Volume 13, Issue 10 , Pages 1145-1152, October 2007
Chronic Graft-Versus-Host Disease (cGVHD) following Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT): Higher Response Rate In Recipients of Unrelated Donor (URD) Umbilical Cord Blood (UCB)
Article Outline
Abstract
We present a comparative analysis of clinical presentation and response to treatment in 170 patients with chronic graft versus host disease (cGVHD) (123 following transplant from an unrelated donor [URD] and 47 from umbilical cord blood [UCB]). URD transplant recipients were significantly younger (median age 25 versus 39 years, P = .002; and the donor grafts were mostly HLA matched (67% versus 10%, P < .0001). UCB recipients had more frequent responses (complete remission [CR] + partial remission [PR]) to treatment (URD 48% versus UCB 74% at 2 months [P = .005]; 49% versus 78% at 6 months [P = .001] and 51% versus 72% at 1 year [P = .03] in the URD and UCB groups, respectively). Nonrelapse mortality (NRM) after diagnosis of cGVHD was worse after URD grafts. (1 year NRM 27% [19%-35%] URD versus 11% [2%-20%] UCB, P = .055). Separate multivariate analyses were performed in each cohort. In both, thrombocytopenia and no CR or PR at 2 months were independently associated with increased mortality. In addition, progressive onset of cGVHD was a significant predictor of increased mortality in URD cohort. These data suggest that cGVHD following UCB transplant may be more responsive to therapy and also lead to a lower NRM.
Key Words: Umbilical cord blood transplant, cGVHD, Hematopoietic stem cell transplantation
Introduction
Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). Large observational studies have shown that cGVHD is the leading cause of nonrelapse mortality (NRM) 2 years after transplantation [1]. Many factors are associated with higher risks of cGVHD. These include older age, certain diagnoses (chronic myelogenous leukemia (CML) and aplastic anemia), history of prior acute GVHD (aGVHD), an HLA mismatched donor, and transplant from a parous female donor to a male recipient [2, 3, 4, 5, 6, 7, 8]. Use of peripheral blood stem cells (PBSC) compared to bone marrow from related or unrelated donors (URD) as a source of hematopoietic stem cells (HSC) has also resulted in a higher frequency of cGVHD [9, 10, 11, 12, 13, 14]. In addition, risk factors have been identified that suggest worse outcome with cGVHD treatment. These are “extensive” cGVHD [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17] (multiorgan or extensive cutaneous involvement), poor Karnofsky performance status [15] presence of thrombocytopenia (<100,000 cells/μL) [15, 16, 18, 19], progressive-type onset [16, 18, 20], lichenoid histology [24], elevated bilirubin [20], age >20 years [18], gastrointestinal involvement [18], absence of response to therapy at 6 months [18], and other subjective measures of severity [21].
The use of umbilical cord blood transplants (UCB) as a stem cell source for transplants has dramatically increased over the past decade. Although registry reports indicate that UCB is associated with a reduced incidence of extensive cGVHD [22, 23], there has been no detailed analysis of cGVHD in terms of treatment responsiveness and associated risk factors. Therefore, we evaluated the incidence, clinical presentation, response to treatment, and outcome of cGVHD in recipients of UCB with comparison to results in recipients of adult volunteer URD HSCT.
Patients and Methods
Eligibility Criteria
Patients who underwent HLA matched or mismatched volunteer adult URD or unrelated UCB HSCT at the University of Minnesota between May 1993 and June 2004 were evaluated, and all consecutive patients who developed cGVHD were included in the study. The cohort includes 170 patients with symptomatic cGVHD (123 following URD and 47 after UCB transplants). The diagnosis of cGVHD was made according to standard clinical and/or histologic criteria [2, 18, 24]. For all patients, HLA-A and -B typing was determined at the serologic level, whereas HLA-DRB1 allele level typing was determined by high-resolution molecular techniques.
Treatment Plan of cGVHD
Limited skin involvement was treated with topical steroids (0.1% triamcinolone cream to body, 1% hydrocortisone cream to face) 3 times a day. Most patients were treated with a combination of prednisone at a dose of 0.5 mg/kg/every other day ± calcineurin inhibitor (n = 153), along with initial therapy with high dose methylprednisone at a dose of 15 mg/kg as an i.v. injection given weekly for 8 weeks (n = 92: 79 following URD and 13 following UCB). Additional therapy included azathioprine in 6 patients (URD) and mycophenolate mofetil (MMF) in 11 patients (5 URD, 6 UCB). Salvage therapy was required in 51 patients (38 URD, 13 UCB) and included pulse methyprednisolone (15 mg/kg/day i.v. for 5 days) in 4 URD, 1 UCB recipient. Twenty-eight patients received MMF (17 URD, 11 UCB), 8 received thalidomide (all URD), and 10 received antithymocyte globulin (ATG; 9 URD, 1 UCB). Treatment was continued for 6-9 months following the last clinical signs or symptoms of active cGVHD followed by a taper over 3 months.
Measurement of Response
Response was assessed at 2 months, 6 months, 1 year, and 2 years after diagnosis of cGVHD. Because patients did not always return to the transplant center on the scheduled dates, 2-4 month window periods were used to maximize the completeness of evaluation. After diagnosis of cGVHD, the median follow-up of surviving patients was 5 years (range 0.5-10.8 years) in the URD group and 1.5 years (range 0.4-8.8 years) in the UCB group.
Complete response (CR) was defined as resolution of all reversible signs and symptoms of cGVHD. Partial response (PR) was defined as improvement in 1 or more organs of involvement and no evidence of worsening in any organ. Progression was defined as worsening in 1 or more organs of involvement to be more severe than at baseline. Flare included patients with PR or CR followed by worsening of cGVHD, which was less severe than at the baseline evaluation. No response (NR) included patients not meeting criteria for PR or progression. Improvement or worsening of disease was determined through both subjective and objective criteria. Subjective criteria were symptomatic change in cough, dyspnea, anorexia, nausea, vomiting, diarrhea, arthralgia, or dry eyes. Objective criteria included physical exam of skin, oral mucosa, weight change, and/or liver function tests, pulmonary function tests, Schirmer’s test, biopsies, and radiologic studies. All patients who died of complications related to cGVHD (infections, multiorgan dysfunction) were considered as nonresponders, regardless of cGVHD symptoms premortem. Responses were assigned retrospectively by review of all medical records and laboratory data.
Statistical Analysis
The study was a retrospective cohort study using data from the University of Minnesota HSCT database, which includes demographic data, type of onset of cGVHD, dates of diagnosis of cGVHD and treatment, organ involvement with cGVHD at diagnosis, complications, and causes of death/relapse. Data collection and entry is carried out by trained personnel. This was supplemented by chart reviews for specific organ involvement with cGVHD at defined follow-up periods, response assessment, complications, and continuation of therapy. Grading of response was performed without knowledge of the subsequent survival. Statistical analysis of response was performed before analysis of survival to maintain objectivity.
Response to therapyResponse to therapy was evaluated serially. Patients with disease recurrence or progression were subsequently excluded from response evaluation. Of the 170 patients identified with cGVHD, the number of patients evaluable for response was 168, 159, 151, and 148 at 2 months, 6 months, 1 year, and 2 years, respectively. Twenty-two (13%) patients relapsed (16 URD, 6 UCB group) and died within 2 years without complete assessment of response. Of these, 2 had relapsed by 2 months, 11 relapsed by 6 months, 19 relapsed by 1 year, and 22 by 2 years. Twenty-seven, 8, 14, and 25 patients were only observed outside the defined window periods or had inadequate information for evaluation at 2 months, 6 months, 1 year, and 2 years, respectively. Pearson’s chi-square test was employed to compare the proportion of subjects with response to therapy between the 2 groups.
Predictors of responseTen potential predictors were evaluated, including recipient age at transplant (≤30 versus >30 years), gender of recipient and donor (female donor and male recipient versus others), type of transplant (URD versus UCB), HLA mismatch (0 or 1 versus >1), conditioning regimen (myeloablative versus nonmyeloablative), GVHD prophylaxis (T cell depletion versus others), prior grade II-IV aGVHD, type of onset of cGVHD (de novo + quiescent versus progressive), organ involvement with cGVHD (eyes, mouth, skin, lungs, gastrointestinal, liver) and platelet count at presentation (≥100,000/μL versus <100,000/μL). Pearson’s chi-square test was employed to compare the proportion of subjects with response to therapy within each category of potential predictors. Multivariate logistic regression was used to evaluate the independent effect of study variables on treatment response. A stepwise regression with forward selection was used.
SurvivalPatient survival was determined using the Kaplan-Meier [25] estimation with 95% confidence intervals (CI) derived from standard errors. Patients were censored at the date of last contact. Survival was estimated from onset of cGVHD.
Predictors of mortalityPotential factors associated with mortality were studied. The Kaplan-Meier product limit method [25] and log rank testing were used to compare survival in the subsets and the Cox regression model [26] was used to assess the independent effect of the predictors on survival as well as any potential confounding on the effect of treatment. A stepwise regression with forward selection was used. Cumulative incidence rates were used to estimate the probability of relapse, NRM, and discontinuation of all immunosuppressive treatment [27] over the complete period of follow-up.
Results
The overall incidence of cGVHD was 25% (21%-29%) and 17% (13%-21%) in patients undergoing URD and UCB transplants, respectively. Table 1 shows the characteristics of the patients developing cGVHD. The median age at transplantation was 25 and 39 years in the URD and UCB groups, respectively. URD recipients were more likely to receive myeloablative conditioning (93% versus 57%) and to receive an HLA matched graft (67% versus 10%). There was no difference in the time to onset (186 days versus 178 days), type of onset, or distribution of organ involvement by cGVHD comparing URD and UCB groups. Skin was the most frequent organ involved (64% versus 53%), followed by oral (44% vs 45%) and gastrointestinal tract (29% versus 34%). High-risk disease (as defined by progressive onset and thrombocytopenia) was seen in 76 patients (45%) overall. Of these, progressive onset was seen in 33 (27%) patients in the URD cohort versus 9 (19%) in the UCB cohort (P = .15). Thrombocytopenia (platelet count <100,000/μL) was seen more frequently in the URD cohort (44 (54%) versus 7 (23%), P = .003).
Table 1. Demographics and Disease Characteristics
| Demographics | URD No. (%) | UCB No. (%) | P |
|---|---|---|---|
| N | 123 | 47 | |
| Diagnosis | |||
 Acute leukemia | 38(31) | 25(53) | <.001 |
| CML | 36(29) | 4(9) | |
| Nonmalignant diseases | 43(35) | 9(19) | |
| Other malignancies | 6(5) | 9(19) | |
| Age | |||
| Median (range) | 25(0.5-57) | 39(0.2-61) | .002 |
| ≤20 years | 55(45) | 16(34) | .003 |
| 21-40 years | 40(33) | 8(17) | |
| >40 years | 28(23) | 23(49) | |
| Donor /recipient sex mismatch | |||
| Male recipient with Female donor | 34(28) | 12(26) | |
| Type of conditioning | |||
| Myeloablative | 114(93) | 27(57) | <.0001 |
| Nonmyeloablative | 9(7) | 20(43) | |
| Cell source | |||
| Marrow | 121(98) | ||
| PBSC | 2(2) | ||
| UCB | 47(100%) | ||
| HLA match | |||
| 6/6 | 82(67) | 5(10) | <.0001 |
| 5/6 | 38(31) | 13(28) | |
| 4/6 | 3(2) | 29(62) | |
| Conditioning regimens | |||
| TBI + cyclophosphamide | 77(63) | 10(21) | <.0001 |
| Busulfan + cyclophosphamide ± other | 10(8) | 3(6) | |
| Fludarabine + TBI + Cyclophosphamide/busulfan | 11(9) | 29(62) | |
| Other | 25(20) | 5(11) | |
| GVHD prophylaxis | |||
| Methotrexate + CSA | 65(53) | 0 | <.0001 |
| T depletion | 40(33) | 0 | |
| CSA + Prednisone | 0 | 16(34) | |
| CSA + MMF | 9(7) | 30(64) | |
| Other | 9(7) | 1(2) | |
| aGVHD | |||
| None | 29(24) | 7(15) | .17 |
| Grade I-II | 74(60) | 27(57) | |
| Grade III-IV | 20(16) | 13(28) | |
| Onset of cGVHD | |||
| De novo | 29(23) | 7(15) | .15 |
| Quiescent | 61(50) | 31(66) | |
| Progressive | 33(27) | 9(19) | |
| Time to cGVHD | |||
| (days post transplant):median (range) | 186(73-886) | 178(75-505) | .67 |
| Organ involvement with cGVHD | |||
| Skin | 79(64) | 25(53) | .18 |
| Oral | 54(44) | 21(45) | .9 |
| Liver | 17(14) | 4(9) | .34 |
| GI | 36(29) | 16(34) | .5 |
| Lungs | 7(6) | 1(2) | .3 |
| Eyes | 19(15) | 7(15) | .9 |
| Thrombocytopenia | |||
| N (%) with platelet count <100,000/μL at onset of cGVHD (n = 111) | 44(54)(n=81) | 7(23)(n=30) | .003 |
| Follow-up [median (range), years] | 5(0.14-10.8) | 1.5(0.02-8.8) |
Response to Therapy
Response was assessed serially at 2 months, 6 months, 1 year, and 2 years in all patients (Table 2, Table 3). Overall response rates (CR + PR) to treatment were higher in UCB recipients at all time points. Similar rates of CR were attained in both groups. The speed of attainment of CR, however, was faster in the UCB group.
Table 2. Frequency of Early Response
| 2 Months N (%) Evaluable = 168 | 6 months N (%) Evaluable = 159 | |||||
|---|---|---|---|---|---|---|
| Response | URD | UCB | P | URD | UCB | P |
| N | 102 | 39 | 110 | 41 | ||
| CR | 19(19) | 15(38) | .014 | 34(31) | 14(34) | .004 |
| PR | 30(29) | 14(36) | 20(18) | 18(44) | ||
| SD | 42(41) | 6(15) | 46(42) | 6(15) | ||
| Flare | — | — | 9(8) | 2(5) | ||
| Progression | 11(11) | 4(10) | 1(1) | 1(1) | ||
| CR+PR | 49(48) | 29(74) | .005 | 54(49) | 32(78) | .001 |
| SD+Flare | 53(52) | 10(26) | 56(51) | 9(22) | ||
Table 3. Frequency of Late Response
| 1 Year N (%) Evaluable = 151 | 2 Years N (%) Evaluable = 148 | |||||
|---|---|---|---|---|---|---|
| Response | URD | UCB | P | URD | UCB | P |
| N | 105 | 32 | 100 | 23 | ||
| CR | 40(38) | 12(38) | .02 | 40(40) | 12(52) | .13 |
| PR | 13(12) | 11(34) | 7(7) | 4(17) | ||
| SD | 41(39) | 6(19) | 46(46) | 5(22) | ||
| Flare | 11(11) | 3(9) | 7(7) | 2(9) | ||
| CR+PR | 53(51) | 23(72) | .03 | 47(47) | 16(70) | .05 |
| SD+Flare | 52(49) | 9(28) | 53(53) | 7(30) | ||
The response rates (CR + PR) were URD 48% versus UCB 74% at 2 months (P = .005), 49% versus 78% at 6 months (P = .001), 51% versus 72% at 1 year (P = .03), and 47% versus 70% (P = .05) at 2 years, respectively. The CR rates were 19% versus 38% at 2 months (P = .01), 31% versus 34% at 6 months (P = .7), 38% versus 38% at 1 year (P = .9), and 40% versus 52% (P = .3) at 2 years.
Predictors of Response
We analyzed 10 clinical factors as potential predictors of early (at 2 months) and late response (at 2 years). In univariate analysis, early and late responses were more frequent in patients with de novo/quiescent onset of cGVHD (64% versus 33%, P = .0006 at 2 months, 66% versus 31%, P = .0004 at 2 years), platelet count of ≥100,000/μL (64% versus 41%, P = .03 at 2 months, 64% versus 40%, P = .03 at 2 years), UCB transplant (74% versus 48%, P = .005 at 2 months, 70% versus 47%, P = .05 at 2 years), and in patients without liver involvement (58% versus 31%, P = .05 at 2 years). In multivariate analysis, de novo/quiescent onset of disease (OR 3.2, P = .03) and UCB transplant (odds ratio [OR] 3.8, P = .02) remained important predictors of more frequent early (2 months) and late responses (Table 4, Table 5). Myeloablative (versus nonmyeloablative) conditioning (P = .3) and recipient age <30 years (versus ≥30 years) had similar response rates (P = .3).
Table 4. Predictors of Early Response (2 Months) (CR or PR)
| Predictor | OR (CI) | P |
|---|---|---|
| Umbilical cord blood | 3.8(1.3-11.1) | .02 |
| De novo or quiescent onset | 3.2(1.1-9.3) | .03 |
| Age ≤30 | 1.12(0.4-3.4) | .80 |
| Myeloablative conditioning | 2.6(0.5-13.4) | .96 |
Table 5. Predictors of Late Response (2 Years) (CR or PR)
| Predictor | OR (CI) | P |
|---|---|---|
| Umbilical cord blood | 6.6(1.9-23.8) | .003 |
| De novo or quiescent onset | 3.8(1.1-12.8) | .03 |
| Age ≤30 | 1.8(0.6-5.6) | .3 |
| Myeloablative conditioning | 3.4(0.4-26.1) | .3 |
Survival
Overall survival (OS) after onset of cGVHD was 59% (50%-67%) in URD versus 71% (53%-83%) in UCB recipients at 2 years and 54% (44%-63%) versus 64% (42%-79%) (P = .1) at 4 years (Figure 1Ai). Nearly all deaths (85%) occurred within 2 years of cGVHD diagnosis, and most (n = 45, 63%) died of complications related to cGVHD. Two patients (3%) died of a second malignancy and 1 patient (1.4%) died of complications unrelated to HSCT. Twenty-three patients (32%) relapsed (22 within 2 years of cGVHD) and died. Eleven late deaths (beyond 2 years from diagnosis) occurred. Of these, 8 patients died of complications related to cGVHD, 1 of a second malignancy, 1 relapsed, and 1 died of other complications. The disease-free survival (DFS) was 55% (46%-63%) in URD versus 71% (55%-82%) in UCB at 2 years and 51% (41%-60%) versus 55% (30%-74%) at 4 years, P = .4 (Figure 1Aii).
Figure 1.
Survival, relapse and non relapse mortality after onset of cGVHD.
Relapse and NRM
The cumulative incidence of relapse was similar in the 2 groups (12% [6%-18% in URD versus 18% [8%-28%] in UCB), P = .3 (Figure 1Bi).
Higher NRM after cGVHD was seen in recipients of URD transplant. The NRM was 13% (95% CI 7%-19%) versus 7% (95%CI 1%-13%) at 3 months and 27% (95% CI 19%-35%) versus 11% (95% CI 2%-20%) at 1 year in the URD group and UCB group, respectively, P = .055 (Figure 1Bii).
Predictors of Mortality
In univariate analysis, progressive onset of cGVHD (P < .0001), platelet count <100,000/μL (P < .0001), liver involvement (P < .0001), and no CR or PR at 6 months (P < .0001) were each significant predictors of poor survival.
Because of a strong concordance of risk factors (low platelet count and poor response) within the donor groups, multivariate analysis for survival was performed separately in the URD and UCB cohorts. As shown in Table 6, in the URD cohort, no CR or PR by 2 months (relative risk [RR], 2.5, 95% CI 1.1-1.5, P = .02), progressive onset of disease (RR 2.7, 95% CI 1.3-6.0, P < .0001), and platelets <100,000/μL (RR 4.6, 95% CI 1.7-12.3, P =.001) were independently significant predictors of poor survival. Similarly in the UCB recipients, no CR or PR at 2 months (RR 12.5, 95 CI 1.8-87.0, P = .01) and platelets <100,000/μL (RR 6.6, 95% CI 1.1-43.4, P = .05) were independently significant predictors of poor survival. Neither intensity of conditioning regimen nor patient age was a significant predictor of survival in either cohort.
Table 6. Predictors of Mortality
| URD | UCB | |||
|---|---|---|---|---|
| Predictor | RR (CI) | P | RR (CI) | P |
| No CR/ PR at 2 months | 2.5(1.1-5.5) | .02 | 12.5(1.8-87.0) | .01 |
| Progressive onset | 2.7(1.3-6.0) | <.0001 | 1.03(0.04-26.1) | .9 |
| Platelet <100,000/μL | 4.6(1.7-12.3) | .001 | 6.6(1.0-43.4) | .045 |
| Age >30 years | 1.2(0.6-2.6) | .6 | 0.2(0.007-1.8) | .2 |
| Non myeloablative conditioning | 0.8(0.2-2.4) | .6 | 0.3(0.01-3.8) | .3 |
Duration of Treatment and Outcome
Seventy-seven patients survived 2 years or more after diagnosis of cGVHD. Of these, 40 (57%) patients were still receiving immunosuppression. The cumulative incidence of successful discontinuation of immunosuppressive treatment was 48% in URD versus 55% in the UCB cohort at 2 years, 63% versus 56% at 3 years, and 77% versus 73% at 4 years, P = .7 (Figure 2).
Figure 2.
Cumulative incidence of discontinuation of immunosuppression.
Discussion
Experience in unrelated UCB transplantation indicates that UCB transplantation is associated with a lower incidence of severe aGVHD and cGVHD despite greater donor:recipient HLA disparity [22, 23]. We report our comparative analysis of the outcomes of patients with cGVHD following URD and UCB HSCT using the uniform clinical management and supportive care at our center.
We found that UCB grafts were associated with both a lower incidence of cGVHD and a higher response rate to immunosuppressive therapy compared to URD HSCT. We noted a lower incidence of cGVHD in our URD cohort. However, 33% of these patients had received T cell depletion. Importantly, patients receiving UCB transplant were significantly older and more frequently received HLA mismatched grafts. However, because of the retrospective nature of this study, further details about disease characteristics and patient-reported improvement in symptoms could not be assessed. Response assessments were based on physician’s assessment at particular time points. More prospective studies are required to define the disease course and response in patients undergoing HSCT.
The clinical presentation of cGVHD (organ involvement and time to onset of cGVHD) was similar in both groups. A higher early response rate in UCB recipients was observed, which was sustained at 2 years after transplant. Similar to other studies reporting mostly sibling donor HSCT, de novo or quiescent onset [18, 28] of cGVHD was associated with good response.
cGVHD is one of the most important causes of NRM after transplant. In this study we observed a lower NRM in UCB transplant recipients. Factors that have been associated with higher mortality in cGVHD include “extensive” cGVHD [15, 16, 17], poor Karnofsky performance status [19], thrombocytopenia (<100,000 cells/μL) [15, 16, 18, 19], progressive-type onset [16, 18, 20], lichenoid histology [20], elevated bilirubin [20], age >20 years [18], gastrointestinal involvement [18], absence of response to therapy at 6 months [18], and other subjective measures of severity [21]. In this cohort, organ involvement was similar in both the groups, and URD transplant recipients were significantly younger than UCB transplant. However, thrombocytopenia was seen more frequently in URD transplant recipients.
A trend toward better survival was also seen in the UCB transplant recipients. Similar to other studies, thrombocytopenia, progressive onset, and lack of CR or PR were identified as significant prognostic factors associated with poor survival [16, 18, 28, 29, 31] in both URD and UCB recipients.
Despite higher response rates in the UCB group, the incidence and timing of discontinuing immunosuppression was similar in the 2 cohorts. About half of the patients still required treatment for >2 years, with nearly a quarter continuing immunosuppressive therapy beyond 4 years. These data are similar to prior studies documenting the need for prolonged immunosuppression in all these patients [18, 30, 31]. Stewart et al. [30] and Koc et al. [31] reported only 50% of patients had discontinued therapy after 5-7 years.
In conclusion, in this first detailed analysis of outcomes of patients with cGVHD following UCB and URD transplants, we found that cGVHD may be less frequent and more responsive after UCBT. NRM is also lower after UCB HSCT. Recognition of a high-risk group (progressive onset, no PR at 2 months, and platelet count <100,000/μL) should facilitate assignment of more intensified regimens to these patients after HSCT from either graft source.
Acknowledgments
This work was supported by grants from National Institutes of Health (NIH 1 P01-CA65493-01A8), Cord Blood Transplantation Study (COBLT Study: NO1-HB67139), T-Cell Depletion Trial (TCD trial: NO1-HB-47095), and Children’s Cancer Research Fund.
Daniel J Weisdorf and Mukta Arora participated in designing the study, performing the analysis and writing the paper. John E Wagner participated in designing the analysis and writing the paper. Sriharsha Nagaraj participated in data collection, coding and analysis. Juliet N. Barker, Claudio G. Brunstein, Linda J. Burns, Margaret McMillan, and Jeffrey S. Miller provided input in writing the paper. Todd E Defor participated in data analysis. All authors checked the final version of the manuscript.
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PII: S1083-8791(07)00320-5
doi:10.1016/j.bbmt.2007.06.004
© 2007 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 13, Issue 10 , Pages 1145-1152, October 2007
