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Indian Pediatr 2016;53:
207-210 |
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Comparative Efficacy and Safety of Oral Iron
Chelators and their Novel Combination in Children with
Thalassemia
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Sunil Gomber, Prachi Jain, *Satender Sharma and
Manish Narang
From Departments of Pediatrics and *Pathology,
University College of Medical Sciences and Guru Teg Bahadur Hostital,
Delhi, India.
Correspondence to: Dr Prachi Jain, Department of
Pediatrics, UCMS and GTB Hospital, Delhi 110 095, India.
Email:
[email protected]
Received: March 02, 2015;
Initial review: June 01, 2015;
Accepted: January 13, 2016.
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Objective: To compare the efficacy and safety of oral iron chelators
(Deferiprone and Deferasirox) when used singly and in combination in
multi-transfused children with thalassemia.
Design: Prospective comparative
study.
Setting: Thalassemia Center of a
medical college affiliated hospital
Participants and Intervention: 49
multi-transfused children with thalassemia with a mean (SD) age 11.6
(6.21) y received daily chelation therapy with either deferiprone alone
(75 mg/kg/day in 3 divided doses), deferasirox alone (30 mg/kg/day
single dose) or their daily combination (same dose as monotherapy) for
12 months.
Outcome measures: Serum ferritin
levels at the start of study, after 6 months and after 12 months. MRI
T2* of liver and heart initially and after 6 months of follow up.
24-hour urinary iron excretion values at the outset and after 12 months
of chelation therapy. At every visit for blood transfusion, all patients
were clinically assessed for any adverse effects; liver and renal
functions were monitored 6-monthly.
Results: After 12 months of
respective chelation therapy, serum ferritin values decreased from a
mean of 3140.5 ng/mL to 2910.0 ng/mL in deferiprone alone group, 3859.2
ng/mL to 3417.4 ng/mL in deferasirox alone group and from 3696.5 ng/mL
to 2572.1 ng/mL in the combination group. The combination therapy was
more efficacious in causing fall in serum ferritin levels compared to
deferiprone and deferasirox monotherapy (P=0.035 and 0.040,
respectively). Results of MRI T2* were equivocal. Combined drug usage
produced maximum negative iron balance in the body by maximally
increasing the iron excretion in urine from 61.1 µmol/day to 343.3
µmol/day (P=0.002). No significant adverse reactions were
noticed in either the monotherapy or the combination group.
Conclusion: Oral combination
therapy of deferiprone and deferasirox appears to be an efficacious and
safe modality to reduce serum ferritin in multi-transfused children with
thalassemia.
Key words: Blood transfusion,
Thalassemia, Deferiprone, Deferasirox, Combination Iron Chelation
therapy.
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I ron overload causes significant complications in
patients with transfusion-dependent thalassemia major.
These complications can be managed effectively by
iron chelation therapy. The three iron chelators presently in use:
Desferoxamine, Deferiprone and Deferasirox when used as monotherapy can
prevent some of these complications. Combination of parentral
desferoxamine with oral deferiprone [1] or deferasirox [2] has been
successfully used in some studies but at the cost of multiple painful
injections and decreased compliance [3].
A few studies have also used oral chelators deferiprone
and deferasirox in combination
[4-6] in some "difficult to treat thalassemics", but
there is paucity of studies evaluating combined use of oral iron
chelation drugs in children with thalassemia. The present study aimed to
evaluate the efficacy and safety of oral iron chelators alone and in
combination.
Methods
This prospective comparative study was conducted at
the Thalassemia day care unit of a tertiary care hospital. Forty-nine
patients of thalassemia major having serum ferritin levels >1500 ng/mL
were included in the study. Those patients who had a history of
anaphylaxis due to deferiprone and/or deferasirox, or those with serum
creatinine value above the upper limit of normal for that age were
excluded. An informed written consent was taken from the
parents/guardians of these patients. Ethical clearance was obtained from
the institutional ethical committee before starting the study.
From the patients fulfilling the inclusion criteria,
44 were already on either deferiprone (23 patients) or deferasirox (21
patients) monotherapy. By computer generated random number table, we
selected 6 children each from those already receiving deferiprone
monotherapy and deferasirox monotherapy to from a third group to be
given combination of two oral iron chelators. Five new patients who were
not on any chelating agent and fulfilling the inclusion criteria were
also included in the study (2 in group 2 and 3 in group 3). Thus, Group
1 (Deferiprone alone): consisted of 17 patients (23–6=17), who received
deferiprone monotherapy in the dose of 75 mg/kg/day in 3 divided doses
daily. Group 2 (Deferasirox alone): consisted of 17 patients ([21–6] +
2=17), who received deferasirox monotherapy in the dose of 30 mg/kg/day
single dose daily. Group 3 (Deferiprone and Deferasirox Combination):
consisted of 15 patients ([6+6] + 3 = 15), who received daily
combination of both deferiprone (75 mg/kg/day in 3 divided doses daily)
and deferasirox (30 mg/kg/day single dose daily). All patients received
packed red blood cell transfusion every 3 weekly to maintain
pre-transfusion hemoglobin of 9-9.5 g/dL.
Serum ferritin levels were measured at the start of
study, at 6 months and at 12 months of respective chelation therapy.
C-reactive protein (CRP) was also measured along with all measured
values of serum ferritin in all the patients to rule out any acute
infection which could cause a factitious rise of serum ferritin values.
MRI T2* of liver and heart was done in five patients of each group (due
to financial constraints) at the time of enrolment and at 6 months of
respective chelation therapy. This was performed with an iron
quantification T2*-weighted multi-slice multi-echo (8) sequence 1.5
Tesla MRI scanner using a phased-array surface coil. Iron content in the
liver and heart was then calculated using GE Healthcare software. These
values were measured in milliseconds (msec). A higher reading meant a
lower iron loading for both liver and heart. Iron overload in liver was
graded as None if MRI T2* values were >6.3 msec, Mild (6.3-2.7 msec),
Moderate (2.7-1.4 msec) and Severe (<1.4 msec) while that in heart was
graded as None if MRI T2* valves were >20 msec, Mild (12-20 msec),
Moderate (8-12msec) and Severe <8 msec [7,8]. 24-hour urinary iron
excretion was measured in all patients at the beginning of the study and
after 12 months of treatment with equal number of age- and sex-matched
controls.
Safety measures were assessed clinically at each
visit for blood transfusion, for any adverse events like joint pains,
rashes, pain abdomen, nausea or vomiting. Complete blood counts were
carried out during each visit for blood transfusion. Liver and kidney
function tests with urinary protein detection using uristix were done
along with viral markers and HIV status at the start of study and at 6
monthly intervals.
Statistical analysis was carried out using SPSS 20.0
version. Repeated measure two way ANOVA was used for comparing serum
ferritin values with fixed factor as group and repeated factor as
time. As serum ferritin levels are not normally distributed and have
high variances, the log base 10 transformation was used to stabilize the
variances across the groups. Analysis of covariance (ANCOVA) was carried
out taking baseline serum ferritin values as covariate and marginal
means were estimated. Paired T-test was used for analysing MRI T2*
values of liver and heart and 24-hour urinary iron excretion values.
Pearson correlations were used to find correlations between values of
MRI T2* of liver, heart and serum ferritin levels.
Results
A total of 49 children (30 males) with a mean (SD)
age of 11.6 (6.21) years fulfilled the criteria and were included in the
study. The mean values of serum ferritin measured at the start of study,
at 6 months and at 12 months of chelation therapy are depicted in
Fig. 1. The baseline serum ferritin values were similar in all
of the three groups (Table I). A decrease was noticed in
serum ferritin values in all the three groups after 6 months and 12
months of chelation therapy. The decrease in serum ferritin observed in
group 3 was significantly higher than that observed in group 1 (P=0.035)
and group 2 (P=0.04). Both the drugs when used alone had almost
similar efficacy. CRP was negative in all patients at all time points.
TABLE I Serum Ferritin Values at the Start, at 6 Months and at 12 Months in Study Participants
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Serum Ferritin levels Geometric Mean
(95% CI of GM) (ng/mL) |
|
Deferiprone monotherapy |
Deferasirox monotherapy |
Combination therapy* |
Time Points |
(n=17) |
(n=17) |
(n=15) |
At start |
3140.5 (2617.5-3767.9) |
3859.2 (3168.8-4700.0) |
3696.5 (3079.6-4438.1) |
At 6 months |
3010.9 (2548.5-3557.1) |
3671.1 (3098.1-4350.1) |
2977.1 (2384.5-3717.1) |
At 12 months |
2910.0 (2220.7-3812.4) |
3417.4 (2734.6-4270.7) |
2572.1 (2138.9-3093.1) |
P=0.008 for comparison by ANOVA; Multiple comparison (using
Tukey’s Test) found no pairs of two time points to be
significant in both monotheraphy groups; however, baseline S.
ferritin was significantly different with 6 month and 12 month
S. ferritin value. |
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Fig. 1 Geometric Mean S. Ferritin
(ng/mL) in all groups at start, 6 months and 12 months of
chelation therapy.
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All the patients in whom MRI T2* of liver was
performed showed values indicating mild hepatic iron overload, ranging
from 5.1 – 5.4 msec. These values were higher in all the three groups in
the follow up MRI performed after 6 month of respective therapy which
meant a reduced iron load on liver (Table II), but the
values still remained in the category of mild hepatic iron overload (5.4
-5.6 msec). There was no statistically significant increase in values in
any of the groups. The individual and the mean values of MRI T2* of
heart were almost similar at the baseline (29.5–33.3 msec) and at follow
up (31.2-32.3 msec). No correlation could be established in MRI T2*
values of heart or liver with serum ferritin values. 24-hour urinary
iron excretion showed an increase at 12 months from a mean value of
200.2 µmol/day to 381.9 µmol/day in group 1, 28.8 µmol/day to
30.6 µmol/day in group 2 and 61.1 µmol/day to 343.3 µmol/day in the
combination group. Clinical evaluation revealed arthropathy of large
joints in one patient within 4 weeks of administration of combination of
deferiprone and deferasirox. Arthropathy subsided after discontinuation
of deferiprone. Two patients on deferasirox developed mild abdominal
pain which subsided with oral proton pumps inhibitors given for 7-10
days. None required discontinuation of chelation therapy. No other side
effects were observed in any of the patients. No mortality was noticed
during the study period. None of the patients developed neutropenia,
thrombocytopenia, or derangements of kidney function tests. There was no
detectable protein excretion in urine (as measured by uristix) in any of
the patient at any time during the study. Mild derangements in liver
enzymes (less than twice the upper limit of normal) was present which
did not manifest clinically.
TABLE II Mean (SD) Values of MRI T2* Liver and Heart at the Baseline and Follow-up
Groups |
Deferiprone (N= 5) |
Deferasirox (N= 5) |
Combination therapy (N= 5) |
MRI T2* Liver (msec) |
Baseline |
5.4 (0.20) |
5.1 (0.52) |
5.3 (0.26) |
|
Follow up |
5.6 (0.26) |
5.4 (0.58) |
5.5 (0.40) |
MRI T2* Heart (msec) |
Baseline |
33.3 (1.44) |
32.0 (2.00) |
29.5 (1.99) |
|
Follow up |
32.3 (1.66) |
31.7 (2.65) |
31.2 (2.57) |
Discussion
The combination of deferiprone and deferasirox
was found to be the most efficacious in the present study which produced
a significant fall in mean serum ferritin values. These results are in
agreement with those of Farmaki, et al. [6] and a few
other case reports [4,5]. As the serum ferritin values mainly indicate a
trend of iron overload over a period of time and not the actual iron
overload in various tissues, we tried analyzing other parameters of iron
overload like MRI T2* of liver and heart and 24-hour urinary iron
excretion. MRI T2* provides a rapid, non-invasive, reproducible means
for hepatic and myocardial iron overload which cannot be predicted from
serum ferritin [9-12]. The present study did not reveal any cardiac iron
overload and only minimal iron overload of liver tissue. The
insignificant difference in the follow-up MRI values of liver and heart
may be due to the lesser time interval between these values [7,13]. The
maximum increase in excretion of iron in urine observed in group 3 in
our study signifies the synergistic effect of both the oral iron
chelators in reducing the iron overload.
The study has the limitations of a non-randomized
design, small sample size and short follow-up. We also could not perform
MRI studies in majority of the included patients.
The present study highlights the efficacy of oral
iron chelators, deferiprone and deferasirox, both as single agent
therapy or when used in combination. The combination therapy appears to
be more efficacious than each of these agent in isolation. We recommend
larger studies with well-controlled design to substantiate the efficacy
and safety of combination of oral iron chelators in children with
thalassemia.
Acknowledgement: Dr VK Khanna for providing
technical consultation.
Contributors: SG: conceived the study design and
helped in writing the manuscript along with revision; PJ: collected and
analyzed the data and wrote the manuscript; SS: analyzed and evaluated
the data; MN: helped in study design and writing of manuscript.
Funding: Thalassemics India for carrying out MRI
T2* of liver and heart. Competing interests: None stated.
What Is Already
Known?
• Iron overload and its complications in
patients with thalassemia have been managed with iron chelators
used singly or in combination with parentral chelator.
What This
Study Adds?
• Combination of oral iron chelators is
efficacious and safe for use in children with thalassemia.
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