Busulfan–fludarabine- or treosulfan–fludarabine-based myeloablative conditioning for children with thalassemia major

2022 ◽  
Author(s):  
Roswitha Lüftinger ◽  
Natalia Zubarovskaya ◽  
Jacques-Emmanuel Galimard ◽  
Annamaria Cseh ◽  
Elisabeth Salzer ◽  
...  
Keyword(s):  
Thalassemia Major ◽  
Myeloablative Conditioning

scholarly journals Related and unrelated donor transplantation for β-thalassemia major: results of an international survey

2019 ◽  
Vol 3 (17) ◽  
pp. 2562-2570 ◽  
Author(s):  
Chunfu Li ◽  
Vikram Mathews ◽  
Soyoung Kim ◽  
Biju George ◽  
Kyle Hebert ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Thalassemia Major ◽  
Early Age ◽  
Unrelated Donor ◽  
Event Free Survival ◽  
Matched Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Suitable Alternative ◽  
Free Survival ◽  
Donor Type

Abstract We studied 1110 patients with β-thalassemia major aged ≤25 years who received transplants with grafts from HLA-matched related (n = 677; 61%), HLA-mismatched related (n = 78; 7%), HLA-matched unrelated (n = 252; 23%), and HLA-mismatched unrelated (n = 103; 9%) donors between 2000 and 2016. Ninety percent of transplants were performed in the last decade. Eight-five percent of patients received ≥20 transfusions and 88% were inadequately chelated. All patients received myeloablative-conditioning regimen. Overall and event-free survival were highest for patients aged ≤6 years and after HLA-matched related and HLA-matched unrelated donor transplantation. The 5-year probabilities of overall survival for patients aged ≤6 years, 7 to 15 years, and 16 to 25 years, adjusted for donor type and conditioning regimen were 90%, 84%, and 63%, respectively (P < .001). The corresponding probabilities for event-free survival were 86%, 80%, and 63% (P < .001). Overall and event-free survival did not differ between HLA-matched related and HLA-matched unrelated donor transplantation (89% vs 87% and 86% vs 82%, respectively). Corresponding probabilities after mismatched related and mismatched unrelated donor transplantation were 73% vs 83% and 70% vs 78%. In conclusion, if transplantation is considered as a treatment option it should be offered early (age ≤6 years). An HLA-matched unrelated donor is a suitable alternative if an HLA-matched relative is not available.

Allogeneic Hematopoietic Stem Cell Transplantation for Pesaro IIIβ-Thalassemia Major Using Fludarabine-Based Myeloablative or Non-Myeloablative Conditioning Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3822-3822
Author(s):  
Kanger Zhu ◽  
Jian Gu ◽  
Tao Zhang ◽  
Juan Zhong
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Thalassemia Major ◽  
Organ Damage ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem

Abstract Objective : To explore the efficacy of Fludarabine-based myeloablative or non-myeloablative conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for classIII thalassemia major with regard to regimen toxicity, graft rejection, and disease-free survival (DFS). Methods: From June 2001 to October 2004, 8 patients underwent allo-HSCT in our BMT unit, including 5 male and 3 female, with median age 5 (3 ~ 19) years. Four patients received graft from sibling donor, including cord blood and peripheral blood stem cells, and the remaining 4 patients received graft from unrelated donors, including bone marrow and peripheral blood stem cells. Fludarabine (FDR) was added into the standard BU/CY regimen, consisting of FDR, BU, CY and ATG. Six patients received myeloablative stem cell transplantation and the remaining 2 patients with evidence of organ damage from iron-overload received nonmyeloablative unrelated donor stem cell transplantation. All patients received Cyclosporine A and Methotrexate for GVHD prophylaxis. Results: Eight patients were successfully engrafted with the median time of absolute neutrophil count (ANC) more than 0.5 ×109 /L was day +13 (+9 ~ +14), and the median time of platelet count more than 20 ×109 /L was day +25 (+8 ~ +39). Two patients died of grade IV aGVHD. The regimen-related toxicity (gradeImucositis, gradeII hemorrhagic cystitis, and gradeIhepatic toxicity) occurred in 3 patients. At a median follow up of 24 (8~48) months, the probability of DFS was 75%, including the two patients given nonmyeloablative stem cell transplantation from unrelated donor. Conclusion: Fludarabine-based conditioning regimen for allo-HSCT in Pesaro III thalassemia major was well tolerated, without increasing toxicity, and associated with durable engraftment and higher rate of DFS (75%). The successful transplantation from unrelated donors using nonmyeloablative conditioning showed that thalassemia clone can be eradicated by the reduced intensity HSCT, which relies upon immunosuppressive rather than myeloablative conditioning to facilitate engraftment of donor cells, and is a novel approach for the treatment of the patients with evidence of organ damage from iron-overload.

First US Phase I Clinical Trial Of Globin Gene Transfer For The Treatment Of Beta-Thalassemia Major

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 716-716 ◽  
Author(s):  
Farid Boulad ◽  
Isabelle Riviere ◽  
Xiuyan Wang ◽  
Shirley Bartido ◽  
Susan E. Prockop ◽  
...  
Keyword(s):  
Copy Number ◽  
Lentiviral Vector ◽  
Globin Gene ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Myeloablative Conditioning ◽  
Gradual Rise ◽  
Beta Thalassemia Major ◽  
Cd34 Cells ◽  
Vector Copy Number

Abstract To date, the only curative therapeutic approach for beta-thalassemia major has been allogeneic stem cell transplantation (SCT) for patients with HLA-matched siblings. For the majority of patients who do not have a matched sibling, allogeneic SCT is associated with major risks of morbidity and mortality. The stable transfer of a functional globin gene into the patient’s own hematopoietic progenitor cells (HPCs) yields a perfectly matched graft that does not require immunosuppression to engraft. We previously demonstrated successful globin gene therapy in murine thalassemia models, using a lentiviral vector that encodes the human ß-globin promoter and arrayed regulatory elements uniquely combined to achieve high level and erythroid-specific globin expression. In vivo in thalassemic mice, the vector termed TNS9.3.55, increased hemoglobin levels by an average 4-6 g/dL per vector copy. We obtained in 2012 the first US Food and Drug Administration (FDA) approval to proceed to a clinical study in adult subjects with beta-thalassemia major (NCT01639690). We have to date enrolled 5 patients and recently treated the first three, administering the transduced HPCs after non-myeloablative conditioning. Engraftment data are available for the first two patients. Patient 3 was recently infused with CD34+ cells and is at this time too early to evaluate. Patient 1 is a 23 year old female with a ß039 – IVS1,110 mutation. Patient 2 is an 18 year old female with a ß039 – IVS1,6 mutation. Both patients underwent mobilization of peripheral blood stem cells (PBSCs) with filgrastim and mobilized 25 x 10^6 and 9.9 x 10^6 CD34 cells/Kg respectively. CD34+ PBSCs were transduced with the lentiviral vector TNS9.3.55 encoding the normal human beta-globin gene. The average vector copy number (VCN) in bulk CD34+ cells for these two patients was respectively 0.39 and 0.21 copies per cell. Both patients underwent non-myeloablative cytoreduction with busulfan administered at 2 mg/Kg/dose Q12H x 4 doses (total 8 mg/Kg), followed by reinfusion of 11.8 x 10^6 and 8.4 x 10^6 CD34+ cells/Kg, respectively. Both patients tolerated cytoreduction well and recovered their blood counts. While they continue to be transfusion dependent, both patients show a gradual rise in vector copy number in peripheral blood white blood cells and neutrophils, steadily increasing by 1-2% every month, reaching an average VCN of 5-7% 3-6 months after transplantation. In summary, patients with thalassemia major underwent safe and effective mobilization followed by excellent transduction of mobilized CD34+ cells. The transplant non-myeloablative conditioning was well tolerated, and followed by rapid engraftment and gradual rise in VCN. Continued clinical and molecular monitoring is on-going and will be presented. Disclosures: No relevant conflicts of interest to declare.

Moyamoya Syndrome in a Child with β-Thalassemia Major

2020 ◽  
Vol 18 (04) ◽  
pp. 214-216
Author(s):  
Soumya Roy
Keyword(s):  
Magnetic Resonance ◽  
Cerebrovascular Accident ◽  
Muscle Wasting ◽  
Thalassemia Major ◽  
Blood Transfusions ◽  
Moyamoya Syndrome ◽  
Magnetic Resonance Angiogram ◽  
Joint Contractures ◽  
Gradual Development ◽  
The Right

AbstractA 9-year-old girl patient presented with left-sided weakness and joint contractures developing over a period of 18 months. She was known to be suffering from β-thalassemia major and was on regular blood transfusions. Eighteen months ago, she had suffered from an episode of ischemic cerebrovascular accident affecting the right side of her brain. Magnetic resonance angiogram revealed vaso-occlusive disease affecting mainly the anterior cerebral circulation, resembling Moyamoya disease. She was advised to carry out regular physiotherapy but her parents discontinued it, which resulted in the gradual development of joint contractures and muscle wasting.

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