Comparison Between Deferoxamine and Deferiprone (L1) in Iron-Loaded Thalassemia Patients

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Eur J Haematol 2001: 67: 30±34 Copyright # Munksgaard 2001 Printed in UK. All rights reserved EUROPEAN JOURNAL OF HAEMATOLOGY ISSN 0902-4441 Comparison between deferoxamine and deferiprone (L1) in iron-loaded thalassemia patients

Taher A, Sheikh-Taha M, Koussa S, Inati A, Neeman R, Mourad F. Ali Taher1,2, Comparison between deferoxamine and deferiprone (L1) in iron-loaded Marwan Sheikh-Taha3, thalassemia patients. Suzanne Koussa1, Adlette Inati1, Eur J Haematol 2001: 67: 30±34. # Munksgaard 2001. Roger Neeman1,4, Fadi Mourad2 1The Chronic Care Centre, Beirut-Lebanon, Abstract: Introduction: Iron-chelating therapy with deferoxamine in 2Department of Internal Medicine, The American patients with thalassemia major has dramatically improved the University of Beirut Medical Centre, Beirut-Lebanon, prognosis of this disease. However, the limitations of this treatment have 3Lebanese American University, Byblos-Lebanon, and stimulated the design of alternative orally active iron chelators. 4Hotel Dieu de France, Beirut-Lebanon Objective: To compare the effectiveness and safety of, and compliance with, oral deferiprone (L1), and deferoxamine, in thalassemia major patients. Methods: All patients were followed up in one center in Lebanon. Sixteen patients were on L1 (75 mg/kg/d), and 40 patients on subcutaneous deferoxamine (20±50 mg/kg/d). Serum ferritin level, urinary iron excretion (UIE) and side effects were monitored over a two year period. Results: Patients on L1 had an initial serum ferritin concentration of 3663t566 mg/l (meantSEM), that dropped to 2599t314 at 6 months (p<0.02; paired t-test), and stabilised at that level over the 24 months follow up. Patients on deferoxamine had an initial Key words: deferiprone; deferoxamine; thalassemia; mean serum ferritin concentration of 3480t417 (NS compared to the L1 iron chelation group), which dropped gradually to 3143t417 (p<0.05) and 2819t292 (p<0.02) at 6 and 24 months, respectively. The most common adverse Correspondence: Ali Taher, MD, American University of Beirut Medical Centre, PO Box 113±6044, Beirut- reactions associated with L1 were arthralgia and nausea, but they did not Lebanon necessitate stopping the drug. Conclusion: L1 had comparable ef®cacy as Tel:+961 3 755669 deferoxamine with minimal side effects and better compliance. Provided Fax:+961 1 744464 long term side effects are not encountered, L1 seems to be a valuable Email: [email protected] alternative iron chelator for patients unable or unwilling to use deferoxamine effectively. Accepted for publication 26 February 2001

In patients with b-thalassemia major, an adequate body iron burden, prevention of organ dysfunction, transfusion program prevents the complications of and consequently an improved survival (4, 5). anemia and compensatory bone marrow expansion, Deferoxamine is currently the only iron-chelating permits normal development throughout child- agent approved internationally for clinical use (1, 3, hood, and extends survival (1). However, due to 4). In a dose of 25±50 mg/kg/d, it results in a lack of an effective means for excreting excess iron, negative iron balance in most patients with a body blood transfusion results in an inexorable accumu- iron burden about 5±10 times the normal level (2, 6, lation of tissue iron that may cause hepatic and 7). endocrine abnormalities, growth retardation, dia- However, treatment with deferoxamine is cum- betes mellitus and cardiac failure (2, 3). Clinical bersome, expensive, unpleasant and presents some trials with deferoxamine (Desferal1) have proved long term toxic effects (8). First, many patients ®nd the effectiveness of iron chelation as a therapeutic dif®culty in complying with daily subcutaneous approach to iron overload, with a decrease in the deferoxamine administration which is burdensome,

30 Deferoxamine and deferiprone in thalassemia painful, and time consuming. Second, infusions are One patient was not compliant and was lost for not given continuously, allowing toxic non-trans- follow-up, so he was dropped out from the study. ferrin bound iron (NTBI) to accumulate in plasma The remaining 40 patients with thalassemia major, between infusions (2, 6). Third, over 90% of the aged 17t4 yr (21 males and 19 females) received world's patients with thalassemia can not afford deferoxamine, (Novartis, Basel, Switzerland). The deferoxamine ($5000 to $15,000 a year) (9). Fourth, daily dose of deferoxamine ranged from 25 to adverse effects are associated with deferoxamine 50 mg/kg/d to be taken at least 5 d each week. The including allergy, pain at the site of infusion, ocular drug was given by subcutaneous infusions overnight and auditory abnormalities, neurotoxicity, changes for 8±12 h. The study was approved by the Ethical in renal function, and failure of linear growth in Committee of the Chronic Care Center. young children (1). We assessed the ef®cacy of the chelators by Thus, in spite of the proven ef®cacy of deferox- periodic measurements of serum ferritin concentra- amine, there was a great need for the development tions over a 24-month follow up period. In addition, of an alternative iron chelator based on three main in patients on L1, a 24-h urinary iron excretion was criteria, namely oral activity, low cost, and low performed initially one week after starting the drug toxicity (5, 10). Of all the new iron-chelating drugs and at 6 and 12 months. Statistical analysis was available today, only deferiprone (1, 2-dimethyl-3- performed using Student's t-test. hydroxypyridin-4-one; L1) has been introduced for Safety was determined by regular patient follow clinical use as an orally effective substitute for up with detailed clinical examination. In addition, deferoxamine (1, 5, 11). The ef®cacy of L1 in patients were asked to ®ll in side effects ques- reducing body iron burden in patients with iron tionnaires. Regular laboratory tests were performed overload has been uncertain, despite an increase in for patients on L1 including full blood count, liver urinary iron excretion (1, 12). Adverse reactions and renal function, serum immunoglobulins, and associated with the use of deferiprone include antinuclear and rheumatic factor. Urinary zinc agranulocytosis, arthropathy, zinc de®ciency, and excretion was measured one week after starting L1 gastrointestinal side effects (13). We hereby report and every 6 months thereafter. the results of an open trial comparing subcuta- neously administered deferoxamine with orally administered L1. Results Ef®cacy of L1 In the 16 patients receiving L1, mean serum ferritin Patients and method level showed a decline with time from an initial We studied 57 patients with transfusion-dependent meantSEM of 3663t566 mg/l (range 1005±9787) thalassemia major, ranging in age between 12 and to 2599t314 (range 575±4206) at 6 months, and 28 yr, who were evaluated periodically in the 2716t461 (range 944±7117) at 24 months after Chronic Care Center, a Lebanese charitable institu- starting treatment (p<0.03 and p<0.05, respec- tion. Each patient received regular transfusions of tively) (Fig. 1). packed red cells at 3- to 4-week intervals to Urinary iron excretion (UIE) one week after maintain their hemoglobin concentration at a starting L1 therapy was 20.7t3.2 mg/24 h (range level above 9 g/dl. All patients were on deferox- 0.3±42.7) and dropped to 10.5t1.7 (range 0.07±25) amine for a period ranging from 4 to 24 yr. and 13.7t1.8 (range 0.3±28) at 6 and 12 months Seventeen patients (15 had thalassemia major, 1 after starting L1 (both p<0.01 compared to initial thalassemia intermedia and 1 sickle-thalassemia) UIE). There was a positive correlation between received L1 because they were not compliant or initial serum ferritin level and UIE (r=0.57, unable to take deferoxamine because of severe p<0.019), but this correlation did not persist over reactions to the drug. Non-compliance was de®ned the follow up period (r=0.006 and r=0.3 at 6 and as discontinuation of the drug for at least one 12 months, respectively). month or intake of less than 70% of the recom- mended dose which ranged from 25 to 50 mg/kg/d according to ferritin level and taken 5 times/week. Ef®cacy of deferoxamine These patients, aged 20t1 yr (9 males and 8 In the 40 patients receiving deferoxamine, mean females), were given deferiprone (Lipomed, Basel, serum ferritin level showed a decrease with time Switzerland) orally at a total daily dose of 75 mg/kg from an initial meantSEM of 3480t417 mg/l body weight. L1 was given in three divided doses (range 829±10,540) to 3143t378 (range 591± before meals. The effect of L1 on these patients over 11734) (p<0.05) at 6 months, and 2819t292 a 12 month period was previously reported (14). (453±8602) (p<0.02) at 24 months (Fig. 1).

31 Taher et al.

subgroup, there was no change in the level of AST during L1 therapy (85t14 and 96t19 IU/l at time 0 and 24 months, respectively). The other ®ve patients had a transient increase in AST (50t7, 79t10, 51t9 and 47t5 at times 0, 6, 12 and 24 months, respectively). All patients maintained normal levels of blood urea, serum creatinine, as well as normal fasting glucose tolerance tests.

Safety of deferoxamine The most common side effects observed in patients Fig. 1. Effect of deferiprone (L1) and deferoxamine on on deferoxamine were pain, tenderness, itching, serum ferritin level in thalassemia patients during 24 months follow up. *p<0.03 and **p<0.05 compared with initial erythema, swelling, induration, lipodystrophy, and ferritin level (time 0). Values are expressed as mean and a burning sensation at the site of infusion reported SEM. in 34 patients (85%). In a few cases, increased heart rate (6 patients), disturbances of vision and hearing Safety of L1 (5 patients), dizziness (4 patients), growth retarda- The most common reaction that was associated tion (3 patients), and leg cramps (one patient) were with the administration of L1 was an orange also observed. discoloration of the urine. The most common adverse effect was joint pain (mostly large joints), Compliance stiffness or swelling reported in six patients (37.5%), In patients on L1, compliance was apparently two of whom had moderate to severe symptoms excellent in all patients as assessed by the patient's that did not require a decrease or discontinuation of history, parental evidence, and usage of tablets L1 and the other four had mild symptoms. Nausea, provided in just-suf®cient quantities between check especially in the ®rst month of treatment, was up visits. On the other hand, in patients on reported in seven patients (43.7%). Other side deferoxamine, compliance was considered to be effects included headache (4 patients), skin rash (2 rated good in 24 patients (60%), and poor in 16 patients), occasional decrease in appetite (2 patients (40%), assessed mainly by counting vials patients), fatigue (2 patients), abdominal discom- given to patients and returned after usage. fort, mouth ulcers, and sore throat (each in one patient). Complete blood counts, obtained periodically in Discussion all patients, did not change signi®cantly during The results here con®rm that L1 is effective at treatment. Neither reduction of dose nor cessation increasing urinary iron excretion in patients with of L1 was required because of a change in the blood transfusional iron-overload. However, although count in any patient. Only two patients had a patients received comparable doses of L1, urinary transient decrease in neutrophil count to 1.38r109 9 iron excretion varied considerably from patient to and 1.44r10 /l that was not reproduced on weekly patient. The wide variation in iron excretion among follow up studies. These two patients had a history the patients may relate partly to a wide range in of recent viral infection. body iron stores, with iron excretion being greater There was a non-signi®cant increase in urinary in those with higher serum ferritin level (r=0.56, Zn excretion from 441t37 to 515t73 mg/24 h p<0.02) assuming that serum ferritin level may (p=0.35). correlate with total iron body burden. Iron excre- Because of few report of L1-associated systemic tion also relates to the area under the curve of free lupus erythematosus, tests for antinuclear anti- deferiprone in plasma after a single oral dose (15). bodies and rheumatoid factor were performed every The drug is glucuronidated at a different rate in 3 months. No signi®cant changes in antinuclear different patients. Ef®cacy will be affected, since antibodies or rheumatoid factor were noted; we did glucuronidation inactivates the drug's iron binding not detect any positive qualitative ANF at any time sites. The lack of ef®cacy in some patients, despite during the trial. high iron body loads, may be the result of Abnormal liver enzymes, de®ned as an increase in particularly fast glucuronidation of deferiprone serum aspartate transaminase (AST) of >2 times (15). the upper limit of normal, were detected in 13 In general, the mean daily intake of iron from patients, eight of whom were HCV positive. In this transfusion is 0.5 mg/kg/d. Five of 16 patients tested

32 Deferoxamine and deferiprone in thalassemia showed UIE greater than this on a daily total dose tively). Later on, the drop in ferritin was almost a of 75 mg/kg/d one week after L1 administration. similar in the two groups. Our results are similar to After 6 months and one year, this rate of excretion previous studies that showed similar effect of the was sustained in only one patient. The reduction in two drugs on serum ferritin concentration in doses UIE with time could be secondary to a reduction in similar to those used in the present study (27±29), body iron stores (as assessed indirectly by serum although in one study there was an increase in liver ferritin level); however, in our study there was no iron with L1 (27). correlation between UIE and serum ferritin level at L1 was well tolerated, neither the reduction nor 6 and 12 months after starting L1. This ®nding is the cessation of L1 was required because of adverse similar to results of other studies where UIE effects. Only one patient was lost to follow up. The decreased with time without any correlation with arthropathy observed in six patients was transient serum ferritin (16). The other possible cause for the and mild to moderate in severity. Pain was relieved decrease in UIE over time could be the reduced by a short course of NSAIDs. There was no relation absorption associated with long term use of L1 or between the presence of these symptoms and the increased metabolism with a progressive decrease in presence of the different autoantibodies tested serum L1 trough levels (17). Since excretion before or after the therapy. The changes in the depends mainly on the dose of L1 (11, 18), this liver enzyme ALT in patients who were HCV raises the question whether L1 at this dose can negative were also transient and settled without induce a negative iron balance in these patients. In a discontinuation of L1 therapy. previous report (18), a negative iron balance could In our trial, adverse effects associated with be achieved with higher L1 doses; the mean UIE at a Desferal use can be grouped into two main dose of 85±119 mg/kg/d was comparable with that categories, namely local skin reactions and more achieved with deferoxamine at a dose of 40 to serious toxic effects including visual and auditory 50 mg/kg/d. A fall in serum ferritin was noted in 14/ abnormalities or growth retardation. It has been recognized that most toxic effects of deferoxamine 16 patients (87.5%) after 6 months, and in 12/16 have been observed in patients during administra- patients (75%) after 12 and 24 months of L1 tion of doses exceeding 50 mg/kg/d, or smaller doses administration. There was a statistically signi®cant in the presence of very modestly elevated body iron decrease in mean serum ferritin concentration at 6, burdens (1). These toxic complications can be 12 and 24 months after starting L1 (Fig. 1). minimized by proper dose adjustments. One such Changes in serum ferritin was not encountered in method is limiting the daily dose/kg body weight to all previous studies, some showing a signi®cant a deferoxamine to ferritin ratio of 0.025 (3). decrease (18±21); while others showing no change In conclusion, L1 appears to be a relatively safe (22±24). This discrepancy could be explained by the chelator at a dose of 75 mg/kg/d. However, at this different duration of treatment, severity of iron dose urinary iron excretion was not enough to overload before starting L1, dosage, compliance induce a negative iron balance in our patients. On and possibly drug source. In our study, serum the other hand, based on ferritin level, it was found ferritin concentration dropped abruptly at 6 months that L1 is as effective as deferoxamine, which may and then seemed to plateau. Although a previous be related to a better compliance. All patients stated study showed a decline of serum ferritin over time a clear preference for using L1 compared with (19), Olivieri et al. (25) found a plateau or even an subcutaneous deferoxamine, and the patients upward trend of serum ferritin similar to our apparent compliance with the drug throughout ®ndings, indicating a need for a higher dosage (26). the trial was excellent. Increasing the dose of In patients taking deferoxamine, a fall in serum L1 or combining subcutaneous deferoxamine with ferritin was noted in 23/40 patients (57.5%) after 6 L1 therapy are two methods by which ef®cacy months, and in 25/40 (62.5%) after 24 months of of iron chelation with L1 can be improved in starting the trial. The mean drop was signi®cant at patients inadequately chelated by a daily dose of those follow-up periods. 75 mg/kg/d. At the beginning of the trial, the two groups had comparable mean serum ferritin levels (p=0.637). In the L1 group, the mean drop in serum ferritin was higher after 6 months and after 12 months than References with deferoxamine, although this difference was not 1. OLIVIERI N, BRITTENHAM G. Iron-chelating therapy and the statistically signi®cant (1063t440 mg/l compared to treatment of thalassemia. Blood 1997;89:739±761. 337t189 mg/l (p=0.270) at 6 months; and 2. HERSHKO C, LINK G, CABANTCHIK I. Pathophysiology of iron overload. Ann NY Acad Sc 1998;850:191±201. 684t449 mg/l versus 389t284 mg/l at 12 months 3. HERSHKO C, KONIJN AM, LINK G. Iron chelators for (p=0.578) in L1 and deferoxamine groups, respec- thalassemia. Br J Haematol 1998;101:399±406.

33 Taher et al.

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