Efficacy of Deferasirox as an Oral Iron Chelator in Paediatric Thalassaemia Patients

Shikha Jaiswal¹, Rajesh Hishikar², Onkar Khandwal³, Manju Agarwal⁴, Usha Joshi⁵, Ajay Halwai⁶, Basant Maheshwari⁷, Raka Sheohare<sup>8

1</sup> Assistant Professor, Department of Pharmacology, PT JNM Medical College, Raipur, Chhattisgarh, India.
² Professor and Head, Department of Pharmacology, PT JNM Medical college, Raipur, Chhattisgarh, India.
³ Professor, Department of Paediatrics, PT JNM Medical College, Raipur, Chhattisgarh, India.
⁴ Assistant Professor, Department of Pharmacology, PT JNM Medical College, Raipur, Chhattisgarh, India.
⁵ Associate Professor, Department of Pharmacology, PT JNM Medical College, Raipur, Chhattisgarh, India.
⁶ Assistant Professor, Department of Pharmacology, PT JNM Medical College, Raipur, Chhattisgarh, India.
⁷ Associate Professor, Department of Pharmacology, PT JNM Medical College, Raipur, Chhattisgarh, India.
⁸ Consultant Diabetologist and Non Invasive Cardiologist, Lifeline Hospital, Raipur, Chhattisgarh, India.


NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR: Dr. Shikha Jaiswal, Assistant Professor, Department of Pharmacology, PT JNM Medical College, Raipur, Chhattisgarh, India.
E-mail: dr.shikhajaiswal @gmail.com

Thalassaemia Major patients require frequent blood transfusion leading to iron overload and deposition of iron in liver, anterior pituitary, pancreas joints and heart. Physiologic mechanisms to excrete iron are limited, so patients with iron overload and its complications need safe and effective chelation therapy. This therapy is required to get rid of this excess iron deposited in various vital organs of body [1]. Iron chelation therapy forms an important part of treatment for patients receiving red blood cell transfusions. Iron chelation therapy is a supportive therapy for chronic anaemias, such as β-thalassaemia, Sickle Cell Disease (SCD), and the Myelodysplastic Syndromes (MDS). Iron chelators currently available include deferoxamine (DFO), which is administered subcutaneously or intravenously, and the oral chelators’ Deferiprone (DFP) and Deferasirox (DFX).

The reports stated-standard iron chelator, Deferoxamine (DFO), has a safety and efficacy profile established through many years of clinical use, but the regimen of prolonged 12 hour subcutaneous infusions, 5–7 days per week is extremely demanding and can result in poor adherence, thereby, compromising efficacy and outcomes [2].

DFP (Ferriprox; L1), a three times daily oral chelating agent, became licensed in Europe, and other regions for the treatment of iron overload in year 1999 [3]. The drug may be more effective than DFO in chelating cardiac iron [4,5]. The most common side effects of DFP are nausea, vomiting, abdominal pain, diarrhea, joint pain, liver dysfunction, and also have some rare side effects like neutropenia and agranulocytosis [6–8]. Because of the risk of agranulocytosis, a weekly assessment of white blood cell counts is recommended. In some clinical studies, it was found that DFO alone is less effective then DFO and DFP combination therapy in cardiac iron overload reduction [9].

DFX, a convenient, once-daily oral therapy, has demonstrated good efficacy and acceptable safety in adult and paediatric patients with wide range of chronic anaemias [10–12]. The unique feature of DFX, not shared with other single agent is long half life of 8-16 hour which provides sustained chelation coverage of 24 hour [13,14]. DFX, approved, by FDA in year 2005 [15] is safe, oral iron chelator. S. ferritin concentration is a convenient, nonexpensive and the most widely used measure of assessing total body iron [16,17]. We prospectively assessed serum ferritin levels in an enrolled group of multitransfused thalassaemia patients to evaluate the efficiency of DFX as an iron chelator.

This prospective, observational study assessed the serum ferritin levels of thalassaemia patients who were on DFX and evaluated the efficacy of DFX in these patients. Study was conducted in registered thalassaemia society Raipur, between January 2013 to December 2013, on 45 multitransfused thalassaemic patients of age 1- 18 years and were receiving DFX. Study is done to monitor the effect of DFX on total body iron load. This study was conducted in accordance with Good Clinical Practice guidelines and was approved by the college Ethical Committee.

Male/female between 1-18 years

Receiving multi blood transfusion and Chelation therapy

Base line S. ferritin >1000 ng/ml

Patients of other chronic medical illnesses (SLE, Rheumatoid arthritis, Hepatitis ABC, Epstein Barr virus infection).

Patient of severe kidney problem, abnormal decrease in platelet count, dehydration.

Patients who received Packed RBC transfusions at one to two week intervals to maintain the haemoglobin concentration at a level above 10 gm/dl were enrolled in study. Informed consent was obtained in written from the patient’s guardian recruited in our study. The nature of study was discussed with each patient’s guardian in the manner they understand. Single peripheral venous blood sample was drawn from the ante cubital vein. Serum ferritin was estimated by using an automatic immunoassay analyser (360 clinitek Siemens). Serum ferritin estimated at time of registration in study and subsequently every three monthly (i.e., four times in a year). The recommended initial dose of DFX was 20 mg/kg per day given empty stomach in morning for patients receiving approximately 6 to 8 units of Packed RBC Per year, which could be discontinued or adjusted in increments of 5 to 10 mg/kg per day done to a maximum of 40 mg/kg/day when necessary based on serum ferritin levels [1]. Serum ferritin level is directly proportional to total body iron store. Iron chelation therapy decrease total body iron and hence, decline the serum ferrtin level. Dose reduction was done if any side effect was noted or if S. ferritin fall below 500 ng/ml. The relevant data were recorded in specified proforma. The primary end point of the study was to evaluate the difference in serum ferritin after 12 months of DFX therapy as compared to baseline values.

The data was compiled in the formats and subjected to descriptive and statistical analysis. Data were presented as mean±SD and variables analysed by paired t-test for statistical significance. The p <0.05 was considered statistically significant.

Fifty patients were enrolled for the study; five were lost to follow up; 45 patients completed the study. In our study, maximum affected age group of thalassaemia requiring iron chelation therapy is between ages of 0-5 years (20%), 6-10 years (48.89%), 11-15 years (24.40%) and 16-18 years (6.67%) [Table/Fig-1].

[Table/Fig-1]:

Distribution of cases according to age group.

S. No.	Age group (year)	Number (n = 45)	Percentage
1	0-5	9	20.00
2	6-10	22	48.89
3	11-15	11	24.44
4	16-18	03	6.67
	Total	45	100

Twenty seven males (60%) and18 females (40%) received regular transfusion with a mean age of 8.68±3.9 years (3.6-17 years) [Table/Fig-2].

[Table/Fig-2]:

Distribution of cases according to gender.

S. No.	Gender	Number	Percentage
1	Male	27	60
2	Female	18	40
	Total	45	100

Mean decline in serum ferritin level after three months is 270.36±1274.86: p-value of 0.08 (non-significant) after six months is 549.24±1206.22: p-value of 0.0019 (significant) after nine months is 1079.71±1466.28: p-value of 5.8x10^-6 (highly significant) and after 12 months is 1207±1315.50; p-value of 9.96x10^-8 (highly significant) [Table/Fig-3].

[Table/Fig-3]:

Time Vs mean difference in serum ferritin level.

S. No	BaselineS.Ferritin (ng/ml)B	D1After 3mths(B-FU1)	D2After 6mths(B-FU2)	D3After 9mths(B-FU3)	D4After 12mths(B-FU4)
Mean	3727.02	270.36	549.24	1079.71	1207.11
SD	1405.10	1274.86	1206.22	1466.28	1315.50
95% CI		372.48	352.42	428.40	384.35
p-value		0.08	0.0019	5.8x10-6	9.96x10-8

D1= Mean decline in serum ferritin level after three months D2=Mean decline in serum ferritin level after six month D3=Mean decline in serum ferritin level after nine months is and D4=Mean decline in serum ferritin level after 12 months. CI=Confidence Interval, SD=standard deviation. FU=Follow up B=Baseline

Significant decline in S. ferritin observed after 6 months of DFX therapy 3177.78±1379.10 p-value-0.06 (<.05) [Table/Fig-4].

[Table/Fig-4]:

Time Vs Mean serum ferritin level.

S. No.	Time	Mean SF	SD	95%CI	p-value
1	Baseline	3727.02	1405.10
2	3 month (fu1)	3456.67	1595.01	900.06	0.39
3	6 month (fu2)	3177.78	1379.10	1132.49	0.06
4	9 month (fu3)	2647.31	1335.21	1653.93	0.003
5	12 month (fu4)	2519.91	1204.97	1755.46	0.001

FU=Follow up SF= Serum Ferritin

DFX 20 mg/kg/day was started initially but due to non-appreciable decline in S. ferritin, upgradation of dose was done to 30 -40 mg/kg/day over next six month. A total of 16 (35.5%) patients required 35-40 mg/kg/day dose for control of ferritin level. Dose of 30-35mg shows max decline of S. ferritin level from 4450±2717.08 to 2176.67±1391.56 over one year. The p-value 0.001 (<0.05) which is highly significant [Table/Fig-5].

[Table/Fig-5]:

Effect of different dose of deferasirox on serum ferritin level.

		Serum Ferritin Levels (Time in Interval)
S. No	Dose (mg/kg)	Baseline		3 month				6 month				9 month				12 month
		Mean	SD	Mean	SD	95%CI	p	Mean	SD	95%CI	p	Mean	SD	95%CI	p	Mean	SD	95%CI	p
1	20-25	3370	2729.43	3050	2899.14	1499.6	0.591	3000	2828.43	1534.43	0.5294	2675	2368.81	1765.64	0.204	2465	1887.17	1887.17	0.07
2	25-30	3406.67	1773.28	2965	1781.83	1186.39	0.2417	2430	941.44	1578.44	0.0015	1443.33	347.9	2498.68	0.001	1576.67	87.37	2355.96	0.001
3	30-35	4450	2717.08	3610	2025.41	1843.96	0.099	2895	1844.34	2527.85	0.0021	2091.67	1364.81	3259.1	0.001	2176.67	1391.56	3177.68	0.001
4	35-40	3752.67	1244.29	3539.58	1569.96	806.55	0.477	3302.08	1347.12	993.86	0.102	2807.61	1334.84	1485.66	0.0008	2644.61	1225.62	1625.46	0.001
	Total	3727.02	1405.1	3456.66	1595.01			3177.78	1379.1			2647.31	1335.21			2519.91	1204.97

Iron overload is one of the serious side effects associated with frequent blood transfusion in thalassaemia patients. Since, regular blood transfusion is mainstay of thalassaemia therapy, iron chelation therapy become mandatory when serum ferritin level crosses 1000 ng/ml. DFX is commonly used as oral iron chelator among various iron chelators available. DFX shows significant decline in serum ferritin level.

In our study, 60% patients were males and mean age group was found to be 8.6±3.9 years.

Rashid Merchant et al., have found 73.3% males as sufferer and in his study, mean affected age group was 15.7±6.8 years (study population of age 6.5 years to 29 years) [18].

In our study 80% patients were on Mean dose of 38 mg/kg.

Reports of Rashid Merchant et al., M. Domenica Cappellini et al., YR Lai et al., suggested mean DFX dose 21.6±6.4 mg/kg and 33mg/kg and 33.6 mg/kg respectively for iron chelation [18–20].

This study shows significant decline in serum ferritin from 3727.02 to 2519.91 ng/ml i.e., 1207.11 ng/ml at end of one year, p-value 9.96×10^-8 (<.05). The mean difference 1207.11 is >1000 ng/ml indicating that all of them need further chelation therapy in forthcoming years.

M. Domenica Cappellini et al., found median decline in S. ferritin from 2117 to 1124 (p-value <.001) [19]. Ali Taher et al., in Escalator Study found median decline in S. ferritin of 517 ng/ml (p-value <.001) [16]. Rashid Merchant et al., in year observed mean decline in serum ferritin of 30.2% (p-value < 0.001) over 12-18 months of DFX therapy [18]. YR Lai et al., found median ferritin decline of -756 ng/ml (p-value 0.0397) [20]. Kamrthi et al., found, the decrease in the S. ferritin levels from 4362.5 ng/ml (range 1337.8-17217 ng/ml) to 1869.25 ng/ml (range 634.4-3486.1 ng/ml) during DFX therapy [21].

In this study, 47% cases (n=21) had drug compliance of 80-100% and 53% cases (n=24) had drug compliance of 100%.

In 2.2% (n=1) cases by changing drug brand desired response was obtained, which can be explained by difference in bioequivalence of different brands.

In current study out of 50 patients registered, one patient died due to cardiac haemosiderosis.

The limitations of present study were that, liver biopsy was not done for estimation of ferritin level due to lack of facilities, patient’s number were limited and follow-up was done for one year only.

In conclusion we state that, our findings underline the importance of iron chelation therapy and regular monitoring of S. ferritin levels in thalassaemia patients treated with frequent blood transfusion. If S. ferritin level is > 1000 ng/ml then three monthly estimation of serum ferritin should be practiced. Iron chelation therapy, if given concurrently with blood transfusion, decreases the risk of morbidity and mortality due to iron overload in thalassaemia. DFX monotherapy has a good safety profile and effectively chelates total body iron. Our results should serve as a benchmark for using DFX chelation therapy in heavily iron overloaded Indian Thalassaemia major cases.

D1= Mean decline in serum ferritin level after three months D2=Mean decline in serum ferritin level after six month D3=Mean decline in serum ferritin level after nine months is and D4=Mean decline in serum ferritin level after 12 months. CI=Confidence Interval, SD=standard deviation. FU=Follow up B=BaselineFU=Follow up SF= Serum Ferritin

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