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We compared outcomes of patients with severe aplastic anemia (SAA) who received G-CSF stimulated bone marrow (G-BM) (n=78), unstimulated bone marrow (BM) (n=547), or peripheral blood progenitor cells (PBPC) (n=134) from an HLA-matched sibling. Transplantations occurred in 1997–2003. Rates of neutrophil and platelet recovery were not different among the three treatment groups. Grade 2–4 acute graft-versus-host disease (GVHD) (RR 0.82, p=0.539), grade 3–4 acute GVHD (RR 0.74, p=0.535) and chronic GVHD (RR 1.56, p=0.229) were similar after G-BM and BM transplants. Grade 2–4 acute GVHD (RR 2.37, p=0.012) but not grade 3–4 acute GVHD (RR 1.66, p=0.323) and chronic GVHD (RR 5.09, p<0.001) were higher after PBPC transplants compared to G-BM. Grade 2–4 (RR 2.90, p<0.001), grade 3–4 (RR 2.24, p=0.009) acute GVHD and chronic GVHD (RR 3.26, p<0.001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR 0.63, p=0.05). These data suggest no advantage to using G-BM and the observed higher rates of acute and chronic GVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA matched sibling transplants for SAA.
Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for patients with severe aplastic anemia (SAA) when a HLA-matched sibling donor is available. Recent years have seen increasing use of hematopoietic cells other than bone marrow (BM). These alternative graft sources include peripheral blood progenitor cells (PBPC) and granulocyte colony stimulating factor (G-CSF) bone marrow (G-BM). Several groups have demonstrated that PBPC transplantation has faster neutrophil and platelet engraftment compared to BM in patients with hematological malignancies1–4. HLA-matched sibling PBPC transplants may offer an improved survival rate for patients with advanced leukemia despite higher graft-versus-host disease (GVHD)4–6. Others have examined transplant outcomes after G-BM in transplantation for hematological malignancies7–9. Results show similar rates of hematopoietic recovery and lower acute and chronic GVHD after G-BM and PBPC transplants10,11.
Use of PBPC from HLA-matched siblings for SAA is associated with higher risks of chronic GVHD and in children, higher mortality compared to BM12. To date, there are no reports that have compared use of G-BM for SAA to BM or PBPC. Therefore, we report on transplant-outcomes after G-BM (n=78) compared to BM transplants (n=547) and, G-BM compared to PBPC (n=134) transplants reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).
Patient, disease and transplant characteristics and outcome data were reported to the Center for International Blood and Marrow Transplant Research. The CIBMTR is a voluntary working group of over 400 transplant centers worldwide that contribute data on consecutive hematopoietic transplantations to a Statistical Center at the Medical College of Wisconsin. Participating transplant centers are required to register all consecutive transplantation and detailed patient, disease and transplant characteristics and outcome data are collected on a subset of registered transplantations using a weighted randomized scheme. The study population includes only patients selected for detailed reporting. Compliance and data quality are monitored by on-site audits, computerized error checks and physician review of submitted data. All patients are followed longitudinally, annually. This study was approved by the Institutional Review Board of the Medical College of Wisconsin.
Included are patients who underwent an HLA-matched sibling transplant for SAA. The diagnostic criteria of SAA are similar to those of Camitta et al., modified so that a marrow with < 50% cellularity and < 30% hematopoietic cells also satisfies the criteria for marrow aplasia (in addition to the original criteria of < 25% cellularity)13. All transplantations occurred in 1997 to 2003. Seventy-eight patients received G-BM grafts, 547 patients received BM grafts and 134 patients received PBPC grafts. Excluded were patients older than 50 years, recipients of cord blood grafts, and T-cell depleted BM or CD34 selected PBPC grafts.
Neutrophil recovery was defined as achieving an absolute neutrophil count ≥ 0.5 × 109/L for 3 consecutive days, and platelet recovery ≥ 20 × 109/L for seven days, unsupported. Grades 2–4 and 3–4 acute GVHD and chronic GVHD were determined using standard criteria14,15. Overall mortality was defined as death from any cause.
Patient-, disease-, and transplant-related variables are shown in Table 1. Characteristics of the three groups were compared between the three groups using the χ2 statistic for categorical variables and the Kruskal-Wallis test for continuous variables16. Probabilities of overall survival were calculated using Kaplan-Meier estimator. Cumulative incidence rates for neutrophil and platelet recovery and acute and chronic GVHD were calculated using standard technique16; for neutrophil and platelet recovery and acute and chronic GVHD, death without an event was the competing risk. 95% confidence intervals were calculated using the standard error of the survival function obtained by Greenwood formula. Adjusted probability of overall survival was estimated using the Cox proportional hazards method to adjust for patient-, disease-, and transplant-related variables included in the final multivariate models. Logistic regression was employed to model the probability of neutrophil recovery at 30 days and platelet recovery at 100 days after the transplantation.
Multivariate models were built using the backward selection method with a significance level of 0.05. The primary objective of this study was to compare the outcomes after G-BM, BM and PBPC transplantation. Therefore, the variable for graft type (G-BM vs. BM vs. PBPC) was held in all steps of model building and independent of level of significance. Other variables considered were recipient age, performance score, time from diagnosis until transplant (≤ 6 months vs. > 6 months), number of red blood cell transfusions prior to transplantation (≤ 20 vs. > 20 vs. not reported), inclusion of ATG to conditioning regimen, use of hematopoietic growth factor within first 7 days of transplantation, sex of recipient and donor, cytomegalovirus (CMV) serostatus of donor and recipient and year of transplantation. In Cox models, all variables met the proportional hazards assumption which was tested by using a time-varying covariate method. First-order interactions between graft type and each variable of interest were examined by fitting the proportional hazards model, and examining the interaction between the variable of interest and graft type. All the p-values are two-sided. Analyses were performed using SAS software, version 9.1 (SAS Institute, Cary, NC).
Patient, disease, and transplant characteristics are presented in Table 1. 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 (Table 2A). 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).
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 (Table 2A). 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).
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 (Table 2B). Grade 2–4 acute GVHD but not grade 3–4 acute GVHD was higher after PBPC transplants compared to G-BM transplants (Table 2B). Grade 2–4 and 3–4 acute GVHD were higher after PBPC transplants compared to BM transplants (Table 2B). 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).
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 (Table 2B). 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 (Table 2B). 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 (Figure 1). 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.
The causes of death are shown in Table 3. 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.
The primary objective of the current analysis was to compare rates of acute and chronic GVHD and overall survival after transplantation of G-BM to BM and PBPC from an HLA-matched sibling for SAA. Compared to G-BM transplants, hematopoietic recovery, grade 2–4 acute GVHD and chronic GVHD rates were not different to that after BM transplants. However, there was a survival advantage to transplantation of BM compared to G-BM. The observed survival advantage was primarily in patients younger than 21 years of age at transplantation. To our knowledge this is the first report comparing transplant-outcomes after G-BM and BM for SAA.
Hematopoietic recovery rates were similar after G-BM and PBPC transplants but grade 2–4 acute GVHD and chronic GVHD were higher after PBPC transplants. Despite higher GVHD rates after PBPC transplants, we did not observe differences in survival after transplantation of G-BM and PBPC. These findings are consistent with the report by Morton and colleagues where patients were randomized to receive G-BM or PBPC from their HLA-matched sibling10. That trial included patients with malignant and non-malignant diseases; rates of hematopoietic recovery and acute GVHD were similar but chronic GVHD was higher after transplantation of PBPC. Serody and colleagues in their report comparing transplantation of G-BM and PBPC for malignant diseases observed similar rates of hematopoietic recovery but higher acute and chronic GVHD after transplantation of PBPC11. Consistent with our observations, neither report showed differences in overall survival after G-BM and PBPC transplants.
Compared to BM transplants, acute and chronic GVHD rates were higher after PBPC transplants. However, this did not translate into higher mortality in PBPC recipients. Reports that have shown lower survival rates after PBPC transplants compared to BM transplants have been in children with acute leukemia or SAA and adults with good risk chronic myeloid leukemia.12,17,18 In the current analysis 51% (390 of 759) of the study population is younger than 21 years, but only 12% (45 of 390) of patients in this group received PBPC grafts. The relatively small number of younger PBPC recipients in this analysis may explain our inability to show significant differences in survival after BM and PBPC transplantation. Further, in the report that compared transplantation outcomes after HLA-matched sibling BM and PBPC transplants for SAA, in patients older than 20 years, survival rates were not significantly different after BM and PBPC transplant.12 The observed higher chronic GVHD after transplantation of PBPC may yet translate into a survival disadvantage for these patients and only with longer follow-up of a larger cohort can this be examined satisfactorily. Survival after transplantation was lower in patients with poor performance score and older patients and consistent with other reports after transplantation for SAA. We observed lower mortality risks with use of ATG, a surrogate for the transplant conditioning regimen, cyclophosphamide and ATG. Over 95% of patients who received ATG also received cyclophosphamide.
There are several limitations to consider when interpreting data presented herein. Numbers of patients who received G-BM transplants are relatively small (approximately 80 patients) and transplant outcome data on several hundreds of G-BM transplants are needed to conclusively demonstrate equivalency of G-BM transplants to BM transplants. The choice of intervention (i.e., graft source) was at the discretion of the transplant center and even though a controlled analysis was performed adjusting for known risk factors there may be unmeasured or unknown factors that may influence transplant-outcomes. We do not collect dose and duration of G-CSF administration and both these factors are known to influence cell dose collected19,20. Further, total nucleated cell dose and CD34+ dose at infusion was not collected in a systemic manner and prevented us from exploring an association between cell dose and transplant outcomes.
These data suggest lower survival after transplantation of G-BM compared to transplantation of BM in younger patients and no advantage compared to transplantation of PBPC. The higher chronic GVHD after PBPC transplants warrants cautious use of this graft for SAA. Therefore, BM grafts from HLA matched sibling donors are the preferred graft for patients with SAA.
The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical, Inc.; Biovitrum AB; Blood Center of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children’s Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech, an Invitrogen Company; Eisai, Inc.; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell, Ltd.; GE Healthcare; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; MGI Pharma, Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Pall Life Sciences; Pfizer Inc; Saladax Biomedical, Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; Soligenix, Inc.; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; THERAKOS, Inc.; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals, Inc.; ViraCor Laboratories; ViroPharma, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. Government.
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