HLA-identical siblings (patients aged under 40)
The results of allogeneic BMT for sAA are generally very good, with over 90% of patients with sAA aged younger that 16 who receive a BMT from an HLA-identical sibling after conditioning with 200 mg/kg of cyclophosphamide surviving.r The major challenges facing BMT in sAA are graft failure and GvHD.
BMT in sAA is associated with a high rate of graft rejection (10%; range 5 to 15%) – which is correlated with the number of transfusions and the duration of disease before undergoing transplantation. Severe acute GvHD is uncommon although extensive chronic GvHD occurs in 30-40% of patients and has a significant impact on quality of life, second malignancies and mortality.r Donor-recipient sex mismatching affects GvHD and graft failure, although the use of ATG abrogates the negative effect of sex mismatching.r
Outcome following BMT in all age groups are inferior with peripheral blood stem cell transplants compared to bone marrow transplants, due largely to higher rates of chronic graft-versus-host disease.r Consequently there is uniform agreement that patients being transplanted for sAA should receive bone marrow as the preferred haematopoietic stem cell source.
The combination of cyclophosphamide 200mg/kg and ATGAM (30mg/kg/d for 3 days) remains the most accepted conditioning regimen for matched sibling allografts for sAA. Long-term follow-up of patients treated with Cy/ATGAM has demonstrated a low rate of graft rejection (<5%) and 88% overall survival after a median of 9.2 years follow up, which is higher than historical controls using Cy alone. It is important to note, however, that one prospective randomised trial was unable to demonstrate a difference in OS when Cy/ATG was compared to Cy alone, however the OS of patients conditioned with Cy/ATG in this study was comparatively lower than other reported cohorts and the study was under-powered to detect a survival difference.rrr
Therefore, there is general agreement regarding the optimal conditioning and GvHD prophylaxis in patients with sAA who have an HLA-identical sibling donor. The standard of care for HLA-identical sibling donors should therefore be cyclophosphamide 50 mg/kg/day for 4 days with 3 days of ATG, followed by transplantation of unmanipulated bone marrow and CsA plus MTX as GvHD prophylaxis. There is no role for irradiation in BMT for sAA in patients with HLA-identical sibling donors.
HLA-identical siblings (patients aged over 40)
While the results of allogeneic BMT for patients with HLA-identical sibling donors are excellent, survival rates are highly correlated with age with overall survival at 10 years for patients aged 1-20, 21-30, 31-40 and greater than 40, being 83%, 73%, 68% and 51% respectively.r
As a consequence there has been considerable interest in whether the combination of low-dose cyclophosphamide (1200mg/m2) and fludarabine may be associated with reduced transplantation-related mortality and improved outcomes. Recent reports suggest that the combination of Flu-Cy and ATG may reduce the TRM compared with cyclophosphamide alone in older patients undergoing allogeneic transplant.rr
Historically, UDT for sAA has been associated with a high mortality rate, due largely to increased graft rejection and GvHD. A number of factors have been consistently shown to reduce survival, including older age, conditioning without ATG, high-dose radiotherapy and a long interval between diagnosis and transplantation.rr
Survival following UD transplant for sAA in patients aged less than 20-30 has, however, improved significantly over the past 20 years, due largely to improved donor-recipient matching and improved supportive care, with survival rates over 60% at 10 years. Maury et al and Kojima et al have shown that results for young patients who are fully HLA-matched at the allelic level with their donor are comparable to those observed after stem cell transplantation from a related donor.rr
The optimal conditioning for BMT from a matched unrelated donor in sAA has not been adequately defined. TBI has been added to conditioning in order to increase immunosuppression and reduce rejection.rrr While the addition of TBI has reduced graft failure (2-11%) and produced survival rates greater than 60% in younger patients, it is associated with increased chronic GvHD and interstitial pneumonitis.r For these reasons, partial T-cell depletion using fludarabine-containing conditioning with ATG has been used to avoid the risks of irradiation and to decrease the risk of severe GvHD while still maintaining sufficient donor T-lymphocytes to ensure engraftment.rrrrr While the addition of ATG has been shown to reduce both acute and chronic GvHD, however the optimal ATG preparation for UDT in sAA has not been defined. While most evidence exists for ATGAM, thymoglobulin has also been used successfully.rr Currently the combination of fludarabine, cyclophosphamide and ATG has been recommended by the EBMT to be the standard of care for unrelated donor transplants in sAA.rrrr
Umbilical cord blood or haploidentical donors
Currently, the role of using umbilical cord blood for sAA especially in adult population remains undefined with respect to optimal conditioning, stem cell dose, GVHD prophylaxis and concerns of increased risk of graft failure (up to 50%). A small Japanese study with 31 patients showed estimated 2-year overall survival of 41.1%.r More recently, haploidentical related donor transplant using post transplant cyclophosphamide in sAA has been piloted with encouraging engraftment result and acceptable GVHD risk in small series.r