Comparison of efficacy, safety, and humanistic outcomes of iron-chelation therapy in pediatrics suffering from transfusion-dependent β-thalassemia major

Narayana Goruntla; P Stephen Azarya; Mahitha Chalagundla; Dasaratha Ramaiah Jinka; Pradeepkumar Bhupalam; Vishnuvandana Bandaru

doi:10.4103/INJMS.INJMS_23_20

ORIGINAL ARTICLE

Year : 2020 | Volume : 11 | Issue : 3 | Page : 137-142

Comparison of efficacy, safety, and humanistic outcomes of iron-chelation therapy in pediatrics suffering from transfusion-dependent β-thalassemia major

Narayana Goruntla¹, P Stephen Azarya¹, Mahitha Chalagundla¹, Dasaratha Ramaiah Jinka², Pradeepkumar Bhupalam³, Vishnuvandana Bandaru⁴
¹ Department of Pharmacy Practice, Raghavendra Institute of Pharmaceutical Education and Research (RIPER) - Autonomous, Anantapur, Andhra Pradesh, India
² Department of Paediatrics, RDT Hospital, Anantapur, Andhra Pradesh, India
³ Department of Pharmacology, Raghavendra Institute of Pharmaceutical Education and Research (RIPER) - Autonomous, Anantapur, Andhra Pradesh, India
⁴ Department of Pharmaceutical Analysis, Balaji College of Pharmacy, Anantapur, Andhra Pradesh, India

Date of Submission	10-Apr-2020
Date of Decision	12-Jun-2020
Date of Acceptance	08-Jul-2020
Date of Web Publication	25-Aug-2020

Correspondence Address:
Mr. Narayana Goruntla
Department of Pharmacy Practice, Raghavendra Institute of Pharmaceutical Education and Research (RIPER) - Autonomous, K.R. Palli Cross, Anantapur - 515 721, Andhra Pradesh
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/INJMS.INJMS_23_20

Abstract

Introduction: Beta-thalassemia major (β-TM) is a severe form of genetic disorder that affects the patient's quality of life. Iron-chelation therapy (ICT) is recommended in these patients to reduce the complications (iron overload) associated with repeated blood transfusion. Objective: The present study aims to compare the efficacy, safety, and Pediatric Quality of Life (PedsQL) of the single and combinational ICT regimens in β-TM. Materials and Methods: This prospective, comparative study was conducted in the outpatient department of a daycare pediatric hospital located in South India. Patients diagnosed with β-TM, ages between 2 and 12 years, under ICT regimens were recruited. A suitable data collection form and PedsQL questionnaire was used to obtain demographics, blood transfusion, serum ferritin, hematological, biochemical, and PedsQL data of the study participants. One-way ANOVA and Chi-square test were used to compare the safety, efficacy, and PedsQL. Results: A total of 97 participants who met the study criteria were enrolled in the study and divided into three groups: Group I (n = 45) Deferasirox alone, Group II (n = 28) Deferasirox + Deferiprone, and Group III (n = 24) deferasirox + deferoxamine. The mean difference of ferritin concentration in Group III (695.3 ± 1252.4) was high compared to Group I (91.31 ± 702.6) and Group II (392.5 ± 1083.5) regimens with a P = 0.0053. In Group III, a significant reduction in physical and school functioning was observed. Conclusion: Oral Deferasirox combined with subcutaneous deferoxamine shows a great significant reduction in ferritin levels, but this combination is associated with a significant rise in hepatic enzymes, and poor physical and school functioning. An oral Deferasirox combined with oral Deferiprone is a safe and effective regimen in the treatment of β-TM, without affecting any domain of the Health-Related Quality of Life.

Keywords: Beta thalassemia, combination, deferasirox, deferiprone, deferoxamine, pediatrics

How to cite this article:
Goruntla N, Azarya P S, Chalagundla M, Jinka DR, Bhupalam P, Bandaru V. Comparison of efficacy, safety, and humanistic outcomes of iron-chelation therapy in pediatrics suffering from transfusion-dependent β-thalassemia major. Indian J Med Spec 2020;11:137-42

How to cite this URL:
Goruntla N, Azarya P S, Chalagundla M, Jinka DR, Bhupalam P, Bandaru V. Comparison of efficacy, safety, and humanistic outcomes of iron-chelation therapy in pediatrics suffering from transfusion-dependent β-thalassemia major. Indian J Med Spec [serial online] 2020 [cited 2023 Jun 7];11:137-42. Available from: http://www.ijms.in/text.asp?2020/11/3/137/293323

Introduction

Globally, it is estimated that 56,000 conceptions would have thalassemia disorder, among them nearly 30,000 are suffering from beta-thalassemia major (β-TM), the majority are born in the middle- and low-income countries.^[1] Beta thalassemia is the most common single-gene disorder. In India, the overall prevalence is 3%–4% with an estimated 10000 to 12000 babies are born every year with β-TM.^[2]

Blood transfusion is a prominent management strategy to control the complications (severe anemia, hepatosplenomegaly, and facioskeletal changes) associated with hemolysis of erythrocytes in b-TM.^[3] One unit of blood comprises 200–250 mg of elemental iron. Iron overload is the major problem observed in regular blood transfusion, and it is strongly associated with growth retardation, endocrine dysfunction, and cardiac failure.^[4]

Iron-chelating agents such as deferoxamine (desferrioxamine), deferiprone, and deferasirox are widely available options to reduce the iron load by forming soluble complexes, which eliminate easily from the body. Iron-chelation agents will improve the metabolic and endocrine functions as well as decrease the cardiac risk by decreasing ferritin levels. Among these three options, deferasirox is the novel iron chelator having long half-life, so it can be administered in a once-daily dose.^[5] Whereas, desferioxamine and deferiprone need to be administered frequently due to short half-life. Evidence on the safety and efficacy of deferasirox alone and in combination with Desferioxamine or Deferiprone is not available in the literature. In β-TM, there is a regular and continuous need for repeated blood transfusions, daily consumption of chelators, self-care, and monitoring of serum ferritin levels. This will have a great impact on the Health-Related Quality of Life (HRQoL) of the patients. This is the prime that study aims to compare the efficacy, safety, HRQoL of deferasirox alone, or in combination with desferioxamine or deferiprone in children suffering from transfusion-dependent β-TM.

Materials and Methods

This is a prospective, observational, comparative study that was conducted in an outpatient department of a daycare pediatric hospital located in the rural settings of Anantapur district, Andhra Pradesh, India. The study was performed, after getting ethical clearance from the Institutional Review Board (Reg. No.: RIPER-IRB-PP-031), and following ICH-GCP and STROBE guidelines. The study was conducted for 1-year period from February 2018 to January 2019.

Pediatric patients, aged between 2 and 12 years, irrespective of gender, suffering from transfusion-dependent β-TM, and undergoing iron chelation therapy (ICT) for not more than 3 months were included in the study. These patients were followed for a period of 9 months to evaluate the outcome status. Parents or guardian of children were also included in the study to obtain HRQoL scores. A patient suffering from nontransfusion hemosiderosis, patients not giving assent, or parents/guardian not giving consent to participate were excluded from the study.

A total of 97 participants who met the study criteria were enrolled into the study and divided into three groups: Group I (n = 45) under treatment with deferasirox, Group II (n = 28) under treatment with deferasirox and deferiprone, and Group III (n = 24) under treatment with deferasirox and deferoxamine. The complete dosage of mono and combinational ICT, and serum ferritin concentration limit is presented in [Table 1].

Table 1: Threshold level of serum ferritin and dosage of iron-chelation therapy

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Data collection

A suitably designed data collection form was used to collect the data related to the sociodemographic profile of the participants, and to obtain efficacy and safety parameters of ICT. Patient demographic and clinical variables such as age, gender, consanguinity, weight, height, and total transfusion blood volume, hemoglobin level, and splenectomy status were recorded. The serum ferritin levels were recorded at the initial and end of the study to evaluate the efficacy of ICT. The safety of ICT was evaluated by using hematological (white blood cell and platelet counts) and bio-chemical (blood urinary nitrogen, serum creatinine, total bilirubin, direct bilirubin, indirect bilirubin, serum glutamic oxaloacetic transaminase [SGOT], serum glutamic pyruvic transaminase [SGPT], alkaline phosphatase [ALP], sodium, chloride, potassium, albumin, and total protein) parameters. All groups of the parents were provided a diary to record any adverse drug reaction (ADR) observed.

Pediatric Quality of Life

The Pediatric Quality of Life (PedsQL) of the study participants was assessed by using the PedsQL questionnaire. The PedsQL scores for toddlers (ages 2–4 years) will be reported by only parents/guardians of the children. The PedsQL scores for children ages 5–12 years will be reported by both parents/guardians and children. The PedsQL questionnaire comprises four dimensions, includes physical, emotional, social, and school functioning. Parent and children reports of the PedsQL for children ages 5–12 years comprises 23 number of items (physical = 8; emotional = 5; social = 5; school = 5). Parent reports of the PedsQL for children ages 2–4 years comprise 21 number of items (physical = 8; emotional = 5; social = 5; school = 3). Permission to use the PedsQL questionnaire was obtained from Mapi Research Trust (PedsQL™, Copyright^© 1998 JW Varni, Ph. D. All rights reserved).^[6],[7]

Each item kept on a 5-point Likert scale; comprises never a problem = 0, almost never a problem = 1, sometimes a problem = 2, often a problem = 3, and almost always problem = 4. The responses given by young children ages 5–7 years were scaled on a 3-point scale comprises not at all problem = 0, sometimes a problem = 2, and a lot problem = 4. All items are reversed scored and linearly transformed to a 0–100 scale as follows: 0 = 100, 1 = 75, 2 = 50, 3 = 25, and 4 = 0. Each dimension score was calculated by the sum of the scores of all items in the dimension and divided by the number of items.

Data analysis

Descriptive statistics such as mean, standard deviation, frequency, and proportion were used to represent the demographic, clinical, and ADR profile of the study participants. A Chi-square test was used to match the categorical variables between the three groups. One-way ANOVA was used to compare the clinical, safety, efficacy, and PedsQL between three groups. P < 0.05 was considered a statistically significant result.

Results

A total of 97 patients were enrolled in the study. The study findings reveal that, more than half of the study participants are males. All the demographic and clinical variables such as gender, age, consanguinity, weight, amount of blood transfusion, initial hemoglobin values, and history of splenectomy are equally distributed between three groups, as shown in [Table 2].

Table 2: Demographic and clinical characteristics of the study population

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The mean difference of the serum ferritin levels was very high in Group III compared to Group II and Group I. Initial ferritin concentration in three groups was nearly similar with a P = 0.0759, but at end of the study, there was a significant difference between three groups with a P = 0.0004. The Group III regimen achieves a significant reduction in serum ferritin concentrations, as shown in [Table 3].

Table 3: Comparison of efficacy and safety parameters of iron chelation therapy

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The hematological parameters such as platelet count (1.7 ± 1.2 Lakhs cells/mm³) and hemoglobin levels (11.2 ± 1.4 g/dL) significantly declined in Group III, but these levels are under normal limits. Few of the biochemical parameters such as total bilirubin (3.9 ± 4.3) and ALP (613.9 ± 134.2) are significantly high in Group III, and blood urea nitrogen (BUN) (23.4 ± 10.0) in Group I. Other biochemical measures such as creatinine, SGOT, SGPT, sodium, potassium, albumin, and total protein concentrations are under normal limits and no significant difference between three groups, as shown in [Table 3]. Diarrhea, rashes, and elevated liver enzyme levels are some of the ADRs observed among the three groups. The complete list of the ADRs experienced by the patients on ICT is depicted in [Table 4].

Table 4: Distribution of adverse drug reaction among study groups

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The PedsQL reported by the parents shows that the mean percentage of physical, emotional, social, and school functioning of children (2–12 year ages) was more than or near to 60% in all groups with an equal distribution, as depicted in [Table 5]. The findings of PedsQL reported by children revealed; a significant reduction in the physical and school functioning among children ages 5–7 years in Group III, as shown in [Table 6].

Table 5: Comparison of pediatric quality of life of patients under iron chelation therapy responded by parents

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Table 6: Comparison of pediatric quality of life of patients (8-12 years) under iron-chelation therapy responded by children

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Discussion

The perfect treatment strategy for β-TM includes gene therapy and bone marrow transplantation, both are high cost and difficult to implement in resource-limited settings. Repeated blood transfusion is the mainstay of management in our study settings. Iron overload is one of the major obstacles faced with repeated blood transfusion. ICT is mandatory to reduce this iron overload during blood transfusion in β-TM. Majority of the trials have limited their work to examine only the safety and efficacy of ICT. However, this is the primary study, which examines the safety, efficacy, and PedsQL of ICT in transfusion-dependent β-TM.

In the current study, among 97 patients, majority (60; 61.8%) are male patients. The underlying cause for male gender predominance in β-TM was not well documented. Whereas, a similar type of findings (65.4%) are also observed in the study performed at Ahmadabad, India.^[8] The mean age of the study participants was 7.1 ± 3.3 years, which was neatly similar to the study conducted by Siva et al. In the current study, the consanguineous marriage of parents was observed in 48.4% of the children. These findings support, consanguineous marriage is a major factor for the Thalassemia. There is a need to educate the community about the complications of consanguineous marriage and importance of premarital screening for beta-thalassemia trait. As this study was carried out in the rural hospital settings, where the majority of the patients have no formal education.

The study findings reveal that, deferasirox combined with deferiprone or desferioxamine will bring a significant reduction in the serum ferritin concentration compared to deferasirox alone. In combination therapy, oral deferasirox combined with parenteral desferioxamine will bring a maximum reduction of ferritin levels than oral deferasirox combined with oral deferiprone. The combination of iron-chelating agents shows maximal effectiveness than single iron chelation agent, similar types of findings are also observed in the studies conducted by Karami et al. at Iran and Gomber et al. in New Delhi, India.^[9],[10] Hence, the combination therapy is preferred in cardiac failure conditions where there is a need for early reduction of serum ferritin concentration.

The biochemical profile of the study participants between three groups was almost same except total bilirubin, and ALP was significantly high in Group III compared to Group I and II. Hyperbilirubinemia in Group III may be an indication of greater degree of hemolysis, which was supported by the low hemoglobin value in this group. The elevated ALP may be associated with bone mineral diseases which is not under this study.^[11] These findings suggest that Desferioxamine is associated with elevated liver enzyme levels. Hence, Desferioxamine combination ICT should be cautiously recommended in liver failure patients. These findings are slightly contrasted with a study conducted by Hagag et al., in which there was no significant difference in hematological and clinical profile between all groups.^[12] Higher BUN in Group 1 may be due to high blood volume transfusion in this group. Evidence shows that repeated and large volume of blood transfusions is associated with acute renal failure.^[13]

Our study shows that diarrhea, abdominal pain, rashes, raised creatinine and hepatic enzyme levels are the most common ADRs observed in all study groups. These ADRs are very common in ICT, which were already documented in various clinical trials.^{[14],[15],[16]} The low frequency of ADRs in Group II and III despite getting two drugs compared to one drug in Group 1, may be because patients have developed ADRs with one drug already (tolerance to side-effects), or because of lower dose of individual drugs that may be used when combination therapy is employed.

The findings of the PedsQL reported by parents; the physical, social, emotional and school functioning of the children was more than 60 mean percentages, and there was no significant difference between three groups. The findings of PedsQL reported by children ages revealed that a significant reduction in the physical and school functioning among children ages 5–7 years. This poor quality of life (physical and school function) in Group III in 5–8 years age group may be partly because of the need for subcutaneous injections of Desferioxamine. As this is the prime study which attempted to evaluate the quality of life of the children, few more studies are required to make choice of ICT based on humanistic outcomes.

Limitation

The prime limitation of the study was, less sample size. Even, the study incorporates wide range of clinical (safety and efficacy) and humanistic (HRQoL) outcomes, due to less sample size and nonrandomness of trial design, these findings may not extrapolated to all pediatrics suffering from β-TM.

Conclusion

Oral deferasirox combined with subcutaneous desferioxamine shows a great significant reduction in ferritin levels, but this combination is associated with a significant raise in hepatic enzymes, and poor physical and school functioning. An oral deferasirox combined with oral deferiprone is safe and effective regimen in the treatment of β-TM, without affecting any domain of the HRQoL.

Acknowledgment

The authors would like to thank all participants who are involved in this research study. We also thank Dr. Sudheer Kumar, Director, RDT Hospital, Anantapur, for his support to conduct the study in hospital. All the authors are whole heartedly thankful to the people who are directly or indirectly responsible for the completion of the work.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

References

1.	De Sanctis V, Kattamis C, Canatan D, Soliman AT, Elsedfy H, Karimi M, et al. β-thalassemia distribution in the old world: An ancient disease seen from a historical standpoint. Mediterr J Hematol Infect Dis 2017;9:e2017018.
2.	Aggarwal R, Aggarwal M, Prakash A. Thalassemia: An overview. J Sci Soc 2014;41:3. [Full text]
3.	Toman HA, Hassan R, Hassan R, Nasir A. Craniofacial deformities in transfusion-dependent thalassemia patients in Malaysia: Prevalence and effect of treatment. Southeast Asian J Trop Med Public Health 2011;42:1233-40.
4.	Vichinsky E, Neumayr L, Trimble S, Giardina PJ, Cohen AR, Coates T, et al. Transfusion complications in thalassemia patients: A report from the centers for disease control and prevention (CME). Transfusion 2014;54:972-81.
5.	Saliba AN, Harb AR, Taher AT. Iron chelation therapy in transfusion-dependent thalassemia patients: Current strategies and future directions. J Blood Med 2015;6:197-209.
6.	Varni JW, Seid M, Kurtin PS. PedsQL 4.0: Reliability and validity of the pediatric quality of life inventory version 4.0 generic core scales in healthy and patient populations. Med Care 2001;39:800-12.
7.	Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL 4.0 as a pediatric population health measure: Feasibility, reliability, and validity. Ambul Pediatr 2003;3:329-41.
8.	Thakor DR, Desai CK, Kapadia JD, Dikshit RK, Mehariya KM. Efficacy and safety of deferasirox in pediatric patients of thalassemia at a tertiary care teaching hospital. Indian J Med Paediatr Oncol 2017;38:103-10. [PUBMED] [Full text]
9.	Karami H, Kosaryan M, Amree AH, Darvishi-Khezri H, Mousavi M. Combination Iron chelation therapy with deferiprone and deferasirox in iron-overloaded patients with transfusion-dependent β-thalassemia major. Clin Pract 2017;7:912.
10.	Gomber S, Jain P, Sharma S, Narang M. Comparative efficacy and safety of oral iron chelators and their novel combination in children with thalassemia. Indian Pediatr 2016;53:207-10.
11.	Saraç F, Saygılı F. Causes of high bone alkaline phosphatase. Biotechnol Biotechnol Equip 2007;21:194-7.
12.	Hagag AA, Hamam MA, Taha OA, Hazaa SM. Therapeutic efficacy of different iron chelators in Egyptian children with Beta Thalassemia with iron overload. Infect Disord Drug Targets 2015;15:98-105.
13.	Karrowni W, Vora AN, Dai D, Wojdyla D, Dakik H, Rao SV. Blood Transfusion and the risk of acute kidney injury among patients with acute coronary syndrome undergoing percutaneous coronary intervention. Circ Cardiovasc Interv 2016;9:e003279.
14.	Hassan MA, Tolba OA. Iron chelation monotherapy in transfusion-dependent beta-thalassemia major patients: A comparative study of deferasirox and deferoxamine. Electron Physician 2016;8:2425-31.
15.	Hagag AA, Elfaragy MS, Elrifaey SM, Abd El-Lateef AE. Therapeutic value of combined therapy with deferiprone and silymarin as iron chelators in Egyptian children with beta thalassemia major. Infect Disord Drug Targets 2015;15:189-95.
16.	Elalfy MS, Saber MM, Adly AA, Ismail EA, Tarif M, Ibrahim F, et al. Role of Vitamin C as an adjuvant therapy to different iron chelators in young β-thalassemia major patients: Efficacy and safety in relation to tissue iron overload. Eur J Haematol 2016;96:318-26.