Overview of the current issues and advances in haemopoietic stem cell transplantation for β-thalassemia major

  • S.S. Anak | paola.granata@pagepress.org Istanbul University, Istanbul School of Medicine, Dept. of Pediatric Hematology/Oncology/BMT, Italy.

Abstract

Bone marrow transplantation (BMT) is the only possible curative treatment for β-thalassemia major. The largest experience occurred in Pesaro, Italy, where the BMT was applied after a standard risk assessment. The patients were divided into 3 risk classes based on liver size by physical examination, the presence or absence of fibrosis by liver biopsy, and adherence to regular iron chelation. Outcomes were mainly affected by the risk status. After modifications to the conditioning regimens, the risk of transplantation-related complications in highrisk recipients reduced considerably. As a result, outcomes after transplantation have become more similar across risk categories. For BMT, most centers use bone marrow instead of peripheral blood in thalassemia. Some studies showed that peripheral blood stem cell transplantation (PBSCT) is better than BMT with regard to hematologic recovery, hospitalization period, leukemia-free survival, overall survival (OS), and transplant-related mortality (TRM). No significant differences were seen in grade II to IV acute GVHD (aGVHD); but the incidence of chronic GVHD (cGVHD) was significantly higher in the PBSCT group. BMT from unrelated donors may offer similar results to those obtained using HLA-identical family donors, at least for patients who are not fully compliant with conventional treatment and do not yet show severe complications of iron overload. All studies conclude that MUD BMT might be a good alternative for patients with less risk factors. Another study concluded that, at present, due to high graft failure and GVHD rates, BMT from alternative donors should be restricted to patients who have poor life expectancies because they cannot receive adequate conventional treatment or because of alloimmunization to minor blood antigens. In another study unrelated cord blood transplantation (CBT) was compared to related donor transplantation for children with β-thalassemia. The results were comparable to the survival rates of related-donor BMT for thalassemia. It has always been a dream for parents to have a new baby who might be a donor for his/her sibling and save his/her life. Today some families tried to learn the HLA group of the fetus using prenatal diagnosis. The last step in this development was preimplantation genetic diagnosis (PGD). PGD has become available as an alternative to prenatal diagnosis in order to avoid the risk for pregnancy termination, because PGD allows selection of unaffected embryos before a pregnancy is established. Gene therapies, the ultimate idea, involves replacing allogeneic stem cell transplantation with the transfer of normal globin genes into patientderived autologous haematopoietic stem cells, bypassing the need for allogeneic donors and the immunosuppression required to achieve engraftment of the transplanted cells and to eliminate the risk of donor-related graft-versus-host disease. The successful preclinical studies in thalassaemia mousemodels, the accumulating data on lentiviral vector-mediated HSC transduction and the anticipated increased safety of lineage-restricted globin SIN lentiviral vectors strongly support the initiation of Phase I gene therapy clinical trials in β-thalassaemia.

 

骨髓移植(BMT)是治疗β重型地中海贫血唯一可能的有效疗法。 意大利的佩萨罗获得了最多的骨髓移植经验,在标准风险评估过后,在这个地方进行了骨髓移植。 患者被分成了 3 种风险类别,其分类根据是通过体检获得的肝脏大小、通过肝脏活检确定是否存在纤维化、以及是否坚持定期铁螯合。 结果主要受到风险状态的影响。 在修改预处理方案之后,大大减少了高风险接受者的移植相关并发症风险。 结果是,通过风险分类来看,移植后的成果变得更加相似。 关于骨髓移植,大多数的中心使用骨髓来代替地中海贫血中的外周血液。 一些研究表明,就血液回收、住院期、无白血病存活、总体存活(OS)、以及移植相关死亡率(TRM)而言,外周血干细胞移植(PBSCT)更优于骨髓移植。 急性 GVHD(aGVHD)的第二至第四等级中没有重大差异;但是外周血干细胞移植群体中的慢性GVHD(cGVHD)发病率要明显高一些。 来自不相关捐赠者的骨髓移植可能提供和使用相同人体白细胞抗原(HLA)家庭捐赠者的骨髓移植类似的结果,至少对不符合常规治疗的患者和还没有显现出严重的铁过载并发症患者来说是这样的。 所有的研究得出结论,MUD骨髓移植可能是带更少风险因素患者的最佳替代方法。 另外一项研究表明,目前,由于移植风险高以及高GVHD发病率,应该限制低生命期望的患者使用来自替代捐赠者的骨髓移植,因为他们无法接受充足的常规治疗或者是因为对小血抗原具有异源免疫。 另一项研究将无关的脐血移植(CBT)和相关的对β地中海贫血儿童的捐赠移植进行了比较。 其结果相当于地中海贫血相关捐赠者骨髓移植的存活率。 父母一直梦想有个新生儿,这个新生儿可以成为他/她的同胞的捐赠者并拯救其生命 现在,一些家庭进行产前诊断来了解胎儿的人体白细胞抗原组 这一进步的最后一步称为胚胎植入前遗传诊断(PGD)。 胚胎植入前遗传诊断已经可用作产前诊断的替代方法,目的是避免终止妊娠的风险,因为胚胎植入前遗传诊断允许在建立妊娠之前选择没有受影响的胚胎。 最终的想法是基因疗法,包括将正常的珠蛋白基因移入病人自身造血干细胞来代替异基因造血干细胞移植,排除对异基因捐赠者和免疫压制的需要。免疫压制要求必须植入到移植的细胞中,并可消除捐赠者相关移植物抗宿主病的风险。 成功的地中海贫血小鼠模型临床前研究、慢性病毒载体调节的肝星状细胞(HSC)转导、以及血统限制珠蛋白SIN慢病毒载体安全水平的预期上升,大力支持进行β地中海贫血的第一期基因治疗临床试验。

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Published
2011-12-30
Keywords:
HSCT, thalassemia major.
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How to Cite
Anak, S. (2011). Overview of the current issues and advances in haemopoietic stem cell transplantation for β-thalassemia major. Thalassemia Reports, 1(1), e8. https://doi.org/10.4081/thal.2011.s2.e8