combined chelation therapy in thalassemia major with deferiprone and desferrioxamine: a...

Combined chelation therapy in thalassemia major withdeferiprone and desferrioxamine: a retrospective studyPaolo Ricchi1, Massimiliano Ammirabile1, Anna Spasiano1, Silvia Costantini1, Patrizia Cinque1, TizianaDi Matola2, Leonilde Pagano1, Luciano Prossomariti1

1Dipartimento di oncoematologia, U.O.C. Centro delle Microcitemie ‘‘A. Mastrobuoni’’, AORN A. Cardarelli, Naples; 2Centro Traumatologico

Ortopedico ASLNA1, Naples, Italy

Iron chelation therapy remains one of the main objec-

tives of clinical management of the patients affected by

thalassemia major. The combined treatment with defe-

roxamine (DFO) and deferiprone (DFP) has been

observed to increase the efficacy of chelation therapy.

Trials on combined therapy reported different schedules

of treatment and dosages: DFP ranged from 60 to

110 mg ⁄Kg per d and DFO from 20 to 60mg ⁄Kg per d

subcutaneously for 2–6 d a wk (1–9). In literature, nei-

ther within a single study nor through a meta-analysis

study, it has been evaluated whether the number of days

of DFO infusion and ⁄or the dosage of DFP could signif-

icantly influence the safety and the effectiveness of iron

chelation therapy. Furthermore, no trial has been

designed to evaluate DFO administration in combination

with DFP at a dosage lower than them suggested by the

manufacturer. The present retrospective study aimed to

compare efficacy and safety of combined chelation ther-

apy with conventional or reduced dosage of DFP in

combination with DFO administered for 3 or 5 d a wk.

Patients and methods

We analyzed patients with homozygous b-thalassemia

major who received regular blood transfusion with

packed red blood cells every 3–4 wk to maintain

hemoglobin concentration above 9 g ⁄dL. Previously,

patients had received DFO (Novartis Pharma AG, Basel,

Abstract

Objectives: The benefits of combined chelation therapy with daily deferiprone (DFP) and subcutaneous

desferrioxamine (DFO) have been widely reported in literature. We retrospectively evaluated the efficacy

of different schedules of combined chelation therapy and the incidence of adverse events. Methods: We

evaluated 36 patients affected by thalassemia major treated with combined chelation therapy. Patients

were subdivided into four treatment arms according to severity of iron overload and previous onset of

adverse events to DFP therapy: Group 1 (13 pts) DFP 75 mg ⁄ kg per d plus DFO (25–35 mg ⁄ kg per d for

5 d); Group 2 (6 pts) DFP 50 mg ⁄ kg per d plus DFO (25–35 mg ⁄ kg for 5 d), Group 3 (10 pts) DFP

75 mg ⁄ kg per d plus DFO (25–35 mg ⁄ kg for 3 d), and Group 4 (7 pts) DFP 50 mg ⁄ kg per d plus DFO (25–

35 mg ⁄ kg for 3 d). Change in serum ferritin level was evaluated in all patients. Results: Overall, ferritin

decreased from 2592 ± 1701 to 899 ± 833 ng ⁄ mL (P < 0.001). All treatments were able to reduce ferritin

levels, but in patients of group 1 and group 2 the highest mean decrease in serum ferritin level and the

greatest improvement in liver iron concentration (LIC) and in T2* values were observed. Conclusions: This

study showed that the administration of DFO for 5 d a wk in combination with daily administration of DFP

at 75 mg ⁄ Kg seemed to be the most efficacy and rapid method for reducing iron overload at liver and

heart level. Furthermore, the use of different schedules of combined DFO and DFP administration was not

associated with different incidence of adverse effects between the groups.

Key words thalassemia; iron overload; iron chelator; agranulocytosis

Correspondence Paolo Ricchi, U.O.C. Microcitemia, Azienda Ospedaliera di Rilievo Nazionale ‘‘A.Cardarelli’’, Via A.Cardarelli 9,

80131 Napoli, Italy. Tel: +39 081 7472256; Fax: +39 081 7472250; e-mail: [email protected]

Accepted for publication 7 December 2009 doi:10.1111/j.1600-0609.2010.01447.x

ORIGINAL ARTICLE

European Journal of Haematology 85 (36–42)

36 ª 2010 John Wiley & Sons A/S

Switzerland) at daily dose of 30–40 mg ⁄Kg per d by sub-

cutaneous infusion for 10–14 h on 3–5 nights a wk or

DFP (Apotex, Toronto, Canada) at daily dose of 60–

80 mg ⁄Kg per d. All patients had had low compliance

with subcutaneous DFO or had showed unresponsiveness

and ⁄or adverse events (intolerance) to a previous DFP

administration; however, because of these reasons, they

showed a worsening of their iron overload. Conse-

quently, most of enrolled patients had moderate to

severe iron overload documented by serum ferritin levels

higher than 1500 ng ⁄mL and ⁄or by the presence of mod-

erate to sever liver iron concentration (LIC) (mgFe ⁄ gliver dry weight > 6.5) assessed by Superconductum

quantum interference device (SQUID) and ⁄or by an

increased myocardial iron concentration evaluated by

magnetic resonance T2* technique (T2 < 20 ms).

Study design

Study data referred to patients with homozygous beta-

thalassemia major attending in our Thalassemia Unit,

Centro delle Microcitemie, Ospedale Cardarelli, Napoli,

from January 2001 to December 2007. Patients were

included into four treatment arms considering their iron

overload and response to previous treatments; they were

divided according to the severity of iron overload in

the first two groups: daily DFP combined with DFO

(25–35 mg ⁄Kg) 5 d a wk when the ferritin level was

>2000 ng ⁄mL or, liver dry weight was >9 mgFe ⁄g or mean

myocardial T2* was <13 ms; DFO (25–35 mg ⁄Kg) was

administered 3 d a wk to remaining population. This

rationale allowed patients with severe myocardial sidero-

sis or considerably increased LIC to receive an intensive

chelation therapy. Patients were further divided into

other two arms according to the presence of previous

DFP adverse reaction: in particular, daily DFP was used

at dosage of 50 mg ⁄Kg for patients who previously had

experienced neutropenia, nausea ⁄ vomiting or transient

increase in Alanine transferase (ALT) level; daily DFP

was used at a dosage of 75 mg ⁄Kg per d for remaining

population.

The inclusion criteria to entry into the retrospective

analysis were the follows:

1. A complete blood cell count had to be available

every wk for the first month of therapy, than every 7–

10 d. A neutrophil count was defined as neutropenia if it

was lower than 1.5 · 109 ⁄L and as agranulocytosis if it

was lower than 0.5 · 109.

2. Patients who did not experience serious adverse

events (agranulocytosis) had to be treated for a period of

at least 8 months.

Exclusion criteria were as follows:

1. any change in mean annual blood consumption

(mL ⁄kg per yr);

2. changes in dose of DFP and DFO and ⁄or number of

d a wk of DFO administration;

3. lack of compliance to therapy. Compliance was peri-

odically assessed by checking the pills of DFP and the

number of the infusions recorded by micropump.

Efficacy of chelating regimen was evaluated in all

patients by changes in serum ferritin on a 3 monthly

basis. Alanine transferase (ALT) levels (U ⁄L) had to be

carried out every month.

All patients were treated with the aim to obtain exten-

sive iron depletion; for this reason a different time on

treatment, depending on baseline iron overload, was

used. However, in the subset of patients that were

enrolled on RMN or SQUID basis, hepatic and cardiac

hemosiderosis were re-evaluated after 18 ± 6 months of

treatment and then the treatment was stopped.

Overall, 36 patients aged between 15–64 (Table 1)

were evaluated retrospectively. The patients were allo-

cated into the following groups:

Group 1: 13 patients received DFO 25–35 mg ⁄Kg for

5 d a wk in combination with daily DFP 75 mg ⁄kg;Group 2: 6 patients received DFO 25–35 mg ⁄Kg for



3 d a wk in combination with daily DFP 50 mg ⁄kg.However, five patients (Table 2) were allocated into

previous groups under different criteria for the following

reasons: two patients (1.F, 1.N) asked to receive DFO

for 5 d a wk instead of DFO for three d because of

excessive anxiety toward mild level of ferritin; three

patients (3.I, 3.L and 4.F) because of a severe intolerance

to DFO, preferred DFO for three d a wk to DFO for

5 d a wk. Four patients (two belonging to group 1, one

to group 2 and one to group 4) that were found non-

compliant to DFO therapy were excluded from the

study; during an interview they admitted taking only

DFP regularly.

Full blood counts and indices were measured by a

Cell-Dyn 3700 (Abbott USA). Cardiovascular magnetic

resonance (MR) acquisition was performed using a 1.5 T

MR scanner (Pisa, Italy). Measurement of myocardial

iron overload by T2* gradient-echo multiecho sequence

was used. Biventricular function parameters were assessed

in a standard way, using MASS_ software (Medis,

Leiden, the Netherlands). Image signal analysis of T2*

gradient multiecho sequences was analyzed by custom-

written software. Serum ferritin was measured by Imx

Ferritin assay, a Microparticle Enzyme Immunoassay

(MEIA) (Abbott USA). The study was approved by the

Ethical Committee of the Cardarelli Hospital, Napoli.

Informed consent was obtained from all patients and ⁄ortheir parents.

Ricchi et al. Combined chelation therapy in thalassemia

ª 2010 John Wiley & Sons A/S 37

Statistical evaluation

Differences between values were examined by the

U Mann–Whitney test (non parametric analysis); differ-

ences into the same groups were statistically assessed by

the t-test. P-value below 0.05 was considered as signifi-

cant. Data were reported as mean ± SD.

Results

The characteristics of patients and the time on treatment

are shown in Table 1. A total of 36 patients were

assessed, which underwent combined regimen from 2.7

to 96 months. As a consequence of stratification, 23

patients (group 1 and 3) were treated with DFP at dose

of 75 mg ⁄Kg while 13 patients received DFP at

50 mg ⁄Kg per d (group 2 and 4). On the other hand, 19

patients (group 1 and 2) received DFO 25–35 mg ⁄Kg for

5 d a wk, while 17 (group 3 and 4) received 30 mg ⁄Kg

for 3 d a wk. Overall, the age of the patients at the time

of enrollment ranged from 15 to 64 yr, (median of

32 yr). Fifty-eight percent of the patients were female.

Splenectomy had been performed in 23 patients (64%).

Nineteen patients (53%) had hepatitis C virus (HCV)

RNA test positive (Table 1). Owing to the small number

of patients enrolled into the study, only same characteris-

tics were homogeneously distributed; however, except

from the patients of group 2 (mean drug exposure of 2.6

patient-yr), the time on treatment was comparable

among all others groups (Table 1).

Figure 1 and Table 3 show the effect of treatments on

ferritin serum level for each group of patients and for

each patient, respectively. No statistically significant dif-

ference in serum baseline ferritin level was found between

patients of groups 2 and 4 treated with DFP at dose of

50 mg ⁄kg (2735 ± 1994 ng ⁄mL) and those of groups 1

and 3 treated with DFP at dose of 75 mg ⁄Kg

(2341 ± 1021 ng ⁄mL), indicating that DFP dose-assign-

ment was not associated with selection of patients with

respect to baseline ferritin level (data not shown). Con-

sidering all patients together, ferritin decreased from

Table 1 Baseline characteristics of the patients

Overall (n = 36) Group 1 (n = 13) Group 2 (n = 6) Group 3 (n = 10) Group 4 (n = 7)

Age (y) (range)1 32 (15–64) 33 (15–45) 32 (17–36) 31 (15–45) 33 (24–64)

Sex (M ⁄ F) 15 ⁄ 21 6 ⁄ 7 3 ⁄ 3 4 ⁄ 6 2 ⁄ 5HCV+ 19 ⁄ 36 9 ⁄ 13 5 ⁄ 6 3 ⁄ 10 2 ⁄ 7Splenectomy (n) 23 ⁄ 36 9 ⁄ 13 2 ⁄ 6 7 ⁄ 10 5 ⁄ 7Total drug exposure (patient-yr) 56.5 20.0 16.0 12.0 8.5

Mean ± SD drug exposure (patient-yr) 1.6 ± 1.4 1.5 ± 1.2 2.6 ± 2.7 1.2 ± 0.4 1.2 ± 0.7

Extension of treatment months (range) (2.7 – 96) (8.2 – 60) (11 – 96) (9 – 22) (2.7 – 30)

HCV, hepatitis C virus.1Data represent median value.

Table 2 Effects of combined therapy on ferritin level, liver, and heart

measures; data are presented on individual basis

I.D.

Ferritin(ng ⁄ mL)

L.I.C.(mgFe ⁄ g) T2*ms LVEF (%)

Basal Last Basal Last Basal Last Basal Last

Group 1 1.A 4700 1244 – – – – – –

1.B 9500 381 – – – – – –

1.C 2400 227 – – 14 22 59 66

1.D 2250 450 – – 5 6 44 39

1.E 5200 116 – – – – – –

1.F 1750 924 – – – – – –

1.G 2920 2300 6.5 2.2 – – – –

1.H 2050 899 – – – – – –

1.I 3045 2900 12 5.9 – – – –

1.L 2150 1733 – – 22 25 67 63

1.M 2189 550 – – – – – –

1.N 1533 96 – – – – – –

1.O 4770 1425 – – – – – –

Group 2 2.A 3086 140 – – 7 13 49 54

2.B 3065 1515 – – – – – –

2.C 3200 2800 – – 40 40 60 61

2.D 3360 552 – – – – – –

2.E 1585 180 – – 8 9 46 58

2.F 3906 2019 10.8 3 – – – –

Group 3 3.A 1466 567 – – 18 25 66 69

3.B 1815 211 – – – – – –

3.C 950 212 – – – – – –

3.D 640 109 4.6 3.7 – – – –

3.E 1193 472 8.0 2.8 – – – –

3.F 1490 970 – – – – – –

3.G 1545 186 7.8 5.6 – – – –

3.H 1980 494 – – – – – –

3.I 2852 1168 – – – – – –

3.L 4550 2703 – – – – – –

Group 4 4.A 1985 1600 – – – – – –

4.B 895 154 6 3 – – – –

4.C 1750 742 9 2.4 – – – –

4.D 880 257 1.6 1 – – – –

4.E 1400 499 – – – – – –

4.F 3342 1155 – – 37 38 55 56

4.G 1980 427 – – – – – –

LVEF, left ventricular ejection fraction.

Combined chelation therapy in thalassemia Ricchi et al.


2592 ± 1701 to 899 ± 833 ng ⁄mL, P < 0.001). All

schemes of treatment were effective in reducing ferritin

levels (P < 0.05), but in patients treated with DFO for

5 d a wk and DFP at 75mg ⁄Kg or at 50 mg ⁄Kg, it was

observed a higher mean decrease of ferritin level

(147 ng ⁄mL and 106 ng ⁄mL per month of treatment,

respectively) compared to that observed in patients trea-

ted with DFO for 3 d a wk and DFP at 75mg ⁄Kg or at

50 mg ⁄Kg (76 ng ⁄mL and 88 ng ⁄mL per month of treat-

ment, respectively). Except two patients (1.I and 1.L) in

group 1 and one patient (2.C) in group 2, all other

patients of both groups recorded a marked decrease in

ferritin level (>600 ng ⁄mL) after treatment (Table 2).

Interestingly, in two of these patients, measures of heart

iron overload were in normal range before and after

treatment suggesting a poor correlation between ferritin

serum level and heart iron stores. Tables 2 and 3 show

the effect of treatments on hepatic and cardiac hemoside-

rosis for each group of patients and for each patient,

respectively; serum ALT levels were evaluated in all

patients at baseline and at the end of treatment

(Table 3); on the contrary, only 8 out of 36 patients

underwent cardiac MR and 9 patients SQUID exam. As

in the case of serum ferritin levels, statistical analysis did

not point out a significant difference in MR T2* and

SQUID parameters at baseline between the groups of

patients treated with DFP at 50 mg ⁄kg and those treated

with DFP at 75 mg ⁄Kg (data not shown). As shown in

Table 3, there was a significant decrease (P < 0.05) in

ALT between baseline levels (77 ± 48 UI ⁄L) and those

of the last determination (41 ± 23 UI ⁄L) in patients of

group 1; this decrease was also observed in all HCV

RNA test–positive patients enrolled into the study (data

not shown). However, a decrease in ALT levels was

observed also in groups 2 and 3, but it was not statisti-

cally significant. Tables 2 and 3 show the effect of treat-

ments on Left Ventricular Ejection Fraction (LVEF) and

on T2* values; overall, the differences were not statisti-

cally significant: LVEF increased from a mean baseline

value of 55.7% ± 8.8% to a mean value of

58.2% ± 9.25% at the end of treatment, and myocardial

T2* improved from a mean baseline value of

18.9 ± 13.4 ms to a mean value of 22.2 ± 12.5 ms at

the end of intervention. The increase in T2* values was

higher in patients of group 1 than in those of others

groups (from a mean T2* value of 13.7 ms to a mean

T2* value of 17.7 ms). Furthermore, T2* value was

improved also in a patient in group 2 (from 7 ms to

13 ms). Tables 2 and 3 show also the effect of treatments

on LIC values: overall, there was a statistically signifi-

cant decrease (P < 0.01) in LIC values between those

Figure 1 Black and white bars represent mean serum ferritin levels

(ng ⁄ mL) ± SD before and after combined regimen, respectively.

Group 1: patients treated with DFO 5 d per wk and DFP daily at

75 mg ⁄ kg; Group 2: patients treated with DFO 5 d per wk and DFP

daily at 50 mg ⁄ kg; Group 3: patients treated with DFO 3 d per wk

and DFP daily at 75 mg ⁄ kg; Group 4: patients treated with DFO 3 d

per wk and DFP daily at 50 mg ⁄ kg.

Table 3 Effects of combined therapy on liver and heart measures

ALT (U ⁄ L) (mean ± SD)L.I.C. (mgFe ⁄ g)(mean ± SD) (n = 9) T2*ms (mean ± SD) (n = 8)

LVEF (%) (mean ± SD)(n = 8)

Basal Last Basal Next Basal Next Basal Next

Overall

(n = 36)

63.6 ± 43.7 44.9 ± 35.2 7.4 ± 3.2 3.3 ± 1.61 18.9 ± 13.4 22.2 ± 12.5 55.7 ± 8.8 58.2 ± 9.25

Group 1

(n = 13)

77.1 ± 46.0 40.6 ± 22.62 9.2 ± 3.9

(n = 2)

4.0 ± 2.6

(n = 2)

13.7 ± 8.5

(n = 3)

17.7 ± 10.2

(n = 3)

56.7 ± 11.7

(n = 3)

56 ± 14.8

(n = 3)

Group 2

(n = 6)

90.2 ± 50.8 59.8 ± 29.0 10.8 (n = 1) 3.0 (n = 1) 18.3 ± 18.8

(n = 3)

20.6 ± 16.9

(n = 3)

51.7 + 7.4

(n = 3)

57.7 ± 3.5

(n = 3)

Group 3

(n = 10)

48.2 ± 26.2 40 ± 26.3 6.8 ± 1.9

(n = 3)

4.0 ± 1.4

(n = 3)

18.0 (n = 1) 25.0 (n = 1) 66.0 (n = 1) 69.0 (n = 1)

Group 4

(n = 7)

41.6 ± 38.8 45.4 ± 61.7 5.5 ± 3.72

(n = 3)

2.1 ± 1.0

(n = 3)

37.0 (n = 1) 38.0 (n = 1) 56.0 (n = 1) 56.0 (n = 1)

1Significantly different from Basal value (P < 0.001)2Significantly different from Basal value (P < 0.05)



recorded at baseline and those at the end of therapy

(from 7.4 ± 3.2 mg ⁄ g dry weight to 3.3 ± 1.6 mg ⁄ g dry

weight).

Side effects were not common (Table 4). The incidence

of neutropenia was not influenced by the different treat-

ment regimens with the only exception of group 2 in

which two cases (33%) of neutropenia were observed;

however, as shown in Table 1, patients of group 2 were

those treated for the longest time. All patients but one

which required DFP discontinuation for persistent neu-

tropenia, developed neutropenia in absence of serious

complications and its average extent was one wk. Simi-

larly, the incidence of non-hematological side effects was

not significantly different among all groups. No patients

developed arthropathy and ⁄or joint symptoms. Overall,

6 patients (16.7%) experienced gastrointestinal symptoms

(nausea ⁄vomiting) and 7 patients (19.4%) a transient

increase in ALT level. The incidence of adverse events

was not different between the four arms and between

splenectomized (23 patients, 63%) and unsplenectomized

patients, HCV RNA test–positive and negative patients

(data not shown). No predictive factors of incidence of

side effects were found. Interestingly, 8 patients (22%)

showed a transient increase in body weight; this effect

was frequently observed in groups of patients receiving

DFP at 75 mg ⁄Kg (group 1 and 3, 23% and 30%,

respectively) without significant differences related to the

dose of DFO. Patients described a transient increase in

the need of food intake during first months of therapy

that caused a maximum rise of 5% in body mass index

(BMI) (data not shown).

Agranulocytosis was observed in two patients (5.6%).

The first patient was splenectomized and was receiving

DFP 50 mg ⁄kg per d plus DFO for three d a wk. The

onset of agranulocytosis was 88 d after the start of DFP

therapy; the patient experienced agranulocytosis [abso-

lute neutrophil count (ANC) = 0.012 · 109] thereafter

one episode of neutropenia [happened 1 month before,

(ANC = 1.120 · 109] and 4 months after discontinua-

tion of PEG-IFN-therapy for HCV hepatitis; Interest-

ingly, during PEG-IFN therapy the patient had never

showed neutropenia and ANC had been always upper

2.300 · 109. The other case was observed in a unsplenec-

tomized patient after 13 months of therapy, while he was

treated with PEG-IFN and DFP 75 mg ⁄Kg plus DFO

for five d a wk. Before assuming PEG-IFN, ANC ranged

from 2.300 · 109 to 3200 · 109. Agranulocytosis was

subsequent to three episode of severe neutropenia, and

the patient had eluded previous recommendation to

interrupt DFP assumption when neutropenia was

detected. Both episodes of agranulocytosis resolved after

interruption of DFP therapy and the administration of

granulocyte colony-stimulating factor.

Discussion

Recent trials with DFO in combination with DFP have

clearly shown that this treatment is effective in reducing

iron overload in thalassemia major patients; however,

any standardized treatment in term of days of DFO

administration and dose of DFP has not been yet estab-

lished. To better understand whether DFO administra-

tion at variable number of days a wk associated with

lower standard DFP dosages could modify either iron

chelation efficacy or incidence of side effects, we retro-

spectively evaluated 36 iron-overloaded patients with TM

not responding or previously intolerant to treatment with

chelating agent in monotherapy. Our study confirmed

the efficacy of iron chelation therapy when it was used in

combined regimen with different schemes of drugs

administration, as assessed by serum ferritin values. In

our sample, mean ferritin baseline levels were lower than

those reported in previous studies on combined regimen

(1–9), but the fall in serum ferritin level was comparable.

These findings highlighted the ability of combined ther-

apy to reduce the burden of iron overload also in not

severely overloaded patients. Furthermore, based on

drop in ferritin level, our results also indicated that the

efficacy of combined therapy was mainly in function of

DFO dosage, in other words the efficacy increased

depending on the number of days a wk of DFO adminis-

tration; however, it is worth noticing that, comparing

groups of patients with similar baseline ferritin level

(group 1 and group 2, mean drug exposure of 1.5 and

2.6 patient-yr, respectively), the use of DFP at 75 mg

allowed an extremely faster reduction in serum ferritin

Table 4 Adverse events in patients with thalassemia major during combination therapy

Agranulocytosis(%)

Neutropenia(%)

IncreasedALT (%)

Nausea ⁄ vomiting(%)

Increasedweight (%)

Joint symptoms(%)

Overall (n = 36) 2 ⁄ 36 (5.55) 3 ⁄ 36 (8.33) 5 ⁄ 36 (13.88) 6 ⁄ 36 (16.67) 8 ⁄ 36 (22.22) 0 ⁄ 36 (0.00)

Group 1 (n = 13) 1 ⁄ 13 (7.69) 0 ⁄ 13 (0.00) 1 ⁄ 13 (7.69) 2 ⁄ 13 (15.38) 3 ⁄ 13 (23.08) 0 ⁄ 13 (0.00)

Group 2 (n = 6) 0 ⁄ 6 (0.00) 2 ⁄ 6 (33.33) 1 ⁄ 6 (16.67) 1 ⁄ 6 (16.67) 1 ⁄ 6 (16.67) 0 ⁄ 6 (0.00)

Group 3 (n = 10) 0 ⁄ 10 (0.00) 1 ⁄ 10 (10) 1 ⁄ 10 (10.0) 2 ⁄ 10 (20.0) 3 ⁄ 10 (30.0) 0 ⁄ 10 (0.00)

Group 4 (n = 7) 1 ⁄ 7 (14.28) 0 ⁄ 7 (0.00) 2 ⁄ 7 (28.57) 1 ⁄ 7 (14.28) 1 ⁄ 7 (14.28) 0 ⁄ 7 (0.00)

ALT, Alanine transferase.



levels. Unfortunately, because of the lack of MR with

software for T2* analysis and SQUID facility inside our

hospital, only a minority of patients in each arm under-

went myocardial and liver iron overload evaluation.

However, our data clearly indicated that iron clearance

was considerably slower from heart than from liver. In

fact, data on mean T2* values showed that the rate of

clearance of myocardial iron was poor and acceptable

only in all patients of group 1 and only in one patient of

group 2. On the other hand, combined chelation therapy

with DFP at 75 mg ⁄kg DFO for five d a wk has been

recently demonstrated to give evident benefit in the treat-

ment of cardiac siderosis (10). Therefore, in our opinion,

the decrease of daily dose of DFP to 50 mg ⁄kg could

result in a lower efficacy particularly at heart level. This

could be because that DFP is not a very potent chelator

on a molar basis, because it is a bidentate and three mol-

ecules are needed per iron and its kinetics of binding go

as the third power of its concentration. As cardiac failure

is the primary cause of death in thalassemia, our data

suggest that in case both of heart failure and severe

degree of cardiac siderosis, combined regimen with DFP

at 50 mg ⁄kg should be avoided.

On the contrary, a hallmark of this study was that a

significant improvement in liver parameters was observed

with all therapeutic regimens. In fact, the change in LIC

was statistically significant in all arms indicating that all

regimens efficiently reduced liver iron overload. How-

ever, the reduction in liver siderosis was particularly

important in the groups 1 and 2 that used DFO for 5 d

a wk and where a marked decrease in ferritin levels was

also detected. The observation that the effect of com-

bined therapy on hepatic iron concentration was in rela-

tionship with the change in serum ferritin values was

already shown and this could explain the reduction in

ALT level detected particularly in patients of group 1.

However, the reduction in intensity of DFO chelation

(total wk ly DFO dose infusion) from 5 to 3 d a wk did

not seem to influence iron liver clearance. Thus, our data

suggested that whatever schedule of combined therapy

was adopted in our study, it significantly reduced liver

siderosis.

Less satisfactory results appeared from the analysis of

data on Deferiprone toxicity. Our data showed that the

incidence of side effects could not be minimized or

avoided by reducing total daily DFP dose. The incidence

of adverse events was not different among groups of

patients treated with different dosages of DFP while it

was comparable with the incidence reported in other

trials on combined therapy. This suggested that the

intolerance was the main mechanism responsible for

DFP-induced side effects. The only exception was the

incidence in body weight gain that was more frequently

observed in patients treated with DFP at 75 mg ⁄Kg; a

similar observation was reported for DFP in monothera-

py at 100 mg ⁄Kg per d (11).

In this study, agranulocytosis was found in two

patients (5%). This relatively higher incidence of agranu-

locytosis during our study than that commonly reported

(1%) suggested the presence of a risk factor. Among

anamnestic, clinical, and biochemical data, the only rele-

vant common factor in both patients was the previous or

concomitant exposure to PEG-IFN for the treatment of

concomitant chronic hepatitis C (HCV). However, the

small number of patients recruited into the study and the

lack of similar observation in literature make this link

questionable; further studies are needed to clarify the

role of IFN in the DFP-induced agranulocytosis, the

most serious undesirable effect of deferiprone treatment.

For most patients, at the beginning of the treatment

there were no guidelines for planning the start of com-

bined iron chelation therapy, for choosing the doses ⁄d of

iron chelators and for monitoring the efficacy of com-

bined chelation therapy. However, following the results

of this study, several changes in our clinical practice were

carried out.

The evaluation of our data suggested that after treat-

ment with combined regimen, the changes in serum ferri-

tin levels rarely predicted the changes both in the liver

and in the myocardial iron burden, evaluated by SQUID

and T2* MRI, respectively. Serum ferritin was a poor

parameter to judge iron overload status, and its changes

in serum levels could not be used as unique tool for

monitoring chelation efficacy in combined regimen or

in any chelation strategy. These observations led us to

consider that elevated serum ferritin levels should not be

utilized as the only parameter for selecting patients to

be treated with combined regimen.

Therefore, our current clinical practice is to select

patients through a complete panel of indexes of iron

overload including serum ferritin level, MRI, or SQUID

assessment of liver iron burden, and MRI assessment of

cardiac iron overload and cardiac function. In our opin-

ion, patients showing heart T2* less than 13 msec or

with signs of iron-related cardiomyopathy should be

treated with combined chelation therapy independently

from serum ferritin levels. Furthermore, because of the

evidence that decreasing the dose of DFP and the fre-

quency of DFO infusion, the clearance of cardiac criti-

cally decreased, our patients with documented severe

siderotic cardiomyopathy are currently treated with DFO

25–35 mg ⁄Kg for 5 d a wk in combination with daily

DFP 75 mg ⁄kg, also in agreement with recent guidelines

and recommendations of the Italian Society of Thalasse-

mia and Hemoglobinopathies (SITE) (12).

Because of the lack of well-recognized cutoff value

also for liver iron overload (either by SQUID or by T2*

MRI evaluation) to select patients to be treated with



intensive chelation therapy, a more intensive schedules of

combined regimen should be used in patients with more

severe liver iron burden to obtain a faster reduction in

liver iron store. Finally, we currently based the duration

of treatment and the decision to stop combined treat-

ment on hepatic and cardiac parameters re-evaluation

(every on 18 ± 6 months) rather than on the decrease in

ferritin level to avoid under- or over-treatment.

In conclusion, we explored the effect of different dos-

age and days of administration of DFP ⁄DFO in com-

bined therapy. Despite the small number of patients, our

data showed that the administration of DFO for 5 d a

wk in combination with daily administration of DFP at

75 mg ⁄Kg seemed to be the most efficacy and rapid

method for reducing iron overload at liver and heart

level. Furthermore, the use of different schedules of com-

bined DFO and DFP administration was not associated

with different incidence of adverse effects.

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