Abstract
We conducted a nested case-control study within a cohort of 6,244 patients to assess risk factors for avascular necrosis (AVN) of bone in children and adolescents following allogeneic transplantation. Eligible patients were ≤21 years of age, received their first allogeneic transplant between 1990 and 2008 in the United States and had survived ≥ 6 months from transplantation. Overall, 160 cases with AVN and 478 controls matched by year of transplant, length of followup and transplant center were identified. Cases and controls were confirmed via central review of radiology, pathology and/or surgical procedure reports. Median time from transplant to diagnosis of AVN was 14 months. On conditional logistic regression, increasing age at transplant (≥5 years), female gender and chronic graft-versus-host disease (GVHD) were significantly associated with increased risks of AVN. Compared to patients receiving myeloablative regimens for malignant diseases, lower risks of AVN were seen in patients with non-malignant diseases and those who had received reduced intensity conditioning regimens for malignant diseases. Children at high risk for AVN include those within the age group where rapid bone growth occurs as well as those who experience exposure to myeloablative conditioning regimens and immunosuppression post-HCT for the treatment of GVHD. More research is needed to determine whether screening strategies specifically for patients at high risk for developing AVN with early interventions may mitigate the morbidity associated with this complication.
Keywords: Avascular necrosis, late complications, hematopoietic cell transplantation
Introduction
Avascular necrosis (AVN) of the bone is a debilitating late complication of allogeneic hematopoietic cell transplantation (HCT) that can be associated with significant morbidity.1,2 The incidence and risk factors for AVN have been well described in adult transplant recipients with an estimated cumulative incidence of 3–10% at 5-years after transplantation.1,3–9 Graft-versus-host disease (GVHD), exposure to corticosteroids or calcineurin inhibitors, cumulative dose of corticosteroids, older age, female gender and use of total body irradiation (TBI) as part of conditioning regimen have been identified as risk factors for AVN in adult HCT recipients. Although its pathogenesis is poorly understood, potential mechanisms for development of AVN include local vascular damage that leads to increased marrow edema and ischemia, ineffective osteoblastic repair processes due to metabolic factors and mechanical stresses.1,10
Large studies that have specifically focused on evaluating risk factors for AVN in pediatric HCT survivors are lacking. Factors such as immaturity and ongoing growth of bones and endocrine dysfunction related to growth and sex hormones are exclusive to children and may modulate the risks of AVN in a different way than adults. Hence, extrapolating findings from studies that have only included adults or have combined adults with children can be a challenge. Also, it is not known whether the relatively recent less toxic preparative regimens (non-myeloablative/reduced intensity conditioning) are associated with lower risks of AVN than conventional myeloablative regimens in this population. To better understand the risk factors for AVN after allogeneic HCT in children and adolescents, we conducted a case-control study using data from the Center for International Blood and Marrow Transplant Research (CIBMTR). We evaluated risk factors that can be considered ‘older approaches’ (myeloablative regimens, greater use of sibling donors) as well as ‘contemporary approaches’ (non-myeloablative/reduced intensity regimens, greater use of unrelated donors) in our analysis.
Methods
Data Source
The CIBMTR is a working group of more than 450 transplantation centers worldwide that contribute detailed data on hematopoietic cell transplantations to a Statistical Center at the Medical College of Wisconsin in Milwaukee and the National Marrow Donor Program (NMDP) in Minneapolis. Participating centers are required to report all transplants consecutively and patients are followed longitudinally. Computerized checks for discrepancies, physicians’ review of submitted data and on-site audits of participating centers ensure data quality. Data are collected before transplant, 100 days and six months after transplant, and annually thereafter, or until death. The followup research forms specifically inquire whether a recipient has developed AVN post-transplantation. Observational studies conducted by the CIBMTR are performed under guidance of the Institutional Review Board of the NMDP and are in compliance with all applicable federal regulations pertaining to the protection of human research participants.
Patients
For our study, we selected first allogeneic HCT recipients of age ≤ 21 years at transplantation who had been reported to the CIBMTR between 1990 and 2008. Since screening and management practices for AVN can vary by region, we restricted our cohort to patients who had received their transplant at a center in the United States. We also limited our cohort to patients who had survived at least 6 months or more following transplantation as our analysis was focused on long-term HCT survivors and on transplant related risk factors for AVN. Patients with any diagnosis and recipients of both myeloablative and reduced intensity/non-myeloablative regimens were eligible.
Selection of Cases and Controls
Overall, 6,244 patients met study eligibility criteria and were the basis for selection of cases and controls for our study. Cases included patients who had a diagnosis of AVN reported on post-transplant followup. AVN of any joint was considered. For all patients identified as potential cases, we requested diagnostic and/or treatment information from centers to ascertain the diagnosis of AVN (e.g., copies of radiologic investigations, pathology reports or surgical operative notes). We excluded 2 patients from our analysis for whom we were not able to confirm the diagnosis of AVN from their transplant center.
We established a pool of controls using eligible patients who had received their transplant at the same centers as cases and did not have a diagnosis of AVN reported to the CIBMTR. For each case, we chose a control that was matched by year of transplantation (± 1 year) and followup duration (followup post-transplant no less than the interval from HCT to onset of AVN for the corresponding case). Controls were selected from the same center as the case, if available. If a control could not be identified for a case from the same center, controls were selected from another center that had patients with AVN included in this study. Each case was matched with up to three controls. For cases with several matched controls, three were selected randomly for the analysis. For each selected control, we contacted transplant centers and requested them to review medical records and confirm that the patient did not have AVN. On this review, four controls were identified to have AVN post-transplantation and they were subsequently considered as cases. Controls were excluded from the analysis if they had a pre-HCT diagnosis of AVN (N=1) or if centers were not able to confirm the absence of AVN diagnosis (N=26).
We identified 160 confirmed cases with AVN and 478 matched controls. Among these case-control pairs, 407 (85%) were matched within the same center as the case. One hundred and fifty nine cases had 3 matched controls and 1 case had 1 matched control.
Study Definitions and Statistical Analysis
Conditioning regimens were defined as myeloablative, reduced-intensity and non-myeloablative using established guidelines.11 As there are no clear guidelines for classifying conditioning regimens for non-malignant diseases, they were considered as a separate category when describing conditioning regimen intensity. Disease status for malignant diseases was assigned as early, intermediate or advanced.12 Early disease included acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in first complete remission, chronic myeloid leukemia (CML) in first chronic phase, myelodysplastic syndrome (MDS) refractory anemia or refractory anemia with ringed sideroblasts or unspecified MDS with <5% marrow blasts. Patients with AML or ALL in second or greater remission, CML in second or greater chronic phase or CML in accelerated phase were classified as intermediate risk disease. All other patients, including patients with lymphoma, were classified as advanced disease. The National Marrow Donor Program’s classification of HLA-matching status was used for unrelated donor transplant recipients (well matched, partially matched or mismatched).13
The goal of our case-control study was to assess potential risk factors for developing AVN in children and adolescents following allogeneic HCT. For comparing characteristics between cases and controls, we used the Chi-square or Fisher’s test (as applicable) for categorical variables and Wilcoxon two-sample test for continuous variables. To evaluate risk factors, we performed multivariable analyses using conditional logistic regression on all matched sets. The following variables were considered in this analysis: age at transplantation, gender, diagnosis, disease status, conditioning regimen intensity, dose of total body irradiation, donor source and history of GVHD prior to AVN. If feasible, categories with a small number of patients were combined with related categories. Patients receiving transplant from HLA-mismatched related donors (N=23), patients with unknown conditioning regimen intensity (N=2) and patients with unknown date of GVHD onset (N=14) were excluded from the risk factor analysis
All P-values are two-sided. All analyses were carried out using SAS statistical software (SAS Institute Inc., Cary, NC, USA).
Results
Characteristics of Cases and Controls
Table 1 shows the characteristics of the 160 AVN cases and 478 controls. The median age at transplantation was 15 years for cases and 8 years for controls. The primary diagnosis of non-malignant disorder was higher in the control group (32%) compared to AVN cases (13%). A greater proportion of AVN cases had received a TBI containing myeloablative regimen compared to controls (65% vs. 48%). Related, unrelated and umbilical cord blood donors were used in 21%, 64% and 16% of AVN cases and 11%, 69%, and 21% of controls, respectively. Fifty-six percent of cases had a history of chronic GVHD prior to the onset of AVN compared to 49% in the control group.
Table 1.
Characteristics of AVN cases and their controls (matched by transplant center, year of transplant and duration of followup)
| Characteristics | Cases | Controls | P-value |
|---|---|---|---|
| Number of patients | 160 | 478 | |
| Number of centers | 54 | 52 | |
| Age at transplant, years, median (range) | 15 (2–21) | 8 (<1–21) | <0.01 |
| Age at transplant, years, N (%) | <0.01 | ||
| <5 | 5 (3) | 154 (32) | |
| 5–9 | 16 (10) | 112 (23) | |
| 10–14 | 56 (35) | 94 (20) | |
| 15–21 | 83 (52) | 118 (25) | |
| Patient gender, N (%) | <0.01 | ||
| Male | 78 (49) | 289 (60) | |
| Female | 82 (51) | 189 (40) | |
| Lansky/Karnofsky score prior to transplant, N (%) | 0.99 | ||
| <90 | 22 (15) | 66 (15) | |
| ≥ 90 | 121 (85) | 362 (85) | |
| Missing | 17 | 50 | |
| Patient race, N (%) | 0.88 | ||
| White | 128 (80) | 385 (81) | |
| Non-White | 32 (20) | 93 (19) | |
| Disease, N (%) | <0.01 | ||
| Acute myeloid leukemia | 47 (29) | 119 (25) | |
| Acute lymphoblastic leukemia | 57 (36) | 128 (27) | |
| Chronic myeloid leukemia | 14 (9) | 31 (6) | |
| Myelodysplastic syndrome | 18 (11) | 32 (7) | |
| Non-Hodgkin lymphoma | 2 (1) | 15 (3) | |
| Hodgkin lymphoma | 1 (1) | 0 | |
| Severe aplastic anemia | 11 (7) | 42 (9) | |
| Inherited abnormality of erythrocyte differentiation | 5 (3) | 36 (8) | |
| SCID & other immune system disorders | 2 (1) | 42 (9) | |
| Inherited disorder of metabolism | 2 (1) | 20 (4) | |
| Histiocytic disorders | 1 (1) | 13 (3) | |
| Disease risk prior to transplant, N (%) | <0.01 | ||
| Early | 62 (39) | 130 (27) | |
| Intermediate | 55 (34) | 147 (31) | |
| Advanced | 22 (14) | 43 (9) | |
| Non-malignant disease | 21 (13) | 153 (32) | |
| Unknown | 0 | 5 (1) | |
| Interval from diagnosis to transplant, months, N (%) | 0.02 | ||
| <6 | 60 (38) | 135 (28) | |
| 6–11 | 31 (19) | 100 (21) | |
| ≥ 12 | 66 (41) | 205 (43) | |
| Unknown | 3 (2) | 38 (8) | |
| Year of transplant, N (%)† | -- | ||
| 1990–1994 | 5 (3) | 19 (4) | |
| 1995–1999 | 13 (8) | 40 (8) | |
| 2000–2004 | 60 (38) | 215 (45) | |
| 2005–2008 | 82 (51) | 204 (43) | |
| Total TBI dose, cGy, N (%) | <0.01 | ||
| No TBI | 45 (28) | 191 (40) | |
| <1200 cGy | 14 (9) | 53 (11) | |
| ≥ 1200 cGy | 100 (63) | 234 (49) | |
| Missing | 1 | 0 | |
| Conditioning regimen intensity, N (%) | <0.01 | ||
| Myeloablative (with TBI) | 102 (65) | 229 (48) | |
| Myeloablative (no TBI) | 27 (17) | 68 (14) | |
| Non-myeloablative/reduced intensity | 8 (5) | 28 (6) | |
| Non-malignant diseases | 21 (13) | 153 (32) | |
| Missing | 2 | 0 | |
| Graft type, N (%) | 0.38 | ||
| Bone marrow | 93 (58) | 268 (56) | |
| Peripheral blood ± bone marrow | 42 (26) | 112 (23) | |
| Umbilical cord blood* | 25 (16) | 98 (21) | |
| Donor type, N (%) | 0.01 | ||
| HLA-matched sibling | 23 (14) | 37 (8) | |
| Other related | 11 (7) | 12 (3) | |
| Well matched unrelated | 60 (38) | 194 (41) | |
| Partially/mismatched unrelated | 40 (25) | 135 (28) | |
| Unrelated, match unknown | 1 (1) | 2 (<1) | |
| Umbilical cord blood | 25 (16) | 98 (21) | |
| GVHD prophylaxis, N (%) | 0.51 | ||
| FK506 + MMF ± others | 13 (8) | 26 (5) | |
| FK506 + MTX ± others (except MMF) | 28 (18) | 86 (18) | |
| FK506 ± others (except MTX, MMF) | 9 (6) | 18 (4) | |
| CSA + MMF ± others | 13 (8) | 41 (9) | |
| CSA + MTX ± others (except MMF) | 58 (36) | 161 (34) | |
| CSA ± others (except MTX, MMF) | 24 (15) | 72 (15) | |
| T-cell depletion | 10 (6) | 56 (12) | |
| Other/unknown | 5 (3) | 18 (4) | |
| History of GVHD, N (%)# | 0.05 | ||
| No GVHD | 43 (27) | 179 (37) | |
| Acute GVHD only | 28 (18) | 66 (14) | |
| Chronic ± acute GVHD | 89 (56) | 233 (49) | |
| Interval from transplant to AVN, months, median (range) | 14 (<1–172) | -- | |
| Follow-up of survivors, months, median (range)† | 61 (11–194) | 63 (7–225) |
Abbreviations: SCID – Severe combined immunodeficiency; TBI – total body irradiation; HLA – human leukocyte antigen; GVHD – graft-versus-host disease; MMF – mycophenolate mofetil; MTX – methotrexate; CSA - cyclosporine
Variable used for matching cases and controls
Includes 6 related umbilical cord blood transplants (1 case, 5 controls)
History of GVHD prior to AVN for cases; for controls, any history of GVHD within the corresponding followup time period for the matched case
Among AVN cases, the median time from HCT to the onset of AVN was 14 months (range, <1–172 months). Thirty-seven percent of cases occurred within 1 year of HCT, 59% occurred 1–5 years after HCT and 4% occurred more than 5 years after transplantation. Detailed information was available for 59 patients to completely characterize the extent of joint involvement by AVN. Among these patients, collectively 119 joints were affected by AVN with a median of 2 (range, 1–6) joints. Femoral head (82%) was the most common site of involvement and was followed by the knee joint (78%), the vertebral column (12%) and the ankle joint (10%). AVN of the shoulder joint was rare (5% of patients). Pathologic fracture was the initial presentation of AVN in 3 patients.
We also evaluated the characteristics of patients included in our study by donor source (related = 83 patients [41% cases, 59% controls], unrelated = 432 patients [23% cases, 77% controls], umbilical cord blood = 123 [20% cases, 80% controls]). There were notable differences among related, unrelated and umbilical cord blood HCT recipients with respect to median age at HCT (14 years vs. 12 years vs. 6 years, P<0.001), time from diagnosis to transplant (HCT within 6 months of diagnosis in 53% vs. 25% vs. 35% patients, P<0.001), use of TBI as part of conditioning (45% vs. 68% vs. 57%, P<0.001) and history of chronic GVHD (37% vs. 55% vs. 43%, P<0.001), respectively. There were also differences in GVHD prophylaxis regimens by donor source; for example, 2% of related donor, 15% of unrelated donor and 0% of umbilical cord blood HCT recipients received ex-vivo or in-vivo T-cell depletion to prevent GVHD.
Risk Factor Analysis
Table 2 shows the results of conditional logistic regression analysis. Risk factors independently associated with increased risks for AVN included older age at HCT (>5 years), female gender, and a history of chronic GVHD. The use of non-myeloablative/reduced-intensity regimens for conditioning patients with malignant disease and the diagnosis of non-malignant disease, regardless of conditioning intensity, were associated with statistically significantly lower risks for AVN when compared to patients receiving a myeloablative regimens for conditioning patients with malignant diseases. The risks of AVN were similar in patients who received and did not receive TBI as part of myeloablative conditioning for malignant diseases. Interestingly, the use of unrelated donors was observed to be associated with a lower risk of AVN. We tested for and found no significant interactions between donor source and other variables (including GVHD) considered in multivariate analyses.
Table 2.
Risk factors identified to be independently associated with post-transplant AVN on conditional logistic regression analysis
| Risk-factor | Category† | Cases N (%) | Controls N (%) | Hazard ratio (95% CI) | P-value |
|---|---|---|---|---|---|
| Age | <5 years | 5 (3) | 148 (33) | 1.00 | <0.01* |
| 5–9 years | 14 (10) | 103 (23) | 3.40 (1.17–9.89) | 0.03 | |
| 10–21 years | 128 (87) | 201 (44) | 19.83 (7.23–54.42) | <0.01 | |
| Gender | Male | 71 (48) | 271 (60) | 1.00 | |
| Female | 76 (52) | 181 (40) | 1.65 (1.05–2.58) | 0.03 | |
| Diagnosis and conditioning | Malignant disease, MA regimen, TBI | 97 (66) | 215 (48) | 1.00 | <0.01* |
| Malignant disease, MA regimen, no TBI | 22 (15) | 64 (14) | 0.64 (0.32–1.26) | 0.20 | |
| Malignant disease, NMA/RIC regimen | 7 (5) | 25 (6) | 0.31 (0.11–0.88) | 0.03 | |
| Non-malignant disease | 21 (14) | 148 (33) | 0.30 (0.14–0.63) | <0.01 | |
| Donor | HLA-identical sibling | 23 (16) | 36 (8) | 1.00 | <0.01* |
| Unrelated | 100 (68) | 321 (71) | 0.26 (0.12–0.56) | <0.01 | |
| Umbilical cord blood | 24 (16) | 95 (21) | 0.41 (0.17–1.03) | 0.06 | |
| GVHD | None | 41 (28) | 175 (39) | 1.00 | 0.08* |
| Acute GVHD only | 23 (16) | 63 (14) | 1.45 (0.71–2.97) | 0.31 | |
| Chronic GVHD ± acute GVHD | 83 (56) | 214 (47) | 1.88 (1.09–3.23) | 0.02 |
Abbreviations: CI – confidence intervals; MA – myeloablative; NMA/RIC – non-myeloablative/reduced intensity; TBI – total body irradiation; GVHD – graft-versus-host disease
Patients receiving transplant from HLA-mismatched related donors (N=23), patients with unknown conditioning regimen intensity (N=2) and patients with unknown date of GVHD onset (N=14) were excluded from the risk factor analysis
Overall P-value
Discussion
Our study identifies important risk factors for AVN in a large cohort of pediatric allogeneic HCT recipients and lays the foundation for further research on screening and prevention of AVN in this population. We observed that risks increased with recipient age at transplantation. This has been reported by other relatively smaller studies in pediatric allogeneic HCT recipients,14,15 and suggests that children within the age group when rapid bone growth occurs are most susceptible to AVN. Other identified risk factors including female gender and history of chronic GVHD are similar to what has been previously reported by studies that have primarily included adults (Table 3).3,5,9,16–18 Of note, the observations from relatively smaller published studies are inconsistent when describing the gender-related differences in risk of AVN. Some studies have reported an increase risk among females, whereas others have demonstrated an increased risk in males, and some have failed to show a gender preference.
Table 3.
Summary of contemporary studies that have investigated risk factors for AVN after allogeneic HCT in children
| Reference | AVN cases | Median age | Risk Factors |
|---|---|---|---|
| Socie et al (1997)8 | 77 (21 cases age <20 years) | 25 years | Age ≥ 16 years at HCT, diagnosis of aplastic anemia or acute leukemia, acute GVHD, chronic GVHD |
| Kaste et al (2004)23 | 19 (all children) | 10 years | Female gender |
| Faraci et al (2006)24 | 43 (all children) | 13 years* | Chronic GVHD, TBI, older age at HCT |
| Leung et al (2007)14 | 20 (all children) | 10 years | Female gender, older age at HCT |
| Campbell et al (2009)7 | 75 (46 cases age <35 years; 73% allogeneic HCT) | 34 years | Male gender, chronic GVHD, exposure to calcineurin inhibitors and prednisone |
| McAvoy et al (2010)6 | 66 (15 cases age ≤ 18 years) | 29 years | Cumulative dose of corticosteroids |
| Sharma et al (2012)15 | 44 (all children) | 11 years | Age ≥ 10 years at HCT, pre-HCT history of AVN |
| Present study | 160 (all children) | 15 years | Older age at HCT, female gender, chronic GVHD, myeloablative conditioning regimen |
Abbreviations: AVN – avascular necrosis of bone; GVHD – graft-versus-host disease; TBI – total body irradiation; HCT – hematopoietic cell transplantation
Mean age
The risks of AVN with non-myeloablative/reduced-intensity conditioning have not been previously described and an important finding from our study is our observation that use of less intense conditioning regimens is associated with lower risks for AVN. Compared to recipients of myeloablative conditioning, patients with malignant diseases receiving non-myeloablative/reduced intensity regimens had a 70% lower risk of developing AVN. Similarly patients with non-malignant diseases, who tend to receive conditioning of comparable intensity as reduced intensity preparative regimens, had significantly lower risks of developing AVN. The decision to pursue myeloablative or non-myeloablative/reduced intensity conditioning for transplantation is frequently complex and has to take into account various factors such as diagnosis, disease status, performance status and presence of comorbidities. Risk for complications is also a consideration, and our study will inform the decision process for patients who are at high risk for developing AVN.
The lower risk of AVN in patients receiving unrelated donor HCT is in contrast to what has been previously reported in the literature.1 We did not find any significant interactions between donor source and GVHD. This may be due to different exposures; for example, regimens for prevention or treatment of GVHD in unrelated donor HCT recipients may contain no corticosteroids or lesser doses of corticosteroids in combination with other agents. Indeed, a greater proportion of unrelated donor recipients had received T-cell depletion for GVHD prophylaxis in our study. It is also possible that ascertainment bias might partly explain this finding. Diagnostic testing for AVN is more likely to occur among patients who are followed up long-term at transplant centers, where providers are more aware of this complication. Centers may preferentially follow more unrelated donor over HLA-identical sibling donor HCT recipients, especially because the former have a greater likelihood of developing chronic GVHD and need ongoing specialized care at the transplant center. Indeed, we had more controls who were unrelated donor HCT recipients than HLA-identical sibling donor HCT recipients (controls included 11% related donor, 69% unrelated donor and 21% umbilical cord blood recipients). Other risk factors that are not captured by the CIBMTR may also explain this observation and need further evaluation in future studies.
Some limitations of our study have to be considered. AVN is frequently an underdiagnosed and hence, underreported late complication of transplantation. Exposure to calcineurin inhibitors and corticosteroids and the cumulative dose of corticosteroids has been shown to be an important risk factor for AVN.6,7,19 Similarly, pre-transplant chemotherapy, radiation and corticosteroid exposures and post-transplant events such as endocrine late effects may also modulate the risks of post-transplant AVN. The CIBMTR does not routinely collect data on these variables and these risk factors could not be evaluated in our study. Even though our study represents the largest analysis of AVN in pediatric HCT recipients, we were not able to evaluate some risk factors due to the small number of cases (e.g., specific diagnoses where pre- and post-transplant exposures may be different). One such notable risk factor is the diagnosis of acute lymphoblastic leukemia, which is a well-established risk factor for AVN in pediatric patients who do not receive a transplant. Centers may have different practices for followup of patients post-transplantation and for diagnosis and screening for AVN. To account for this, we tried to identify controls from the same centers as cases or from other centers that had reported a case (85% of case-control pairs were from the same center). We excluded patients with a pre-HCT diagnosis of AVN. However, subclinical AVN may begin pre-transplantation and manifest clinically post-transplantation.
In conclusion, older age at HCT, female gender, exposure to myeloablative conditioning regimen and chronic GVHD are risk factors for AVN after allogeneic HCT in children and adolescents. Screening strategies specifically for patients at high risk for developing AVN with early initiation of interventions (e.g., physical therapy, limited surgery) might mitigate the morbidity associated with this complication. Our study, by highlighting important risk factors, lays the foundation for future research in this area. Clinicians taking care of pediatric allogeneic HCT survivors should maintain vigilance for this complication and have a high index of suspicion for AVN in patients with risk factors who present with new bone related symptoms. Until more research is available, clinicians should follow published consensus guidelines for long-term followup that recommend early screening for AVN with magnetic resonance imaging in patients with such symptoms.20–22
Acknowledgments
CIBMTR sources of support: The Center for International Blood and Marrow Transplant Research (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 Allos, Inc.; Amgen, Inc.; Angioblast; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children’s Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience, Inc.; THERAKOS, 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.
Footnotes
Contributions: XL, RB, ZW, NM designed the study, and analyzed the results; XL, NM wrote the manuscript; RB, ZW performed statistical analysis; all authors contributed to the study design, interpreted data and critically reviewed the manuscript. All authors approved the final version of the manuscript.
Conflict-of-interest disclosure: The authors have no interests to disclose.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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