Hematopoietic stem cell transplantation for children with β-thalassemia major: multicenter experience in China

Thalassemia is the most common single-gene disorder worldwide and is considered a major public health issue. β-Thalassemia major (β-TM) occurs in homozygous or compound heterozygous states for β-hemoglobin gene mutations that either reduce (β⁺-thal) or abolish (β⁰-thal) expression of the affected β-globin genes [1]. The patients require long-term regular blood transfusions and chelation therapy, and children with untreated or partially treated β-TM die in the first or second decade of life [2]. β-TM has become a public health problem in mainland China. In the 1980s, a large-scale survey of hemoglobinopathies was carried out [3]. In recent years, 13,397 samples from Guangdong Province have been analyzed for both hematological and molecular parameters showing a high prevalence of carriers of α-thal (8.53%), β-thal (2.54%), and both α- and β-thal (0.26%) [4]. Hematopoietic stem cell transplantation (HSCT) has remained the only cure for β-TM [5] since the first bone marrow transplantation (BMT) for β-TM reported in December 1981 [6]. This expensive procedure was not successfully performed in mainland China until 1998 [7]. In China, many patients with β-TM cannot afford life-long regular blood transfusions and iron chelation. Although HSCT is expensive, it is a one-time treatment that is possible for some patients. Due to differences in medical, socioeconomic and cultural situations, there is wide variation in the treatment of β-TM between developed and developing countries. The disease-free survival rates after HSCT have ranged 52–82% in China [8‐12]. The majority of patients with β-TM are distributed throughout southern China and HSCT is performed by several qualified hospitals. Each center has reported a few cases, though most are without systemic analysis [8‐10, 12‐15]. To provide a comprehensive review of the outcomes of children receiving HSCT for β-TM in China, the present study retrospectively analyzed the data from children receiving HSCT for β-TM between 1998 and 2009 in a multicenter study group of the Pediatric Branch of the Chinese Medical Association.

In our study, BMT has been proven to be the safest and most efficient technique for treating β-TM. However, in cases of younger sibling donors and unrelated donors, the bone marrow volume harvested is usually limited. Other types of grafts and combined transplantation were considered and developed. UCBT, which used to be popular in China due to its low cost and less traumatic procedures, has been used to cure leukemia with outcomes similar to those of sibling donor transplantation, as reported previously by our study group [18]. However, the situation was exactly the opposite in β-TM, as shown by the results. Compared with reports from other centers, UCBT in mainland China did not provide equivalent outcomes. According to the previous reports in mainland China, most UCBT recipients achieved autologous recovery or eventually died of complications; by contrast, the implantation after PBSCT was much better [8]. Global data have suggested that UCBT from related donors had similar engraftment levels compared to BMT but lower incidences of GVHD, which further promoted the use of UCBT in treating β-TM [19‐22]. Similar to the global experience, doctors from Taiwan District reported their experiences with UCBT in 2009, suggesting that an adequate NC count was the key to successful UCBT [23]. In 2012, researchers in Taiwan of China presented another informative single-center experience reporting that the most important risk factors for a poor prognosis were iron overload and the elevated panel-reactive antibody (PRA) caused by hypertransfusion. Thus, they recommended the use of UCBT at a young age, when the transfusion volume is not large [24]. Researchers from Europe claimed that the NC was not relevant to the outcome. UCBT from unrelated donors resulted in lower TFS (21%), whereas UCBT from matched sibling donors had a similar TFS to that of BMT [22]. However, in the UCBT group, related donor transplantation did not produce more favorable TFS results compared to unrelated donor transplantation (related donor versus unrelated donor: 55.6 ± 12.6 versus 20.0 ± 17.9%, P = 0.217). According to a retrospective study, graft rejection after UCBT may be related to conditioning regimens and GVHD prophylaxis. The use of MTX for GVHD prophylaxis was associated with a greater risk of treatment failure [21]. In the present study, NC and the use of MTX were controlled as recommended but graft failure was still the major cause of UCBT failure. The conditioning regimen, elevated PRA and cellular activities of UCB were presumed to be the main reasons.

Before 2000, most patients accepted whole-blood transfusions without white cell depletion, which induced elevated PRA levels and thus increased the risks of graft rejection and interfered with stem cell proliferation [25]. Furthermore, irregular and inadequate transfusions led to the expansion of bone marrow and extramedullary hematopoiesis. Hypertransfusion and the suppression of hematopoiesis have proven to be successful in improving engraftment [26, 27]. However, due to the limited blood resources in mainland China, more relatives were needed as blood donors to the recipients when hypertransfusion was required, inducing elevated minor histocompatibility antigen alloimmunization as well as rejection incidence and primary graft failure [28, 29]. Overcoming extramedullary hematopoiesis without stimulating PRA is probably the major task for controlling the incidence of complications.

As reported lately, the appropriately modified conditioning regimen can successfully improve the outcomes of class 3 recipients [30]. For the impaired heart and liver functions of class 3 recipients, these patients had difficulty tolerating the intensified conditioning regimen that was previously recommended [31‐33]. The BUCYATG + Flu + Hu conditioning regimen has been performed since 2001. This modified protocol in the retrospective cohort has shown improvements in disease-free survival and reductions of treatment-related mortality in high-risk patients. Before transplantation, patients, especially those who tended to be high risk, strongly required regular transfusions and iron chelation, which tend to reduce extramedullary hematopoiesis. Unlike in Protocal 26 reported by Sodani et al. from Italy [26], granulocyte colony-stimulating factor, erythropoietin and growth factor were not provided to recipients due to the inconvenient procedures. By contrast, the comparably shorter courses of Hu and Aza prevented outpatient infections and severe liver damage. This new and simple conditioning regimen should be promoted, and further study should be conducted to conclusively demonstrate its efficiency and safety.

Previous studies recommended intensified conditioning regimens for Asian populations. Increasing the dose of Bu to 20 mg/kg [34] and the addition of Mel and TT [13] both helped to decrease the rejection rate. Those conditioning regimens that were not sufficiently intensified were not able to maximally eliminate marrow and extramedullary hematopoiesis, which might explain why the BUCYATG conditioning regimen did not achieve the highest TFS among the three groups. The recipient’s T lymphocytes, which may be responsible for the rejection of a donor’s grafted cells, are effectively depleted by ATG, but the value of including ATG in conditioning regimens is still controversial [17, 19, 26, 27, 35‐37]. In the present study, all but two patients accepted ATG-containing conditioning regimens for the most intensive depletion of recipient T lymphocytes without the use of other T cell-depleting agents. The use of ATG in HSCT from different donors and different types of grafts should be further investigated, and designing an accurate regimen for each individual would be an important step toward successful HSCT.

In conclusion, in HLA-matched HSCT for β-TM performed between 1998 and 2009, probabilities of 5-year accumulated OS and TFS found in this study were 83.1 ± 6.9 and 67.3 ± 7.9%, respectively. GF was the main cause of transplantation failure, especially in UCBT. UCBT from related donors did not produce favorable TFS. For patients with β-TM in mainland China, a variety of factors affecting OS and TFS after HSCT seem to exist. A suitable conditioning regimen is a key factor for the success of HSCT. The modified myeloablative regimen of BUCYATG + Flu + Hu warrants further clinical study, and the combined transplantation of UCB and BM could improve the prognosis of UCBT. However, this was a non-prospective and non-randomized study, and the conditioning regimens and GVHD prophylaxis were too heterogeneous to allow robust conclusions. We strongly recommend conducting a prospective randomized clinical trial to evaluate risk factors and the new protocols. We also recommend increased attention to be directed toward the quality of life of post-HSCT patients.