ReviewAdvances in the allogeneic transplantation for thalassemia
Introduction
The thalassemias refer to a diverse group of hemoglobin disorders characterized by a reduced synthesis of one or more of the globin chains (α, β, γ, δβ, γδβ, δ and εγδβ) and are the most common monogenic disorders to cause a major public health problem in the world.1 It is estimated that there are 270 million carriers of haemoglobin disorders, of which 80 million are carriers of β thalassemia. Worldwide about 60, 000 children with a major thalassaemia and 250, 000 with a sickle cell disorder are born annually, giving a rate of more than 2.4 affected children per 1,000 births.2 Though originally endemic to the tropics and subtropics, the thalassemias are now found worldwide as a result of migration and have become an important part of clinical practice in Europe, the US and Australasia.
In patients with β-thalassemia major the absent or extremely reduced production of the β chain of hemoglobin causes severe ineffective erythropoiesis, massive erythroid hyperplasia in the bone marrow and extramedullary sites, and hemolytic anemia necessitating chronic transfusions. Both ineffective erythropoiesis and chronic transfusion therapy inevitably lead to iron overload resulting in progressive multiple organ damage which cause endocrine deficiencies, liver disease, and cardiac disease leading to poor quality of life and increased mortality. Regular blood transfusion and iron chelation have improved both survival and quality of life of patients with thalassemia and have changed a previously fatal disease with early death to a chronic, although progressive disease compatible with prolonged survival.2, 3, 4 Despite the prolonged life expectancy, a recent study from U.K. Thalassemia Registry showed a steady decline in survival starting from the second decade, with fewer that 50% of patients remaining alive beyond 35 years mainly because of poor compliance with chelation therapy.5 In the developing world where thalassemia is more common, most children die before the age of 20 years because of the unavailability of safe blood products and/or expensive iron chelating drugs. Two recently developed oral iron-chelators (deferiprone and deferasirox) could allow better compliance with chelation, and therefore could have a favorable impact on survival of patients with thalassemia although their efficacy compared to desferrioxamine in the long-term has not yet been determined. However, even an ideal iron- chelator with rigorous adherence only substantially reduces, but does not eliminate, the iron overload of patients on lifelong transfusions.
Stem cell gene therapy for β-thalassemia requires gene transfer into autologous hematopoietic stem cells using integrating vectors that direct regulated expression of β globin at therapeutic levels. Despite promising results of gene-therapy in animal models, their clinical potential remains uncertain and the safety of these vectors to use for gene therapy of hemoglobinopathies remains to be seen. Early attempts using conventional oncoretroviral vectors carrying the human β globin gene and portions of the locus control region (LCR) have suffered from problems of vector instability, low titers and variable expression.6 Recently human immunodefficiency virus-based lentiviral (LV) vectors were shown to stably transmit the human β globin gene and a large LCR element, resulting in correction of the mouse thalassemia intermedia phenotype, with variable levels of β globin expression.7 The levels of β globin expression achieved from insulated self-inactivating LV vectors were sufficient to phenotypically correct the thalassemia phenotype from 4 patients with thalassemia major in vitro, and this correction persisted long term for up to 4 months, in xeno-transplanted mice in vivo.8 Accumulating preclinical and clinical data show that gene therapy may induce several unexpected side effects such as: 1) insertional mutagenesis; 2) interference of transgene product with cellular signaling networks; 3) loss of homing potential of genetically modified cells; 4) fusiogenic properties of viral envelop proteins; 5) elimination of modified transgenic cells by antibodies; 6) cytotoxic T cells directed against transgene-encoded antigens; and 7) side effects of regimen used to selectively engraft or expand manipulated cells.9
Hematopoietic stem cell transplantation (SCT) has been used in attempts at curing thalassemia. The first two transplant procedures for the treatment of thalassemia with marrow from matched related donors were performed in December 1981, in Seattle, WA, and in Pesaro, Italy. The Seattle approach was based on the assumption that the risks associated with BMT would be increased by the iron overload and by sensitization to human leukocyte antigens (HLAs) induced by hypertransfusion. Therefore, it was decided that early clinical studies would be conducted in very young patients who had received very few transfusions. On December 3, 1981 a 14-month-old child with β-thalassemia major who had been transfused with a total of 250 mL of packed RBCs received BMT from his HLA-identical sister in Seattle with successful outcome.10
The Pesaro approach was based on an assessment that restricting transplants to untransfused patients was impracticable. On December 17, 1981 the Pesaro team performed a transplant in a 16-year-old thalassemic patient who had received 150 RBC transfusions, using marrow from his HLA identical brother. This patient rejected the graft and was the first of an extensive series of transplants for thalassemia performed by the Pesaro Team.11, 12
The acute toxicities of transplantation are challenged by the observation that in the developed world patients with thalassemia are well served by medical treatment, and in some countries patients receiving regular blood transfusion and chelation could have a better survival rate.3, 13 Unfortunately, these same patients with increasing age currently experience poor outcome on conventional treatment, even in well-resourced countries with universal access to good medical treatment.5, 14
The purpose of allogeneic SCT for hemoglobinopathies is to correct the basic genetic defect by repleting genes essential for normal hematopoiesis through allogeneic stem cells as vectors following conditioning to overcome the immunological barrier. Therefore allogeneic SCT in these diseases could be considered as allogeneic stem cell gene therapy.
Advances in hematopoietic SCT, supportive care and tissue typing techniques have steadily led to consider this curative approach also for patients who lack matched related donors using alternative donors such as matched unrelated and mismatched related donors. In this review we provide our experience of transplantation in thalassemia and summarise the published data on SCT in this disease.
Section snippets
Preparatory regimens
Preparatory regimens for BMT of patients with thalassemia must achieve two objectives: elimination of the disordered marrow and establishment of a tolerant environment that will permit transplanted marrow to survive and thrive. Total body irradiation (TBI) can satisfy both these objectives, but there are many reasons to avoid the use of this marrow-ablative modality. These include the known growth-retarding effects of TBI in young children and the increased risk of secondary malignancies which
Class 1 and Class 2 patients
Between October 1985 and August 2007 five hundred and fifteen class 1 and class 2 patients with median age of 7 years (range 1 to 16 years) were given bone marrow transplantation following conditioning with Bu 3,5 mg/kg/day for 4 consecutive days and CY 50 mg/kg/day for subsequent 4 days. Since 2003 patients aged less than 4 years were also given thiotepa 10 mg/kg/day in addition to BUCY. Four hundred and seventy eight of these patients were given transplant at the Hospital of Pesaro12, 28 and
Alternative related donors
Approximately 25% to 30% of patients with thalassemia could have an HLA matched related donor. As HSCT is the only cure for thalassemia there is need to develop alternative stem cells donations. Our past experience with BMT from alternative donors for 29 patients with β-thalassemia major who received phenotypically matched grafts or haploidentical grafts mismatched for one, two, or three antigens was characterized by higher graft failure (55%), and low thalassemia-free survival (21%).45
Graft failure or rejection
Patients with engraftment failure and without functioning marrow have a bleak prospect because an early second transplant with a second course of conditioning is usually not a reasonable option. However, occasionally patients have late graft failure without thalassemia recurrence and in this situation second transplant attempts with intensive conditioning may provide the only treatment option to offer a chance of prolonged survival.
Patients who reject their grafts and have a return of host
Mixed chimerism
Mixed hematopoietic chimerism (MC) is a common phenomenon after myeloablative transplantation for thalassemia. In fact the incidence of MC at 2 months was 32.2%.53 While none of the patients with complete chimerism at 2 months rejected their grafts, 35 of 108 patients with MC determined at the same time lost the graft suggesting that MC after BMT for thalassemia is a risk factor for rejection. The percentages of residual host hematopoietic cells (RHCs) after transplant were predictive for graft
Reduced intensity hematopoietic stem cell transplantation
Unlike hematological malignancies where mixed chimerism may predict relapse, in nonmalignant disorders, the development of stable mixed chimerism has a potential for ameliorative effect that was well documented for β-thalassemia major and sickle cell anemia.54, 56 Stable mixed chimerism is not uncommon in thalassemia major patients after transplantation. It appears that when stable mixed chimerism is established, even a minority of donor cells is sufficient to overcome an underlying genetic
Management of the ex-thalassemics
After a successful transplantation, ex-thalassemic patients still carry the clinical complications acquired during years of transfusion and chelation therapy. Among the issues requiring long-term management in such patients are iron overload, chronic hepatitis, liver fibrosis and endocrine dysfunction. Management of these complications in ex-thalassemics is an important issue. Iron stores after transplantation remain elevated in most patients receiving HSCT in advanced stage of disease (class 2
Conclusion
Hematopoietic stem cell transplantation offers the only chance of cure and the return of both life expectancy and quality of life to normal. Current results of HSCT clearly demonstrate that 80% to 87% of patients with thalassemia could be cured if transplants are given from HLA-matched related donors. Improvements in molecular tissue typing have allowed allogeneic transplantation to be expanded to a much wider cohort of patients lacking a matched related donor with very encouraging results.
Acknowledgements
We thank all physicians, nurses, and support personnel at the Hospital of Pesaro and at the Mediterranean Institute of Hematology for their dedicated care of patients on this study.
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