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Inherited and Genetic Disorders

Hematopoietic stem cell transplantation for homozygous β-thalassemia and β-thalassemia/hemoglobin E patients from haploidentical donors


Thalassemia-free survival after allogeneic stem cell transplantation (SCT) is about 80–90% with either matched-related or -unrelated donors. We explored the use of a mismatched-related (‘haplo- ’) donor. All patients received two courses of pretransplant immunosuppressive therapy (PTIS) with fludarabine (Flu) and dexamethasone (Dxm). After two courses of PTIS, a conditioning regimen of rabbit antithymocyte globulin, Flu and IV busulfan (Bu) was given followed by T-cell-replete peripheral blood progenitor cells. GvHD prophylaxis consisted of cyclophosphamide (Cy) on days SCT +3 and +4 (post-Cy), and on day SCT +5 tacrolimus or sirolimus was started together with a short course of mycophenolate mofetil. Thirty-one patients underwent haplo-SCT. Their median age was 10 years (range, 2–20 years). Twenty-nine patients engrafted with 100% donor chimerism. Two patients suffered primary graft failure. Median time to neutrophil engraftment was 14 days (range, 11–18 days). Five patients developed mild to moderate, reversible veno-occlusive disease, while nine patients developed acute GvHD grade II. Only five patients developed limited-chronic GvHD. Projected overall and event-free survival rates at 2 years are 95% and 94%, respectively. The median follow up time is 12 months (range, 7–33 months).


Thalassemia is a hemoglobinopathy which, in its more severe forms, has a quite poor prognosis. Patients with severe thalassemia commonly suffer disease-related morbidities, and their survival is on average about 20 years without state of the art supportive care.1 The only curative treatment is allogeneic hematopoietic stem cell transplantation (allo-SCT).2, 3 Allo-SCT is cost effective compared with the conventional transfusion support and chelation therapy for severe thalassemia patients.4, 5 However, the probability of finding a histocompatible-related or -unrelated donor is <50%. These patients also have an active, or even hyperactive immune system, and the use of chronic blood transfusions as part of standard management contribute to allo-immunization against donor-specific HLA antigens. This translates into a high risk (HR) for both regimen-related mortality and for graft rejection, typically in the range of 5–30%, even if a highly immunosuppressive myeloablative conditioning program is used.2, 6, 7, 8, 9

We recently reported an alternative strategy; we hypothesized that a pharmacological pretransplant immunosuppressive (PTIS) program, based on fludarabine (Flu), given in combination with dexamethasone (Dxm), would immunosuppress the patients to facilitate engraftment when it was followed by a reduced-toxicity conditioning (RTC) regimen consisting of ‘early’ rabbit antithymocyte globulin (ATG) and Flu with IV busulfan (Bu) to prepare HR thalassemia patients for allo-SCT. Further, we employed a high dose of peripheral blood progenitor cells (PBPC) rather than bone marrow to be able to consistently target a large number of CD34+ progenitor cells in the graft. This strategy has been working well; so far all the patients (n=26) who had at most one HLA antigen-mismatched donor engrafted,10, 11 and ultimately it resulted in an event-free survival (EFS) of over 90%. In contrast to previous reports, we found no increased risk for (serious) treatment-related complications associated with unrelated donors.10, 11 Our data indicated that this new approach would be an improvement over the existing allo-SCT standard of care when applied with HLA-compatible donors.

In addition, there is a rapidly increasing interest in using alternative donor stem-cell sources, primarily cord blood cells or grafts from haplo-identical-related donors (haplo-SCT). This strategy has mostly been investigated for advanced leukemia/lymphoma patients lacking matched donors. In a later development, some investigators reported excellent outcomes in patients with hematologic malignancies using various conditioning programs followed by T-cell-replete/unmanipulated marrow or PBPC12, 13, 14, 15, 16 and post-transplant GvHD prophylaxis based on cyclophosphamide (post-Cy).12, 13, 14, 15

Until now, there have been only two studies that reported on haplo-SCT in patients with hemoglobinopathies; in one, the investigators used reduced-intensity conditioning with haplo-SCT and GvHD prophylaxis with post-Cy in patients with sickle cell anemia (SCA).17 This trial had a high incidence of graft failures and unstable mixed chimerism, necessitating long-term immunosuppressive therapy. It was still deemed successful, as no patient died acutely after the conditioning or in the early post-transplant phase.17 In the second investigation, a myeloablative regimen was followed by T-cell-depleted PBPC for thalassemia patients.18, 19 Both investigations reported an EFS of around 40–60%, and described more than 30% graft failures. The overall conclusion was that haplo-SCT is feasible in sickle cell anemia and thalassemia.

We hypothesized that our PTIS-based strategy could be extended to haplo-SCT, using T-cell-replete grafts, and suitably modified to include post-Cy-based GvHD prophylaxis. This would allow a parent or mismatched sibling to serve as stem cell donor, securing access to transplant therapy for virtually all patients with severe thalassemia. We further postulated that our modified strategy would allow consistent engraftment, yet carry a low risk of GvHD, and that it should provide long-term disease control. Initially we explored this approach to haplo-SCT in severe thalassemia; PTIS was followed by a modified Flu–IV Bu RTC regimen (adapted from Russell et al.20 and De Lima et al.21) incorporating post-Cy GvHD prophylaxis, the details are outlined in Figure 1. This manuscript summarizes our experience with this novel approach for the first 31 consecutive, severe thalassemia patients who did not have an available HLA-matched donor. We did not exclude any patient based on age alone, nor did we exclude any class 3 patients with hepatomegaly or iron overload (Table 1).

Figure 1

Depiction of the transplant program with first pharmacological PTIS, followed by RTC with ATG, Flu and IV Bu. For the haplo-identical donors, we used post-Cy-based GvHD prophylaxis and delayed-calcineurin inhibitor−/ sirolimus therapy, and short-course mycophenolate mofetil, the latter two starting on day SCT +5. Please see Patients and Methods section for details.

Table 1 Patient characteristics at transplantation for 31 thalassemia patients

Patients and methods

Inclusion criteria

Severe thalassemia patients, defined as thalassemia with onset of transfusion dependence during the first 3 years of age, a pretransfusion hemoglobin level 7 gm/dL, hepatosplenomegaly and thalassemia facies, and who did not have an HLA-compatible-related or -unrelated donor available, were eligible for treatment in this study. All severe thalassemia patients were confirmed by genotype study and had a history of blood transfusion more than 225 mL/kg/year. Therefore, both homozygous β-thalassemia and β-thalassemia/hemoglobin E patients who met those criteria were included in this study. The class 3 patients were classified according to the criteria proposed by Lucarelli et al.2 Patients who were 7 years old and had a liver size 5 cm below the costal margin constitute what Mathews et al. and the Center for International Blood and Marrow Transplant Research working group defined as a very HR subset of a conventional HR class 3 group.9, 22 This subset of class 3 HR patients has an excessive risk of graft rejection and regimen-related toxicity, especially veno-occlusive disease, leading to multiorgan failure and death.9, 22 However, based on our favorable results using HLA-matched donors,10, 11 we decided to include class 3 HR patients in this trial. All patients’ care givers/parents gave written informed consent to participate in this trial according to institutional guidelines.

Either parent, who did not have a clinical hemoglobinopathy, and who was generally in good health was volunteered as the stem cell donor. The parent with fewest HLA allele mismatches was favored (HLA high-resolution typing; A, B, C, DRB1 and DQB1). If the degree of allele mismatch between the patient and both parents was same, the mother was favored as the donor.23, 24 Samples for donor-specific anti-HLA antibodies were obtained and analyzed from all of the patients; blood component transfusion therapy is a part of conventional management for thalassemia, and frequently contributes to the development of donor-specific anti-HLA antibodies that contribute to graft failure.25, 26 We did not make any modification to the program based on HLA antibody titers, as we did not have any data supporting such alteration beyond the modifications described, including the PTIS to accommodate the patients’ generally high immunoreactivity, and that necessitated by using a T-cell-replete haplo-SCT with post-Cy. Detection of antibodies was performed using a single antigen bead assay (Lambda, Canoga Park, CA, USA) according to the manufacturer’s instruction. The beads were analyzed on the Luminex (Bio-Rad, Hercules, CA, USA). The cut-off for a positive reaction was set at the normalized mean fluorescence intensity value 1000.

PBPC were collected after filgrastim administration. The PBPC collection target was set at 10 × 106 CD34+ cells/kg recipient body weight.

Pharmacological PTIS and RTC therapy

All HR (class 3) patients received hydroxyurea 20 mg/kg/day daily for at least 3 months to decrease erythroid marrow expansion, and chelation therapy for iron overload before starting the PTIS.

The PTIS, the RTC regimen and all supportive care procedures have been described.10, 11 The program was modified as follows to facilitate the use of highly HLA-disparate donors (Figure 1):

Phase I: Sequential pharmacological PTIS

The PTIS consisted of Flu 40 mg/m2/day IV together with Dxm 25 mg/m2/day IV, each for a total of 5 days, and administered in two courses on days SCT −68 to −64 and on days SCT −40 to −36, to suppress recipient T-cell function and facilitate engraftment. Figure 1 summarizes the timing and sequence of events during the program.

Phase II: RTC regimen and GvHD prophylaxis based on post-transplant-Cy

We administered ‘early’ ATG (Thymoglobulin; Sanofi-Genzyme Canada, Ontario, CA, USA), 1.5 mg/kg/day on days SCT −12 to −10. The conditioning chemotherapy consisted of Flu 35 mg/m2/day IV over 60 min once daily on days SCT −8 to −3, each dose of Flu was followed by IV Bu 130 mg/m2 IV over 3 h once daily on days −8 to −5. The GvHD prophylaxis consisted of Cy 50 mg/kg/day on days SCT +3 and SCT +4, and on day SCT +5 tacrolimus or sirolimus was started (total administration time: 6–12 months), together with mycophenolate mofetil, 15 mg/kg orally twice daily for 60 days.

Supportive care

All patients received penicillin V and ciprofloxacin as antibacterial prophylaxis, together with an antifungal agent, starting on day SCT +5, and continued through the end of immunosuppressive medications. Standard Pneumocystis jiroveci and anti-HSV/VZV prophylaxis was given for 1 year. Patients were monitored for CMV, adenovirus and BK-virus reactivation through PCR measurement of viral copy numbers in plasma and urine. Preemptive therapy with ganciclovir was initiated when CMV reactivation was detected and cidofovir was used when adenovirus or BK virus was detected in plasma, or in urine together with clinical symptoms of hemorrhagic cystitis. Patients with a viral load 1000 copies/mL were preemptively treated as described above.

Chimerism studies were performed on peripheral blood on the day of engraftment, then every 2 weeks till day SCT +100, monthly until 1 year post-transplantation and then every 3 months. Chimerism was measured by PCR-based analysis of variable number of nucleotide tandem repeats. Alternatively, when there was a sex mismatch between patient and donor, we employed FISH analysis of XX/XY ratios in a few patients who had a sex-mismatched donor.27

Survival probability after transplantation was estimated as described.28 The significance of difference between survival curves was estimated by log-rank test.


Thirty-one patients received haplo-SCT. The clinical characteristics of patients and donors are reported in Table 1. The patients’ median age was 10 years (range, 2–20 years), and only 9 were younger than 7 years. Four patients had homozygous β-thalassemia and 27 had β-thalassemia/hemoglobin E. As incidence of β-thalassemia/hemoglobin E in Thailand and Southeast Asia is higher than homozygous β-thalassemia, most of our patients were β-thalassemia/hemoglobin E. Fifteen subjects had clinical HR class 3 disease, their median age was 15 years (range, 10–20 years).2, 3, 9, 10, 11, 22 One of the 31 patients had haplo-SCT as a second SCT. This patient had endured a matched-related donor transplant, complicated by primary graft failure with autologous marrow reconstitution 3 years before the current haplo-SCT (Table 1, patient UPN 14). We decided to perform haplo-SCT for this patient as her previously used matched-related donor was unavailable, and likewise, there was no matched-unrelated donor available. Eleven patients received PBPC from the father and 20 patients from the mother. Fifteen patients received a 5/10 HLA allele-matched graft, 8 patients received a 6/10 HLA allele-matched graft, 7 patients received a 7/10 HLA allele-matched graft and 1 patient received a 8/10 HLA allele-matched graft.

No patient developed any complications/side effects during or following the PTIS treatment phase. During this time, they were evaluated weekly in the outpatient clinic. All patients were admitted to the inpatient unit on day −13 before starting ATG as part of the conditioning program.

After completion of the conditioning program the T-cell-replete PBPC were given. The median CD34+ cell dose was 11.6 × 106 cells/kg body weight (range, 4.0–19.0 × 106). The median time to neutrophil engraftment in 29 evaluable patients was 14 days (range, 11–18 days). Median time to platelet engraftment of 20 × 109/L was 30 days (range, 20–45 days). All patients had donor-specific anti-HLA antibody testing performed and three of them had high antibody titers (>1:3000), two of whom suffered primary graft failure. Both patients received additional immunosuppression with Flu and Cy followed by a boost of PBPC to facilitate engraftment. One of them engrafted successfully, but unfortunately developed grade IV GvHD and later died. The second patient had autologous marrow recovery and is alive, stable, 14 months post-allo-SCT.

Eleven patients got grade I–II mucositis and three grade III mucositis. Five patients developed mild to moderate veno-occlusive disease,29, 30 all of which resolved with supportive care measures. Six patients had CMV reactivation. Four patients got BK-virus cystitis and two patients developed adenovirus cystitis. Finally, one patient reactivated herpes zoster. All viral infectious episodes resolved with therapy. Two patients had gram-negative septicemia, which responded to appropriate antibiotic therapy.

Nine patients developed grade II acute GvHD that resolved with steroids, one patient had severe, grade IV, acute GvHD, followed by a second PBPC infusion as described above. Five patients developed limited-chronic GvHD. All surviving patients who developed GvHD were off systemic immunosuppression within 6–12 months after SCT.


The 2-year overall survival (OS) and EFS were 95% (95% confidence interval; 69.5–99.3%) and 94% (95% confidence interval; 76.6–98.4%), respectively (Figure 2). One patient died of GvHD complications, as described above. The median follow up of surviving patients is 12 months (range; 7–33 months). No other patient died of complications, and we have so far not had any secondary graft failure(s).

Figure 2

EFS and OS of 31 thalassemia patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-SCT).


Allo-SCT provides the only definitive solution to the serious, long-term complications of severe thalassemia. It is also cost effective in view of recent developments that lower the risk for serious posttransplant complications.4, 5, 10, 11 Most of the literature reports a thalassemia-free survival after allo-SCT of class 3 patients with complicating features, such as higher age and hepatomegaly, that ranges from about 50% to 80–90%, depending on whether matched-related or -unrelated donors were used.2, 6, 8, 9, 31, 32, 33 Early transplant related mortality typically ranges from 5 to 20% and the risk of graft failure is of a similar magnitude. Because of the risk for transplant related mortality and for graft failure in patients who have a serious, albeit non-malignant disease, we introduced a conceptually new approach; we use an initial pharmacological PTIS phase consisting of Flu and Dxm, followed by a reduced-toxicity Flu–IV Bu conditioning program.10, 11 All patients in our initial cohort who had matched-related or -unrelated donors engrafted, assessed by full donor chimerism within the first 60 days. The only deaths among those first 26 patients were from a fungal infection (one patient) and a motor cycle accident (one patient). Both events occurred several months after stable engraftment and we have not encountered any secondary graft failures. The conditioning regimen itself was adapted from our standard nucleoside analog-alkylating agent platform.20, 21 The excellent tolerance to the program and consistent, stable engraftment encouraged us to revise it and incorporate post-Cy-based GvHD prophylaxis to allow the use of related-haplo-identical donors.12, 14 We use T-cell-replete grafts, which facilitate rapid engraftment and convenient processing of the progenitor cell product. The preamble of our new strategy included that we should have <10% graft failures, and low transplant related mortality, preferably <5% in the first year post transplantation. These assumptions were adapted from the European Group for Blood and Marrow Transplantation (EBMT) expert panel’s recommendations regarding management and treatment outcome after allo-SCT for severe thalassemia.3 Our anticipation was that the use of an alternative donor should not decrease the program’s expected success rate. Thus, we must demonstrate ‘non-inferiority’ when using haplo-identical compared with HLA-matched donors, similar to what is being advocated for using alternative donors for leukemia patients.16, 34, 35 This will be necessary for the proposed strategy to be considered a valid alternative to more commonly used treatments. Further, our program demonstrates two features that contrast with what commonly accepted views regarding allo-SCT for severe thalassemia. First, older patients (more than 7 years), with hepatomegaly and other comorbid conditions, who were hitherto considered as being at too HR for transplant related mortality,9, 22 can now be safely treated even if there is only a haplo-identical-related donor available. Second, the risks of graft failure and other serious complications appear no higher than what is considered acceptable for standard-risk patients having a matched-related donor.3, 10, 11, 32, 33 When we compared our outcomes of haplo-SCT with that of our patients transplanted with matched-related or -unrelated donors,10, 11 the results are very similar. Our results obtained with PTIS and Flu–IV Bu overall support the notion of a significantly decreased host-immunologic function that facilitates engraftment regardless of donor type.

We hypothesize that the two patients who suffered primary graft failure had this event caused primarily by their high titers of donor-specific anti-HLA antibodies.25, 26 In the first patient this may have been compounded by excessive busulfan clearance, indirectly testified by his autologous marrow recovery, which is otherwise something not typically seen at myeloablative IV Bu dosing. However, it has been described in thalassemia patients who have significantly altered glutathione-S-transferase(s) activity leading to increased Bu clearance.36 The second patient was appropriately myeloablated, but received by far the lowest CD34+ cell dose in her first infusion (Table 1). She engrafted rapidly after a PBPC boost, but unfortunately developed severe, lethal, acute GvHD. We suggest that the combined effects of high titers of donor-specific HLA antibodies and these additional factors may be responsible for primary graft failure. Prospectively we intend to implement pharmacokinetic dose guidance of Bu, such that a consistent and reproducible systemic target exposure can be ascertained regardless of individual differences in metabolic Bu handling.7, 8, 14, 37, 38, 39 Such a strategy should allow optimization of the delivered dose to assure long-term stable engraftment while minimizing the risk for excessive toxicity.38, 39, 40 We will also implement strategies to more effectively eliminate host plasma cells and memory B-cells, and to eliminate preformed anti-HLA antibodies during the PTIS phase.41

In conclusion, the present study demonstrated that outcomes after haplo-SCT in patients with severe thalassemia are acceptable. The key success factors in our new program are pharmacological PTIS, followed by a Flu–IV Bu RTC program, supplemented with ‘early’ ATG and post-Cy-based GvHD prophylaxis. Engraftment is further facilitated by a large number of T-cell-replete PBPC. This resulted in a low incidence of serious complications, with rapid and durable engraftment, yet a low risk for serious acute GvHD in this group of mostly HR class 3 thalassemia patients. Once the early findings are confirmed in a larger series of patients, our program design will expand the patient population that can be offered SCT by several fold. Additionally, the program can be adapted to accommodate patients with sickle cell anemia and other non-malignant diseases (Hongeng et al., in preparation, 2015).


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This work was supported in part by grants from the Ramathibodi Foundation, the National Research University Grant, the Mahidol University Research Grant, the Office of the Higher Education Commission and Mahidol University under the National Research University Initiative, Thailand Research Fund, Research Chair Grant from the National Science and Technology Development Agency (NSTDA) and the National Institutes of Health of United States (CCSG CA16672).

Author contributions

SH and BSA designed the research. SH, SP and UA performed the research. SH, UA, RS and BSA analyzed the data and performed the statistical analyses. SH, SP, UA, RS and BSA wrote the manuscript. NS, DS, AC, PC, AJ, KS, PR, AM, YL, PI, PS, WS, SS, PA, AU and SI enrolled the patients.

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Correspondence to S Hongeng or S Pakakasama.

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The authors declare no conflict of interest.

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Anurathapan, U., Hongeng, S., Pakakasama, S. et al. Hematopoietic stem cell transplantation for homozygous β-thalassemia and β-thalassemia/hemoglobin E patients from haploidentical donors. Bone Marrow Transplant 51, 813–818 (2016).

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