Volume 17, Issue 5 , Pages 703-709, May 2011
Evaluating the Impact of Antithymocyte Globulin on Lung Function at 1 Year after Allogeneic Stem Cell Transplantation
Article Outline
The use of antithymocyte globulin (ATG) in hematopoietic stem cell transplantation (HSCT) conditioning regimens has reduced the incidence of graft-versus-host disease, particularly in its chronic form. The impact of this approach on the prevention of lung dysfunction has not been well characterized, however. We performed a retrospective analysis of pulmonary function in patients who underwent HSCT after conditioning with oral busulfan followed by either cyclophosphamide or fludarabine with or without the addition of ATG. A total of 393 patients were included; 75 patients received ATG, and 318 did not. No differences between the 2 groups were seen in the mean percentage of the predicted values for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), total lung capacity, and lung CO diffusing capacity at 80 days or 1 year after transplantation. However, the mean value of FEV1/FVC ratio at 1 year was higher in the patients who received ATG. The difference in mean change in pulmonary function parameters from baseline to 1 year post-HSCT was statistically nonsignificant for all parameters except FEV1/FVC ratio, which demonstrated less decline in the ATG group. The risk of developing severe airflow obstruction or a restrictive pattern was similar in the 2 treatment groups at 1 year post-HSCT. Incorporation of ATG into the HSCT conditioning regimen provided protection against a decline in FEV1/FVC ratio but did not decrease the risk of other pulmonary events that we evaluated within the first year after HSCT. Further evaluations in larger numbers of patients are needed to better clarify the role of ATG in the development of delayed pulmonary complications.
Key Words: Pulmonary complications, Bone marrow Transplantation, Thymoglobulin
Introduction
Pulmonary complications represent a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), developing in 40%-60% of recipients 1, 2. Although some of these complications are related to infections, many are due to noninfectious complications, such as pulmonary edema, diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, and bronchiolitis obliterans 3, 4. The latter, which represents a pulmonary manifestation of chronic graft-versus-host disease (GVHD), is reflected by significant decreases in lung function after HSCT 5, 6, 7, 8, 9, 10. Some studies indicate that the use of reduced-intensity conditioning or T cell–depleted transplants might reduce the incidence of bronchiolitis obliterans syndrome, supporting the hypothesis that the conditioning regimen influences the risk for development of late pulmonary complications [11]. Indeed, it has been suggested that allogeneic HSCT with reduced-intensity conditioning regimens may protect against declining lung function by reducing tissue damage secondary to intensive chemoradiotherapy [12].
GVHD is the main risk factor for significant lung function deterioration after HSCT [13]. In an effort to reduce the incidence of GVHD, several studies have incorporated antithymocyte globulin (ATG) into conditioning regimens. Available data suggest that this strategy is associated with a lower incidence not only of acute and chronic GVHD 14, 15, 16, 17, but also possibly of chronic lung dysfunction [18]. However, patients receiving ATG experience a more prolonged period of immune deficiency and thus may be more prone to infectious complications.
Based on previous reports of a potential beneficial effect of ATG on lung function, we conducted a retrospective analysis of multiple pulmonary outcomes in patients who received ATG as part of a conditioning regimen. Our aim was to evaluate the potential impact of ATG on the development of pulmonary complications within the first year post-HSCT.
Methods
Patient Selection
This was a retrospective analysis of data collected prospectively on patients who underwent allogeneic HSCT at Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA) between January 2001 and December 2005. Since a wide variety of conditioning regimens was used, we restricted this analysis to patients who received busulfan (BU) in combination with either cyclophosphamide (CY) or fludarabine (FLU). Only first transplantations after high-dose conditioning were included. Rabbit ATG in the form of thymoglobulin was administered on days -3 to -1 to a total dose of 4.5-6 mg/kg as described previously [14], with the aim of reducing the incidence of GVHD. Additional GVHD prophylaxis consisted of methotrexate in combination with either cyclosporine or tacrolimus. Patients without data on pretransplantation pulmonary function tests (PFTs) (n = 11) were excluded. Throughout the study period, all patients with radiographic signs of lower tract airway infection underwent bronchoalveolar lavage. Bronchoalveolar lavage specimens or biopsy or autopsy tissue (or both) were tested for respiratory viruses (respiratory syncytial virus, parainfluenza virus type 1-4, influenza virus A and B, adenovirus, and rhinovirus) by direct immunofluorescence and conventional culture [19].
Each patient’s underlying disease was categorized as standard risk or high risk, based on previously described criteria [20]. Donors were HLA-identical siblings or unrelated individuals matched for HLA-A, -B, -C, -DRB1, and -DQB1, based on high-resolution typing using sequence-specific oligonucleotide probe hybridization or sequencing. Acute GVHD was graded using standard criteria based on stages of organ involvement and categorized as acute GVHD grade 0-IV [21]. The diagnosis and staging of chronic GVHD were based on National Institutes of Health (NIH) consensus criteria [22].
Pulmonary Function Testing
All PFTs were performed at FHCRC in accordance with American Thoracic Society guidelines [23], using the Sensormedics V-Max 22 with Autobox 6200 (Sensormedics Co., Yorba Linda, CA). Published equations for adults were used to determine predicted values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), and lung carbon monoxide diffusing capacity (DLCO) [24]. All DLCO measurements were corrected for the most recent hemoglobin value obtained [25]. All PFT values, except FEV1/FVC ratio, were expressed as a percentage of predicted values and assessed categorically. Day 80 PFTs were defined as PFTs obtained at 80 ± 20 days post-HSCT, and 1-year PFTs, as those obtained at 365 ± 100 days post-HSCT. PFT findings were categorized as normal (≥80%), mildly abnormal (70%-79%), moderately abnormal (60%-69%), or severely abnormal (<60%). In accordance with NIH recommendations, a lung function score (LFS) was calculated according to the day 80 FEV1 and DLCO, each of which was categorized as follows: (1, ≥80%; 2, 70%-79%; 3, 60%-69%; 4, 50%-59%; 5, 40%-49%; 6, <40%) 13, 14. Scores for FEV1 and DLCO were then summed and categorized as 0-3 as defined by NIH recommendations (LFS score 2 = category 0 [normal]; LFS score 3-5 = category 1 [mildly abnormal]; LFS score 6-9 = category 2 [moderately abnormal]; LFS score 10-12 = category 3 [severely abnormal]).
Pulmonary function abnormalities were categorized into 2 major groups. Restrictive pattern (RP) was defined as a TLC <80% of the predicted normal and FEV1/FVC ≥ 0.7 [25]. New airflow obstruction (AFO) was defined according to recently modified NIH guidelines 26, 27: FEV1/FVC < 0.7, FEV1 ≤75%, and FEV1 decrease ≥10% from the pretransplantation level. A patient who required mechanical ventilation for >24 hours for a nonelective reason was considered to have early respiratory failure.
Statistical Methods
All statistical analyses were performed using Stata 10.0 (StataCorp, College Station, TX). A P value <.05 was considered statistically significant. For univariate analyses, categorical variables were assessed using the χ2 test, and continuous variables were assessed using the Student t test. A least-squares regression line was used to estimate the overall annualized rate of FEV1 decline from baseline to 1 year according to previously described methods [7].
Because PFTs are routinely performed at 1 year only if the patient survives to age 1 year, a multivariate logistic regression model, adjusted for covariates that might influence changes in pulmonary function (eg, age, acute and chronic GVHD, disease risk, cell source, GVHD prophylaxis) [7], was used to evaluate the association between FEV1/FVC ratio at 1 year (dichotomized as <0.7 vs ≥0.7) and ATG exposure, restricted to patients with available 1-year PFT data. A Cox proportional hazards model was used to evaluate the risk of respiratory failure and development of AFO and RP, censoring for death and relapse. The model was adjusted for other potential causes of AFO and RP (eg, age, conditioning regimen, disease risk, cell source), with acute and chronic GVHD considered time-dependent covariates. The probability of survival was estimated using the Kaplan-Meier method.
Results
Patient Characteristics
Between January 1, 2001, and December 31, 2005, a total of 404 patients underwent first allogeneic HSCT following high-dose conditioning. Eleven patients (3%) were excluded due to a lack of PFT data before transplantation, leaving 393 patients for the final analysis (75 in the ATG group and 318 in the non-ATG group). Eight patients did not receive the prescribed dose of ATG due to reactions at the time of the infusion or patient preference; 6 of these 8 patients received 3.5 mg/kg and 2 received <1 mg/kg.
Patient, transplantation, and graft characteristics, stratified by treatment group, are summarized in Table 1. The median patient age was 49 years for both the ATG group (range, 9-65 years) and the non-ATG group (range, 7-66 years). The median time of follow-up observation also was similar in the 2 groups, at 31.8 months (range, 0.6-69 months) for the ATG group and 31.3 months (range, 0.2-89.9 months) for the non-ATG group. Cyclosporine (CSP) or tacrolimus (TAC) in combination with methotrexate was the most widely used prophylaxis for GVHD; 18 patients (4%) in the non-ATG group received a different prophylaxis consisting of CSP or TAC in combination with mycophenolate mofetil. There was a nonsignificant trend for high-risk disease in the ATG group (48% vs 36%; P = .06). More patients in the non-ATG group received bone marrow as the source of stem cells (14.6% vs 5.3%; P = .03). There was a higher incidence of grade II-IV acute GVHD in the non-ATG group (71.7% vs 56%; P = .008), but no statistically significant difference between the groups for grade III-IV acute GVHD (18.7% vs 12%; P = .16). As expected, patients who received ATG were less likely to have chronic GVHD (49.1% vs 69.6%; P = .002) and had a higher incidence of lower respiratory tract viral infections in the first 100 days post-HSCT (6% vs 1%; P = .002).
Table 1. Characteristics of the 393 HSCT Recipients in the Study Cohort
| ATG (n = 75) | Non-ATG (n = 318) | P Value | |
|---|---|---|---|
| Age at transplantation, years, mean ± SD | 45.0 ± 14.2 | 46.8 ± 12.4 | .28 |
| Sex, n (%) | |||
 Female | 39 (52) | 148 (46) | .39 |
| Male | 36 (48) | 170 (54) | |
| Disease risk, n (%)∗ | |||
| Standard | 39 (52) | 203 (64) | .06 |
| High | 36 (48) | 115 (36) | |
| Donor type, n (%) | |||
| Related matched | 35 (47) | 131 (41) | .52 |
| Related mismatched | 1 (1) | 10 (3) | |
| Unrelated | 39 (52) | 177 (56) | |
| Cell source, n (%) | |||
| Bone marrow | 4 (5) | 49 (15) | .03 |
| Peripheral blood | 71 (95) | 269 (85) | |
| GVHD prophylaxis, n (%)† | |||
| Cyclosporine + methotrexate | 52 (69) | 236 (79) | .06 |
| FK506 + methotrexate | 23 (31) | 61 (20) | |
| Cytomegalovirus status, n (%) | |||
| D/R-/- | 19 (25) | 77 (24) | .67 |
| D/R-/+ | 8 (10) | 43 (14) | |
| D/R+/- | 27 (37) | 95 (30) | |
| D/R+/+ | 21 (28) | 103 (32) | |
| Respiratory viral infections, n (%) | 5 (6) | 3 (1) | .002 |
| Conditioning regimen, n (%) | |||
| BU + FLU | 10 (13) | 41 (13) | .91 |
| BU + CY | 65 (87) | 277 (87) | |
| Acute GVHD, n (%) | |||
| Grade II-IV | 42 (56) | 228 (72) | .008 |
| Grade III-IV | 9 (12) | 60 (18) | .160 |
| Chronic GVHD, n (%) | 29 (49) | 184 (70) | .002 |
∗Disease risk: Standard refers to aplastic anemia, chronic myelogenous leukemia in chronic phase, myelodysplastic syndromes without excess blasts, and leukemia and lymphoma in remission. High refers to all other hematologic malignancies. |
†In the non-ATG group, 18 patients received a different GVHD prophylaxis. |
Pulmonary Function Tests
Table 2 displays the distribution of the PFT data collected at day 80 and 1 year post-HSCT. The proportion of patients with PFT data was similar in the 2 groups at day 80 (ATG, 78.6%; non-ATG, 78.8%) and 1 year (ATG, 49.3%; non-ATG, 54.6%). The mean distribution of the predicted values of FEV1, FVC, TLC, and DLCO did not differ significantly between the 2 groups at any of the 3 time points studied. Changes in pulmonary function from baseline to 1 year were also similar in the 2 groups, with a trend toward a smaller FEV1 decrease in the ATG group (P = .08) (Table 3). The ATG group had a significantly higher mean FEV1/FVC ratio at 1 year (0.81 ± 0.05 vs 0.77 ± 0.09; P = .003), as well as a smaller change in the mean FEV1/FVC ratio (0.4 ± 3.9 vs -2.8 ± 7.3; P = .03). Univariate analysis demonstrated the beneficial effect of ATG on FEV1/FVC ratio at 1 year regardless of the conditioning regimen used (data not shown); however, when this analysis was stratified by donor type, the difference was significant only in patients who underwent transplantation from an unrelated donors (related donor: ATG, 0.79 ± 0.04; non-ATG, 0.78 ± 0.09; P = .37; unrelated donor: ATG, 0.83 ± 0.07; non-ATG, 0.77 ± 0.09; P = .002). In multivariate logistic regression analysis, which included age, acute and chronic GVHD, disease risk, cell source, and GVHD prophylaxis, dichotomization of the ratio as <0.7 versus ≥0.7 failed to show a significant difference between the 2 groups (ATG: odds ratio [OR], 4.3; 95% confidence interval [CI]0.5-35.4; P = .17).
Table 2. Pulmonary Function Data at Pretransplantation, Day 80 Posttransplantation, and 1 Year Posttransplantation
| Non-ATG | ATG | P Value | |
|---|---|---|---|
| Time of PFT | |||
| Pretransplantation | -28.4 ± 14.9 | -26.5 ± 10.1 | .29 |
| Day 80 posttransplantation | 80.2 ± 5.1 | 81.4 ± 4.5 | .10 |
| 1 year posttransplantation | 365.5 ± 34.2 | 364.7 ± 39.2 | .30 |
| FEV1 | |||
| Pretransplantation | 94.0 ± 14.1 | 93.4 ± 11.7 | .71 |
| Day 80 posttransplantation | 88.9 ± 13.9 | 87.8 ± 12.9 | .59 |
| 1 year posttransplantation | 89.5 ± 17.0 | 92.6 ± 13.1 | .31 |
| FVC | |||
| Pretransplantation | 94.0 ± 14.1 | 93.4 ± 13.1 | .71 |
| Day 80 posttransplantation | 90.7 ± 14.6 | 90.1 ± 12.6 | .75 |
| 1 year posttransplantation | 93.8 ± 14.9 | 93.9 ± 13.7 | .97 |
| FEV1/FVC ratio | |||
| Pretransplantation | 0.79 ± 0.05 | 0.80 ± 0.05 | .78 |
| Day 80 posttransplantation | 0.79 ± 0.05 | 0.79 ± 0.06 | .75 |
| 1 year posttransplantation | 0.77 ± 0.09 | 0.81 ± 0.05 | .003 |
| TLC | |||
| Pretransplantation | 101.9 ± 13.5 | 104.1 ± 11.8 | .20 |
| Day 80 posttransplantation | 98.5 ± 12.5 | 100.2 ± 13.1 | .36 |
| 1 year posttransplantation | 102.2 ± 13.4 | 103.1 ± 14.5 | .71 |
| DLCO | |||
| Pretransplantation | 90.2 ± 17.3 | 93.7 ± 21.5 | .19 |
| Day 80 posttransplantation | 84.5 ± 16.3 | 85.7 ± 17.1 | .62 |
| 1 year posttransplantation | 75.6 ± 15.7 | 78.4 ± 19.1 | .36 |
Table 3. Changes in Pulmonary Function Parameters between Pretransplantation and 1 Year Posttransplantation
| Non-ATG | ATG | P Value | |
|---|---|---|---|
| FEV1 | -3.3 ± 13.8 | -0.9 ± 12.1 | .08 |
| FVC | -0.8 ± 11.6 | 0.1 ± 11.7 | .32 |
| FEV1/FVC ratio | -2.6 ± 7.0 | -0.1 ± 3.0 | .03 |
| TLC | 0.2 ± 10.3 | 1.2 ± 12.0 | .23 |
| DLCO | -13.8 ± 17.2 | -19.8 ± 17.8 | .07 |
We also examined the rate of decline in pulmonary function as measured by the annualized rate of FEV1 decrease during the first year post-HSCT. As shown in Figure 1, the rate of FEV1 decline, categorized as <5%, 5%-15%, or >15% per year, did not differ significantly in the 2 treatment groups (P = .40). Evaluation of LFSs before HSCT and at 1 year post-HSCT also revealed no significant differences between the 2 groups (Table 4).
Figure 1
Annualized rate of FEV1 decline during 2 time intervals (pretransplantation to 1 year posttransplantation) for the ATG and non-ATG groups. The rate of FEV1 decline is categorized as <5%, 5%-15%, or >20% per year. P = .409, pretransplantation to 1 year posttransplantation.
Table 4. LFS Comparison
| Non-ATG | ATG | P Value | |
|---|---|---|---|
| Pretransplantation, n (%) | |||
| 0 | 204 (65) | 48 (64) | .44 |
| 1 | 101 (32) | 27 (36) | |
| 2 | 9 (3) | 0 (0) | |
| 3 | 1 (<1) | 0 (0) | |
| 1 year posttransplantation, n (%)∗ | |||
| 0 | 49 (34) | 12 (33) | .70 |
| 1 | 78 (55) | 22 (62) | |
| 2 | 13 (9) | 2 (5) | |
| 3 | 3 (2) | -- |
∗Thirty patients were missing DLCO values at 1 year posttransplantation. |
Development of AFO and RP, Respiratory Failure, and Nonrelapse Mortality
The rate of AFO at 1 year post-HSCT was higher in the non-ATG group; the difference between groups was not statistically significant, however (7% vs 5%; P = .56). Similarly, the rates of an RP at 1 year were 5% for the non-ATG group and 3% for the ATG group (P = .42). The risk of developing AFO (ATG: hazard ratio [HR], 0.4; 95% CI, 0.1-1.08; P = .27) or an RP (ATG: HR, 1.1; 95% CI, 0.4-2.7; P = .78), as determined by Cox proportional hazards modeling, did not differ significantly between the 2 groups, even when the AFO and RP events were combined as a single variable (HR, 0.8; 95% CI, 0.4-1.8; P = .73). The risk of developing early respiratory failure was also similar in the 2 groups (ATG: HR, 0.9; 95% CI, 0.42-2.07; P = .87).
A total of 185 patients died, including 36 (48%) in the ATG group and 149 (47%) in the non-ATG group. Kaplan-Meier estimates of survival rates at 2 years post-HSCT did not differ significantly between the 2 groups (66% for non-ATG vs 60% for ATG; P = .14). The risk of nonrelapse mortality in a multivariate model adjusted for age at HSCT, underlying diagnosis, acute and chronic GVHD, and stem cell source also was not statistically significantly different between the 2 groups (ATG: HR, 0.94; 95% CI, 0.34-2.59; P = .91).
Discussion
Administration of ATG during conditioning for allogeneic HSCT has been shown to reduce the number of recipient T cells, thereby possibly facilitating engraftment of donor cells [28]. Available data also suggest a reduction in the incidence of acute and chronic GVHD 12, 13, 14, presumably related to the prolonged half-life of antibodies contained in the ATG preparation. Chronic GVHD is known to be the most powerful predictive factor for the development of chronic lung dysfunction [29]. Thus, incorporating ATG into the conditioning regimen should decrease the incidence and degree of post-HSCT pulmonary impairment. Indeed, in a randomized study of patients receiving cyclophosphamide/TBI conditioning for unrelated allogeneic HSCT, Bacigalupo et al. [18] found that adding ATG to the conditioning regimen provided at least partial protection against chronic lung dysfunction and prevented declines in FEV1 and FVC. In the present study, univariate analysis revealed higher FEV1/FVC ratios at 1 year post-HSCT in the patients who received ATG. This finding is consistent with the observations by Bacigalupo et al. suggesting that ATG-treated patients are less prone to early airflow decline. The inclusion of ATG did not decrease the risk of other pulmonary events that we evaluated, including the development of RP and respiratory failure. Of note, FEV1 decline was similar in the 2 groups, and the rate of airflow decline during the first year is reportedly useful for predicting the development of pulmonary complications and is also associated with mortality risk beyond the first year [7]. However, a limitation of this analysis is that the predictor of interest (development of pulmonary complications after HSCT) was assessed only during the first year after HSCT. It is very likely that pulmonary impairment can occur beyond the first year as well, leading to an underestimation of the true benefit of ATG in preventing the late onset of respiratory complications.
Thus, some of the results of the present analysis complement those previously reported by Bacigalupo et al. [18]. The 2 studies differ in certain aspects, however. For example, our analysis focused on different time periods after transplantation. The outcomes reported here were basically restricted to the first year post-HSCT because of the limited number of patients with PFT data in the ATG group beyond the first year. The positive effects reported by Bacigalupo et al. occurred more than 1 year after transplantation. Also, we compared a broader range of transplantation conditions, including both related and unrelated donor transplants and different conditioning regimens (BU-FLU or BU-CY with or without ATG). Although BU and TBI are both associated with lung toxicity 30, 31, 32, 33, 34, 35, FLU is less toxic to the pulmonary system than CY, and related donor transplants are known to have a lower incidence of noninfectious pulmonary complications [36]. Importantly, the study by Bacigalupo et al. was prospective and randomized, whereas the present study was retrospective and thus not powered to determine the pulmonary effects of ATG. However, the randomized study was limited by small numbers of patients (38 in the ATG group and 37 in the non-ATG group) and was restricted to the use of FEV1 and FVC decline as parameters for comparison of the 2 treatment arms. In the present study, we used a complete set of PFTs, as well as an annualized rate of decline and the lung function score. This allowed for a more uniform presentation of data and may more accurately reflect PFT changes in the study cohorts.
The 2 studies also differ in terms of the ATG dose used. Bacigalupo et al. extracted the results from a previous randomized ATG trial that enrolled 109 patients with various diagnoses who underwent transplantation from unrelated donors and compared results in patients given ATG 7.5 or 15 mg/kg with results in patients who did not receive ATG [17]. In our cohort, patients received ATG at doses of 4.5-6 mg/kg. A review of other data 37, 38 suggests that ATG at dosages of 4.5-8 mg/kg may reduce the incidence of both acute and chronic GVHD after unrelated (and probably also related) donor transplantation. Taken together, these data raise questions regarding the optimum dose of ATG to benefit pulmonary function and quality of life.
Another observation of note is that patients undergoing HSCT from unrelated donors (but not from related donors) and given ATG maintained a higher FEV1/FVC ratio at 1 year posttransplantation, and that the changes in this ratio since the pretransplantation assessment were more profound in those patients who did not receive ATG. This finding is consistent with the observations by Bacigalupo et al. [15] in that ATG may be beneficial, especially for patients receiving a transplant from an unrelated donor. In our study, we did confirm that the patients who received ATG were more prone to respiratory viral infections. Thus, we can speculate that during the first year after HSCT, ATG’s beneficial effect in GVHD prevention might be counterbalanced by an increased risk of acquiring an respiratory infection. This would confirm that the pathogenesis of early pulmonary complications is multifactorial, involving tissue damage 34, 35, the GVH reaction, and infections [39]. This impression remains to be confirmed in a study of a larger population.
In summary, the addition of ATG to HSCT conditioning regimens in the present patient cohort did not have a substantial impact on pulmonary function and did not decrease the incidence of pulmonary complications within the first year after HSCT. However, the limited number of patients treated with ATG and of patients with PFT data beyond 1 year post-HSCT means that conclusions must be drawn with caution. Clearly, our analysis reinforces the need for prospective trials comparing results in patients given ATG and controls to evaluate whether incorporation of ATG into pretransplantation conditioning regimens can decrease the rate of late pulmonary events.
Acknowledgments
Author contributions: Filippo Milano analyzed and interpreted data and wrote the manuscript. Margaret Au provided statistical expertise, analyzed data, and critically reviewed the manuscript. Michael Boeckh critically reviewed the manuscript. Joachim Deeg critically reviewed the manuscript. Jason Chien designed and performed the research, collected data, and critically reviewed the manuscript.
Financial disclosure: This work was supported by NIH Grants HL088201 HL036444, CA015704, CA018029, and HL93294. The authors have no conflicts of interest to disclose.
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Financial disclosure: See Acknowledgments on page 708.
PII: S1083-8791(10)00351-4
doi:10.1016/j.bbmt.2010.08.012
© 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 17, Issue 5 , Pages 703-709, May 2011
