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Volume 1 (2018) Issue 1 No.2 Pages 9-17

Review Article
Recent advances and current challenges in allogeneic stem cell transplantation in patients with acquired severe aplastic anemia
Sung-Eun Lee and Jong Wook Lee

Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Maryʼs Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Key words
severe aplastic anemia, hematopoietic stem cell transplantation, age, conditioning regimen, iron overload
Submitted:March 6, 2018
Accepted:May 19, 2018
Published online:August 29, 2018
Issued online:November 25, 2018

Abstract

Allogeneic stem cell transplantation (SCT) from a human leukocyte antigen (HLA) -matched sibling donor (MSD-SCT) is the preferred first-line treatment option for young patients with severe aplastic anemia (SAA). However, only 25% of patients may find an HLA-MSD. SAA patients, who lack a suitable MSD and fail first-line immunosuppressive therapy, may consider SCT from an unrelated donor (URD-SCT) as a treatment option. The results of haplo-identical stem cell transplantation from a related mismatched donor (Haplo-SCT) have improved due to recent advances in controlling graft failure and graft-versus-host disease (GVHD). The use of Haplo-SCT has recently been extended to SAA patients. However, it is important for physicians to select the appropriate conditioning regimen and GVHD prophylaxis to ensure engraftment with reduced toxicity, such as infectious complications and GVHD.

This review summarizes recent advances in allogeneic SCT for patients with acquired SAA. Current challenges, including the age of the patients and the effects of donor age, stem cell source, and iron overload on transplantation outcomes are also discussed.

Introduction

Aplastic anemia (AA) is an immune-mediated clinical syndrome characterized by fatty replacement and decreased number of hematopoietic precursors in the bone marrow (BM), resulting in peripheral pancytopenia1. Allogeneic stem cell transplantation (SCT) from a human leukocyte antigen (HLA) -matched related donor (MSD-SCT) is the preferred first-line treatment option for young patients with severe AA (SAA), whereas immunosuppressive therapy (IST), mainly based on antithymocyte globulin (ATG) with cyclosporine A (CSA), is an alternative option for other patients2. However, patients who fail to achieve hematological response after IST are considered for SCT from unrelated donors (URD-SCT)3 and other alternative stem cell sources, including unrelated cord blood (CB) or haplo-identical related mismatched donors (Haplo-SCT)4.

This review article summarizes recent advances in allogeneic SCT for patients with acquired SAA, with the exception of CB transplantation. Current challenges, including the age of patients and the effects of donor age, stem cell source, and iron overload on transplantation outcomes are also discussed.

Transplantation from HLA-matched sibling donors

MSD-SCT is an established treatment for young patients with acquired SAA5-7. In a study by the European Group for Blood and Marrow Transplantation (EBMT), failure-free survival (FFS) was compared between patients receiving first-line MSD-SCT and first-line IST8. Young patients (<20 years) with low neutrophil count benefited from first-line MSD-SCT, whereas patients over 40 years old with higher neutrophil count did not. Patients with intermediate age (21-40 years old) and average neutrophil count had comparable survival irrespective of the type of first-line therapy. Similar results were observed in an extended group of patients with SAA from the EBMT Registry9.

Regarding the conditioning regimen for SAA patients who receive MSD-SCT, many protocols have been explored for successful engraftment with minimal complications, mainly graft-versus-host disease (GVHD). In an initial attempt of conditioning with cyclophosphamide (Cy) alone, graft failure remained a significant concern, particularly in previously transfused patients10. The subsequent addition of radiation to the conditioning regimen resulted in lower rates of graft failure10-13; however, these radiation-based regimens were also associated with higher transplantation-related long-term morbidity and mortality12-14. Later, several investigators attempted a combination of ATG with Cy, which promoted both excellent engraftment and long-term outcome through adequate lymphoablation. Storb et al. reported excellent outcomes using Cy+ATG, with 95% engraftment, 15% acute GVHD, and 34% chronic GVHD. Overall survival (OS) rate at three years was 92% in 39 patients conditioned with Cy+ATG compared with 72% for 39 historical patients conditioned with Cy alone15 (Table 1). In a French retrospective study with 133 patients receiving MSD-SCT with Cy+ATG conditioning or Cy+thoracoabdominal irradiation (TAI), TAI was associated with higher rates of acute and chronic GVHD and lower OS compared to Cy+ATG5. Based on these results, Cy+ATG has been widely used as the standard conditioning regimen for MSD-SCT. However, transplantation-related mortality remains high in old patients administered this regimen. Champlin et al. did not find any significantly different outcomes between Cy alone and Cy+ATG7. More recently, EBMT examined the role of a fludarabine (Flu) -containing conditioning regimens16. In a retrospective analysis of 30 patients over 30 years old receiving MSD-SCT with a Flu-based conditioning regimen, patients conditioned with Flu had better OS than the standard regimen group (Cy±ATG) (P=0.04) when adjusting for recipient age. This might be due to considerably reduced incidence of primary graft failure in patients receiving Flu (0% vs. 11%, P=0.09) (Table 1). These results suggest that a Flu-based conditioning regimen might reduce the negative impact of age in old patients with SAA receiving MSD-SCT16,17 (discussed below in Current challenges).

Table 1. Reported outcomes of SAA patients who received MSD-SCT
GVHD, acute graft-versus-host disease; OS, overall survival; Cy, cyclophosphamide; ATG, anti-thymocyte globulin; TAI, thoraco-abdominal irradiation; NA, not available; Flu, fludarabine.
*Primary and secondary graft failure
Acute GVHD≥grade 2

Transplantation from unrelated donors

For patients with SAA who fail first-line IST or require urgent allogeneic SCT, URD-SCT is considered as an alternative therapy, if there is no suitable MSD. Until the late 1990 s, 30-40% of AA patients who underwent URD-SCT survived long-term3, while improved survival rates (70-80%) can now be expected through better selection of HLA-matched URD donors due to improved highresolution DNA typing18 and modified conditioning regimens19-22.

The optimal conditioning regimens of URD-SCT for patients with SAA have been studied. In a study conducted by the EBMT using Flu (120 mg/m2) +Cy (1200 mg/m2) +ATG (7.5 mg/kg) for URD-SCT, the incidence of graft failure was 18% and the OS rate was 73% at two years23 (Table 2). In this study, patients older than 14 years old showed a significantly higher incidence of graft failure (32% vs. 5%; P=0.030) with a lower trend of OS rate (61% vs. 84% at two years; P=0.200) compared with younger patients. Subsequent EBMT analyses tested a combination of Flu+Cy+ATG with or without lowdose (2 Gy) total body irradiation (TBI) and showed that TBI (2 Gy) for URD-SCT extended the benefit of transplantation to adult AA patients19. However, the relatively high incidence of mortality due to graft failure (7%), post-transplantation lymphoproliferative disease (4%), and GVHD (4%) shown in this study remains a challenge. The high proportion of rejections prompted the EBMT group to suggest an increase in the Cy dose to 120 mg/kg. In contrast, the Seattle group determined the minimal dose of TBI required when added to horse ATG (ATGAM, 30 mg/kg×3) +Cy (50 mg/kg×4) t o achieve engraftment of unrelated donor marrow in 87 patients with AA who failed to respond to IST20. They found that the optimum TBI dose was 1×200 cGy, suggesting that TBI dose de-escalation was effective in reducing transplantation-related toxicity without jeopardizing engraftment. Recently, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN protocol 0301) evaluated different doses of Cy (0, 50, 100, or 150 mg/kg) combined with a regimen of Flu+ATG+TBI (2 Gy) for URD-SCT in AA patients and identified that Cy 50 mg/kg was the optimal dose for engraftment and better short-term survival24. In a Japanese cohort of 301 AA patients who received URD-SCT using the Japan Marrow Donor Program, the superiority of a Flu (100 mg/m2) + Cy (3000 mg/m2) +ATG (5 or 10 mg/kg) +TBI (3 Gy) regimen over a Cy+ATG+TBI regimen was demonstrated by matched pair analysis25.

Table 2. Reported outcomes for SAA patients who received URD-SCT
GVHD, acute graft-versus-host disease; OS, overall survival; EBMT, European Group for Blood and Marrow Transplantation; Flu, fludarabine; Cy, cyclophosphamide; ATG, anti-thymocyte globulin; TBI, total body irradiation; LFI, limited field irradiation.
*Primary and secondary graft failure
Acute GVHD≥grade 2
38 SAA patients who underwent SCT from unrelated (n=33) or family mismatched (n=5) donors were enrolled.
§The patients were divided into two groups: group 1 (n=25) received HLA-matched (8/8) bone marrow (BM) without ATG; group 2 (n =58) received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n=26), which served as a historical cohort, and group 2B (with ATG, n=32).

Early results from a pilot prospective study by Kim et al. to determine a safe and sufficient dose of TBI to be used in combination with Cy (120 mg/kg) as a conditioning regimen for URD-SCT in adult patients with SAA demonstrated the superiority of TBI (800 cGy) compared to higher TBI doses (1000 or 1200 cGy)26. In a subsequent report regarding the long-term outcomes for patients who received URD-SCT using TBI (800 cGy) + Cy (120 mg/kg) conditioning, all patients achieved sustained myeloid engraftment with acceptable incidence of acute and chronic GVHD (46% and 50%, respectively) and a relatively high OS rate (88% at five years)27. However, because URD-SCT showed higher incidence of GVHD than MSD-SCT5-7,28,29, the incorporation of lowdose ATG (1.25 mg/kg/day for two days) into the conditioning regimen for patients with SAA who receive stem cells from either an HLA-mismatched donor or peripheral blood (PB) was tested as a strategy to prevent GVHD30. The results demonstrated the beneficial effect of low-dose ATG in reducing the incidence of acute and chronic GVHD and improving the GVHD-free FFS (GFFS) (Table 2).

Alternative donor transplantation: Haplo-SCT

Use of Haplo-SCT for patients who lack suitable donors is challenging31-33. A graft from a related mismatched donor is available for most patients and has the advantages of prompt use and low cost. However, there are no recommendations regarding graft composition and conditioning regimens for Haplo-SCT for SAA patients, due to insufficient data34.

Several investigators have explored the optimal conditioning regimens and strategies for graft manipulation for SAA patients who receive Haplo-SCT. An initial retrospective study by the Seattle group showed that patients who received Haplo-SCT using a more intensified conditioning regimen consisting of TBI (1200 cGy) +Cy (120 mg/kg) achieved a higher rate of sustained engraftment (83% vs. 29%; P<0.050) and OS (50.0% vs. 0%; P< 0.050) than patients with Cy conditioning alone (200 mg/kg)32. Tzeng et al. also added TBI (800 cGy) to Cy (200 mg/kg) to achieve sustained engraftment33. Later, Studies from China have shown that a conditioning regimen consisting of Flu+Cy+ATG±busulfan (Bu) following unmanipulated PBSC and BM infusion for Haplo-SCT promoted both sustained engraftment and good survival rate35,36 (Table 3).

Table 3. Reported outcomes for SAA patients who received Haplo-SCT
GVHD, acute graft-versus-host disease; OS, overall survival; Flu, fludarabine; Cy, cyclophosphamide; ATG, anti-thymocyte globulin; TBI, Total body irradiation.
*Majority of patients received unmanipulated PB+BM.
**Primary and secondary graft failure
Acute GVHD≥grade 2
Three are different studies in terms of study design and study subjects.

TBI-based conditioning for SAA patients who receive Haplo-SCT was applied in a few studies including a small number of SAA patients37,38 (Table 3). Im et al. reported that 3/12 patients receiving Haplo-SCT with T cell-depleted grafts experienced graft failure (GF), including early graft rejection in two patients. In their study, GF occurred in 3/6 patients who did not receive TBI, whereas it did not occur in six patients who received 400 cGy TBI31. Recently, Lee et al. prospectively performed a step-by-step ATG and TBI de-escalation study to determine an optimal conditioning regimen for Haplo-SCT in SAA patients39. They found that 800 cGy TBIbased conditioning with Flu and ATG (10 mg/kg) ensured successful engraftment, while conditioning with TBI (600 cGy) +Flu+ATG (5 mg/kg, reduced based on the occurrence of transplantation-related mortality [TRM]) also proved sufficient for engraftment with T-cell repleted PBSCs with a two-year OS rate of 91.7% and two-year GFFS rate of 78.4%.

In a multicenter study from China, conditioning with Cy (200 mg/kg) +ATG (2.5 mg/kg) with i.v. Bu (6.4 mg/kg) following G-CSF-primed BM and mobilized PBSC infusion was used for Haplo-SCT40. They showed acceptable incidences of acute and chronic GVHD (33.7% and 25.8%, respectively) and an OS rate of 89% at three years. They also performed an upfront Haplo-SCT study using the same conditioning regimen and showed incidences of acute and chronic GVHD of 30.3% and 39.3%, respectively, and an OS rate of 86.1% at three years41 (Table 3).

In addition, various strategies including use of posttransplant Cy (PTCy) and selective CD3+ T cell depletion have been attempted to improve the outcomes of patients who receive Haplo-SCT. DeZern et al. reported that GVHD and graft rejection can be prevented in SAA patients over 40 years old with the addition of PTCy to conventional immunosuppression at days +3 and +442. In contrast, earlier studies on a T cell-depleted strategy showed that GVHD can be prevented with in vitro CD3 depletion, to remove T cells, in 12 children and adolescents with SAA who received Haplo-SCT31.

Although these limited data suggest that Haplo-SCT might be feasible for SAA patients who lack suitable donors, further research to increase OS by the reduction of GVHD, while maintaining stable engraftment is required in the future.

Current challenges

Effect of recipient age

Current issues for MSD-SCT in AA patients are the upper age limit and optimal conditioning regimens for old patients. The risks of morbidity and mortality arising from SCT increase with age. However, because survival after IST is also associated with lower OS for old patients, the age limit for determining transplantation as first-line treatment is still under debate.

A study by the EBMT/Center for International Blood and Marrow Transplant Research (CIBMTR) with 1307 patients with SAA analyzed the effect of patient age, adjusting for other significant factors that affect outcomes43. Neutrophil recovery was similar in all age groups; however, patients over 40 years old showed a lower likelihood of platelet recovery compared to those below 20 years old. The mortality risk was higher for patients over 40 years old (relative risk [RR] 2.70, P<0.0001) and 20-40 years old (RR 1.69, P<0.0001) compared to patients below 20 years old. The mortality risk was also higher for patients over 40 years old than patients between 20-40 years old (RR 1.60, P=0.008). These data showed that mortality risk increased with age. However, several recent studies have attempted reducedintensity conditioning with Flu+attenuated-dose Cy+ATG to reduce the negative impact of age in old patients with SAA44-47. This is supported by the EBMT study, which reported a significantly higher age-adjusted OS rate for patients who received a Flu+attenuated-dose Cy±ATG conditioning regimen compared with those who received Cy±ATG (P=0.04). In addition, there was no significant difference in OS rate between patients 30-39 year old and≥40 years old in the Flu+attenuated-dose Cy±ATG group (P=0.30)16. Recently, Shin et al. analyzed 117 consecutive adult patients with SAA who received MSD-SCT using a Flu+half-dose Cy (100 mg/kg) +ATG conditioning regimen and showed that the older age group (>40 years) had comparable outcomes to the younger age group (≤40 years), with incidences of acute gradeⅡ-Ⅳ GVHD (9.5% vs. 9.3% at day 100; P =0.42), chronic GVHD (8.1% vs. 9.5% at five years; P =0.80), secondary graft failure (20.8% vs. 7.9% at five years; P=0.11), FFS rate (73.7% vs. 81.0% at five years; P=0.73), and OS rate (93.7% vs. 88.9% at five years; P =0.20)17.

Effect of donor age

In the registry-based study from Japan, the outcomes of transplantation in patients with SAA who received URD-SCT using BM were compared between younger and older donors. This analysis revealed inferior outcomes for the older donor group, with lower OS for the recipients48, consistent with previous reports that showed a positive correlation between donor telomere length and increased survival of SAA patients who had received SCT49. In addition, hematopoietic stem cells from older donors show reduced repopulation efficiency in murine studies50,51, and grafts from older donors have a higher ratio of memory-to-naive T cells52, which could in part explain the higher incidence of GVHD with older donors. Therefore, donor age is a consideration when selecting a donor for URD-SCT to improve transplantation outcome.

Stem cell source

Two registry-based studies have shown that BM transplantation results in a superior outcome compared with PB transplantation in MSD-SCT53,54. A combined EBMT/CIBMTR analysis showed a significant survival advantage for young patients (<20 years) transplanted with BM but not for older patients (≥20 years)54. EBMT analysis on a large number of patients (N=1886), who received MSD-SCT, demonstrated that BM transplantation is superior to PB transplantation due to lower acute and chronic GVHD and a comparable risk of rejection in all age groups53. In addition, BM provided a survival advantage in URD-SCT over PB55,56. These evidence indicate that BM should be the standard stem cell source for SCT in SAA patients.

Despite these data, use of PB as a graft source has increased, and some patients unavoidably receive URD-SCT using PB due to donor preference. In addition, it is expected that PB transplantation would overcome the rejection, especially in patients with a heavy transfusion history and high risk of graft failure57. Literature from developing countries presents a different aspect for PB grafts57-59. Recent pooled analysis from CIBMTR (n=1814) and the Japan Society for Hematopoietic Cell Transplantation (n=560) examined the differences in outcomes in different economic regions using BM or PB as graft sources, and found no significant difference in OS between these two sources in middle- and low- income countries60. Therefore, although BM should definitely be the preferred graft source for MSD-SCT in SAA patients, PBSC may be an acceptable alternative in countries with limited resources when treating patients at high risk of graft failure and infectious complications.

Iron overload

Many patients with AA unavoidably receive blood transfusions as supportive care. Regular transfusions of packed red cells (PRCs) leads to iron overload, which increases the risk of TRM and other complications including fungal infections, hepatic dysfunction, and hepatic veno-occlusive disease after SCT61-64. Recently, Lee et al. evaluated the prognostic impact of pre-transplantation PRC transfusion history on the transplantation outcome in SAA patients who had not receive proper iron chelation therapy (ICT) prior to SCT65. The authors found that a history of higher pre-transplantation PRC transfusion was associated with increased TRM and decreased OS, suggesting that iron overload had a negative impact on the SCT outcome in SAA patients (Figure 1). However, in the pre-deferasirox era, intensive ICT was not widely used for the treatment of patients with iron overload because of poor compliance with deferoxamine treatment. Deferasirox is now available as an oral chelating agent, and further studies examining whether intensive ICT for patients with iron overload will improve the transplantation outcomes are warranted. Notably, most patients, who plan to undergo URD-SCT, were transfusion-dependent after failed IST. For these patients, pretransplantation intensive ICT would be expected to improve transplantation outcomes66.

Figure 1. Kaplan-Meier estimates of overall survival (OS) (a) and transplant-related mortality (TRM) (b) according to pretransplant transfusion (≤32 PRC units vs. >32 PRC units). Solid line, ≤32 PRC units; dashed line, >32 PRC units.
Adapted from Lee et al. PRC, packed red blood cells.

Conclusions

As MSD-SCT leads to long-term survival, it has become the standard first-line treatment for younger patients with SAA. However, whether MSD-SCT or IST is the best first-line treatment option for older patients remains a current topic of debate. The results of URD-SCT have recently been improved by the use of a reduced intensity conditioning regimen and better donor selection; therefore, URD-SCT can now be considered in young patients who failed first-line IST or as a front-line therapy for patients requiring urgent allogeneic SCT, if there is no suitable MSD. Haplo-SCT and other novel approaches are being pursued with substantial progress. Larger prospective studies are required to address currently unresolved questions regarding treatment of patients with SAA.

Authors’ Contribution

JWL and S-EL wrote this manuscript.

Conflict of Interest

The authors declare no conflict of interest.

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