Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes

Abstract

Allogeneic bone marrow transplantation (BMT) from a genotypically identical family donor is an accepted therapeutic option for homozygous beta-thalassemia. However, only a minority of patients have access to this curative procedure. The aim of this study is to explore the feasibility of matched unrelated transplants in thalassemia and the possibility of reducing the risk of immunologic complications through careful selection of donor/ recipient pairs. Since November 1992, 32 patients (age range, 2-28 years) have been enrolled. There were 4 patients assigned to risk-class I, 11 to risk-class II, and 17 to risk-class III of the Pesaro classification. Extended haplotype analysis and family segregation studies were employed for identification of suitable donors. Of the 32 donor/recipient pairs, 24 were identical for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 loci; 7 pairs were identical for 2 extended haplotypes, and 15 pairs shared one extended haplotype. Grade II-IV acute graft-versus-host disease (GVHD) developed in 11 cases (41%) and chronic GVHD in 6 (25%) out of 24 patients at risk. There are 22 patients (69%) who are alive and transfusionindependent after a median follow-up of 30 months (range, 7-109 months). There were 6 patients (19%) who engrafted and subsequently died from transplant-related complications. In 4 cases (12.5%) graft rejection was observed within 30 days and it was followed by autologous IntroductionAllogeneic bone marrow transplantation (BMT) from a genotypically identical family donor has radically changed the prognosis of patients with homozygous beta-thalassemia. For young patients at an early stage of disease, the reported percentage of thalassemiafree survival and the mortality risk were 91% and 8%, respectively. 1,2 Transplantation performed on older, heavily iron-loaded patients, in particular those with liver abnormalities, has a lesssatisfactory outcome, the probability of thalassemia-free survival and mortality being 51% and 32%, respectively. 3 The probability of finding an HLA-identical donor within the family is less than 30% in western countries. 4 For the remaining 70% of patients with thalassemia, there was until recently no option other than treatment based on chronic transfusion and ironchelating therapy. Although optimization of protocols for transfusion and chelation has dramatically improved the life expectancy of these patients, complications of iron overload cannot be completely avoided. 5,6 Full compliance with a chronic transfusion regimen and a daily, lifelong injective chelation therapy has been shown to be difficult to maintain with advancing age. 7 Multiple endocrine dysfunctions, myocardiopathy, progressive liver fibrosis, and consequences of posttransfusion viral infections affect the quality of life and increase the mortality risk with age. [7][8][9] During the past 10 years, BMT from unrelated donors has been increasingly employed for hematologic malignancies and lifethreatening inborn errors. [10][11][12] At first, results were characterized by el...

The changing role of stem cell transplantation in childhood

“…16 Support for this conclusion is provided by the recent results obtained using an unrelated donor in children with ALL in second CR, with juvenile myelomonocytic leukemia or with thalassemia. [17][18][19][20] The greatest challenge: transplantation of HSC from an HLA-haploidentical relative…”

Allogeneic stem cell transplantation from matched related and unrelated donors in thalassemia major patients using a reduced toxicity fludarabine-based regimen

“…7 Because of the limited availability of matched family members, attention has turned to alternative donors such as mismatched family members, and/or matched unrelated donors (MUD), but the outcome of these transplants has been confounded by increase of transplant-related complications including early and late toxicity, mortality and rejection. 8 The major obstacles for the application of allo-SCT even from matched family members have been the lack of durable engraftment resulting from rejection by multiple transfused patients or autologous stem cell reconstitution. 8,9 The outcome of allo-SCT from HLAidentical family donors is largely dependent on the age of the recipient as well as on pretransplant parameters reflecting the degree of organ damage from iron overload.…”

Unrelated peripheral blood and cord blood hematopoietic stem cell transplants for thalassemia major

“…Hematopoietic stem cell transplantation from unrelated donors has met with mixed success previously [3]. Recently, however, Nasa et al from the Italian group showed that, with extended haplotype matching, results with unrelated donor marrow transplants could be comparable with those achieved with HLA-identical family donors [4]. Fang et al has also reported success with umbilical cord blood transplantation for this disease [5].…”

“…However equally intense regimens were used for the two failed unrelated transplants that were performed in Paris and Seattle, respectively [3]. In their recent report, however, the Italian group added thiotepa to their regimen after the 4 th patient to improve the chance of engraftment in their series of unrelated donor transplants [4].…”