Advances in allogeneic stem cell transplantation for hemoglobinopathies

Hematopoietic stem cell transplantation (SCT) is currently the only potential curative therapy for thalassemia and sickle cell disease. A myeloablative conditioning regimen has been in use to eradicate the disease. Nowadays, improved preparative and conditioning methods are used including reduced intensity conditioning regimens. Such developments have allowed transplantation of more advanced hemoglobinopathy diseases. Stem cell transplant sources became more accessible including umbilical cord blood and alternate donor. However, donor human leukocyte antigen (HLA) disparity still carries a significant risk of morbidity and mortality.     

Marrow transplantation for thalassemia

Ten patients with homozygous beta thalassemia, aged from 1 year 7 months to 13 years, underwent bone marrow transplantation from siblings or parents. The first case received 12 mg/kg busulfan, 120 mg/kg cyclophosphamide, and 300 cGy total body irradiation before transplantation; he survives, with a graft, more than 680 days after transplantation. The other nine patients received 16 mg/kg busulfan and 200 mg/kg cyclophosphamide. Two died of transplantation-related complications on days 30 and 55. Seven survive 170 to 580 days after transplantation. Three of the seven surviving patients have durable engraftment (greater than 230 to greater than 550 days) while four patients have autologous hematopoietic recovery. Four of five patients who had less than 50 prior transfusions achieved engraftment. Only one of five patients who had more than 50 prior transfusions achieved engraftment (P less than 0.05). The six-month actuarial survival was 80%; six-month actuarial disease-free survival was 40%. These data demonstrate that bone marrow transplantation may cure thalassemia, but engraftment may be jeopardized among patients who have been heavily transfused or have received marrow from a donor who is not HLA-identical.     

Stem cell transplantation for thalassemia

Thalassemia, one of the most common genetic disorders, is considered to be a global problem. Several millions of the patients suffer from severe thalassemic diseases. Stem cell transplantation is currently the only curative therapy. Bone marrow transplantation offers a high probability of cure when performed in young children. There is a higher risk as the patient becomes older, especially the high incidence of graft rejection. Modified conditioning regimens live been developed to overcome graft rejection in patients with class III or full blown manifestations. The alternative use of stem cell from cord blood makes possible earlier transplant with better chance of cure, although the engraftment is slower compared to bone marrow transplantation. More experiences with regard to stem cell transplantation in adult patients, the use of stem cell transplantation from related donors as well as matched unrelated donors are necessary.     

地中海贫血分子诊断技术进展

地中海贫血(简称地贫)是一种最常见的常染色体隐性遗传性血液病。其致病机制为珠蛋白基因发生缺陷引起珠蛋白链合成减少或缺如,使血红蛋白的α-链/非α-链比例失衡,从而导致的一组溶血性疾病。该病目前尚无经济有效的根治方法,通过人群分子筛查和基因诊断,对高风险夫妇孕期胎儿进行产前诊断而避免重型地贫患儿的出生,是国内外公认的首选预防措施。因此,准确实用的分子诊断方法,是实现大规模人群分子筛查、常规基因诊断和产前诊断的前提。该文就当前地贫分子诊断技术进展进行综述,以供参考。     

Hematopoietic stem cell transplantation in thalassemia

SCT still remains the only cure currently available for patients with thalassemia. Results of transplants in this disease have steadily improved over the last two decades due to improvements in preventive strategies, effective control of transplant-related complications and development of new preparative regimens. Currently, high-resolution HLA typing has enabled physicians to perform transplants from unrelated volunteer donors for thalassemia with results comparable with those obtained employing an HLA-identical sibling. The probabilities for obtaining thalassemia-free survival after transplant in thalassemia from an HLA-identical donor, family member or MUD are between 85 and 87%. Therefore, when an HLA-identical donor is present, the transplant of allogeneic stem cell should be performed as allogeneic gene therapy. In the light of advances in transplantation for thalassemia, patients with an HLA-identical donor should be offered SCT.     

Progress in allogeneic transplantation for multiple myeloma

Allogeneic hematopoietic stem cell transplantation to treat multiple myeloma has been attempted since the early 1980s. The original conditioning regimen including high‐dose total body irradiation (TBI) plus cyclophosphamide was myeloablative and associated with a relatively low relapse/progression rate, but high transplant‐related mortality and no obvious improvement in progression‐free survival or overall survival. Some risk groups may benefit from this transplant modality and occasional patients may be cured, but due to the high‐transplant‐related mortality it is mainly abandoned. Reduced intensity conditioning (RIC), non‐myeloablative allogeneic transplantation reduces transplant‐related mortality significantly when compared with myeloablative conditioning, but the relapse/progression rate is somewhat higher. However although the treatment‐related mortality is higher than after autologous transplantation, the progression‐free and overall survival was better or tended to be better in three of five prospective trials comparing tandem autologous/RIC allogeneic transplantation to single or tandem autotransplantation due to lower relapse/progression rate. Adding donor lymphocyte infusions post‐transplant, new drugs like bortezomib, thalidomide, lenalidomide or pomalidomide pre‐ and/or post‐transplant, and more specific antimyeloma cell therapy like NK cells post‐transplant, may in future studies prove to improve results.     

地中海贫血儿童非亲缘造血干细胞移植后BK病毒相关出血性膀胱炎临床特征分析

［摘要］　目的　分析输血依赖型地中海贫血儿童非亲缘造血干细胞移植后BK病毒（BKV）相关出血性膀胱炎的发生率、临床特征和影响因素。方法　回顾性分析2018年2月至2021年2月厦门大学附属中山医院62例输血依赖型地中海贫血儿童接受非亲缘造血干细胞移植后的临床资料,包括患儿年龄、人类白细胞抗原（HLA）相合程度、急性移植物抗宿主病（aGVHD）和慢性移植物抗宿主病（cGVHD）的发生以及与BKV感染的关联性。结果　14例（22.58%,14/62）发生出血性膀胱炎,尿液中均检出BKV感染,BKV copies最高达10⁷/ml,出血性膀胱炎与BKV感染符合率为100.00%。在预处理方案相同情况下,非亲缘全相合、移植物抗宿主病（GVHD）是发生BKV相关出血性膀胱炎的影响因素。结论　BKV感染是输血依赖型地中海贫血儿童非亲缘造血干细胞移植后发生出血性膀胱炎的主要原因,非亲缘全相合、GVHD是发生BKV相关出血性膀胱炎的影响因素。     

Bone marrow transplantation in adult thalassemia.

Early trials of allogeneic marrow transplantation for homozygous thalassemia were disappointing in patients older than 16, with four of six patients dying early of graft-versus-host disease-related complications, one patient dying at 9 months of infection due to graft failure, and one dying at 6 years of recurrent thalassemia. Three classes of risk could be identified in analyses of results of transplantation in younger patients using the criteria of degree of hepatomegaly, the presence or absence of portal fibrosis, and a history of adequate or inadequate chelation therapy. Patients for whom all three criteria were adverse constituted a very high risk group (class 3) for marrow transplantation. On the basis of these analyses, a conditioning regimen was designed that yielded superior results for class 3 patients under 17 years of age. Most patients older than 16 years presenting for transplantation have disease characteristics that place them in class 3 and, because of the improved results with the new class 3 regimen in younger patients, a study was designed to treat patients older than 16 years using treatment regimens assigned on the basis of disease class. Twenty patients were treated using this protocol and, with a minimum follow-up of 9 months, there have been three early deaths, one patient has recurrent thalassemia, and 16 patients are alive disease-free. The actuarial probabilities of survival, disease-free survival, and rejection are 0.85, 0.80, and 0.05, respectively, with a survival plateau extending from 6 months to 3 years. Marrow transplantation is a reasonable option for adults with progressive thalassemia who have suitable donors.     

Mixed chimerism after bone marrow transplantation for thalassemia major

Thirty-four thalassemia patients were studied for chimerism by fluorescent in situ hybridization or variable number tandem repeats after bone marrow transplantation. Mixed chimerism was detected in 9 patients with host cells ranging from 4 to 56%. One had graft rejection and the others were transfusion independent. Mixed chimerism was common but mostly without deleterious effect.     

Hematopoietic transplantation for bone marrow failure syndromes and thalassemia

Several genetic diseases, generally considered as congenital diseases, are characterized by bone marrow failure during early childhood. Hematopoietic stem cell transplantation is the only curative treatment for syndromes involving bone marrow failure and thalassemia. In this slate-of-the-art review, we wish to focus on the results of hematopoietic transplantation in treating some of these diseases, with a special emphasis on congenital bone marrow failure and thalassemia. The results of this procedure have improved over the previous years, mainly when performed by experienced teams. New conditioning regimes based on fludarabine and the use of HLA-identical donors have been related with better survivals. In the previous years, donors other than HLA-identical siblings have been increasingly used in patients not responding to conventional measures, but this approach needs to be evaluated in larger studies.     

Type 1 regulatory T cells are associated with persistent split erythroid/lymphoid chimerism after allogeneic hematopoietic stem cell transplantation for thalassemia

Background

Thalassemia major can be cured with allogeneic hematopoietic stem cell transplantation. Persistent mixed chimerism develops in around 10% of transplanted thalassemic patients, but the biological mechanisms underlying this phenomenon are poorly understood.

Design and Methods

The presence of interleukin-10-producing T cells in the peripheral blood of eight patients with persistent mixed chimerism and five with full donor chimerism was investigated. A detailed characterization was then performed, by T-cell cloning, of the effector and regulatory T-cell repertoire of one patient with persistent mixed chimerism, who developed stable split erythroid/lymphoid chimerism after a hematopoietic stem cell transplant from an HLA-matched unrelated donor.

Results

Higher levels of interleukin-10 were produced by peripheral blood mononuclear cells from patients with persistent mixed chimerism than by the same cells from patients with complete donor chimerism or normal donors. T-cell clones of both host and donor origin could be isolated from the peripheral blood of one, selected patient with persistent mixed chimerism. Together with effector T-cell clones reactive against host or donor alloantigens, regulatory T-cell clones with a cytokine secretion profile typical of type 1 regulatory cells were identified at high frequencies. Type 1 regulatory cell clones, of both donor and host origin, were able to inhibit the function of effector T cells of either donor or host origin in vitro.

Conclusions

Overall these results suggest that interleukin-10 and type 1 regulatory cells are associated with persistent mixed chimerism and may play an important role in sustaining long-term tolerance in vivo. These data provide new insights into the mechanisms of peripheral tolerance in chimeric patients and support the use of cellular therapy with regulatory T cells following hematopoietic stem cell transplantation.     

Sirolimus for GVHD prophylaxis in allogeneic stem cell transplantation

Sirolimus is a novel macrolide immunosuppressant widely used in solid organ transplantation. We have conducted three clinical trials using this compound as prophylaxis against GVHD after allogeneic stem cell transplantation. Our studies have demonstrated excellent GVHD control even when mismatched and unrelated donors were used. The morbidity and mortality associated with transplantation were reduced due to the omission or reduction in methotrexate dose. Furthermore, CMV reactivation and fungal infection rates were low. However, we have noted that sirolimus may be associated with increased rates of thrombotic microangiopathy after transplantation. Sirolimus has other uses, such as the treatment of established acute and chronic GVHD, and may be useful for treatment of post transplant lymphoproliferative disorder and perhaps as an antineoplastic agent against a wide variety of hematologic and solid neoplasms.     

造血干细胞移植治疗珠蛋白生成障碍性贫血

珠蛋白生成障碍性贫血(thalassemia)原称海洋性贫血或地中海贫血,是我国最常见的遗传性溶血性血红蛋白(Hb)病,是由于调控珠蛋白合成的基     

Practical considerations in the use of tacrolimus for allogeneic marrow transplantation

Tacrolimus has been shown to be more effective than cyclosporine for prevention of acute graft-versus-host disease (GVHD). A number of transplant centers have therefore adopted tacrolimus as standard prophylaxis, but with additional experience, current management of tacrolimus differs from that in the clinical studies. Therefore, a consensus conference was convened to assess the current practices. For prevention of GVHD, conference participants recommended administering tacrolimus at 0.03 mg/kg/day (by lean body weight) i.v. by continuous infusion from day -1 or -2 pretransplant, with day -2 used especially for pediatric patients. Therapeutic drug monitoring was considered essential in the management of patients on tacrolimus. The consensus target range for the whole blood concentration was 10-20 ng/ml. Doses were modified for blood levels outside the target range or for nephrotoxicity, and tacrolimus was discontinued for intolerable tremor, hemolytic uremic syndrome, leukoencephalopathy or other serious toxicity. Tacrolimus was employed most frequently in combination with minimethotrexate (5 mg/m2 i.v. days 1, 3, 6 and 11). Tapering was individualized according to center practice. No patient category was excluded from use of tacrolimus based on age, extent of disease, patient-donor histocompatibility or stem cell source. Tacrolimus was also used successfully for treatment of chronic GVHD. The responsiveness of steroid-refractory acute GVHD was marginal, so it was deemed more prudent to use tacrolimus for prophylaxis instead.