-
1.
Population Pharmacokinetics and Exposure-Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With β-Thalassemia.
Chen, N, Kassir, N, Laadem, A, Giuseppi, AC, Shetty, J, Maxwell, SE, Sriraman, P, Ritland, S, Linde, PG, Budda, B, et al
Journal of clinical pharmacology. 2021;(1):52-63
-
-
Free full text
-
Abstract
β-Thalassemia is an inherited blood disorder resulting from defects in hemoglobin production, leading to premature death of red blood cells (RBCs) or their precursors. Patients with transfusion-dependent β-thalassemia often need lifelong regular RBC transfusions to maintain adequate hemoglobin levels. Frequent transfusions may lead to iron overload and organ damage. Thus, there is a large unmet need for alternative therapies. Luspatercept, a first-in-class erythroid maturation agent, is the first approved therapy in the United States for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. The population pharmacokinetics and exposure-response relationship of luspatercept were evaluated in 285 patients with β-thalassemia. Luspatercept displayed linear and time-invariant pharmacokinetics when administered subcutaneously once every 3 weeks. Body weight was the only clinically relevant covariate of luspatercept clearance, favoring weight-based dosing. Magnitude and frequency of hemoglobin increase, if not influenced by RBC transfusions, was positively correlated with luspatercept area under the serum concentration-time curve (AUC), 0.2-1.25 mg/kg, whereas a significant reduction in RBC units transfused was observed in frequently transfused patients. The probability of achieving ≥33% or ≥50% reduction in RBC transfusion burden was similar across the time-averaged AUC (0.6-1.25 mg/kg), with the 1 mg/kg starting dose sufficient for most early responders (71%-80%). Increasing luspatercept AUC (0.2-1.25 mg/kg) did not increase incidence or severity of treatment-emergent adverse events. These results provide a positive benefit-risk profile for the recommended luspatercept doses (1-1.25 mg/kg) in treating adult patients with β-thalassemia who require regular RBC transfusions.
-
2.
Pantoprazole reduces serum ferritin in patients with thalassemia major and intermedia: A randomized, controlled study.
Eghbali, A, Khalilpour, A, Taherahmadi, H, Bagheri, B
Therapie. 2019;(5):507-512
Abstract
AIM: Complications due to iron overload exert a problematic situation in patients with thalassemia. Proton pump inhibitors (PPIs) like pantoprazole are effective agents to reduce acid gastric acid secretion and perhaps to interrupt iron absorption in conditions with increased iron absorption. Our purpose was to study effects of pantoprazole addition to chelators on iron levels in patients with thalassemia major and intermedia. METHODS This randomized, controlled, and single center trial was performed on 60 patients with thalassemia major and intermedia in Amir Kabir hospital, Iran. Patients were randomized 1:1 to pantoprazole group (iron chelator plus pantoprazole) or control group (iron chelator) for 6 months. Serum ferritin was measured by ELISA. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. RESULTS After 6 months of treatment, a significant reduction was seen in serum ferritin levels in the pantoprazole group (1444±613μg/mL to 1197±956μg/mL; P<0.001). A further reduction was seen in patients with thalassmeia intermedia. There were no significant changes in myocardial T2* values in pantoprazole group compared to control group (23.6±7.3ms to 24.1±6.4ms). Compared to the control group, pantoprazole therapy had no effect on hepatic T2* value (9.7±2.3ms to 9.8±2.6ms). However, between-group difference was significant (P<0.05). CONCLUSION Pantoprazole therapy for 6 months has benefits for reducing serum ferritin in patients with thalassemia major and intermedia. Pantoprazole addition to iron chelators seems safe.
-
3.
A randomized controlled trial evaluating the effects of amlodipine on myocardial iron deposition in pediatric patients with thalassemia major.
Khaled, A, Salem, HA, Ezzat, DA, Seif, HM, Rabee, H
Drug design, development and therapy. 2019;:2427-2436
Abstract
BACKGROUND Mortality rates increase due to iron deposition in the cardiac muscles of thalassemia major (TM) patients. Iron overload cardiomyopathy could be treated with a combination therapy of an iron chelator and an L-type calcium channel blocker. We designed a randomized controlled study to assess the potential of amlodipine, alongside chelation, in reducing myocardial iron concentration in TM patients compared with a placebo. OBJECTIVES This study aims to estimate the change in myocardial iron concentration (MIC) determined by magnetic resonance imaging after 6 months of treatment with amlodipine, as well as measuring the changes in the secondary outcomes (liver iron concentration (LIC), serum ferritin level (SF), and left ventricle ejection fraction (LVEF)) of study participants. METHODS A single, randomized, placebo-controlled trial was performed in 40 β-Thalassemia major patients aged between 6 and 20 years old, who received either oral amlodipine 2.5-5 mg/day or a placebo, in addition to a Deferasirox chelation regimen in a 1:1 allocation ratio. RESULTS After 6 months, a significant reduction was noted in the MIC of patients receiving amlodipine (n=20), compared with the patients receiving the placebo (n=20). At baseline, the mean was 0.76±0.11 mg/g dry weight, while at 6 months, the mean was 0.51±0.07 mg/g dry weight (p<0.001). Also, there was a significant change in the myocardial T2* after 6 months; the amlodipine increased the myocardial T2* from 40.63±5.45 ms at baseline to 43.25±5.35 ms (p<0.001). However, amlodipine did not significantly affect the secondary outcomes by the end of the study. CONCLUSION The addition of amlodipine to the standard chelation therapy in transfusion-dependent thalassemia major patients improves myocardial iron overload without increasing the adverse effects.
-
4.
Iron-chelating effect of silymarin in patients with β-thalassemia major: A crossover randomised control trial.
Darvishi-Khezri, H, Salehifar, E, Kosaryan, M, Karami, H, Mahdavi, M, Alipour, A, Aliasgharian, A
Phytotherapy research : PTR. 2018;(3):496-503
Abstract
This study aimed to determine the potential iron-chelating effects of silymarin in patients with β-thalassemia major receiving standard iron-chelation therapy. We evaluated whether addition of silymarin to standard iron-chelation therapy could improve iron burden markers and liver and cardiac function in these patients, via a placebo-controlled, crossover clinical study. Silymarin (140 mg) or placebo were administered thrice daily to all patients (n = 82) for 12 weeks, and after a 2-week washout period, patients were crossed over to the other groups. Silymarin efficacy was assessed by measuring serum iron level, ferritin level, total iron-binding capacity and liver and cardiac function on magnetic resonance imaging. Silymarin treatment resulted in a negative change in the serum iron and ferritin levels and a positive change in the total iron-binding capacity levels (treatment effect, p < .001, p = .06, and p = .05, respectively). Silymarin treatment led to positive changes in cardiac and liver function in both treatment sequences of study; however, this was not statistically significant. There was a negative change in liver iron concentration in both treatment sequences (treatment effect, p = .02). In conclusion, combined iron-chelation and silymarin therapy was effective for improving the iron-burden status in patients with β-thalassemia major.
-
5.
An investigation of the effects of curcumin on iron overload, hepcidin level, and liver function in β-thalassemia major patients: A double-blind randomized controlled clinical trial.
Mohammadi, E, Tamaddoni, A, Qujeq, D, Nasseri, E, Zayeri, F, Zand, H, Gholami, M, Mir, SM
Phytotherapy research : PTR. 2018;(9):1828-1835
Abstract
This study investigated the effects of curcumin, the active polyphenol in turmeric, on iron overload, hepcidin level, and liver function in β-thalassemia major patients. This double-blind randomized controlled clinical trial was conducted on 68 β-thalassemia major patients. The subjects were randomly divided into 2 groups to receive either 500 mg curcumin capsules (total: 1,000 mg) twice daily or placebo for 12 weeks. Dietary intakes and biochemical variables including hemoglobin, transferrin saturation, total iron binding capacity, nontransferrin bound iron (NTBI), ferritin, hepcidin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were assessed at the beginning and end of the trial. Curcumin significantly reduced serum levels of NTBI (2.83 ± 1.08 compared with 2.22 ± 0.97 μmol/L, p = .001), ALT (42.86 ± 11.15 compared with 40.60 ± 9.89 U/L, p = .018), and AST (49.45 ± 12.39 compared with 46.30 ± 10.85 U/L, p = .002) at the end of the study. Based on analysis of covariance, a significant decrease was also observed in levels of NTBI (2.22 ± 0.97 vs. 2.55 ± 0.94 μmol/L, p = .026), ALT (40.60 ± 9.89 vs. 45.01 ± 10.42 U/L, p = .004), and AST (46.30 ± 10.85 vs. 50.99 ± 9.36 U/L, p = .009) in curcumin group in comparison with placebo group. There were no significant changes in hepcidin and other variables in any of the 2 groups. Curcumin administration alleviated iron burden and liver dysfunction by reducing NTBI, ALT, and AST levels in patients with β-thalassemia major.
-
6.
One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation.
Inati, A, Kahale, M, Sbeiti, N, Cappellini, MD, Taher, AT, Koussa, S, Nasr, TA, Musallam, KM, Abbas, HA, Porter, JB
Pediatric blood & cancer. 2017;(1):188-196
Abstract
BACKGROUND Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. PROCEDURE This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT. RESULTS Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy. CONCLUSIONS Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile.
-
7.
The impact of silymarin on antioxidant and oxidative status in patients with β-thalassemia major: A crossover, randomized controlled trial.
Darvishi-Khezri, H, Salehifar, E, Kosaryan, M, Karami, H, Alipour, A, Shaki, F, Aliasgharian, A
Complementary therapies in medicine. 2017;:25-32
Abstract
BACKGROUND & AIMS Blood transfusion therapy is lifesaving for individuals with β-thalassemia major (β-TM). Iron burden following blood transfusion is the main cause of oxidative stress (OS) and organ dysfunction in these patients. The aim of this study was to evaluate the effects of silymarin on serum antioxidant and oxidative status in patients with β-TM. METHODS A crossover, randomized controlled trial was performed on 82 thalassemia patients. In two periods of 12 weeks, patients received 420mg silymarin (divided into three equal 140-mg daily doses) and placebo. The washout period between the two phases was two weeks. Serum malondialdehyde (MDA), protein carbonyl (CO), total antioxidant capacity (TAC), and reduced glutathione (GSH) were measured before and after both periods. RESULTS Sixty-nine patients completed the study. Mean serum MDA and protein CO significantly decreased in all patients with β-TM after three months of treatment with silymarin. At the end of the study, serum MDA decreased from 20.36±20.11 to 4.79±4.71μmol/l (compared to 17.81±16.05μmol/l after administration of placebo), and protein CO dropped from 0.31±0.28 to 0.11±0.09mM/l (compared to 0.24±0.17mM/l with placebo). Additional laboratory parameters (such as serum TAC and plasma GSH) were also significantly elevated after therapy with silymarin. At the end of the study, serum TAC increased in all patients from 620.7±202.64 to 971.83±328.16μmol FeSO4/l (compared to 672.22±206.88μmol FeSO4/l with placebo), and GSH increased from 46.16±41.68 to 195.35±210.98nM/l (compared to 58.52±48.95nM/l with placebo). The treatment effect of silymarin was measured using a mixed-effects model of variance analysis for changes in MDA, protein CO, TAC, and GSH, with significant effects being demonstrated for each laboratory parameter (P<0.001, P=0.002, P<0.001, and P<0.001, respectively). CONCLUSIONS Silymarin was effective in decreasing serum OS and enhancing serum antioxidant capability in patients with β-thalassemia major. Silymarin given as an adjuvant therapy to standard iron chelators may provide an improvement in the OS measurements obtained in these patients, with accompanying benefit.
-
8.
A randomized, controlled study evaluating effects of amlodipine addition to chelators to reduce iron loading in patients with thalassemia major.
Eghbali, A, Kazemi, H, Taherahmadi, H, Ghandi, Y, Rafiei, M, Bagheri, B
European journal of haematology. 2017;(6):577-581
Abstract
AIM: Cardiomyopathy due to iron overload can be fatal in patients with thalassemia major. Calcium channel blockers seem to be effective to reduce iron loading. Our goal was to study effects of amlodipine addition to chelators on iron loading in patients with thalassemia major. METHODS This randomized, controlled, and single-center trial was performed on 56 patients with thalassemia major. Patients were randomized 1:1 to combined group (iron chelator plus amlodipine) or control group (iron chelator) for 1 year. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. Serum ferritin was also measured. RESULTS After 12 months of treatment, myocardial T2* values had significant improvement in combined group (21.9 ± 8.0 ms to 24.5 ± 7.6 ms; P < .05); Difference between two groups was significant (P = .02). Combined treatment had no effect on hepatic T2* value (9.6 ± 2.8 ms to 9.5 ± 3.6 ms); difference between two groups was not significant (P = .2). In addition, a significant reduction was seen in serum ferritin levels in two groups. Mild gastrointestinal upset was the most common untoward effect. CONCLUSION Addition of amlodipine to iron chelators has beneficial effects for reduction of iron loading in patients with thalassemia major. This combination therapy seems safe.
-
9.
Effects of strontium ranelate on bone mass and bone turnover in women with thalassemia major-related osteoporosis.
Morabito, N, Catalano, A, Gaudio, A, Morini, E, Bruno, LM, Basile, G, Tsiantouli, E, Bellone, F, Agostino, RM, Piraino, B, et al
Journal of bone and mineral metabolism. 2016;(5):540-6
Abstract
Subjects affected by thalassemia major (TM) often have reduced bone mass and increased fracture risk. Strontium ranelate (SrR) is an effective treatment for postmenopausal and male osteoporosis. To date, no data exist on the use of SrR in the treatment of TM-related osteoporosis. Our aim was to evaluate the effects of SrR on bone mineral density (BMD), bone turnover markers and inhibitors of Wnt signaling (sclerostin and DKK-1). Twenty-four TM osteoporotic women were randomized to receive daily SrR 2 g or placebo in addition to calcium carbonate (1,000 mg) and vitamin D (800 IU). BMD at the lumbar spine and femoral neck, bone turnover markers (C-terminal telopeptide of procollagen type I [CTX], bone-specific alkaline phosphatase [BSAP]) and insulin-like growth factor-1 (IGF-1), sclerostin and DKK-1 were assessed at baseline and after 24 months. Back pain was measured by visual analog scale (VAS) every 6 months. After 24 months, TM women treated with SrR had increased their spine BMD values in comparison to baseline (p < 0.05). Moreover, they also exhibited a reduction of CTX and sclerostin levels (but not DKK-1) and exhibited an increase of BSAP and IGF-1 (p < 0.05); however, no significant changes were observed in the placebo group. In the SrR group, a reduction of back pain was observed after 18 months in comparison to baseline (p < 0.05) and after 24 months in comparison to placebo (p < 0.05). Our study reports for the first time the effects of SrR in the treatment of TM-related osteoporosis. SrR treatment improved BMD and normalized bone turnover markers, as well as lowering sclerostin serum levels.
-
10.
A randomized trial of amlodipine in addition to standard chelation therapy in patients with thalassemia major.
Fernandes, JL, Loggetto, SR, Veríssimo, MP, Fertrin, KY, Baldanzi, GR, Fioravante, LA, Tan, DM, Higa, T, Mashima, DA, Piga, A, et al
Blood. 2016;(12):1555-61
-
-
Free full text
-
Abstract
Cardiovascular disease resulting from iron accumulation is still a major cause of death in patients with thalassemia major (TM). Voltage-gated calcium-channel blockade prevents iron entry into cardiomyocytes and may provide an adjuvant treatment to chelation, reducing myocardial iron uptake. We evaluated whether addition of amlodipine to chelation strategies would reduce myocardial iron overload in TM patients compared with placebo. In a multicenter, double-blind, randomized, placebo-controlled trial, 62 patients were allocated to receive oral amlodipine 5 mg/day or placebo in addition to their current chelation regimen. The main outcome was change in myocardial iron concentration (MIC) determined by magnetic resonance imaging at 12 months, with patients stratified into reduction or prevention groups according to their initial T2* below or above the normal human threshold of 35 ms (MIC, 0.59 mg/g dry weight). At 12 months, patients in the reduction group receiving amlodipine (n = 15) had a significant decrease in MIC compared with patients receiving placebo (n = 15) with a median of -0.26 mg/g (95% confidence interval, -1.02 to -0.01) vs 0.01 mg/g (95% confidence interval, -0.13 to 0.23), P = .02. No significant changes were observed in the prevention group (treatment-effect interaction with P = .005). The same findings were observed in the subgroup of patients with T2* <20 ms. Amlodipine treatment did not cause any serious adverse events. Thus, in TM patients with cardiac siderosis, amlodipine combined with chelation therapy reduced cardiac iron more effectively than chelation therapy alone. Because this conclusion is based on subgroup analyses, it needs to be confirmed in ad hoc clinical trials. This trial was registered at www.clinicaltrials.gov identifier as #NCT01395199.