scholarly journals Efficacy and safety of ruxolitinib in ineffective erythropoiesis suppression as a pretransplantation treatment for pediatric patients with beta‐thalassemia major

2021 ◽  
Author(s):  
Galina Ovsyannikova ◽  
Dmitry Balashov ◽  
Irina Demina ◽  
Larisa Shelikhova ◽  
Alexey Pshonkin ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Efficacy And Safety ◽  
Ineffective Erythropoiesis ◽  
Beta Thalassemia Major

Recent Progress in Gene Therapy and Other Targeted Therapeutic Approaches for Beta Thalassemia

2019 ◽  
Vol 20 (16) ◽  
pp. 1603-1623 ◽  
Author(s):  
Eman M. Hamed ◽  
Mohamed Hussein Meabed ◽  
Usama Farghaly Aly ◽  
Raghda R.S. Hussein
Keyword(s):  
Gene Therapy ◽  
Cell Transplantation ◽  
B Cell Lymphoma ◽  
Thalassemia Major ◽  
Phase Iii ◽  
Beta Thalassemia ◽  
Ineffective Erythropoiesis ◽  
Hematopoietic Stem ◽  
Beta Thalassemia Major ◽  
Autologous Cell Transplantation

Beta-thalassemia is a genetic disorder characterized by the impaired synthesis of the betaglobin chain of adult hemoglobin. The disorder has a complex pathophysiology that affects multiple organ systems. The main complications of beta thalassemia are ineffective erythropoiesis, chronic hemolytic anemia and hemosiderosis-induced organ dysfunction. Regular blood transfusions are the main therapy for beta thalassemia major; however, this treatment can cause cardiac and hepatic hemosiderosis – the most common cause of death in these patients. This review focuses on unique future therapeutic interventions for thalassemia that reverse splenomegaly, reduce transfusion frequency, decrease iron toxicity in organs, and correct chronic anemia. The targeted effective protocols include hemoglobin fetal inducers, ineffective erythropoiesis correctors, antioxidants, vitamins, and natural products. Resveratrol is a new herbal therapeutic approach which serves as fetal Hb inducer in beta thalassemia. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for beta thalassemia major and is preferred over iron chelation and blood transfusion for ensuring long life in these patients. Meanwhile, several molecular therapies, such as ActRIIB/IgG1 Fc recombinant protein, have emerged to address complications of beta thalassemia or the adverse effects of current drugs. Regarding gene correction strategies, a phase III trial called HGB-207 (Northstar-2; NCT02906202) is evaluating the efficacy and safety of autologous cell transplantation with LentiGlobin. Advanced gene-editing approaches aim to cut DNA at a targeted site and convert HbF to HbA during infancy, such as the suppression of BCL11A (B cell lymphoma 11A), HPFH (hereditary persistence of fetal hemoglobin) and zinc-finger nucleases. Gene therapy is progressing rapidly, with multiple clinical trials being conducted in many countries and the promise of commercial products to be available in the near future.

scholarly journals Assessment of cardiac functions in pediatric patients with beta thalassemia major

2018 ◽  
Vol 7 (1) ◽  
pp. 47-51
Author(s):  
Onur Çaglar Acar ◽  
Serdar Epçaçan ◽  
İbrahim Ece ◽  
Abdurrahman Üner ◽  
Ahmet Faik Öner
Keyword(s):  
Pediatric Patients ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Beta Thalassemia Major ◽  
Cardiac Functions

Nephrolithiasis in Transfusion-Dependent Pediatric Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4895-4895
Author(s):  
Joanne Yacobovich ◽  
Irit Krause ◽  
Rotem Semo-Oz ◽  
Hannah Tamary
Keyword(s):  
Vitamin D ◽  
Pediatric Patients ◽  
Renal Stones ◽  
Thalassemia Major ◽  
Small Sample ◽  
Beta Thalassemia ◽  
Thalassemia Intermedia ◽  
Urine Calcium ◽  
Beta Thalassemia Major ◽  
Vitamin D Levels

Abstract Background: The prolonged survival in patients with beta thalassemia major and other transfusion dependent disorders has exposed the multi-organ effects of multiple transfusions and chelation therapy. Renal deficits were described with the focus on tubular and glomerular function. Nephrolithiasis has not been systematically explored in these patients. Contributing factors to stone formation may include hypercalcuria, abnormal vitamin D homeostasis, and proximal tubulopathy. Objective: We analyzed hematologic and nephrologic parameters of 22 transfusion- dependent pediatric patients to investigate contributors to nephrolithiasis. Methods: The study included patients with beta thalassemia major (TM) (13), transfusion-dependent beta thalassemia intermedia (TDTI) (4), Diamond-Blackfan anemia (DBA) (3), other transfusion-dependent hemoglobinopathies (2). Patients' ages were from 4-20 years (overall median -11 years, TM/TDTI median - 11.5, DBA median - 7.5 years). At the time of analysis 11 received iron chelation with deferasirox, 8 with combined desferoxamine & deferiprone, 2 with combined desferoxamine & deferasirox and one patient received desferoxamine alone. All patients had previously been treated with deferasirox alone and due to either significant adverse events or failure to control iron overload were switched to an alternate regimen. Seven patients were treated with vitamin D supplements for a median of 3 years (range: 0.2-4.3), 6 patients received vitamin D+calcium for a median of 4.5 years (range: 4.3-10). Venous blood samples, 24-hour urine collections and spot urine samples were collected to assess urine chemistry, vitamin D metabolism, electrolytes and renal function. Renal sonography and directed computerized tomography were used to diagnose nephrolithiasis/nephrocalcinosis. Results: Three patients, all with TM/TDTI, had symptomatic and radiographically identified renal stones, an additional TM patient had symptomatic nephrocalcinosis (Table 1). Among the entire cohort hypercalcuria was identified in 75% with increased Ca/Cr in 68%. 25(OH)D3 was abnormal in 81% of patients, mostly in the "insufficient" range (25-75 mmol/L). No significant relationship between presence of nephrolithiasis and chelation regimen, Ca mg/kg/d, Ca/Cr, renal fractional excretion (Fe) of phosphate (FePhos(, FeNa, FeUA, oxalate, cystein, citrate, 25(OH)D3, or treatment with vitamin D± calcium was identified, possibly in part due to the small sample size. Conclusions: The incidence rate of nephrolithiasis in our pediatric transfusion-dependent population was 1000x that published in various pediatric populations. Hypercalcuria and relatively low vitamin D levels were found in the majority of our patients, notably in all with nephrolithiasis. All 4 patients with nephrolithiasis/calcinosis were ≥ 13 years old, receiving vitamin D±calcium supplements and had received deferasirox chelation. Of note none of the patients not receiving vitamin D±calcium therapy presented with renal stones or calcinosis. The pathophysiology of nephrolithiasis/calcinosis is unclear among these adolescents; however the role of vitamin D±calcium supplemental therapy and the contribution of deferasirox must be further studied to find the proper formulation needed to maintain bone health without increasing the risk for renal stones. Abstract 4895. Table 1- Characteristics of patients with nephrolithiasis/nephrocalcinosis Patient Diagnoses Age at onset (years) Chelation (at onset) Duration of vitamin D+Ca supplement (years) Low vitamin D levels (mmol/L) Urine calcium (mg/kg/d) 1 TM/NL 16 DFX 2.3 + 7.6 2 TM/NL 16 DFX 5 - 6.9 3 TDTI/NL 13 DFO&DFP (prior DFX) 0.25 (vitamin D only) + 4.4 4 TM/NC 18 DFX 4 + 2.7 TM-thalassemia major, TDTI-transfusion-dependent thalassemia intermedia, NL-nephrolithiasis, NC-nephrocalcinosis, DFX-deferasirox, DFO-desferoxamine, DFP-deferiprone, Ca-calcium, normal values: vitamin D>75mmol/L, urine calcium<4mg/kg/d Disclosures No relevant conflicts of interest to declare.

A Prospective Study of Tubular Dysfunction in Pediatric Patients with Beta Thalassemia Major Receiving Deferasirox

2013 ◽  
Vol 30 (8) ◽  
pp. 748-754 ◽  
Author(s):  
Majid Naderi ◽  
Simin Sadeghi-Bojd ◽  
Ali Kord Valeshabad ◽  
Alireza Jahantigh ◽  
Shaban Alizadeh ◽  
...  
Keyword(s):  
Prospective Study ◽  
Pediatric Patients ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Tubular Dysfunction ◽  
Beta Thalassemia Major ◽  
A Prospective Study

scholarly journals Efficacy and safety of ruxolitinib in ineffective erythropoiesis suppression as a pre-transplantation treatment for pediatric patients with beta-thalassemia major

2021 ◽  
Author(s):  
Galina Ovsyannikova ◽  
Dmitry Balashov ◽  
Irina Demina ◽  
Larisa Shelikhova ◽  
Alexey Pshonkin ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Rejection Rate ◽  
Thalassemia Major ◽  
Infectious Complications ◽  
Beta Thalassemia ◽  
Ineffective Erythropoiesis ◽  
Short Term ◽  
Initial Size ◽  
Hematopoietic Stem ◽  
System A

Background: Ineffective erythropoiesis (IE) is the most prominent feature of transfusion-dependent beta-thalassemia (TDT), which leads to extramedullary hemopoiesis. The rejection rate in allogeneic hematopoietic stem cell transplantation (HSCT) is clearly superior in heavily transfused patients (pts) with TDT accompanied by prominent IE. Therefore, a pre-transplantation treatment bridging to HSCT is often used to reduce allosensibilization and IE. Ruxolitinib (RUX) is a JAK-1/JAK-2-inhibitor and has showed its efficacy to suppress IE and the immune system. A previously published study on RUX in adult pts with TDT has revealed that this treatment significantly reduces spleen size and is well tolerated. Procedure: Ten pts (5-14 y.o.) with TDT and an enlarged spleen were enrolled. The dose of RUX was adjusted for age: for pts younger < 11 years: 40 - 100 mg/m2 and for pts >11 years: 20 - 30 mg/m2. HSCT was performed in 8 out of the 10 pts. Results: After the first 3 months of RUX therapy the spleen volume decreased in 9 out of the 10 cases by 9.1 – 67.5% (M = 35.4%) compared to the initial size (р = 0.003). The adverse events of RUX included infectious complications, moderate thrombocytopenia as well as headache and were successfully managed by reducing the dose. The outcomes of HSCT were favorable in 7 out of the 8 cases. Conclusion: RUX is promising as a short-term pre-HSCT treatment for pediatric pts with TDT and pronounced IE.

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