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I. Rahal et al.
Introduction
In β-thalassemia, absent or reduced synthesis of the β- globin chain results in ineffective erythropoiesis and periph- eral hemolysis. Anemia of the most severe form of the dis- ease, known as β-thalassemia major (β-TM) or transfusion- dependent thalassemia, is treated with lifelong red blood cell transfusions associated with chelation therapy in order to limit chronic complications and premature deaths related to iron overload. If this conventional therapy has dramati- cally improved survival and quality of life of patients,1,2 allo- geneic hematopoietic stem cell transplantation (HSCT) is, in clinical practice, the only curative treatment. Only recent- ly, patients were treated with β-globin gene therapy using autologous hematopoietic stem cells (HSCs) modified by lentiviral vectors.3
Hematopoietic stem cell transplantation has been suc- cessfully performed over the last 30 years4-7 with current thalassemia-free survival rates of 80-90% in children trans- planted with HLA-matched sibling donor (MSD) before the onset of complications related to their disease or to the sup- portive treatment.8,9
Thalassemia is a rare disease in France. HSCT results from 1985 to 2007 were reported for 108 β-TM patients with 87% survival rate and, for patients treated after 2004, 85% thalassemia-free survival.10
effects. Neither graft failure nor death occurred after two years post transplant.
Patients’ characteristics at HSCT
The clinical characteristics of the 99 patients analyzed are reported in Table 1. Age at HSCT ranged from 8 months to 26 years old (median age 5.9 years). No patient had diabetes or thy- roid dysfunction. Only one patient who was transplanted at 19 years of age had pre-existing IO-related cardiomyopathy. One male and 2 females were treated for hypogonadism. The median duration of clinical follow up after transplantation was 11.9 years (range 2-30 years).
Transplantation procedure
All conditioning regimens were myeloablative, for the most part based on busulfan combined with cyclophosphamide (BuCy). In the first years of the program, 3 patients received irradiation (Table 1). Six patients underwent a second allogeneic HSCT after a medi- an time of 2.8 years after the first transplantation due to graft fail- ure. Ninety-one percent of transplants were from HLA-MSD. Sixty-seven patients received anti-thymocyte globulin as part of conditioning. All patients received cyclosporine A as GvHD pro- phylaxis, combined with methotrexate in 58 patients. Grade II-IV acute GvHD occurred in 22 patients. Chronic GvHD occurred within two years post transplant in 14 patients (limited in 9, exten- sive in 5). Within two years after successful HSCT, immunosup- pressive treatment was stopped in 94 patients (median time dura-
Hematopoietic stem cell transplantation potentially results in a better long-term quality of life than that observed in patients treated with regular transfusion and chelation therapy.11,12 However, β-TM patients are exposed to late transplant-related complications particularly when transplant is performed in older children, adolescents or adults and in patients who have received inadequate chela- tion therapy before HSCT.12-14 Occurrence of late hepatic, endocrine and cardiovascular complications have been described, related to past and residual iron overload (IO) as well as conditioning toxicity, viral infections and chronic graft-versus-host disease (GvHD). Few studies have ana- lyzed the long-term health status after HSCT including fer- tility in thalassemia patients.
Table 1. Patients’ and HSCT characteristics. Number of patients
Male/female
Age at transplantation, years, median (IQR)
Age at last assessment, years, median (IQR)
Follow-up duration, years, median (IQR)
Serum ferritin level before HSCT μg/L, median (IQR) Splenectomy
Height SDS at transplantation, median (IQR)
Weight SDS at transplantation, median (IQR)
Pesaro classification (<18 years) - Class 1/Class 1 or 2/Class 2
- Class 2 or 3/ Class 3
Puberty at transplantation in female patients, n
- Ongoing puberty or post-pubertal
- Delayed puberty and aged ≥ 13 years - Pre-pubertal
Type of donors, n
99
45/ 54
5.9 (3.1-11.2) 20 (14.2-28.3) 11.9 (7-19.3) 1400 (835-2250)
30
-0.2 (-1.66, 0.29) - 0.18 (-1.62, 0.88)
30/15/39 4/3
54
6 2+2* 44
The present report includes almost all patients with β- TM who successfully received an allogeneic HSCT in France between 1985 and 2012 and were alive at least two years after HSCT. The aim of this national retrospective study was to evaluate over time the long-term outcomes in β-TM patients after allogeneic HSCT using post-transplant medical examination data, long-term treatment records, and laboratory test results.
Methods
This retrospective non-interventional study was approved by the national regulatory authorities (CCTIRS ref. 13.425 / CNIL n. 2009-674) and was partly based on data collected in the national registry of β-TM patients.15 Between December 1985 and December 2012, 134 patients had received an allogeneic HSCT for β-TM in 21 French transplantation centers. Fifteen patients died within two years post transplant. Twelve patients resumed regular transfusions after graft failure and 107 of 134 patients were alive at least two years after successful HSCT. Six were not analyzed in the long-term study (e.g. because they had returned to their home country or were lost to follow up) and 2 died of chronic GvHD early in the third year post transplant. Finally, 99 patients were studied for transplant-related long-term
- MSD/matched other related
-URD 3
91/5
84 11/3 1
- Busulfan + cyclophosphamide
- Busulfan + fludarabine ± thiotepa
- Others including irradiation (5 or 6 Gy thoracoabdominal 3
or total body irradiation).
HSCT: hematopoietic stem cell transplantation; IQR: interquartile range; SDS: standard deviation scores; MSD: matched sibling donor; URD: unrelated donor; MAC: myeloablative conditioning; n: number. *Sex hormone replacement for hypogonadism.
Source of stem cells, n
- Bone marrow
- Cord blood/cord blood + bone marrow - Peripheral blood stem cells
Conditioning regimen (MAC = 100%), n
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