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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: paolo.ricchi@ospedalecardarelli.it
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
5 d a wk in combination with daily DFP 50 mg ⁄kg;Group 3: 10 patients received DFO 25–35 mg ⁄Kg for
3 d a wk in combination with daily DFP 75 mg ⁄kg;Group 4: 7 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.
38 ª 2010 John Wiley & Sons A/S
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)
Ricchi et al. Combined chelation therapy in thalassemia
ª 2010 John Wiley & Sons A/S 39
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.
Combined chelation therapy in thalassemia Ricchi et al.
40 ª 2010 John Wiley & Sons A/S
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
Ricchi et al. Combined chelation therapy in thalassemia
ª 2010 John Wiley & Sons A/S 41
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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