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Indian Journal of Medical and Paediatric Oncology
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Year : 2008  |  Volume : 29  |  Issue : 1  |  Page : 39-48 Table of Contents     

Hematopoietic stem cell transplantation for hemoglobinopathies: Progress and prospects

Department of Comprehensive Hemoglobinopathies Program Division of Hematology/Oncology/BMT Children's Hospital of Pittsburgh 3705 Fifth Avenue, Pittsburgh, PA 15213

Date of Web Publication30-May-2009

Correspondence Address:
Lakshmanan Krishnamurti
Department of Comprehensive Hemoglobinopathies Program Division of Hematology/Oncology/BMT Children's Hospital of Pittsburgh 3705 Fifth Avenue, Pittsburgh, PA 15213

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0971-5851.51444

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Allogeneic bone marrow transplantation from an HLA-identical donor is currently the only means of curing thalassemia . Transplant outcome depends upon the presence of risk factors (hepatomegaly, portal fibrosis and poor quality of chelation). patients are defined to have class I - if no risk factor, class II with one or two and class III - if all three risk factors are present. For patients under 16 years of age, for class I, class II and III the probabilities of survival are approximately 95%, >80% and 60-70%, respectively. The risk of transplant related morbidity& mortality is low when transplant is done at an early age. Currently, busulfan, cyclophospahmide and antithymocyte globulin based combination is used for conditioning.
More than 200 patients with sickle cell disease (SCD) have undergone allogeneic SCT with long term survival in >80% of patients. Results are better if donor is an HLA-identical sibling and if transplant is done early in the course of disease. Presently, experience with reduced intensity SCT and matched unrelated donor transplant is limited to recommend their routine use.

How to cite this article:
Krishnamurti L, Gupta D. Hematopoietic stem cell transplantation for hemoglobinopathies: Progress and prospects. Indian J Med Paediatr Oncol 2008;29:39-48

How to cite this URL:
Krishnamurti L, Gupta D. Hematopoietic stem cell transplantation for hemoglobinopathies: Progress and prospects. Indian J Med Paediatr Oncol [serial online] 2008 [cited 2020 Oct 23];29:39-48. Available from: https://www.ijmpo.org/text.asp?2008/29/1/39/51444

  Sickle Cell Disease Top

Advances in the care of children with Sickle cell disease (SCD) including newborn screening, early introduction of penicillin, the pneumococcal vaccines and comprehensive care [1],[2],[3] have resulted in a marked improvement in the life expectancy of patients with SCD. However, mean age of death for patients with SCD is 42 years for males and 48 years females [2] which is 25-30 years less than average life expectancy for African-American. Stroke, organ failure, acute chest syndrome and recurrent pain crises are major complications that shorten life expectancy and impair overall health related quality of life (HRQOL). While hydroxyurea (HU) and chronic transfusion regimens can ameliorate several of the complications of SCD, allogeneic hematopoietic cell transplantation (HSCT) is the only therapeutic option with curative intent.

  Indications Top

Indications for HSCT have been empirically determined from prognostic factors derived from studies of natural history of SCD. [Table 1] describes criteria for transplantation used in the national collaborative study of HSCT for SCD. [4]

  Results Top

Allogeneic HSCT after myeloablative therapy has been performed in approximately >250 young patients (<16 years of age) with SCD [Table 2]. The preparative regimens usually consists of Busulfan (BU) 14-16mg/Kg and Cyclophosphamide (CY) 200mg/kg. Additional immunosuppressive agents. Antithymocyte Globulin( ATG), rabbit ATG (rATG), [5] Ant lymphocyte Globulin (ALG) [6] or Total Lymphoid Irradiation (TLI) [7] are also used. Cyclosporine A (CsA) alone or with Methylprednisolone (MP) or Methotrexate (MTX) has been utilized for post-transplant GVHD prophylaxis.

The outcomes of HSCT from matched siblings is excellent with overall survival of 93-97% and event free survival (EFS) of 85%. [2],[6],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] Stabilization or reversal of organ damage from SCD has been documented after HSCT. [10] Patients who have stable donor engraftment, complications related to SCD resolve, and there are no further episodes of pain, stroke, or acute chest syndrome. Patients who are successfully allografted do not experience sicklerelated CNS complications and have evidence of stabilization of CNS disease by cerebral MRI. [23],[24] However, the impact of successful HSCT on reversal of cerebral vasculopathy has been variable. [25],[26],[27],[28] HSCT for SCD generally does not cause growth impairment in young children; however, diminished growth may occur if HSCT is carried out near or during the adolescent growth spurt. [29] An adverse effect of Busulfan conditioning on ovarian function was demonstrated in five of seven evaluable females who are currently at least 13 years of age. None of the four males tested had elevated serum gonadotropin levels. [10] Radiological improvement of a patient with osteonecrosis of humeral head [30] and correction of splenic reticuloendothelial dysfunction have been reported. [16],[31] There may be differences in recommendations of health care providers and risk accepted by patients or parents. [32] Majority of parents and patients are willing to accept some risk of mortality.

  Thalassemia Top

Thalassemia results from mutations in one or more globin genes or other regulatory elements that result in the decreased or absent synthesis of a or b globins. Nearly 200 different mutations have been described in patients with b Thalassemia and related disorders. [34] It is estimated that there are 200 million carriers of the disease, of which 20 percent are in South East Asia and 10 percent in India alone. More than 9,000 children with Thalassemia major are born every year in India, which signifies the huge disease burden. [35],[36]

  Survival Top

The prospect of improved survival without cardiac disease has greatly increased, especially for children with Thalassemia born since the current treatment became widely available. [37],[38] Nonetheless, there are still cases of iron-related illness and death, even in patients who apparently complied with desferrioxamine therapy. A sustained reduction in iron, as measured by the proportion of serum ferritin measurements that did not exceed 2500 ng per milliliter, is the most consistent predictive factor of survival without cardiac disease. [37] Desferrioxamine treatment is cumbersome and expensive; compliance is a major obstacle especially in children. [39],[40] Deferiprone is also used widely as an oral chelator albeit with limited clinical data in prospective trials.41 Deferasirox, a tridentate iron chelator allows once daily dose orally and has shown promising results in decreasing the liver iron concentration [42] and has been recently licensed for use. However oral iron chelation remains expensive. At present HSCT is the only therapy with curative intent.

  Indications Top

Patients with Thalassemia major who are transfusion dependent have been offered HSCT. Selected patients with severe forms of Thalassemia intermedia such as E/b Thalassemia as well as aThalssemia with hydrops [43] have been offered HSCT. Success of HSCT can be predicted by the (Lucarelli Class I, II, III) on basis of hepatomegaly >2cm, liver fibrosis and inadequate chelation. Sodani et al demonstrated that Class III children less than 17 years have a good outcome after HSCT. [44] A prospective trial on 190 patients has shown that in India has demonstrated a good prognosis in children less than 7 years who come in Class III. [45]

  Results Top

Allogeneic HSCT after myeloablative therapy has been performed in more than 1500 patients [46] [Table 3]. BU 14-16mg/Kg and Cyclophosphamide (CY) 200mg/kg with or without ATG is the backbone of preparative regimens used, although CY/TBI regimens have been used. [47] CsA alone or with MP or MTX has been utilized for post-transplant GVHD prophylaxis. The outcome of HSCT in over 800 patients with Thalassemia is excellent especially in those who are young and do not have advanced disease. [48] The overall survival (OS) and EFS are 95% and 90% for Pesaro class I, 87% and 84% for class II for patients 79% and 58% for Class III patients and 66 % and 62 % for adult patients. Recently, modification of the conditioning regimen for young patients with Class III disease has improved outcomes in these patients. [49] These patients received HU 30mg/Kg and azathioprine(AZA) 3mg/ Kg given daily day -45 to day -11, fludarabine (FLU) 20 mg/m2 /day, from day -17 to day -11 and BU14 mg/Kg. Class 3 patients aged less than 17 years received CY 160 mg/Kg while patients 17 years or older, received CY90 mg/Kg. In this group of 31 Class 3 young Thalassemic patients, OS and EFS were 97% and 90%, respectively.

Following HSCT, 40% of patients attained puberty normally despite clinical and hormonal evidence of gonadal dysfunction in majority. [50] Hormonal dysfunction could be attributed to the cytotoxic effects of alkylating agents, gonadotropin insufficiency or secondary to previous iron overload. In 41 patients treated with phlebotomy after successful HSCT, liver iron concentration decreased from 20.8 (15.5-28.1) to 3 (0.9-14.6) mg/g dry weight (p < 0.0001), suggesting that phlebotomy is a safe and effective method to decrease iron overload in the "ex-thalassemic". [51] Six patients who developed liver cirrhosis before or after their Thalassemia was cured by bone marrow transplantation received iron depletion and antiviral therapies. Follow- up biopsies showed regression of incomplete or definite cirrhosis in all patients. [52] Post HSCT phlebotomy has also helped reverse subclinical cardiac dysfunction. [53] Short stature is present in a significant percentage of transplanted Thalassemic children. [54] While there is a close effect of the age at time of transplant (before or after 7 years) on subsequent growth rate, the growth impairment in these subjects is probably multifactorial.

  Novel Approaches to HSCT for Hemoglobinopathies Top

Paucity of donors, inadequate management early in life, regimen related effects have limited the acceptability of the curative therapy for majority of patients with hemoglobinopathies. Various approaches are being evaluated to increase engraftment and minimize the side effects at the same time. Complete substitution of Cyclophosphamide was done by Fludarabine (30mg/m2/day Χ 6) and rATG (10mg/kg/day Χ 4) with Busulfan orally (3.5mg/kg/day Χ 4) and all the five patients attained engraftment with no case of GVHD more than Grade I. [65] Alemtuzumab with Busulfan at dose of 8mg/kg has also been used in the preparative regimen. Sodani et al report that likelihood of engraftment is increased and graft rejection decreased with use of azathioprine, fludarabine, hydroxyurea coupled with a hypertransfusion and adequate chelation regime prior to HSCT. [66] Short term ATG has also shown to decrease the chances of acute and chronic GVHD. [67] Hydroxyurea has good compliance without severe side effects in patients with SCD and improves the outcome of HSCT when administered before HSCT. [68]

  Nonmyeloablative HSCT and Reduced Intensity Conditioning Top

Myeloablation for the eradication of host hematopoiesis and host immunosuppression has been considered to "create space" in the host marrow and the prevention of immunologic rejection of the graft, respectively. Allogeneic marrow can create its own "space" by a local graft versus host reaction after a Nonmyeloablative preparative regime. [69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83] But the regime related toxicity (RRT) has been the major limiting factor in the trend for a less toxic preparative regime. Nonmyeloablative regimes do not cause eradication of host erythropoiesis and allow hematopoietic recovery without infusion of donor stem cells whereas regimes causing some myeloablation and requiring donor stem cells for recovery are termed as reduced intensity conditioning. [79] Fludarabine, a purine analog is the backbone of most of the nonmyeloablative preparative regimens used. Sauer et al have showed 100 percent engraftment and minimal RRT using Fludarabine, ATG, Busulfan. [65]

  Matched Umbilical Cord Blood from Sibling as Stem Cell Source for HSCT Top

Recently, 44 patients with hemoglobinopathies (33 Thalassemia, 11 SCD) received an umbilical cord blood (UCB) transplantation from a sibling. [22] Forty one UCB donors were HLA matched, and 3 had 1 HLA-A difference. The 2 year OS and EFS were 100% and 81%, respectively. Remote-site collection and directed-donor banking of UCB for sibling recipients with malignancy, SCD, Thalassemia major, non-malignant hematological conditions, and metabolic errors has been accomplished with a high success rate. Sixteen of 17 UCB allograft recipients had stable engraftment of donor cells. [84] The Sibling Donor Cord Blood (SDCB) Program has helped in transplantation of 14 patients of Thalassemia major with HLA matched UCB, of which 11 are free of disease. [85] Thus it is important to emphasize the role of cord blood banking which offers an alternative source of hematopoietic stem cells.

  HSCT from Unrelated Donors Top

While young patients without advanced disease who have received HCT from a matched sibling, have an excellent outcome, the applicability of HSCT for these conditions is limited by the fact that fewer than one third of these patients will find a suitable human leukocyte antigen (HLA) matched related or family donor. [86] Worldwide experience [Table 4] in unrelated donor transplantation for Hemoglobinopathies is limited because in the past, HSCT from unrelated donors (URD) has not been offered to patients with hemoglobinopathies. LaNasa et al have reported results in 68 patients indicating an OS of 79.3%and DFS of 65.8% [87] while Hongeng et al have reported 21 patients indicating an OS of 71%and DFS of 71%. Unrelated UCBT can lead to stable engraftement and amelioration of clinical phenotype but engraftment, GVHD and infections remain the challenges. [88],[89],[90]

Since these diseases may be associated with prolonged survival, the increased regimen related toxicity (RRT) of URD HCT was considered unacceptable. The world-wide number of alternative donor transplants for hemoglobinopathies remains limited to date. [15],[91],[92],[93],[94],[95] The advent of novel strategies for reduction of RRT, including the use of nonmyeloablative preparative regimens [96],[97] and the improvement in outcomes of URD HCT [98] has sparked fresh interest in the consideration of URD HCT for patients with Hemoglobinopathies. A study in north Indian population shows that they have unique HLA haplotypes and possibility of finding a matched sibling is further decreased. [99] Efforts are ongoing to establish bone marrow donor registries in India.[102]

  References Top

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  [Table 1], [Table 2], [Table 3], [Table 4]


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