Introduction

α-Thalassaemia is one of the most common monogenic disorders, where an estimated 5% of the global population carry an α-thalassaemia variant [1, 2]. In Southeast Asia, the prevalence of α-thalassaemia is 23% [3], reaching up to 50% in countries such as United Arab Emirates, Oman, and Saudi Arabia [4]. Historically, haemoglobin Bart’s hydrops foetalis (homozygous α⁰-thalassaemia) was considered a universally fatal condition due to the intrauterine demise of affected foetuses.

In contrast, most patients with haemoglobin H (HbH) disease, do not experience significant symptoms. However, some patients with non-deletional mutations may experience a more severe clinical course and become transfusion-dependent, making them candidates for curative therapy [5].

In haemoglobin Bart’s hydrops foetalis, the absence of α-globin chain production leads to the development of erythroid cells that primarily consist of Hb Bart’s (γ₄) during foetal life, or HbH (β₄) in long-term survivors. Both HbH and Hb Bart’s have an exceptionally high affinity for oxygen, rendering them ineffective oxygen transporters [6]. Consequently, circulating HbH cells are considered non-functional. Unlike the ineffective erythropoiesis seen in β-thalassaemia patients, the predominant mechanism of anaemia in α-thalassaemia is extravascular haemolysis of erythroid cells within the splenic microvasculature [7, 8]. Therefore, even with regular transfusion regimens, patients with haemoglobin Bart’s hydrops foetalis (α-thalassaemia major) continue to display features of hypoxia and severe haemolysis.

Box

Despite the advances in pre-natal management of foetuses with haemoglobin Bart’s hydrops foetalis, surviving infants continue to face major and unique challenges after birth. Even with intrauterine transfusions, chronic transfusions are still (more...)

In the past, parents who received a prenatal diagnosis of haemoglobin Bart’s hydrops foetalis typically elected to terminate their pregnancy due to the severity of the disease and the limited universal availability of therapeutic options [11]. Over the past three decades, however, improvements in early prenatal diagnoses, such as the advent of in-utero transfusions (IUT), and advances in perinatal intensive care have enabled the survival of a growing number of children with this condition. This has led to an increase in the demand for more conclusive therapy.

Box

In contrast to α-thalassaemia, there is tremendous experience garnered with transplantation for β-thalassaemia over the past few decades. Despite the differences in the underlying pathophysiology, the current approach for transplant in (more...)

Allogeneic haematopoietic stem cell transplantation

Allogeneic haematopoietic stem cell transplantation (HSCT) is currently the only available curative option for patients with transfusion dependent α-thalassaemia. The principle of HSCT in thalassaemia is to substitute the ineffective or abnormal erythropoiesis with donor derived red blood cells that will produce adequate functional haemoglobin. The European Society for Blood and Marrow Transplant (EBMT) outlines transfusion dependency as a currently accepted indication for transplant in thalassaemia [12, 13], particularly when matched sibling donors are available. HSCT provides a potential cure for patients with thalassaemia and is a more cost-effective treatment than lifelong blood transfusion and chelation therapy [14].

Risk allocation

The largest reported study of patients with β-thalassaemia who had HSCT occurred in Pesaro, Italy. In 1990, Guido Lucarelli and the Pesaro group developed a pre-transplantation risk assessment scoring system to predict outcomes post-HSCT in thalassaemia, a hallmark for diseases with iron overload [15–17]. This system stratified patients into three risk classes based on the presence of hepatomegaly by physical examination, biopsy proven liver fibrosis, and adherence to regular iron chelation [18, 19] (Table 1). Several early reports showed outcomes after transplantation were significantly affected by the pre-transplantation risk status, where patients with Pesaro class III had the lowest overall survival and thalassaemia-free survival rates.

Table 1

Pesaro risk classification for predicting outcome of haematopoietic stem cell transplantation for thalassaemia major patients.

Outcomes of allogeneic HSCT in transfusion-dependent β-thalassaemia

The results of allogeneic HSCT for β-thalassaemia major have been thoroughly examined in large studies. Despite the differences in pathophysiologies between α- and β-thalassaemia, the valuable transplant experiences gained from β-thalassaemia, provides us with a framework when designing the transplant approach for patients with α-thalassaemia. The 2-year overall (OS) and event-free survival (EFS) in almost 1500 β-thalassaemia patients undergoing HSCT between 2000 and 2010 were 88 and 81%, respectively (Baronciani 2016). A more recent study demonstrated that OS and EFS were statistically higher in patients transplanted at <6 years vs > 16 years (90% vs 63%, 86% vs 63%, respectively) [26].

Box

Many institutions involved in thalassaemia transplantation have adopted transplants at an earlier age since initiating the transplant process before end-organ damage develops has been proven to improve outcomes. Considering thalassaemia is a progressive (more...)

Alternative donors and conditioning regimens

Although an HLA-matched sibling is the preferred donor, about 70% of patients who need allogeneic HSCT do not have a matched sibling and must rely on alternative donors [29]. Racial disparities influencing donor availability have been described where the probability of finding a match within the US registry is estimated to be 0.93 for Whites, 0.82 for Hispanics, 0.77 for Asian Americans and 0.58 for Blacks [30, 31]. More recently, as ethnic diversity continues to increase, there has been an increase in transplants utilizing unrelated and haploidentical donors [32].

Box

Recent advances in the haploidentical transplant (haplo-HSCT) platforms, particularly the development of in vivo and ex vivo T cell depletion, and the application of post-transplantation cyclophosphamide (PTCy) have drastically improved outcomes [33]. (more...)

Traditionally, the standard conditioning regimen implemented was a myeloablative dose of busulfan (Bu) and cyclophosphamide (Cy) which resulted in sustained donor myeloid engraftment. This however was associated with infertility as well as potential significant organ toxicity as well as a long-term burden on HSCT survivors. Reduced toxicity conditioning (RTC) regimens have since been trialled using the addition of fludarabine (Flu) and/or thiotepa (TT) to Bu and Cy or treosulfan with good results [38–40]. Pharmacokinetic model-based dosing of conditioning agents has also been used to reduce cumulative drug exposure and lower toxicity [41].

Sequential immunoablative pre-transplant regimen of fludarabine and dexamethasone, in conjunction with hyper-transfusion and chelation, is one of the novel approaches developed by Anurathapan et al. to establish stable graft function while lowering toxicity [39]. This regimen has demonstrated outstanding results in class III patients who typically had higher transplant related mortality (40%) and rejection rates (~16%). These results were similarly seen when using both matched unrelated and haploidentical donors [39, 42]. Using the risk features identified in previous studies has allowed tailoring donor choice and conditioning regimens in high-risk recipients. The results of transplantation have consequently grown more comparable across risk categories [43].

GVHD prophylaxis

Box

Improvements in the prevention and management of graft-versus-host disease (GVHD) and induction of graft tolerance have encouraged the use of alternative donors as well. Newer targeted agents, such as co-stimulation blockade, are being studied to prevent (more...)

Transplant in α-thalassaemia

Box

In 1998, the first transplant in severe α-thalassaemia was conducted in a 21-month-old girl from a matched sibling donor after conditioning with busulfan (Bu) and cyclophosphamide (Cy). Transfusion independence was achieved post-transplant despite (more...)

Summary of all previous transplants in α-thalassaemia

After the first case published in 1998, 16 additional children have undergone HSCT for α-thalassaemia (Table 2). Due to inadequate prenatal care or parental refusal to test, 6 of the 16 patients (38%) did not receive an antenatal diagnosis of thalassaemia. All these patients were born premature, had evidence of hydrops, and required intensive neonatal support. The remaining 10 patients, who had been antenatally diagnosed with Hb Bart’s, got intrauterine transfusions (IUTs); the earliest recorded start time was 24 weeks gestation. Five of these patients were delivered at term. Among the 10 patients, 6 were delivered vaginally, 2 were via C-sections, and the other 2 had no known method of delivery. In comparison to the patients who had not had IUTs, these patients had less hydrops, needed fewer interventions after delivery, and had higher median birth weights (2100g).

Table 2

Summary of patients who received allogeneic haematopoietic stem cell transplantation for alpha-thalassaemia.

Ten patients (63%) of the 16 recipients of a HSCT were younger than 24 months, with the youngest recipient being 5 months old (range, 5 months–13 years). Nine patients (53%) received a myeloablative, busulfan-based conditioning regimen with different agents including cyclophosphamide alone (5 patients), fludarabine/cyclophosphamide/thiotepa (1 patient), and fludarabine alone (1 patient). The remaining patients were divided into the following groups: 3 received total body or lymphoid irradiation-based conditioning, 1 received a regimen based on treosulfan, 2 were reported as receiving reduced intensity conditioning, but details were not available, and 3 were not reported. Regarding the stem cell source, 5 patients had a matched sibling donor (3 bone marrow grafts, 2 unknown), 5 had matched unrelated donors (2 peripheral blood stem cells, 1 bone marrow, 2 unknown), 2 received mismatched related cord blood cells, 2 received mismatched unrelated cord blood cells, 1 received a haploidentical TCRαβ/CD45 RA depleted maternal graft and 1 patient had an unknown donor and graft source. Most of the patients (62%) were reported to have received serotherapy with anti-thymocyte globulin (ATG). Seven patients were given cyclosporine and methotrexate based GVHD prophylaxis regimen, 1 received tacrolimus and mycophenolate mofetil (MMF), 1 received cyclosporine and MMF, 1 was only given ATG, and 6 were not reported. The eldest patient in this cohort, a 13-year-old, was the only reported death from transplant-related complications.

The median time to neutrophil engraftment was 19 days (range, 11–27 days). One patient (patient 14), who experienced primary graft failure, engrafted using CD34-selected peripheral blood stem cells on day 18 following the second transplant. Time to engraftment was not reported in 6 patients. Six patients achieved full donor chimerism, while 6 patients had stable mixed chimerism, and 4 did not have their chimerism data reported. One patient (patient 17) had declining chimerism down to 59% by day 112 but responded to 5 sessions of donor lymphocyte infusions (1x10⁷ cell/kg). One patient (patient 15) experienced secondary graft failure 7 months post-transplant and continued chronic transfusion and chelation. Otherwise, all the patients that engrafted, even those with mixed chimerism (lowest reported was 66.5%), attained transfusion independence. Of note, only 1 patient (patient 14) required 2 transplants: the first with matched unrelated donor cord blood and the second with CD34 selected peripheral blood stem cells. Corticosteroids were effective in treating the grade III-IV GVHD in 2 patients and grades 1-2 GVHD in 6 patients. Only 1 patient was reported to have developed severe and one patient to have developed mild veno-occlusive disease of the liver from those patients with known iron overload prior to transplant.

Long-term outcomes, post-transplant, were only reported in a subset of patients. Four of 14 (29%) patients that underwent successful engraftment and survived had short stature, and 4 of 14 (29%) had normal growth. Four patients showed mild developmental delays (intellectual disability and speech/language delay), and 3 patients had gross motor delays, 1 of which was stated to have improved by the age of 4. Six patients, of whom 5 had received previous IUTs, were able to reach normal developmental milestones. Five patients needed treatment for iron overload after transplant, the longest of which lasted for 4 years.

A minority of patients with other alpha thalassaemia mutations, such as HbH disease, may similarly benefit from curative therapies [5]. Most patients with HbH disease live normal lives. A small subset however may require regular transfusions for survival. There is a scarcity of data on such patients. Surapolchai et al. reported a case of an 8-year-old boy with transfusion-dependent non-deletional severe HbH disease (--SEA and α2 polyA deletions) who received conventional myeloablative conditioning regimen for HLA matched related HSCT, with a favorable outcome [47].

Box

Due to the variable phenotype of HbH, some people may develop transfusion dependence later in life despite a benign history in childhood. Additional manifestations including iron overload, osteopenia, splenomegaly, and biliary disease may still occur (more...)

It is noteworthy that the data presented above is made available from published case reports, which are inherently subject to publication bias. We recognize that there is a subset of patients with inferior transplant outcomes that may not have been captured in the literature.

Mixed chimera

Box

The level of donor chimerism needed to achieve transfusion independence in patients with thalassaemia post-transplant is not defined. Mixed chimerism (MC) is characterized by the simultaneous presence of donor derived cells and residual host cells (RHCs) (more...)

The persistence of RHCs at >25% in the early post-transplant period, within 2 months, has been linked with a 40% increased risk of thalassaemia recurrence [50, 51]. Nevertheless, patients with persistent mixed chimerism (PMC), which is defined as a stable mixed chimerism for more than two years, were able to become transfusion independent even with >25% RHCs, without the risk of graft failure. PMCs are observed in about 10%–15% of thalassaemic transplanted patients, and even with as little as 20– 30% donor-derived nucleated cells, these patients are clinically cured [52].

In a study on split chimerism, Andreani et al. found that although the proportion of donor derived cells was equally distributed in the different cell lineages in both the peripheral blood and bone marrow, that was not the case for the erythrocyte compartment. Despite the presence of few donor-engrafted nucleated cells, the erythrocytes were almost completely of donor origin. This enrichment of donor RBC in the blood was not observed in erythroid precursors from the marrow, suggesting that the ineffective erythropoiesis that is presumably responsible for this phenomenon works at a later stage of erythroid development. Long-term observation demonstrated that even in the presence of very low percentage donor engrafted nucleated cells (<20%), patients may achieve a functioning graft status.

Extrapolating from the β-thalassaemia data, complete chimerism is likely not required for long term engraftment or attaining transfusion independence post-transplant in α-thalassaemia [53]. However, a distinctive feature in α-thalassaemia is the presence of high degree of erythropoiesis and futility of endogenous HbH cells in the setting of mixed chimerism. While theoretically mixed chimera would entail a lower level of “functional” haemoglobin than the value reported, there is still no existing data to recommend an acceptable chimerism threshold in the clinical setting in the absence of transfusion dependence.

Box

HSCT is the only curative option to date for α-thalassaemia survivors. Patients with α-thalassaemia may require earlier intervention than those with β-thalassaemia as adverse effects of α-thalassaemia starts as early as (more...)

Long-term follow-up after HSCT

Haematopoietic stem cell transplantation, as opposed to supportive blood transfusions, gives patients with thalassaemia the possibility of definitive cure. Caocci et al. reported that the 30-year survival of thalassaemia patients after HSCT was similar to that expected in thalassaemia patients treated with blood transfusions and iron chelation (85.3% vs 82.6%) [54]. Most patients surviving HSCT were cured from thalassaemia (94.2%) [54]. A systematic review by Zhai et al., found that the quality of life (QOL) of patients with β-thalassaemia after HSCT from a sibling donor is higher than that of patients that received blood infusion and iron-chelating therapy [55]. HSCT survivors were found to have a QOL as good as that of a healthy population and the ability to return to normal life. These studies however did not include a large sample size and were limited in terms of donor type and source [55].

The survival of patients who have received treatment has significantly improved because of improvements in transplantation platforms and supportive care practices. However, HSCT survivors remain at risk for developing long-term complications, such as effects on growth, fertility and endocrinopathies among others. The risk of these complications is influenced by pre-HSCT health status and therapeutic exposures, transplantation-related conditioning, and post-transplantation management of GVHD [56].

Systematic monitoring and follow-up are essential for managing potential long-term consequences of HSCT and the residual symptoms of pre-HSCT disease. Late complications vary with age and disease status at HSCT and with transplant variables such as preparative regimen, donor source, human leukocyte antigen (HLA) compatibility, and immune reconstitution. Patients may still require iron reduction therapy post-HSCT with either regular phlebotomy or iron chelators to prevent complications related to iron overload. An international guideline, published in July 2018 and titled “Late Effects Screening Guidelines after Haematopoietic Cell Transplantation (HCT) for Haemoglobinopathy: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT”, summarizes the consensus on long-term follow-up guidelines after HCT for haemoglobinopathy [57].

Conclusion

Haemoglobin Bart’s hydrops foetalis (α-thalassaemia major) was once considered to be fatal. The recent advancement of transplant-care has transformed the landscape for these patients, with transfusion independence and provision of an improved quality of life. With allogeneic HSCT currently being the only potential cure, it is crucial to continue to develop strategies to improve transplant-related outcomes. Meanwhile, transplant of children with haemoglobin Bart’s hydrops foetalis (α-thalassaemia major) should be performed early to reduce the risk of transplant-related morbidity and other complications. The clinical expertise in transplant for α-thalassaemia remains derived from β-thalassaemia protocols despite a clear distinction in disease pathobiology. A different approach for α-thalassaemia may perhaps be warranted and may prove to be even more successful. Until further data is available, however, it is advised that the transplant approach for α-thalassaemia should be based on what has been established for β-thalassaemia.

Summary and recommendations

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