
tion, as gauged by M-mode echocardiography LVEF. Combination therapy
performed best, the L1 only treatment performed second best, followed by
DFO only (9, 10). We also conducted a single study focusing on Gstm1 gene
polymorphisms related to cardiac iron deposition in these same patients
(4). Our results indicated that genetic variations of the GSTM1 enzyme
correlated with greater cardiac iron deposition in patients with b-TM.
In 2006–2007, 10 patients with b-TM were enrolled in a DFRA trial that
examined the effects of iron chelation with the administration of 20–30
mg/kg DFRA per day. Two patients showed skin rashes, one began to lose
 Update on Thalassemia Treatment in Taiwan 307

hair, and four had transient serum creatinine elevation; however, the serum
creatinine levels eventually returned to the normal range without discontin-
uation of the drug. Of the 10 patients, we found that serum ferritin levels
dramatically decreased in two, markedly increased in one patient, and there
was no significant change in five patients (unpublished data). Two patients
eventually dropped out of the study, one due to a refractory skin rash and
the other because of severe hair loss (Figure 1). In general, these findings
suggest that oral DFRA is comparable to DFO for reducing ferritin levels.
All eight patients who completed the study showed trends of decreasing
ALT and slightly increasingly creatinine levels (Figure 2). Nevertheless, if
used, DFRA side effects should be monitored, particularly with regard to
renal function, because creatinine elevation is reversible in most patients.
Once arrhythmia or cardiac dysfunction arises in b-TM patients, aggres-
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sive chelation must be initiated, regardless of the total iron burden. The
current standard of care remains continuous DFO therapy, because it
provides a continuous “sink” for free iron species (10). Continuous admin-
istration of this therapy may overcome the unfavorable transport kinetics of
DFO across myocyte membranes, and cardiac symptoms typically stabilize
over several weeks to months, once the “free” iron level is consistently sup-
pressed. Patients exhibiting congestive heart failure (CHF) signs and symp-
toms require hospitalization and close monitoring. In order to gain the
patients’ collaboration and confidence, the necessity of hospitalization should
be proposed and explained clearly by physicians, as diverse psychological

Ferritin (ng/mL)
14,000
A01
A02
12,000
Changes in serum ferritin(ng/ml)

A03
A04
10,000
A05
A06
8,000
A07
A08
6,000 A09
A10
4,000

2,000

0
B 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Months since start of DFX treatment

FIGURE 1 Monthly serum ferritin level of 10 DFRA trial patients. Patients A02 and A05 showed
dramatic decrease, patient A07 markedly increased and the other five patients stabilized. Patient A06
and A08 dropped out at 8 months due to severe hair loss, and at 1 month due to a refractory skin rash,
respectively.
 308 C.-T. Peng et al.

Cr, ALT
120

100
Changes in serum ALT and Cr.

80

Cr (umol/L)
60
ALT (U/L)

40

20

0
Downloaded By: [China Medical University] At: 08:26 12 November 2009

B 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Months since start of DFX treatment

FIGURE 2 Monthly mean serum ALT and creatinine levels of 10 DFRA trial patients.

matters may arise forthwith. Extensive treatment for decompensated CHF

should follow standard contemporary methods as described for the most
part by Peng et al (10). An intensified course of chelation, including inten-
sive intravenous DFO infusion and oral L1 administration, is paramount in
both asymptomatic high-risk patients and in those with heart failure (10).
Data suggest that this combination has an additive effect.

HEMATOPOIETIC STEM CELL TRANSPLANTATION

IN B-THALASSEMIA MAJOR
Allogeneic HSCT is the only cure for b-TM, as first reported by Lin et al
(11). in 1984 in Taiwan. Previously, they had reported an overall thalas-
semia-free survival rate of only 43% in HSCT patients without strict Pesaro
risk classification (11). Cord blood is a good source of hematopoietic stem
cells and has the additional advantage of extending the donor pool due to
the tolerance of one or two HLA mismatches and the lower incidence and
severity of acute graft-vs.-host disease (12). We performed transplants on
three children (aged 3.4, 4.2, and 5.6 years) having no hepatomegaly, ade-
quate iron therapy (Class I), and unrelated cord blood (HLA, one patient:
5/6, two patients: 4/6 matched). All three patients survived and needed no
blood transfusions for 24, 6 and 4 months, respectively. Thirty b-TM
patients with HLA 4/6 matched or more, unrelated umbilical cord blood
transplantations, have been reported from a single institution in Taiwan.
Estimated 1- and 3-year event-free survival rates were 85 and 78%, respec-
tively (12). Strategies that maximize the pre-frozen total nucleated cell dose
by using non red, cell-reduced, plasma-depleted cord blood with no post-thaw
 Update on Thalassemia Treatment in Taiwan 309

wash and double-cord transplant when necessary, have achieved promising

results. Improved strategies involving cord-blood stem cells and unrelated
donors have expanded the pool of potential donors (12) and achieved
promising results with HSCT in young patients.

DISCUSSION
Currently, extensive improvements in chelation therapy appear to apply
to all patients with b-TM, prompting the saying “it is never too late.” Histori-
cally, heart failure has been responsible for mortality in most b-TM patients.
Mechanisms and kinetics of iron entry and clearance through cell mem-
branes differ significantly between heart and liver. Increased iron loading
in the heart is harmful to myocardial function and can be detected by MRI
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(5, 13). Deferiprone, an oral iron chelator, plays a key role in cardio-protection.
Nevertheless, even before large-scale studies as well as our own study were
conducted, we observed that combination therapies involving both DFO
and L1 exhibited superior effects in decompensated heart failure cases.
Combination therapy has proved far more effective in thalassemic iron
loading-mediated cardiomyopathy than in cardiomyopathy stemming from
other pathophysiologies (6, 8–10). All chelation agents, including DFO, L1,
and DFRA, are available in Taiwan, and gene polymorphisms associated
with cardiac iron deposition have been detected, and the available options
for chelation management will expand as further correlations are uncov-
ered. Chelation can now be tailored to the needs of individual patients
based on these findings and tissue distribution of iron load.
In a previous International Conference on Chelation symposium, the
combination dose protocol for universally effective chelation as recom-
mended by the committee was as follows: L1 at 80–110 mg/kg/day during
the day and DFO at 40–60 mg/kg/day at least 3 days per week at night for
myocardial thalassemic patients (14). Since we began using this option in
1999, no b-TM patients have died of heart complications in our hospital.
Deferasirox has also proved effective in reducing serum ferritin and has
acceptable side effects. Therefore, it is necessary to consider individual
patient needs when selecting the most effective iron chelator for long-term
survival. Hematopoietic stem cell transplantation can be considered for
Class I Lucarelli patients living in countries where blood transfusion and
iron chelation are not available options. Due to the considerable risks and
expense of HSCT and the more realistic prospects for longer survival with
conventional treatment, discussion with the family of a child who is a poten-
tial transplant candidate is especially important in this situation.
To summarize, there are relatively few unrelated HSCT donors for
thalassemia patients in developed countries, as risk of transplant-related
mortality is high and conservative therapy is having improving success. Even
 310 C.-T. Peng et al.

for patients with a matching donor, the limited risk of early mortality from
such an invasive procedure should be recognized as a significant risk. In
developing countries that lack solid conventional treatments, unrelated
donor HSCT provides the possibility of cure for unfortunate children.
Hematopoietic stem cell transplantation carries with it the risk of early
death at the time of transplant, making the choice particularly difficult for
well-chelated young patients who might have a comparatively greater
chance for long-term survival and/or meeting a matched sibling donor;
these patients stand the best chance of a successful transplant. Chelation
therapy is more effective than in the past; however, in the future, both che-
lation therapy and HSCT will likely improve substantially. Our suggestions
for treatment follow.
Downloaded By: [China Medical University] At: 08:26 12 November 2009

CONCLUSIONS
We suggest the following guidelines for treatment of Taiwanese b-TM
patients. A focus on premarital screening can ensure proper prenatal diag-
nosis. For infants and children diagnosed with b-TM, solid conventional
therapy, including good transfusion and chelation management, should be
the first line of treatment. Hematopoietic stem cell transplantation should
only be considered for Pesaro Class I patients with sibling donors. However,
these patients should only consider HSCT if potential non compliance or
non-response to common chelators and combination therapy proves prob-
lematic, especially if experts estimate a progressive shift from Class I. Obvi-
ously, if the patient experiences a severe reaction to transfusion therapy,
HSCT should be carefully considered. We believe that these guidelines are
also valid for other developed countries.

Declaration of Interest: The authors report no conflicts of interest. The

authors alone are responsible for the content and writing of this article.

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