Hemoglobin, 30 (1):125–130, (2006)Copyright © Taylor & Francis Group, LLCISSN: 0363-0269 print/1532-432X onlineDOI: 10.1080/03630260500455581

125

LHEM0363-02691532-432XHemoglobin, Vol. 30, No. 01, December 2005: pp. 0–0Hemoglobin

PROCEEDINGS 15TH ICOC

Taiwan, April 2005

DEFERIPRONE OR DEFEROXAMINE VS. COMBINATION THERAPY

IN PATIENTS WITH �-THALASSEMIA MAJOR: A CASE STUDY

IN TAIWAN

DFO or L1 vs. Combination in β-Thalassemia MajorC.-T. Peng et al.

Ching-Tien Peng,1,4 Kang-Hsi Wu,1 Shu-Fen Wu,1 Der-Cherng Liang,2

Chao-Ping Yang,3 Ren-Chin Jang,5 Lin-Yen Wang,2 and Chih-Cheng Hsiao6

1Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan2Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan3Department of Pediatrics, Chang-Gung Children’s Hospital, Taoyuan, Taiwan4College of Health Sciences, Asia University, Taichung, Taiwan5Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan6Department of Pediatrics, Chang-Gung Children’s Hospital, Kaohsiung, Taiwan

� Deferiprone (L1) has been recommended as an effective oral chelation therapy for patients withβ-thalassemia major (TM). From 1999 to 2004, 114 patients with TM from five treatment centerswere enrolled in this program: iron (Fe) was chelated with L1 in 57 patients, deferoxamine (DFO)in 26, and combined L1/DFO therapy in 31. We found that serum ferritin (SF) was significantlylower in nine patients receiving L1 for more than 5 years (p = 0.04), 22 patients receiving L1 for1–2 years (p < 0.01) and 31 receiving the combined therapy (p = 0.01), yet significantly higher inthose receiving DFO only (p < 0.01). One patient showed transient neutropenia; arthropathy in onepatient and gastrointestinal upset in two were noted, with no significant change in alanineaminotransferase (ALT) level. Of 17 patients who were submitted to a liver biopsy, 15 showed nosignificant change in hepatic fibrosis scores after therapy with L1. None of the 88 patients, includ-ing 31 who received the combined therapy, have abandoned oral L1 treatment due to adverse effects.Results of this study proved that L1 or combined therapy with L1 and DFO is effective in reducingSF; incidence of adverse events was low in patients with TM.

Keywords β-Thalassemia major, Deferiprone (L1), Deferoxamine (DFO), Combinedtherapy

Presented at the 15th ICOC, Taichung, Taiwan 22-26 April 2005.Address correspondence to Dr. Kang-Hsi Wu, Department of Pediatrics, China Medical University

Hospital, 2 Yuh-Der Road, Taichung 404, Taiwan; Fax: +886-4-22032798; E-mail: d5284@www.cmuh.org.tw

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126 C.-T. Peng et al.

INTRODUCTION

Accumulation of iron (Fe) in the liver, heart, and endocrine glands isa serious complication of β-thalassemia major (TM). Over 50% of ironoverload-related mortality occurs before 30 years of age in the Far East.The major cause of death was cardiac failure. Deferoxamine (DFO) is aneffective iron chelator, whose use is limited by the cumbersome method ofadministration, side effects, high cost, and low compliance. Oral chelationis more convenient than the traditional subcutaneous chelator, but thereare concerns about efficacy and side effects. Then again, a number of stud-ies have demonstrated that combined therapy with deferiprone (L1) andDFO yields a greater effect than either one used alone (1,2).

We report here the results of a clinical probe evaluating the safety andeffectiveness of L1 and DFO in reducing iron overload, either alone or incombination therapy in patients with TM. Data for this study were takenfrom five medical centers in Taiwan.

MATERIALS AND METHODS

The registry for controlled use of L1 was managed by a panel of physi-cians experienced in the treatment of patients with TM. The enrollmentprocedure required a request from a treating physician together with thepatient’s medical history. The physicians were committed to supplyresults of occurrence of adverse events and the efficacy. From January1999 to December 2004, 136 patients with transfusion-dependent (every2–4 weeks) TM, from five medical centers in Taiwan, were enrolled inthis study. Thalassemia major was diagnosed by electrophoresis and/orDNA analysis. Exclusion criteria were: 1) patients with congenital anemiaother than TM; 2) patients showing malignancy and/or who requiredradiation or chemotherapy; 3) patients who could not swallow capsules;4) compliance <90%. They received regular red blood cell transfusionsevery 2–4 weeks, in order to maintain a hemoglobin (Hb) level of >9 g/dL.Deferoxamine (Novartis Pharma Schweiz AG, Basel, Switzerland) wassubcutaneously administered (duration: 8–12 hours; 3–7 days per week)at a dose of 30–50 mg/kg per day. Thalassemia major patients weretreated with DFO until January 1999, when we first imported L1 (CiplaLtd., Mumbai, India) for clinical trials in Taiwan. Patients were pre-scribed a total daily dosage of 75–80 mg L1 per kg body weight, dividedinto three doses.

For purposes of analysis, we divided these patients into five subgroups:group 1 patients received L1 for more than 5 years, group 2 from 2–5 years,group 3 from 1–2 years, group 4 continued on DFO subcutaneous therapy,and group 5 received L1 + DFO. We defined this as the combined therapy

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DFO or L1 vs. Combination in �-Thalassemia Major 127

group, as L1 was administered every day and DFO was also administered 2–6days each week.

Assessment and monitoring of adverse events proceeded as follows:1) physical examination, a complete blood count, and white cell differen-tial count were measured prior to transfusion (interval range: 2–4weeks); 2) serum ferritin (SF) level and liver function were measuredevery 2–3 months; 3) cardiac magnetic resonance imaging (MRI),echocardiography, and liver biopsy every year, if patients and parentsagreed. Interruption of treatment was requested in the following cases:1) total white blood cell counts <1.5 × 109/L; 2) neutrophil count <0.5 ×109/L; 3) severe gastrointestinal upset; 4) severe joint pain and/or swell-ing; 5) some cases of increased serum alanine aminotransferase (ALT)levels evaluated on an individual basis, together with other relevant infor-mation of the patient. Seventeen patients, who had received L1 for 23–60months, underwent percutaneous liver biopsy after signing informedconsent forms. We compared fibrosis status of specimens obtainedbefore initiating L1 therapy and final biopsy. Grading of hepatic fibrosiswas performed using the method of the Metavir score system. Data arepresented as mean ± SD. Results were tabulated by analysis of variance,followed by the Student’s t-test. The paired t-test compared data beforeand after therapy in the same group; a p value of less than 0.05 was con-sidered to be statistically significant.

RESULTS

After excluding 22 patients for non compliance, 114 patients wereassessed: 105 were treated with L1 alone or in combination with DFO vs. 31on the DFO regimen alone. We divided these patients into five subgroups(Table 1). After iron chelation therapy from 1999 to 2004, we found thatthe SF was significantly lower in groups 1 (p = 0.04), 3 (p < 0.01), and 5(p <0.01), and higher in group 4 (p <0.01).

In 88 patients receiving L1 for iron chelation, including combined ther-apy, only one (1.1%) showed mild neutropenia (absolute neutrophil count:1,213 μL) in the 5th month of L1 therapy. He did not discontinue the L1therapy or receive any specific treatment, and the neutrophil count recov-ered 24 days later. Arthropathy in one patient (1.1%) and gastrointestinalupset in two (2.2%) were noted, but there was no significant change in ALTlevel among these groups (Table 1). In the 17 patients undergoing liverbiopsy, hepatic fibrosis scores showed no significant change in 15 patients(88.2%) after L1 therapy. None of these 88 patients have abandoned oralL1 treatment due to adverse events, and no treatment-related fatalitiesoccurred during the 6-year study.

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128

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DFO or L1 vs. Combination in �-Thalassemia Major 129

DISCUSSION

Some studies have questioned the efficacy of L1 (3). In our study, wefound the SF level decreasing in three groups iron chelated by L1 alone;significantly decreased in groups 1 and 3. Hence, 25 mg L1 per kg thricedaily was effective in controlling (i.e., reducing or stabilizing) the body ironload, as determined by SF levels. Interestingly, the SF level rose significantlyin group 4 (iron chelated by DFO alone). We speculate that this may haveresulted from poor compliance of DFO in adolescents.

Complications attributed to the use of L1 include neutropenia, agranu-locytosis, arthralgia, gastrointestinal symptoms and transient high livertransaminase levels (4–8). In this study, we found that the adverse eventsassociated with L1 were mild and tolerable. All those with adverse eventsrecovered normally, without interrupting or discontinuing therapy. TheALT levels did not significantly change in the five groups. Olivieri et al. (3)suggested that L1 may lead to progressive hepatic fibrosis, which has notbeen confirmed in larger studies or long-term follow-up (9,10). In ourstudy, hepatic fibrosis improved in 17 such patients, except in two, beforeand after L1 therapy. However, these two were simultaneously positive forhepatitis C virus antibody. Therefore, we cannot definitely attribute hepaticfibrosis to L1 alone; a larger sample of patients treated with L1 and followedlong-term is warranted.

Combined L1 + DFO therapy was reported to produce additive or syner-gistic iron chelating effects (1,2). We have previously reported successfulregression of severe heart failure in two patients with TM with such therapy(11). In this study, no significant adverse effects related to this combinedtherapy were encountered in 31 patients of group 5, for as long as37 months. We also found that SF levels were significantly lower aftercombined therapy. Therefore, the combined therapy with oral L1 every dayand subcutaneous DFO 2–6 days per week is safe and effective in reducingiron burden. In particular, this combined therapy should be consideredin patients with TM and cardiac complications.

In summary, L1 was shown to be safe and efficacious for most patientsin our 6-year study. Higher doses of L1 in clinical use can be encouraged.Combined therapy with L1 and DFO showed no elevated incidence oftoxicity and, in transfusion-dependent patients, might be the best optionfor achieving satisfactory iron chelation therapy, especially in those withcardiac complications.

ACKNOWLEDGMENTS

This study was supported by Grant DMR-92-001 from the ChinaMedical University Hospital, Taiwan.

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130 C.-T. Peng et al.

REFERENCES

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3. Olivieri NF, Brittenham GM, McLaren CE, Templeton DM, Cameron RG, McClelland RA, BurtAD, Fleming KA. Long-term safety and effectiveness of iron-chelation therapy with deferiprone forthalassemia major. N Engl J Med 1998; 339(7):417–423.

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6. Cohen AR, Galanello R, Piga A, Dipalma A, Vullo C, Tricta F. Safety profile of the oral iron chela-tor deferiprone: a multicentre study. Br J Haematol 2000; 108(2):305–312.

7. Barman Balfour JA, Foster RH. Deferiprone: a review of its clinical potential in iron overload inβ-thalassaemia major and other transfusion-dependent diseases. Drugs 1999; 58(3):553–578.

8. Hoffbrand AV, Cohen A, Hershko C. Role of deferiprone in chelation therapy for transfusionaliron overload. Blood 2003; 102(1):17–24.

9. Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A, Galanello R, Gamberini MR, Schwartz E,Cohen AR. Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in sub-jects with transfusion-dependent β-thalassemia. Blood 2002; 100(5):1566–1569.

10. Kontoghiorghes GJ, Pattichi K, Hadjigavriel M, Kolnagou A. Transfusional iron overload andchelation therapy with deferoxamine and deferiprone (L1). Transfus Sci 2000; 23(3):211–223.

11. Wu KH, Chang JS, Tsai CH, Peng CT. Combined therapy with deferiprone and desferrioxaminesuccessfully regresses severe heart failure in patients with β-thalassemia major. Ann Hematol 2004;83(7):471–473.

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