Patient, disease, and transplant characteristics are presented in . All aspects of the transplant regimen, including choice of graft, were at the discretion of the transplant center. Groups were similar in terms of patient sex, performance score, conditioning regimen, and GVHD prophylaxis. There were significant differences in the age of patients receiving G-BM, BM and PBPC. G-BM and PBPC recipients were older with median ages of 25 years and 24 years, respectively compared to BM recipients whose median age was 18 years (p<0.001). Most patients received cyclophosphamide alone or cyclophosphamide with anti-thymocyte globulin (ATG) for transplant conditioning and calcineurin-inhibitor containing GVHD prophylaxis. The median follow-up of surviving patients is 4 years after G-BM transplants and 5 years after BM and PBPC transplants.
The median times to neutrophil recovery were 15 days, 20 days and 13 days after G-BM, BM and PBPC transplantations, respectively. Though median recovery times were faster after transplantation of G-BM and PBPC compared to BM (p<0.001), the cumulative incidence of neutrophil recovery at day 30 was similar after transplantation of G-BM, BM and PBPC, 91% (95% CI, 84–96%), 90% (95% CI, 87–92%) and 93% (95% CI, 88–97%), respectively (p=0.378). In multivariate analysis, the likelihood of achieving neutrophil recovery at 30 days after transplantation was similar in the three groups (). The likelihood of neutrophil recovery was higher with addition of ATG to conditioning regimen (odds ratio [OR] 1.87, 95% CI 1.14–3.07, p=0.013) compared to regimens without ATG and when the interval between diagnosis and transplantation was longer than 6 months (OR 2.21, 95% CI 1.17 – 4.17, p=0.014).
Risk factors associated with hematopoietic recovery
Platelet recovery after transplantation of G-BM was slower compared to BM (p=0.015) and PBPC (p<0.001). Median times to platelet recovery were 31 days, 26 days and 19 days after BM, G-BM, and PBPC transplantation respectively. However, by day-60, the cumulative incidence of platelet recovery after G-BM, BM and PBPC transplantation were 86% (95% CI, 77–93%), 85% (95% CI, 82–88%) and 83% (95% CI, 77–89%) respectively (p=0.742). In multivariate analysis, the likelihood of platelet recovery at day-30 after transplantation was similar in the three groups (). The likelihood of platelet recovery was lower in patients with performance score less than 90 (OR 0.50, 95% CI 0.32–0.78, p=0.002).
Acute and Chronic GVHD
Cumulative incidence of grades 2–4 acute GVHD at day 100 were 14% (95% CI 8–23%), 13% (95% CI 10–16%) and 28% (95% CI 20–35%) after G-BM, BM and PBPC transplantation, respectively. The corresponding cumulative incidence of grades 3–4 acute GVHD were 6% (95% CI 2–13%), 6% (95% CI 4–8%) and 12% (95% CI 7–18%). Compared to G-BM transplants, the risk of grade 2–4 and 3–4 acute GVHD were similar after BM transplants (). Grade 2–4 acute GVHD but not grade 3–4 acute GVHD was higher after PBPC transplants compared to G-BM transplants (). Grade 2–4 and 3–4 acute GVHD were higher after PBPC transplants compared to BM transplants (). Use of ATG was associated with lower acute grade 2–4 (relative risk [RR] 0.64, 95% CI 0.44–0.92, p=0.015) and grade 3–4 acute GVHD (RR 0.50, 95% CI 0.29–0.86, p=0.012). Performance score less than 90 was associated with higher risks of grade 3–4 acute GVHD (RR 3.06, 95% CI 1.75–5.35, p<0.001).
Risk factors associated with acute and chronic GVHD and overall survival
Cumulative incidence of chronic GVHD at 3-years were 10% (95% CI 4–17%), 16% (95% CI 13–19%) and 43% (95% CI 35–52%) after G-BM, BM and PBPC transplantation, respectively. Compared to G-BM transplants, chronic GVHD risks were similar after BM transplants but higher after PBPC transplants (). Chronic GVHD was also higher after PBPC transplants compared to BM transplants. Chronic GVHD was higher in patients aged 35 years or older (RR 1.61, 95% CI 1.09–2.37, p=0.015).
As approximately 60% of BM recipients compared to a third of G-BM and PBPC recipients were aged less than 21 years, we performed a subset analysis restricting to patients 21 years and older. Consistent with the main analysis, risks of grade 2–4 acute GVHD were higher after transplantation of PBPC compared to G-BM (RR 2.36, 95% CI 1.08–5.19, p=0.032) and BM (RR 2.09, 95% CI 1.28–3.39, p=0.003). Similarly, risks of chronic GVHD were also higher after transplantation of PBPC compared to G-BM (RR 5.52, 95% CI 2.35–12.97, p<0.001) and BM (RR 2.62, 95% CI 1.75–3.94, p<0.001).
Risks of overall mortality were similar after transplantation of G-BM compared to PBPC and BM compared to PBPC (). However, mortality risks were lower after transplantation of BM compared to G-BM. Mortality risks were similar after PBPC and BM transplants. Mortality risks for all patients were lower with inclusion of ATG in conditioning regimen (RR 0.53, 95% CI 0.39–0.72, p<0.001), performance score 90–100 (RR 0.54, 95% CI 0.39–0.73, p<0.001) and patients younger than 35 years (RR 0.51, 95% CI 0.37–0.72, p<0.001). The 3-year probabilities of overall survival adjusted for ATG, performance score and patient age were 80%, 72% and 76% after BM, G-BM, and PBPC transplantation, respectively (). In subset analysis restricting to patients aged 21 years and older, after adjusting for patient age, mortality risks are similar after transplantation of G-BM compared to BM (RR 0.94, 95% CI 0.53–1.70, p=0.856). As observed in the main analysis, patients older than 35 years and those with performance scores less than 90 were at higher risk of mortality.
Probabilities of overall survival after BM, G-BM and PBPC transplantation from HLA-Matched Sibling Donors for Patients with Severe Aplastic Anemia adjusted for ATG use, performance score and patient age
The causes of death are shown in . One hundred and eighteen BM recipients (21%), 22 G-BM (28%) and 37 PBPC (28%) are death. Graft failure, organ failure and GVHD were common in the three treatment groups. Death from infection was higher after BM and G-BM transplants and interstitial pneumonitis, higher after PBPC transplants.