Bone marrow transplants for severe aplastic anemia were first performed in the 1970s. Transplant regimens, supportive care, and patient selection have changed substantially since then. Our objective was to determine the impact of these changes on transplant outcome. We studied 1,305 recipients of HLA-identical sibling transplants for aplastic anemia between 1976 and 1992, reported to the IBMTR by 179 centers. We compared survival of transplants performed in three intervals (1976 through 1980 [n = 186], 1981 through 1987 [n = 648], and 1988 through 1992 [n = 471]) using Cox proportional hazards regression. Five-year survival (±95% confidence interval) increased from 48% ± 7% in the 1976-1980 cohort to 66% ± 6% in the 1988-1992 cohort (P < .0001). Risks of graft-versus-host disease (GVHD) and interstitial pneumonia decreased over time, but the risk of graft failure did not. Higher long-term survival resulted primarily from decreased mortality in the first 3 months posttransplantation. Late mortality risks were low and changed little over the intervals studied. In multivariate analysis, changes in transplantation strategies accounted for most but not all of the improved outcome. Use of cyclosporine to prevent GVHD was the most important factor. Changes in patient selection did not seem to explain improved survival. Survival after HLA-identical sibling bone marrow transplantations for aplastic anemia has improved since 1976. Changes in GVHD prophylaxis account for much of this improvement. Other changes may also operate.

BONE MARROW transplantation from an HLA-identical sibling was first used to treat aplastic anemia in the 1970s.1,2 Early studies reported about 50% long-term survival.3-5 More recent studies report survival rates of 60% to 90%.6-16 It is not certain whether these higher survival rates reflect patient selection, earlier transplantation, changes in transplantation regimens, and/or supportive care or some combination of these factors.17 18 

Several patient- and disease-related factors may influence outcome of transplantations for aplastic anemia, including recipient age, disease severity, numbers of pretransplantation transfusions, and donor-recipient sex-match.2,18 Major problems after transplantations are graft failure, graft-versus-host disease (GVHD), and infection. Graft failure occurs in 5% to 30% of patients.19,20 Substantial acute GVHD (grades II-IV) occurs in 30% to 50% and chronic GVHD in 25% to 60% of patients.21,22 The high incidence of graft failure is attributed to sensitization to minor histocompatibility antigens by prior blood transfusions. Strategies designed to reduce graft failure include earlier treatment, adding radiation or antithymocyte globulin (ATG) to cyclophosphamide for pretransplantation conditioning, and adding donor buffy coat cells to the graft.7,9,13,16,23,24 The main approach for preventing GVHD is posttransplantation immune suppression. Methotrexate (MTX) or cyclosporine (CSA), used alone, were common in the early 1980s. Combined MTX and CSA is now the most widely used regimen.6,11,25 26 

Table 1.

Patient-, Disease-, and Transplant-Related Variables of Patients Receiving HLA-Identical Sibling Bone Marrow Transplantations for Severe Aplastic Anemia Between 1976 and 1992

Year of TransplantP
1976-19801981-19871988-1992
186 648 471 
Etiology of SAA, no./no. evaluated (%)    .0001 
Idiopathic 133/186 (72) 512/646 (79) 411/470 (87) 
Hepatitis 24/186 (13) 68/646 (11) 26/470 (6) 
Toxin* 25/186 (13) 61/646 (9) 30/470 (6) 
Other 4/186 (2) 5/646 (1) 3/470 (1) 
Median age in yr (range) 19 (2-56) 20 (1-57) 20 (1-51) NS 
Median no. of prior transfusions (range) 25 (0-690) 23 (0-598) 25 (0-833) NS 
Granulocytes <0.2 × 109/L, no./no. evaluated (%) 173/180 (96) 479/627 (76) 232/448 (52) .0001 
Prior treatment, no./no. evaluated (%) 
None 63/182 (35) 266/630 (41) 240/470 (51) .0001 
Androgens 80/178 (45) 230/637 (36) 115/470 (24) .0001 
Steroids 82/175 (47) 272/639 (43) 134/470 (29) .0001 
ATG 13/168 (8) 86/633 (14) 73/470 (16) .04 
CSA 0/71 (0) 10/306 (3) 32/434 (7) .005 
Median time to transplant in mo (range) 2 (0-118) 2 (0-158) 2 (0-232) NS 
Donor-recipient sex-match, no./no. evaluated (%)    NS 
M-M 64/179 (36) 229/648 (36) 162/470 (34) 
M-F 27/179 (15) 132/648 (20) 104/470 (22) 
F-M 53/179 (30) 168/648 (26) 121/470 (26) 
F-F 35/179 (19) 119/648 (18) 83/470 (18) 
Alloimmunized† donor, no./no. evaluated (%) 12/104 (12) 71/539 (13) 50/442 (11) NS 
Conditioning regimen, no./no. evaluated (%)    .0001 
Cy 90/186 (48) 299/648 (46) 219/471 (46) 
Cy + TBI 50/186 (27) 80/648 (12) 23/471 (5) 
Cy + LFR 27/186 (15) 249/648 (39) 168/471 (36) 
Cy + ATG 10/186 (5) 12/648 (2) 40/471 (9) 
Other 9/186 (5) 8/648 (1) 21/471 (4) 
Median cell dose ×108/kg (range) 3.1 (0.2-13) 3.3 (0.3-13) 3.3 (0.4-17) NS 
Isolation with LAF/HEPA, no./no. evaluated (%) 79/176 (45) 320/635 (50) 352/453 (78) .0001 
Donor buffy coat cells, no./no. evaluated (%) 37/122 (30) 162/639 (25) 40/469 (9) .0001 
GVHD prophylaxis, no./no. evaluated (%)    .0001 
MTX ± other 155/186 (83) 216/648 (33) 7/470 (2) 
CSA ± other 22/186 (12) 297/648 (46) 128/470 (27) 
MTX + CSA 1/186 (0) 99/648 (15) 316/470 (67) 
T-cell depletion 3/186 (2) 25/648 (4) 15/470 (3) 
Other 5/186 (3) 11/648 (2) 4/470 (1) 
Other supportive care,‡ no./no. evaluated (%) 
Antibiotics NA 134/217 (62) 352/471 (75) .001 
Cotrimoxazole NA 77/217 (35) 226/471 (48) .002 
Intravenous immune globulin NA 177/217 (82) 389/471 (83) NS 
Acyclovir NA 114/217 (53) 379/471 (80) .0001 
Growth factorsρ NA 0/217 (0) 29/471 (6) .0001 
Year of TransplantP
1976-19801981-19871988-1992
186 648 471 
Etiology of SAA, no./no. evaluated (%)    .0001 
Idiopathic 133/186 (72) 512/646 (79) 411/470 (87) 
Hepatitis 24/186 (13) 68/646 (11) 26/470 (6) 
Toxin* 25/186 (13) 61/646 (9) 30/470 (6) 
Other 4/186 (2) 5/646 (1) 3/470 (1) 
Median age in yr (range) 19 (2-56) 20 (1-57) 20 (1-51) NS 
Median no. of prior transfusions (range) 25 (0-690) 23 (0-598) 25 (0-833) NS 
Granulocytes <0.2 × 109/L, no./no. evaluated (%) 173/180 (96) 479/627 (76) 232/448 (52) .0001 
Prior treatment, no./no. evaluated (%) 
None 63/182 (35) 266/630 (41) 240/470 (51) .0001 
Androgens 80/178 (45) 230/637 (36) 115/470 (24) .0001 
Steroids 82/175 (47) 272/639 (43) 134/470 (29) .0001 
ATG 13/168 (8) 86/633 (14) 73/470 (16) .04 
CSA 0/71 (0) 10/306 (3) 32/434 (7) .005 
Median time to transplant in mo (range) 2 (0-118) 2 (0-158) 2 (0-232) NS 
Donor-recipient sex-match, no./no. evaluated (%)    NS 
M-M 64/179 (36) 229/648 (36) 162/470 (34) 
M-F 27/179 (15) 132/648 (20) 104/470 (22) 
F-M 53/179 (30) 168/648 (26) 121/470 (26) 
F-F 35/179 (19) 119/648 (18) 83/470 (18) 
Alloimmunized† donor, no./no. evaluated (%) 12/104 (12) 71/539 (13) 50/442 (11) NS 
Conditioning regimen, no./no. evaluated (%)    .0001 
Cy 90/186 (48) 299/648 (46) 219/471 (46) 
Cy + TBI 50/186 (27) 80/648 (12) 23/471 (5) 
Cy + LFR 27/186 (15) 249/648 (39) 168/471 (36) 
Cy + ATG 10/186 (5) 12/648 (2) 40/471 (9) 
Other 9/186 (5) 8/648 (1) 21/471 (4) 
Median cell dose ×108/kg (range) 3.1 (0.2-13) 3.3 (0.3-13) 3.3 (0.4-17) NS 
Isolation with LAF/HEPA, no./no. evaluated (%) 79/176 (45) 320/635 (50) 352/453 (78) .0001 
Donor buffy coat cells, no./no. evaluated (%) 37/122 (30) 162/639 (25) 40/469 (9) .0001 
GVHD prophylaxis, no./no. evaluated (%)    .0001 
MTX ± other 155/186 (83) 216/648 (33) 7/470 (2) 
CSA ± other 22/186 (12) 297/648 (46) 128/470 (27) 
MTX + CSA 1/186 (0) 99/648 (15) 316/470 (67) 
T-cell depletion 3/186 (2) 25/648 (4) 15/470 (3) 
Other 5/186 (3) 11/648 (2) 4/470 (1) 
Other supportive care,‡ no./no. evaluated (%) 
Antibiotics NA 134/217 (62) 352/471 (75) .001 
Cotrimoxazole NA 77/217 (35) 226/471 (48) .002 
Intravenous immune globulin NA 177/217 (82) 389/471 (83) NS 
Acyclovir NA 114/217 (53) 379/471 (80) .0001 
Growth factorsρ NA 0/217 (0) 29/471 (6) .0001 

Abbreviations: SAA, severe aplastic anemia; Cy, cyclophosphamide; TBI, total body irradiation; LFR, limited field radiation; NS, not significant; NA, not available.

*

Aplasia developing after exposure to drugs or other chemicals.

Alloimmunized is defined as prior exposure to alloantigens by pregnancy or transfusion.

Data recorded since 1986; prophylactic use only.

ρ Granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor administered within 1 week of transplantation.

Changes in supportive care measures since the 1970s include protective environments (laminar airflow [LAF] and high efficiency particulate air [HEPA] filtration) to decrease airborne infections, acyclovir to prevent reactivation of herpes viruses, cotrimoxazole to prevent pneumocystis pneumonia, bacterial prophylaxis with systemic antibiotics, intravenous immune globulins to decrease viral and other infections, and growth factors to accelerate bone marrow recovery.27-34 

The purpose of this study was to determine whether outcome of transplantations for aplastic anemia improved from 1976 to 1992 and, if so, to determine whether improvement resulted from changes in patient selection or changes in transplantation technique or both.

Fig. 1.

Probability of survival after HLA-identical sibling transplantation for aplastic anemia for cohorts transplanted in 1976-1980, 1981-1987, and 1988-1992.

Fig. 1.

Probability of survival after HLA-identical sibling transplantation for aplastic anemia for cohorts transplanted in 1976-1980, 1981-1987, and 1988-1992.

Close modal
Table 2.

Outcome (Probability ± 95% Confidence Interval) of HLA-Identical Sibling Bone Marrow Transplantations for Severe Aplastic Anemia Between 1976 and 1992

OutcomeYear of TransplantP*
1976-19801981-19871988-1992
Graft failure (5 yr) 20% ± 7% 11% ± 3% 16% ± 4% NS 
Grade II-IV acute GVHD (100 d) 39% ± 8% 37% ± 4% 19% ± 4% .0001 
Chronic GVHD (5 yr) 37% ± 10% 47% ± 5% 32% ± 5% .001 
Interstitial pneumonia (1 yr) 26% ± 7% 15% ± 3% 11% ± 3% .0002 
Survival (5 yr) 48% ± 7% 61% ± 4% 66% ± 6% .0001 
OutcomeYear of TransplantP*
1976-19801981-19871988-1992
Graft failure (5 yr) 20% ± 7% 11% ± 3% 16% ± 4% NS 
Grade II-IV acute GVHD (100 d) 39% ± 8% 37% ± 4% 19% ± 4% .0001 
Chronic GVHD (5 yr) 37% ± 10% 47% ± 5% 32% ± 5% .001 
Interstitial pneumonia (1 yr) 26% ± 7% 15% ± 3% 11% ± 3% .0002 
Survival (5 yr) 48% ± 7% 61% ± 4% 66% ± 6% .0001 
*

Log-rank test for trend.

Patients.A total of 1,577 patients receiving an HLA-identical sibling transplant for severe aplastic anemia between 1976 and 1992 were reported to the International Bone Marrow Transplant Registry (IBMTR) by 179 teams worldwide. Congenital forms of aplastic anemia were not considered. Of these patients, 1,305 had ≥2 of the following criteria for severe bone marrow failure: (1) a granulocyte count of less than 0.5 × 109/L; (2) a platelet count of less than 20 × 109/L; and (3) a hemoglobin level of less than 80 g/L or a hematocrit level of less than 20% or a reticulocyte count of less than 50 × 109/L. Patients were considered eligible if they met ≥2 criteria at time of diagnosis and/or pretransplantation. Two hundred and seventy-two patients were excluded, 131 because of insufficient data regarding pretransplantation hematologic parameters and 141 because they met only one or none of these criteria.

Patient-, disease-, and transplant-related characteristics of the 1,305 patients studied are shown in Table 1.

Outcomes.The primary study endpoint was survival. Graft failure was analyzed in patients surviving ≥21 days posttransplantation using published criteria.20 Acute GVHD (grade II-IV) was defined using published criteria35; patients surviving ≥21 days with engraftment were considered at risk. Chronic GVHD was defined by published criteria21; patients surviving ≥90 days posttransplantation with engraftment were considered at risk. Interstitial pneumonia was defined using published criteria36,37; etiology was determined by bronchoalveolar lavage, biopsy, or autopsy in 75% of cases.

Statistical methods.Patients were divided into three cohorts based on year of transplantation, using Cox proportional hazards regression to determine the time periods that best modeled changes in survival over time. Multiple cutpoints were examined and those giving the largest partial likelihood were selected: 1976 through 1980, 1981 through 1987, and 1988 through 1992. Within each of these intervals, survival by year of transplantation was relatively constant.

Patient-, disease-, and treatment-related variables in Table 1 were compared among the cohorts using the χ2 test for discrete variables and the Kruskall-Wallis test for continuous variables. Probabilities of graft failure, acute and chronic GVHD, interstitial pneumonia, and survival were calculated using the Kaplan-Meier estimator. A log-rank test for trend was used to determine if the three groups were ordered for increasing survival and decreasing graft failure, acute and chronic GVHD, and interstitial pneumonia.

A Cox model was fit, using a forward stepwise selection procedure to evaluate the impact of patient-, disease-, and transplant-related variables on survival.38 Data for some variables were collected only after 1985 and therefore were not available for all cohorts. The year of transplantation was included in all steps of model selection, which used a P ≤ .05 significance level for inclusion of other variables. Four models were constructed: (1) including only year of transplantation; (2) including year of transplantation and patient- and disease-related variables; (3) including year of transplantation and patient-, disease-, and treatment-related variables available for most patients; and (4) including year of transplantation and all patient-, disease-, and treatment-related variables. The last model included only patients undergoing transplantation in 1986 or later for whom all variables were available and evaluated only two time periods (1986-1987 and 1988-1992).

Table 3.

Relative Risk of Death After HLA-Identical Sibling Bone Marrow Transplantations for Severe Aplastic Anemia Between 1976 and 1992

VariableNo AdjustmentAdjusted for Patient and Disease-Related VariablesAdjusted for Patient-,
Relative Risk95% CIRelative Risk95% CIDisease-, and Transplant-
Related Variables
Relative Risk95% CI
Year of transplant 
1976-1980 1.003-150  —  1.003-150  —  1.003-150  —  
1981-1987 (≤3 mo) 0.533-151 0.40-0.71 0.553-151 0.41-0.73 0.703-152 0.52-0.95 
1988-1992 (≤3 mo) 0.253-151 0.18-0.36 0.253-151 0.18-0.36 0.423-151 0.27-0.65 
1981-1987 (>3 mo) 0.91 0.60-1.36 0.93 0.62-1.40 1.16 0.76-1.76 
1988-1992 (>3 mo) 1.08 0.71-1.66 1.04 0.68-1.59 1.683-152 1.03-2.74 
Increasing age (per yr of age)   1.023-151 1.02-1.03 1.023-151 1.01-1.03 
>20 Transfusions (v ≤20 transfusion)   1.583-151 1.29-1.92 1.653-151 1.35-2.02 
Prior treatment (v no prior treatment)    —  NS  —  NS 
Time to transplant >2 mo (v ≤2 mo)   1.363-151 1.04-1.76 1.353-152 1.04-1.75 
Neutrophils <0.2 × 109/L (v ≥0.2 × 109/L)    —  NS  —  NS 
Donor-recipient sex-mismatch (v sex-match)     1.29ρ 1.08-1.54 
Cell dose ≥3 × 108/kg (v <3 × 108/kg)      —  NS 
Buffy coat cells (v no buffy coat cells)     1.253-152 1.02-1.54 
Conditioning regimen3-154      —  NS 
GVHD prophylaxis 
MTX + CSA     1.00  —  
CSA     1.19 0.91-1.56 
MTX     1.713-155 1.25-2.34 
T-cell depletion     0.86 0.45-1.66 
Other3-167     4.163-151 2.38-7.28 
VariableNo AdjustmentAdjusted for Patient and Disease-Related VariablesAdjusted for Patient-,
Relative Risk95% CIRelative Risk95% CIDisease-, and Transplant-
Related Variables
Relative Risk95% CI
Year of transplant 
1976-1980 1.003-150  —  1.003-150  —  1.003-150  —  
1981-1987 (≤3 mo) 0.533-151 0.40-0.71 0.553-151 0.41-0.73 0.703-152 0.52-0.95 
1988-1992 (≤3 mo) 0.253-151 0.18-0.36 0.253-151 0.18-0.36 0.423-151 0.27-0.65 
1981-1987 (>3 mo) 0.91 0.60-1.36 0.93 0.62-1.40 1.16 0.76-1.76 
1988-1992 (>3 mo) 1.08 0.71-1.66 1.04 0.68-1.59 1.683-152 1.03-2.74 
Increasing age (per yr of age)   1.023-151 1.02-1.03 1.023-151 1.01-1.03 
>20 Transfusions (v ≤20 transfusion)   1.583-151 1.29-1.92 1.653-151 1.35-2.02 
Prior treatment (v no prior treatment)    —  NS  —  NS 
Time to transplant >2 mo (v ≤2 mo)   1.363-151 1.04-1.76 1.353-152 1.04-1.75 
Neutrophils <0.2 × 109/L (v ≥0.2 × 109/L)    —  NS  —  NS 
Donor-recipient sex-mismatch (v sex-match)     1.29ρ 1.08-1.54 
Cell dose ≥3 × 108/kg (v <3 × 108/kg)      —  NS 
Buffy coat cells (v no buffy coat cells)     1.253-152 1.02-1.54 
Conditioning regimen3-154      —  NS 
GVHD prophylaxis 
MTX + CSA     1.00  —  
CSA     1.19 0.91-1.56 
MTX     1.713-155 1.25-2.34 
T-cell depletion     0.86 0.45-1.66 
Other3-167     4.163-151 2.38-7.28 

Abbreviations: CI, confidence interval; NS, not significant.

F3-150

Baseline.

F3-151

P < .0001.

F3-152

P < .05.

ρ P < .01.

F3-155

P < .001.

F3-154

Categories considered: cyclophosphamide alone, Cy + ATG, Cy + TBI, Cy + LFR, and other.

F3-167

Other means corticosteroids, no GVHD prophylaxis.

Table 4.

Relative Risk of Death After HLA-Identical Sibling Bone Marrow Transplantations for Severe Aplastic Anemia Between 1986 and 1992

VariableAdjusted for Patient-, Disease-, and Transplant-Related Variables
Relative Risk95% CI
Year of transplant 
1986-1987 1.004-150  —  
1988-1992 (≤3 mo) 0.564-151 0.37-0.84 
1988-1992 (>3 mo) 1.48 0.96-2.30 
Increasing age (per yr of age) 1.024-151 1.01-1.03 
Neutrophils (<0.2 × 109/L v ≥0.2 × 109/L)  —  NS 
>20 Transfusions (v ≤20 transfusions) 2.06 1.50-2.83 
Prior treatment (v no prior treatment)  —  NS 
Time to transplant >2 mo (v ≤2 mo)  —  NS 
Donor-recipient sex-mismatch (v sex-match)  —  NS 
Cell dose ≥3 × 108/kg (v <3 × 108/kg)  —  NS 
Buffy coat cells (v no buffy coat cells)  —  NS 
Conditioning regimen4-155  —  NS 
Intravenous immune globulins (v no intravenous immune globulins) 0.59ρ 0.42-0.79 
Systemic antibiotics (v no antibiotics)  —  NS 
Cotrimoxazole (v no cotrimoxazole) 0.664-151 0.50-0.89 
Acyclovir (v no acyclovir)  —  NS 
Growth factor4-154 (v no growth factors)  —  NS 
HEPA/LAF (v no HEPA/LAF)  —  NS 
GVHD prophylaxis 
MTX + CSA 1.004-150  —  
CSA 1.15 0.85-1.56 
MTX 2.404-151 1.33-4.34 
T-cell depletion 0.65 0.26-1.59 
Other4-167 5.82 2.65-12.77 
VariableAdjusted for Patient-, Disease-, and Transplant-Related Variables
Relative Risk95% CI
Year of transplant 
1986-1987 1.004-150  —  
1988-1992 (≤3 mo) 0.564-151 0.37-0.84 
1988-1992 (>3 mo) 1.48 0.96-2.30 
Increasing age (per yr of age) 1.024-151 1.01-1.03 
Neutrophils (<0.2 × 109/L v ≥0.2 × 109/L)  —  NS 
>20 Transfusions (v ≤20 transfusions) 2.06 1.50-2.83 
Prior treatment (v no prior treatment)  —  NS 
Time to transplant >2 mo (v ≤2 mo)  —  NS 
Donor-recipient sex-mismatch (v sex-match)  —  NS 
Cell dose ≥3 × 108/kg (v <3 × 108/kg)  —  NS 
Buffy coat cells (v no buffy coat cells)  —  NS 
Conditioning regimen4-155  —  NS 
Intravenous immune globulins (v no intravenous immune globulins) 0.59ρ 0.42-0.79 
Systemic antibiotics (v no antibiotics)  —  NS 
Cotrimoxazole (v no cotrimoxazole) 0.664-151 0.50-0.89 
Acyclovir (v no acyclovir)  —  NS 
Growth factor4-154 (v no growth factors)  —  NS 
HEPA/LAF (v no HEPA/LAF)  —  NS 
GVHD prophylaxis 
MTX + CSA 1.004-150  —  
CSA 1.15 0.85-1.56 
MTX 2.404-151 1.33-4.34 
T-cell depletion 0.65 0.26-1.59 
Other4-167 5.82 2.65-12.77 

Abbreviation: NS, not significant.

F4-150

Baseline.

F4-151

P < .01.

P < .0001.

ρ P < .001.

F4-155

Categories considered: cyclophosphamide alone, Cy + ATG, Cy + TBI, Cy + LFR, and other.

F4-154

Granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor administered within 1 week of transplantation.

F4-167

Other means corticosteroids, no GVHD prophylaxis.

For all covariates in the final models, the assumption of proportional hazards was tested using time-dependent covariates. We found that year of transplantation did not meet the assumption of proportional hazards, because it affected early (≤3 months) but not late (>3 months) posttransplantation survival, ie, the relative effect was not constant at all time points. Consequently, year of transplantation was modeled as a time-dependent covariate, considering its effect on early and late survival separately. Within the two posttransplantation time periods (≤3 and >3 months posttransplantation), the proportionality assumption held. Because of multiple comparisons, we considered only P values less than .01 to be statistically significant.39 

The three time periods that best modeled changes in posttransplantation survival were 1976-1980 (n = 186), 1981-1987 (n = 648), and 1988-1992 (n = 471). Five-year probabilities (±95% confidence interval) of survival for the three cohorts were 48% ± 7%, 61% ± 4%, and 66% ± 6%, respectively (P < .0001, Fig 1). Probabilities of graft failure, grade II-IV acute GVHD, chronic GVHD, and interstitial pneumonia are shown in Table 2. There was no significant change in the risk of graft failure over time. Risks of acute and chronic GVHD and interstitial pneumonia were significantly lower in more recent transplant recipients.

Table 1 shows patient-, disease-, and transplant-related variables for the three cohorts. Statistically significant differences over time were noted for etiology of aplastic anemia, severity of granulocytopenia, and extent and type of treatment of aplastic anemia before transplantation. Transplant characteristics significantly different among the three cohorts were pretransplantation conditioning, GVHD prophylaxis, use of donor buffy coat cells posttransplantation, and type of isolation.

A univariate Cox proportional hazards regression model showed significant differences in survival by year of transplantation with decreased risks of death in the first 3 months posttransplantation for cohorts transplanted in 1981-1987 (relative risk in first 3 months [95% confidence interval], 0.53 [0.40 to 0.71]) and in 1988-1992 (relative risk in first 3 months, 0.25 [0.18 to 0.36]) compared with the cohort undergoing transplanted in 1976-1980 (Table 3). The difference in risk of early death between the 1981-1987 and the 1988-1992 cohort was also statistically significant (P < .0001). The risk of death greater than 3 months posttransplantation did not differ by year of transplantation. A second model adjusting for patient- and disease-related characteristics showed the same association between year of transplantation and early survival (Table 3). In a third model, adjustment for treatment-related variables reduced the association between year of transplantation and survival to borderline statistical significance for the 1981-1987 cohort but not for the 1988-1992 cohort (Table 3). Consideration of treatment-related variables also led to a borderline association between year of transplantation and late risks of death for the 1988-1992 cohort. Adjusting for supportive care variables available for the period 1986-92 did not significantly alter results (Table 4). Patients transplanted in 1988-1992 had an early survival advantage with a relative risk of death of 0.49 (0.28 to 0.85; P = .01) compared with patients transplanted in 1986-1987 even after adjusting for transplantation regimen and supportive care; late risks of death were similar. Although none of the variables examined fully explained the improvement in outcome over time, several were significantly associated with posttransplantation survival, including age (P < .0001), number of pretransplantation transfusions (P < .0001), interval between diagnosis and transplantation (P = .03), donor-recipient sex-match (P = .006), donor buffy coat cells posttransplantation (P = .03), GVHD prophylaxis regimen (P = .0001), use of intravenous immune globulins (P = .0006), and cotrimoxazole (P = .004). Neither pretransplantation conditioning nor center size (number of transplantations performed annually) were statistically significant variables.

There were two major findings in this study. First, survival after HLA-identical sibling transplants increased from 48% in 1976-1980 to 66% in 1988-1992. This is consistent with reports from both single centers and the European Group for Blood and Marrow Transplantation.15,40 41 This increase reflects reduced early mortality associated with decreased risks of GVHD and interstitial pneumonia. Risk of graft failure was unchanged.

Second, although some patient- and disease-related variables changed over time, they did not explain changes in survival. Some, but not all, changes in treatment strategies contributed to improved survival, particularly GVHD prophylaxis using CSA. However, none of the variables or combination of the variables examined fully explained the improvement in survival observed during the study period.

In addition to reduced early mortality, the fully adjusted models also show somewhat higher late mortality risks in the 1988-1992 cohort, albeit of borderline significance. A possible explanation is that, for some patients, strategies that improved early survival may have simply delayed death beyond 3 months posttransplantation. For example, some patients with severe acute GVHD may now survive the early posttransplantation period only to later succumb from complications of chronic GVHD.

Changes in conditioning regimens, generally intensification to reduce graft failure, were not associated with improved survival. Decreased graft failure with more intensive conditioning has generally been offset by increased mortality from interstitial pneumonia and GVHD and a higher incidence of second cancers.20,42,43 Adding ATG to cyclophosphamide also did not improve survival, although the numbers of patients receiving ATG in this study were small. This contrasts with a recent report that conditioning with ATG and cyclophosphamide increased survival compared with historical controls treated with cyclophosphamide alone, although the benefit in that study was in decreased chronic GVHD and interstitial pneumonia rather than graft failure.16 Our study suggests that using historical controls may create a bias even after adjusting for patient-, disease-, and treatment-related factors. A randomized trial by the IBMTR comparing cyclophosphamide with or without ATG is in progress.

Cotrimoxazole prophylaxis and intravenous immune globulins were strongly associated with improved survival. In previous studies, intravenous immune globulins decreased GVHD, interstitial pneumonia, hepatic veno-occlusive disease, and transplantation-related mortality after transplantations for leukemia.44 45 This is the first time a benefit of immune globulins is reported in transplantations for aplastic anemia.

A previous IBMTR study showed that T-cell–depleted transplantations for aplastic anemia were associated with increased risks of graft failure.20 In the present study, survival of patients receiving T-cell–depleted transplants was comparable to patients receiving non — T-cell–depleted transplants with posttransplantation MTX and CSA. The number of patients receiving T-cell–depleted transplants was small (n = 43), and all but five received radiation as part of the conditioning regimen, making it difficult to draw any conclusions about the effects of T-cell depletion on outcome. Eleven of 39 evaluable patients receiving T-cell–depleted transplants had graft failure but some were rescued successfully with second transplants; 33 patients were alive at last follow-up.

None of our models fully explains changes in survival over time. Even the model adjusting for all available supportive care variables shows an independent effect of year of transplantation, with more recently treated patients having better survival. This finding suggests that there are other unmeasured factors contributing to improved survival. Possibilities include better transfusion support both pretransplantation and posttransplantation, including more frequent use of filtered, leukocyte-depleted blood products,46 new antibacterial and antifungal antibiotics, and other measures.

In summary, survival after transplantations for aplastic anemia has improved over the past 15 years. The data we review suggest that use of CSA for GVHD prophylaxis was an important factor in this progress. However, some of the improvement results from unknown factors. This underscores the need for concurrent controls to evaluate new strategies of bone marrow transplantation for aplastic anemia.

Submitted June 10, 1996; accepted March 7, 1997.

Supported by Public Health Service Grant No. PO1-CA-40053 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute of the US Department of Health and Human Services; and by grants from Alpha Therapeutic Corp; Amgen, Inc; anonymous; Astra Pharmaceutical; Basel Cancer League, Switzerland; Baxter Healthcare Corp; Bayer Corp; Biogen; Blue Cross and Blue Shield Association; Lynde and Harry Bradley Foundation; Bristol-Myers Squibb Co; Frank G. Brotz Family Foundation; Cancer Center, Medical College of Wisconsin; CellPro, Inc; Centeon; Center for Advanced Studies in Leukemia; Chimeric Therapies, Inc; Ciba-Geigy Jubilaeums Foundation, Switzerland; Charles E. Culpeper Foundation; Eleanor Naylor Dana Charitable Trust; Eppley Foundation for Research; Free Academic Society, Basel, Switzerland; Genentech, Inc; Glaxo Wellcome Co; Hoechst Marion Roussel, Inc; Immunex Corp; Janssen Pharmaceutica; Kettering Family Foundation; Kirin Brewery Co; Robert J. Kleberg, Jr and Helen C. Kleberg Foundation; Herbert H. Kohl Charities, Inc; Eli Lilly Co Foundation; Nada and Herbert P. Mahler Charities; Milstein Family Foundation; Milwaukee Foundation/Elsa Schoeneich Research Fund; Samuel Roberts Noble Foundation; Ortho Biotech Corp; John Oster Family Foundation; Elsa U. Pardee Foundation; Jane and Lloyd Pettit Foundation; Alirio Pfiffer Bone Marrow Transplant Support Association; Pfizer, Inc; Pharmacia and Upjohn; RGK Foundation; Sandoz Pharmaceuticals; Schering-Plough International; Walter Schroeder Foundation; Searle; Stackner Family Foundation; Starr Foundation; Joan and Jack Stein Charities; Swiss National Science Foundation; and Wyeth-Ayerst Laboratories.

Address reprint requests to Mary M. Horowitz, MD, MS, International Bone Marrow Transplant Registry, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.

1
Storb
R
Thomas
ED
Buckner
CD
Clift
RA
Johnson
FL
Fefer
A
Glucksberg
H
Giblett
ER
Lerner
KG
Neiman
P
Allogeneic marrow grafting for treatment of aplastic anemia.
Blood
43
1974
157
2
Young
NS
Barrett
AJ
The treatment of severe acquired aplastic anemia.
Blood
85
1995
3367
3
Santos
GW
Sensenbrenner
LL
Anderson
PN
Burke
PJ
Klein
DL
Slavin
RE
Schacter
B
Bargaonhan
DS
HLA-identical marrow transplantation in aplastic anemia, acute leukemia, and lymphosarcoma employing cyclophosphamide.
Transplant Proc
8
1976
607
4
Bortin
MM
Gale
RP
Rimm
AA
Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia.
JAMA
245
1981
1132
5
Camitta
BM
Thomas
ED
Nathan
DG
Gale
RP
Kopecky
KJ
Rappeport
JM
Santos
G
Gordon-Smith
EC
Storb
R
A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia.
Blood
53
1979
504
6
Hows
JM
Palmer
S
Gordon-Smith
EC
Use of cyclosporin A in allogeneic bone marrow transplantation for severe aplastic anemia.
Transplantation
33
1982
382
7
Storb
R
Doney
KC
Thomas
ED
Appelbaum
F
Buckner
CD
Clift
RA
Deeg
HJ
Goodell
W
Hackman
R
Hansen
JA
Sanders
J
Sullivan
K
Weiden
PL
Witherspoon
RP
Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients.
Blood
59
1982
236
8
Feig
SA
Champlin
R
Arenson
E
Yale
C
Ho
W
Tesler
A
Gale
RP
Improved survival following bone marrow transplantation for aplastic anemia.
Br J Haematol
54
1983
509
9
Ramsay
WKC
Kim
TH
Nesbit
ME
Krivit
W
Coccia
P
Levitt
S
Woods
W
Kersey
JH
Total lymphoid irradiation and cyclophosphamide as preparation for bone marrow transplantation in severe aplastic anemia.
Blood
55
1980
344
10
Bayever
E
Champlin
R
Ho
W
Lenarsky
C
Storch
S
Ladish
J
Comparison between bone marrow transplantation and antithymocyte globulin in treatment of young patients with severe aplastic anemia.
J Pediatr
105
1984
920
11
Storb
R
Deeg
HJ
Farewell
V
Doney
K
Appelbaum
F
Beatty
P
Bensinger
W
Buckner
CD
Clift
R
Hansen
J
Hill
R
Longton
G
Lum
L
Martin
P
McGuffin
R
Sanders
J
Singer
J
Stewart
P
Sullivan
K
Witherspoon
R
Thomas
ED
Marrow transplantation for severe aplastic anemia: Methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute-graft-versus host disease.
Blood
69
1986
119
12
Gluckman
E
Devergie
A
Meletis
J
Traineau
R
Vilmer
E
Lehn
P
Keable
H
Bourhis
JH
Varrin
F
Bone marrow transplantation for severe aplastic anemia: Report of 97 consecutive patients.
Bone Marrow Transplant
2
1987
101
13
Anasetti
C
Storb
R
Longton
G
Witherspoon
R
Doney
K
Sullivan
KM
Thomas
ED
Donor buffy coat cell infusion after marrow transplantation for aplastic anemia.
Blood
72
1988
1099
14
Locasciulli
A
van't Veer
L
Bacigalupo
A
Hows
J
Van Lint
MT
Gluckman
E
Nissen
C
McCann
S
Vossen
J
Schrezenmeier
A
Hinterberger
W
Marin
A
Treatment with marrow transplantation or immunosuppression of childhood acquired severe aplastic anemia: A report from the EBMT SAA Working Party.
Bone Marrow Transplant
6
1990
211
15
Paquette
RL
Tebyani
N
Frane
M
Ireland
P
Ho
WG
Champlin
RE
Nimer
SD
Long-term outcome of aplastic anemia in adults treated with antithymocyte globulin: Comparison with bone marrow transplantation.
Blood
85
1995
283
16
Storb
R
Etzioni
R
Anasetti
C
Appelbaum
FR
Buckner
CD
Bensinger
W
Bryant
E
Clift
R
Deeg
HJ
Doney
K
Flowers
M
Hansen
J
Martin
P
Pepe
M
Sale
G
Sanders
J
Singer
J
Sullivan
KM
Thomas
ED
Witherspoon
RD
Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia.
Blood
84
1994
941
17
Marsh
JC
Socié
G
Schrezenmeier
H
Tichelli
A
Gluckman
E
Ljungman
P
McCann
SR
Raghavachar
A
Marin
P
Hows
JM
Haemopoietic growth factors in aplastic anaemia: A cautionary note. European Bone Marrow Transplant Working Party for Severe Aplastic Anaemia.
Lancet
344
1994
172
18
Storb R, Longton G, Anasetti C, Appelbaum FR, Beatty P, Bensinger W, Crawford S, Deeg HJ, Doney K, Fefer A, Hansen J, Loughran T, Martin P, Pepe M, Petersen FB, Sanders JE, Singer J, Stewart P, Sullivan KM, Thomas ED, Witherspoon RP. Changing trends in marrow transplantation for aplastic anemia. Bone Marrow Transplant 10:45, 1992 (suppl 1)
19
McCann
SR
Bacigalupo
A
Gluckman
E
Hinterberger
W
Hows
J
Ljungman
P
Marin
P
Nissen
C
van't Veer
Kerthof E
Raghavachar
A
Socié
G
Frickhofen
N
Locasciulli
A
Schrezenmeier
H
Graft rejection and second bone marrow transplants for acquired aplastic anaemia: A report from the Aplastic Anaemia Working Party of the European Bone Marrow Transplant Group.
Bone Marrow Transplant
13
1994
233
20
Champlin
RE
Horowitz
MM
van Bekkum
DW
Camitta
BM
Elfenbein
GE
Gale
RP
Gluckman
E
Good
RA
Rimm
AA
Rozman
C
Speck
B
Bortin
MM
Graft failure following bone marrow transplantation for severe aplastic anemia: Risk factors and treatment results.
Blood
73
1989
606
21
Atkinson
K
Horowitz
MM
Gale
RP
Van Bekkum
DW
Gluckman
E
Good
RA
Jacobsen
N
Kolb
HJ
Rimm
AA
Ringdén
O
Rozman
C
Sobocinski
KA
Zwaan
FE
Bortin
MM
Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation.
Blood
75
1990
2459
22
Gluckman
E
Horowitz
MM
Hows
JM
Bacigalupo
A
Biggs
JC
Champlin
RE
Camitta
BM
Gale
RP
Gordon-Smith
EC
Marmont
AM
Masaoka
T
Ramsay
NKC
Rimm
AA
Rozman
C
Sobocinski
KA
Speck
B
Bortin
MM
Bone marrow transplantation for severe aplastic anemia: Influence of conditioning regimens on outcome.
Blood
79
1992
269
23
Castro-Malaspina
H
Childs
B
Laver
J
Shank
B
Brochstein
J
Gillio
A
Flomenberg
N
Young
J
Boulad
F
Black
P
Kernan
N
Fuchs
Z
O'Reilly
R
Hyperfractionated total lymphoid irradiation and cyclophosphamide for preparation of previously transfused patients undergoing HLA-identical marrow transplantation for severe aplastic anemia.
Int J Radiat Oncol Biol Phys
29
1994
847
24
Gluckman
E
Socié
G
Devergie
A
Bourdeau-Esperou
H
Traineau
R
Cosset
JM
Bone marrow transplantation in 107 patients with severe aplastic anemia using cyclophosphamide and thoraco-abdominal irradiation for conditioning: Long-term follow-up.
Blood
78
1991
2451
25
May
WS
Sensenbrenner
LL
Burns
WH
Ambinder
R
Carroll
MP
Griffin
CA
Jones
RJ
Miller
CB
Mellits
ED
Vogelsang
GB
Wagner
JE
Wingard
JR
Yeager
AM
Santos
GW
BMT for severe aplastic anemia using cyclosporine.
Bone Marrow Transplant
11
1993
459
26
Storb
R
Deeg
HJ
Pepe
M
Doney
K
Appelbaum
F
Beatty
P
Bensinger
W
Buckner
CD
Clift
R
Hansen
J
Graft-versus-host disease prevention by methotrexate combined with cyclosporin compared to methotrexate alone in patients given marrow grafts for severe aplastic anaemia: Long-term follow-up of a controlled trial.
Br J Haematol
72
1989
567
27
Sullivan
KM
Meyers
J
Petersen
FB
Bowden
R
Counts
GC
Banaji
M
Schubert
M
Clark
J
Clift
RA
Appelbaum
FR
Bensinger
WI
Stewart
P
Storb
R
Thomas
ED
Buckner
CD
Supportive care of the marrow transplant recipient: the Seattle Experience.
Haematol Bluttransfus
33
1990
539
28
Poe
SS
Larson
E
McGuire
D
Krumm
S
A national survey of infection prevention practices on bone marrow transplant units.
Oncol Nurs Forum
21
1994
1687
29
Prentice
HG
Gluckman
E
Powles
RL
Ljungman
P
Milpied
N
Fernandez
Ranada JM
Mandelli
F
Kho
P
Kennedy
L
Bell
AR
Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group.
Lancet
343
1994
749
30
Wingard JR: Viral infections in leukemia and bone marrow transplant patients. Leuk Lymphoma 11:115, 1993 (suppl 2)
31
Ljungman
P
De Bock
R
Cordonnier
C
Einsele
H
Engelhard
D
Grundy
J
Locasciulli
A
Reusser
P
Ribaud
P
Practices for cytomegalovirus diagnosis, prophylaxis and treatment in allogeneic bone marrow transplant recipients: A report from the Working Party for Infectious Diseases of the EBMT.
Bone Marrow Transplant
12
1993
399
32
Winston
DJ
Prophylaxis and treatment of infection in the bone marrow transplant recipient.
Curr Clin Top Infect Dis
13
1993
293
33
Hoyle
C
Goldman
JM
Life-threatening infections occurring more than 3 months after BMT. 18 UK Bone Marrow Transplant Teams.
Bone Marrow Transplant
14
1994
247
34
Storb
R
Prentice
RL
Buckner
CD
Clift
R
Appelbaum
F
Deeg
HJ
Doney
K
Hansen
J
Mason
M
Sanders
JE
Singer
J
Sullivan
KM
Witherspoon
RP
Thomas
ED
Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow graft from HLA-identical siblings. Beneficial effect of a protective environment.
N Engl J Med
308
1983
302
35
Glucksberg
H
Storb
R
Fefer
A
Buckner
CD
Neiman
PE
Clift
RA
Lerner
KG
Thomas
ED
Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors.
Transplantation
18
1974
295
36
Weiner
RS
Horowitz
MM
Gale
RP
Dicke
KA
van Bekkum
DW
Masaoka
T
Ramsay
NKC
Rimm
AA
Rozman
C
Bortin
MM
Risk factors for interstitial pneumonia following bone marrow transplantation for severe aplastic anaemia.
Br J Haematol
71
1989
535
37
Weiner
RS
Bortin
MM
Gale
RP
Gluckman
E
Kay
HE
Kolb
HJ
Hartz
AJ
Rimm
AA
Interstitial pneumonitis after bone marrow transplantation. Assessment of risk factors.
Ann Intern Med
104
1986
168
38
Cox
DR
Regression models and life tables.
J Roy Stat Soc B
34
1972
187
39
Smith
DG
Clemins
J
Crede
W
Harvey
M
Gracely
EJ
Impact of multiple comparisons in randomized clinical trials.
Am J Med
83
1987
545
40
Storb
R
Bone marrow transplantation for aplastic anemia.
Cell Transplant
2
1994
365
41
Bacigalupo A: Severe Aplastic Anaemia Working Party, in EBMT Working Parties Reports. Harrowgate, UK, European Group for Bone Marrow Transplantation, 1994, p 49
42
Socié
G
Henry-Amar
M
Bacigalupo
A
Hows
J
Tichelli
A
Ljungman
P
McCann
SR
Frickhofen
N
Van't Veer-Korthof
E
Gluckman
E
Malignant tumors occurring after treatment of aplastic anemia. European Bone Marrow Transplantation-Severe Aplastic Anaemia Working Party.
N Engl J Med
329
1993
1152
43
Pierga
JY
Socié
G
Gluckman
E
Devergie
A
Henry-Amar
M
Bridier
A
Girinsky
T
Nguyen
J
Cosset
JM
Secondary solid malignant tumors occurring after bone marrow transplantation for severe aplastic anemia given thoraco-abdominal irradiation.
Radiother Oncol
30
1994
55
44
Siadak MF, Kopecky K, Sullivan KM: Reduction in transplant-related complications in patients given intravenous immune globulin after allogeneic marrow transplantation. Clin Exp Immunol 97:53, 1994 (suppl 1)
45
Sullivan
KM
Kopecky
KJ
Jocom
J
Fisher
L
Buckner
CD
Meyers
JD
Counts
GW
Bowden
RA
Peterson
FB
Witherspoon
RP
Budinger
MD
Schwartz
RS
Appelbaum
FR
Clift
RA
Hansen
JA
Sanders
JE
Thomas
ED
Storb
R
Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation.
N Engl J Med
323
1990
705
46
Bordin
JO
Heddle
NM
Blajchman
MA
Biologic effects of leukocytes present in transfused cellular blood products.
Blood
83
1994
1703

Author notes

 Deceased.

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