Official Journal of the British Blood Transfusion Society
Transfusion Medicine
| ORIGINAL ARTICLE
Combination therapy – deferasirox and deferoxamine – in thalassemia major patients in emerging countries with limited resources N. Arandi,1 S. Haghpanah,1 S. Safaei,1 Z. Zahedi,1 A. Ashrafi,1 P. Eatemadfar,1 T. Zarei,1 A. H Radwan,2 A. T Taher2 & M. Karimi1 Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran , and 2 Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon 1
Received 11 September 2014; accepted for publication 7 March 2015
SUMMARY Background: The problem of iron-overload observed in thalassemia patients can be overcome using chelating agents such as deferiprone (Ferroprox®), deferasirox (Exjade®) and deferoxamine (Desferal®). Although these drugs can be used as monotherapy, combined therapy, especially deferiprone with deferoxamine, has led to promising outcomes in various studies. Methods and Materials: In this quasi-experimental study, serum ferritin levels were evaluated in 32 𝛽-thalassemia major patients with severe iron overload before and after receiving combined deferasirox (30–40 mg kg−1 day−1 ) and deferoxamine (40–50 mg kg−1 day−1 ) 2 days a week. This study was conducted from September 2012 to September 2013 in Southern Iran. Results: The mean of serum ferritin levels significantly reduced from 4031 ± 1955 to 2416 ± 1653 ng mL−1 after 12 months of therapy (P < 0·001). Echocardiograph findings showed significant improvement 1year after end of the study (P < 0·001). No drug toxicity was observed by monitoring serum creatinine, liver enzymes and blood urea nitrogen (BUN) during the study period. We observed no correlation between mean serum ferritin change and age (P = 0·87). In addition, the mean serum ferritin change did not differ between male and female thalassemia patients (P = 0·454). No difference in mean serum ferritin change was observed between patients who had undergone splenectomy compared to those who had not done so (P = 0·307). Conclusion: The study suggests that combination chelating therapy with deferasirox and deferoxamine can effectively
Correspondence: Mehran Karimi, MD, Professor of Pediatric Hematology-Oncology, Hematology Research Center, Shiraz University of Medical Sciences, Nemazee Hospital, Shiraz, Iran. Tel.: +98 711 6473239; fax: +98 711 6473239; e-mail: [email protected]
First published online 19 March 2015 doi: 10.1111/tme.12188
reduce iron burden in 𝛽-thalassemia major patients with heavy iron overload without any significant complications. Key words: 𝛽-Thalassemia, chelation therapy, deferasirox, deferoxamine, serum ferritin. Thalassemia is a form of inherited autosomal recessive blood disorders caused by a defect in haemoglobin synthesis in red blood cells leading to mild to severe anaemia. Accumulation of excessive iron, as a result of repetitive blood transfusion, especially in liver and spleen and to a lesser extent in the heart and pancreas, can cause deleterious organ damage leading to mortality and morbidity (Hershko, 2010). This can be overcome using chelating agents such as deferiprone (DFP), deferasirox (DFX) and deferoxamine (DFO) which effectively bring thalassemic patients into a net negative iron balance (Kwiatkowski, 2011). Deferoxamine was the first chelating drug available since 1970 followed by DFP and DFX, respectively (Kwiatkowski, 2011). Administration of these drugs as a single therapy has been evaluated in some Cochrane reviews (Meerpohl et al., 2012; Fisher et al., 2013a,2013b). Despite that, some patients fail to respond effectively to monotherapy, making combination therapy an alternative way to adjust iron levels in such patients. Consequently, combined therapy, specifically DFP with DFO, has been investigated extensively in various studies and was found to be effective mostly in reducing cardiac iron loading (Galanello et al., 2006; Aydinok et al., 2007; Tanner et al., 2007; Tanner et al., 2008). Since DFX has long plasma half-life (12–18 h) and because of its high affinity to Fe+3 , replacement of DFP with DFX might overcome problems associated with DFP usage (agranulosytosis and neutropenia) (Ceci et al., 2002; Cohen et al., 2003; Galanello et al., 2003; Nisbet-Brown et al., 2003; Yang et al., 2007). There are a few reports on simultaneous administration of DFX and DFO in thalassemia. In this study, we aim to evaluate the efficacy of combined therapy of DFX and DFO as an iron chelation regimen in 𝛽-thalassemia major patients with severe iron overload.
© 2015 British Blood Transfusion Society
Combined chelation therapy in thalassemia
PATIENTS AND METHODS Study design and patient selection This was a quasi-experimental study evaluating combination therapy of DFX and DFO treatment in patients with 𝛽-thalassemia major with severe iron overload. Thirty-two thalassemia patients (12 male and 20 female) with mean age of 20·69 ± 6·11 (minimum age = 7 year, maximum age = 33 year) who were referred to Shiraz Hematology Research Center during September 2012 to September 2013 were enrolled. Diagnosis of the patients was based on complete blood count, haemoglobin electrophoresis and clinical status of the patients. Of all the patients, 11 patients had undergone splenectomy. All of the patients had been on regular blood transfusion with an interval of 2–4 weeks (mean annual blood transfusion volume 190 mL kg−1 year−1 ). Among 32 patients, 14 patients received oral DFP 65–75 mg kg−1 day−1 , 16 patients received DFO 40–50 mg kg−1 day−1 (subcutaneous injection) irregularly because of poor compliance and 2 patients received oral DFX 30–40 mg kg−1 day−1 . Patients were included if they had serum ferritin levels over 2000 ng mL−1 and did not respond adequately to 1 year monotherapy according to a lack of significant change in serum ferritin concentration after 1 year monotherapy compared to its corresponding baseline levels (4031 ± 1955 vs 4854 ± 2131 ng mL−1 ; P = 0·112). Compliance was assessed in two ways; first, subjectively with patients’ self reported compliance and the second, more objectively, when patients were asked to return medication cartridge for receiving next doses. Good compliance was defined as when patients consumed DFO 2 days per week and DFX every day. Patients who consumed DFO less than 2 days per week were considered to have poor compliance. Patients with low serum ferritin level (
Transfusion Medicine
| ORIGINAL ARTICLE
Combination therapy – deferasirox and deferoxamine – in thalassemia major patients in emerging countries with limited resources N. Arandi,1 S. Haghpanah,1 S. Safaei,1 Z. Zahedi,1 A. Ashrafi,1 P. Eatemadfar,1 T. Zarei,1 A. H Radwan,2 A. T Taher2 & M. Karimi1 Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran , and 2 Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon 1
Received 11 September 2014; accepted for publication 7 March 2015
SUMMARY Background: The problem of iron-overload observed in thalassemia patients can be overcome using chelating agents such as deferiprone (Ferroprox®), deferasirox (Exjade®) and deferoxamine (Desferal®). Although these drugs can be used as monotherapy, combined therapy, especially deferiprone with deferoxamine, has led to promising outcomes in various studies. Methods and Materials: In this quasi-experimental study, serum ferritin levels were evaluated in 32 𝛽-thalassemia major patients with severe iron overload before and after receiving combined deferasirox (30–40 mg kg−1 day−1 ) and deferoxamine (40–50 mg kg−1 day−1 ) 2 days a week. This study was conducted from September 2012 to September 2013 in Southern Iran. Results: The mean of serum ferritin levels significantly reduced from 4031 ± 1955 to 2416 ± 1653 ng mL−1 after 12 months of therapy (P < 0·001). Echocardiograph findings showed significant improvement 1year after end of the study (P < 0·001). No drug toxicity was observed by monitoring serum creatinine, liver enzymes and blood urea nitrogen (BUN) during the study period. We observed no correlation between mean serum ferritin change and age (P = 0·87). In addition, the mean serum ferritin change did not differ between male and female thalassemia patients (P = 0·454). No difference in mean serum ferritin change was observed between patients who had undergone splenectomy compared to those who had not done so (P = 0·307). Conclusion: The study suggests that combination chelating therapy with deferasirox and deferoxamine can effectively
Correspondence: Mehran Karimi, MD, Professor of Pediatric Hematology-Oncology, Hematology Research Center, Shiraz University of Medical Sciences, Nemazee Hospital, Shiraz, Iran. Tel.: +98 711 6473239; fax: +98 711 6473239; e-mail: [email protected]
First published online 19 March 2015 doi: 10.1111/tme.12188
reduce iron burden in 𝛽-thalassemia major patients with heavy iron overload without any significant complications. Key words: 𝛽-Thalassemia, chelation therapy, deferasirox, deferoxamine, serum ferritin. Thalassemia is a form of inherited autosomal recessive blood disorders caused by a defect in haemoglobin synthesis in red blood cells leading to mild to severe anaemia. Accumulation of excessive iron, as a result of repetitive blood transfusion, especially in liver and spleen and to a lesser extent in the heart and pancreas, can cause deleterious organ damage leading to mortality and morbidity (Hershko, 2010). This can be overcome using chelating agents such as deferiprone (DFP), deferasirox (DFX) and deferoxamine (DFO) which effectively bring thalassemic patients into a net negative iron balance (Kwiatkowski, 2011). Deferoxamine was the first chelating drug available since 1970 followed by DFP and DFX, respectively (Kwiatkowski, 2011). Administration of these drugs as a single therapy has been evaluated in some Cochrane reviews (Meerpohl et al., 2012; Fisher et al., 2013a,2013b). Despite that, some patients fail to respond effectively to monotherapy, making combination therapy an alternative way to adjust iron levels in such patients. Consequently, combined therapy, specifically DFP with DFO, has been investigated extensively in various studies and was found to be effective mostly in reducing cardiac iron loading (Galanello et al., 2006; Aydinok et al., 2007; Tanner et al., 2007; Tanner et al., 2008). Since DFX has long plasma half-life (12–18 h) and because of its high affinity to Fe+3 , replacement of DFP with DFX might overcome problems associated with DFP usage (agranulosytosis and neutropenia) (Ceci et al., 2002; Cohen et al., 2003; Galanello et al., 2003; Nisbet-Brown et al., 2003; Yang et al., 2007). There are a few reports on simultaneous administration of DFX and DFO in thalassemia. In this study, we aim to evaluate the efficacy of combined therapy of DFX and DFO as an iron chelation regimen in 𝛽-thalassemia major patients with severe iron overload.
© 2015 British Blood Transfusion Society
Combined chelation therapy in thalassemia
PATIENTS AND METHODS Study design and patient selection This was a quasi-experimental study evaluating combination therapy of DFX and DFO treatment in patients with 𝛽-thalassemia major with severe iron overload. Thirty-two thalassemia patients (12 male and 20 female) with mean age of 20·69 ± 6·11 (minimum age = 7 year, maximum age = 33 year) who were referred to Shiraz Hematology Research Center during September 2012 to September 2013 were enrolled. Diagnosis of the patients was based on complete blood count, haemoglobin electrophoresis and clinical status of the patients. Of all the patients, 11 patients had undergone splenectomy. All of the patients had been on regular blood transfusion with an interval of 2–4 weeks (mean annual blood transfusion volume 190 mL kg−1 year−1 ). Among 32 patients, 14 patients received oral DFP 65–75 mg kg−1 day−1 , 16 patients received DFO 40–50 mg kg−1 day−1 (subcutaneous injection) irregularly because of poor compliance and 2 patients received oral DFX 30–40 mg kg−1 day−1 . Patients were included if they had serum ferritin levels over 2000 ng mL−1 and did not respond adequately to 1 year monotherapy according to a lack of significant change in serum ferritin concentration after 1 year monotherapy compared to its corresponding baseline levels (4031 ± 1955 vs 4854 ± 2131 ng mL−1 ; P = 0·112). Compliance was assessed in two ways; first, subjectively with patients’ self reported compliance and the second, more objectively, when patients were asked to return medication cartridge for receiving next doses. Good compliance was defined as when patients consumed DFO 2 days per week and DFX every day. Patients who consumed DFO less than 2 days per week were considered to have poor compliance. Patients with low serum ferritin level (
