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Acute and Chronic Graft-Versus-Host Disease After Allogeneic Peripheral-Blood Stem-Cell and Bone Marrow Transplantation: A Meta-Analysis

From the Division of Hematologic Oncology, Dana-Farber Cancer Institute, and Harvard School of Public Health, Boston, MA.

Address reprint requests to Corey Cutler, MD, FRCPC, Dana-Farber Cancer Institute, 44 Binney St, G540, Boston, MA 02115; email: corey_cutler{at}dfci.harvard.edu

	ABSTRACT

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PURPOSE: Controversy exists as to whether the incidence of graft-versus-host disease (GVHD) is increased after peripheral-blood stem-cell transplantation (PBSCT) when compared with bone marrow transplantation (BMT). We performed a meta-analysis of all trials comparing the incidence of acute and chronic GVHD after PBSCT and BMT reported as of June, 2000. Secondary analyses examined relapse rates after the two procedures.

METHODS: An extensive MEDLINE search of the literature was undertaken. Primary authors were contacted for clarification and completion of missing information. A review of cited references was also undertaken. Sixteen studies (five randomized controlled trials and 11 cohort studies) were included in this analysis. Data was extracted by two pairs of reviewers and analyzed for the outcomes of interest. Meta-analyses, regression analyses, and assessments of publication bias were performed.

RESULTS: Using a random effects model, the pooled relative risk (RR) for acute GVHD after PBSCT was 1.16 (95% confidence interval [CI], 1.04 to 1.28; P= .006) when compared with traditional BMT. The pooled RR for chronic GVHD after PBSCT was 1.53 (95% CI, 1.25 to 1.88; P < .001) when compared with BMT. The RR of developing clinically extensive chronic GVHD was 1.66 (95% CI, 1.35 to 2.05; P < .001). The excess risk of chronic GVHD was explained by differences in the T-cell dose delivered with the graft in a meta-regression model that did not reach statistical significance. There was a trend towards a decrease in the rate of relapse after PBSCT (RR = 0.81; 95% CI, 0.62 to 1.05).

CONCLUSION: Both acute and chronic GVHD are more common after PBSCT than BMT, and this may be associated with lower rates of malignant relapse. The magnitude of the transfused T-cell load may explain the differences in chronic GVHD risk.

	INTRODUCTION

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BONE MARROW transplantation (BMT) is a widely accepted treatment for many hematologic malignancies, including leukemia/myelodysplasia, lymphoma, and multiple myeloma. In recent years, peripheral-blood stem cells (PBSC) have largely replaced bone marrow as the preferred source of autologous stem cells because of their relative ease of collection, quicker engraftment kinetics, and economic advantages.^1-3 The adoption of PBSC for allogeneic transplantation has been slower.

Graft-versus-host disease (GVHD) develops from the infusion of donor T cells with the stem-cell graft. Because peripheral-blood stem-cell transplantation (PBSCT) typically transfers a significantly larger dose of mature, immunocompetent T cells, concern about a proportionate increase in the development of GVHD has resulted in the cautious adoption of this technique. Nonetheless, there is conflicting evidence to suggest that the incidence of chronic GVHD is increased after PBSCT.^4,5-9 Only one published abstract updating the results of a randomized trial has demonstrated an increased incidence of acute GVHD.¹⁰ However, no single trial had sufficient power to detect small changes in acute GVHD incidence.

Meta-analysis is a statistical technique useful in integrating results from independent but related studies. The combination of information across studies increases statistical power to detect small treatment effects that may be missed by individual studies, regardless of each individual study’s size or quality.¹¹ We performed a meta-analysis of all published trials comparing PBSCT and BMT to estimate the relative risks (RRs) of acute and chronic GVHD and malignant relapse after allogeneic HLA-matched sibling transplantation.

	METHODS

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Literature Review
We conducted a systematic qualitative review to identify all randomized trials, and all cohort or case-control studies that compared PBSCT and BMT with GVHD as a clinical outcome that were reported as of June, 2000. Studies were identified through the following methods. A computerized literature search (MEDLINE, CANCERLIT, and Cochrane databases) was conducted with the broad categories of Bone Marrow Transplantation, Hematopoietic Stem-Cell Transplantation, and Bone Marrow Purging. A total of 33,963 articles were identified. The search strategy was narrowed using boolean combinations of the key words: allogeneic, graft-versus-host disease, stem cell, clinical, and malignant. This yielded a final list of 465 papers for which MEDLINE abstract summaries were printed and reviewed.

Inclusion criteria for identified manuscripts included: (1) human studies of malignant disease; (2) original clinical study in a randomized, cohort or a case-control study design; (3) assessment of both PBSCT and BMT; (4) GVHD outcome data; (5) inferential statistics sufficient for the evaluation of the potential confounders; and (6) original studies.

Studies were excluded if they did not compare PBSCT and BMT cohorts, if they were trials of GVHD prophylaxis or if they were relapse-monitoring studies. Studies examining methods of GVHD prevention by either positive (CD34⁺ selection) or negative (T-cell depletion) selection of stem cells were also excluded. Multiple reports of single trials were considered as one study, and all manuscripts were reviewed to obtain the most complete information as possible. Reference lists of all identified articles were reviewed for other relevant articles. Review articles and other meta-analyses were not eligible for inclusion; their reference lists were used to identify potential studies for inclusion.

Data Extraction
Duplicates of relevant manuscripts were distributed to two pairs of reviewers who independently extracted data onto preprinted data extraction forms. Extracted data included assessment of demographic variables (age, sex, indications for transplant, and GVHD prophylaxis), transplant graft characteristics (CD34+ dose and CD3+ dose), and outcome variables (incidence and severity of acute and chronic GVHD, short- and long-term mortality, and relapse rates). All abstracted data was collected by one author who also reviewed the manuscripts when discrepancies in data extraction arose. An attempt was made to contact all primary authors for missing or incomplete information. Responses were obtained from 10 corresponding authors of whom six provided updated or missing data. Updated information obtained from authors was used in all analyses, when available.

Statistical Analysis
Quantitative analysis. The RRs of acute and chronic GVHD in the PBSCT and BMT groups were obtained from the studies, and forest plots were generated. The half-integer correction method was used when rates of 0 were encountered. Data was analyzed using the commercial software package Intercooled Stata v6.0 (STATA Corporation, College Station, Tx). An overall pooled estimate of the RRs for acute and chronic GVHD with 95% confidence limits were obtained. Both a fixed effects model and the random effects model of DerSimonian and Laird¹² were used in all meta-analyses; the random effects model, which provides a more conservative measure of effects, was used for all conclusions.

Assessment of heterogeneity in the studies. Interstudy heterogeneity was assessed using the Q statistic and generation of a Cochran ² value, distributed under (number of studies -1) df. Heterogeneity is present when the Q statistic–derived ² P value is less than .05. Sensitivity analyses were undertaken to explore significant interstudy heterogeneity when appropriate.

Regression analysis. Meta-regression analysis¹³ was undertaken to explore either heterogeneity in the abstracted studies or to test a clinical hypothesis. Because of the limited number of manuscripts used, a limitation of two exploratory ß coefficients per model was enforced.

Publication bias. In an attempt to ascertain whether publication bias influenced the reported outcome of acute and chronic GVHD, we performed adjusted rank correlation tests and regression asymmetry tests according to the methods of Begg and Muzumdar¹⁴ and Eggar et al.¹⁵ Graphical funnel plots were generated to visually inspect for publication bias as well.

	RESULTS

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Literature Review
Four hundred sixty-five abstracts generated from the MEDLINE search were reviewed in detail and forty-six studies initially met the criteria for data extraction. Twenty manuscripts, including five randomized controlled trials,^4-7,9,10 11 cohort studies,^16-26 two earlier publications of republished data,^27,28 and two abstracts of published studies^8,10 involving 2,144 patients were identified as suitable for this meta-analysis. Updates and republications of published data were considered one study for the purposes of this analysis. Reasons for exclusion included insufficient or no data comparing PBSCT and BMT groups,^29,30 trials of stem-cell selection or GVHD prophylaxis,³¹ and trials of leukemic relapse monitoring³² or treatment.³³ A total of 16 studies were included. Data extracted from the 16 studies are listed in Table 1.

Acute GVHD
Fifteen studies, including five randomized controlled trials^4-10 and 10 cohort studies^16-23,25,26 reported the incidence and severity of acute GVHD (Table 1). One cohort study was excluded because historical controls were matched to cases on the basis of acute GVHD status.²⁴

RRs of grades 2 to 4 acute GVHD varied between 0.67 and 1.50 for PBSC when compared with BMT. The pooled RR estimate using the random-effects model for acute GVHD was 1.16 in the PBSC group (95% confidence interval [CI], 1.04 to 1.28) (Fig 1). This estimate was equivalent to the fixed-effects model because of extremely low heterogeneity between studies (Q = 8.65, 14 df, P = .85). The small increase in risk of acute GVHD was statistically significant at the 95% CI (P = .006). Excluding data from the IBMTR/EBMT database review, the RR for any acute GVHD after PBSCT remained at 1.16 (95% CI, 1.03 to 1.32).

View larger version (17K): [in this window] [in a new window]   Fig 1. Forest plot for all trials reporting RRs of acute GVHD. Shaded squares reflect individual study sample size and RR, expressed as within-study variance. The solid vertical line denotes an RR of 1. The diamond reflects the cumulative RR with CIs for the RR (logarithmic scale).

The incidence of severe acute GVHD (grade 3 to 4) was examined by meta-analysis as well. Data regarding the severity of acute GVHD was available from 10 studies.^{5,7-10,17-21,26} The RR for grade 3 to 4 acute GVHD after PBSCT when compared with BMT was 0.99 (95% CI, 0.79 to 1.24). Excluding data from the database review, the RR estimate was 1.29 (95% CI, 0.97 to 1.73).

Chronic GVHD
Fourteen studies, including five randomized controlled clinical trials^4-9 and nine cohort studies,^17-20,22-28 reported the incidence and severity of chronic GVHD (Table 1). RRs of chronic GVHD varied between 0.99 and 3.65 for PBSC when compared with BMT. A pooled RR estimate using the random-effects model for chronic GVHD was 1.53 (95% CI, 1.25 to 1.88; P < .001) (Fig 2). This estimate had a moderate amount of heterogeneity (Q = 42.38, 13 df, P < .001), which was a result of the influence of one study, where the rates of GVHD in the PBSCT and BMT groups were 95% and 96%, respectively.¹⁸ Removing this study from the model, the pooled estimate became 1.56 (95% CI, 1.34 to 1.82), and the heterogeneity dropped dramatically (Q = 14.72, 12 df, P = .26). Excluding data from the IBMTR/EBMT database review study, the RR estimate for chronic GVHD was 1.61 (95% CI, 1.25 to 2.06; P = .003).

View larger version (17K): [in this window] [in a new window]   Fig 2. Forest plot for all trials reporting RRs of chronic GVHD. Shaded squares reflect individual study sample size and RR, expressed as within-study variance. The solid vertical line denotes an RR of 1. The diamond reflects the cumulative RR with CIs for the RR (logarithmic scale).

Twelve studies reported the incidence of clinically extensive versus limited chronic GVHD.^{4,5,7-10,17,18,20,22-26} The RR of developing clinically extensive GVHD after PBSCT when compared with BMT was 1.66 (95% CI, 1.35 to 2.05; P < .001), excluding data from the IBMTR/EBMT database review.

Using data from the randomized, controlled trials only, a meta-regression model with two covariates (stem-cell source and the differences of the T-cell doses delivered between the PBSCT and BMT groups) was developed to explore the differences in chronic GVHD incidence between PBSCT and BMT groups. In this meta-regression model, the RR of chronic GVHD increased as the difference in T cells delivered between the PBSCT and the BMT grafts increased. The relationship was explained by the fitted equation:

equation

This relationship implies that given equal numbers of CD3⁺ T cells in a peripheral-blood stem-cell and marrow graft, one would expect a lower incidence of chronic GVHD with the peripheral-blood stem-cell graft. The relationship did not reach statistical significance, likely because of the small number of observations in some of the trials.

Relapse
Eleven studies reported rates of relapse after PBSCT or BMT.^{4-9,17,18,20,23,24,26} There was a trend towards a protective effect of PBSCT in prevention of recurrence (RR = 0.81; 95% CI, 0.62 to 1.05) (Fig 3). Failure of remission induction and early progression were considered as relapses, regardless of when they were diagnosed after transplantation. Data from the IBMTR/EBMT database review was excluded for this analysis.

View larger version (14K): [in this window] [in a new window]   Fig 3. Forest plot for all trials reporting RRs of relapse after transplantation. Shaded squares reflect individual study sample size and RR, expressed as within-study variance. The solid vertical line denotes RR of 1. The diamond reflects the cumulative RR with CIs for the RR (logarithmic scale).

View larger version (12K): [in this window] [in a new window]   Fig 4. Begg’s funnel plots for publication bias for (A) acute GVHD and (B) chronic GVHD. Solid circles denote individual studies’ estimate of logarithmic RR plotted against SE for that trial. The solid horizontal line denotes combined logarithmic RR. Diagonal lines represent pseudo-95% confidence limits.

	DISCUSSION

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This meta-analysis was undertaken to determine whether there is a relationship between stem-cell source and the development of acute and chronic GVHD after allogeneic transplantation from an HLA-matched sibling. Our results demonstrate a significant effect of stem-cell source on the incidence of both acute and chronic GVHD. A small but statistically significant increase in the risk of acute GVHD was noted after PBSCT when compared with BMT (RR = 1.16, P = .006), even when data from the IBMTR/EBMT database review was excluded. A larger increase in the risk of chronic GVHD after PBSCT was noted, with chronic GVHD occurring one and a half times as often after PBSCT when compared with BMT (RR = 1.53, P < .001). The relative risk of extensive chronic GVHD was also increased significantly (RR = 1.66, P < .001).

Activated donor T lymphocytes are important mediators of GVHD. A meta-regression model using all randomized trials demonstrated that the difference in T cells transferred with the transplant graft could account for the differences seen in GVHD incidence. In this model, once the difference in T cells transferred was controlled for, there was a trend that showed peripheral-blood stem cells to be protective against the development of chronic GVHD, but this did not reach statistical significance (RR = 0.78, P = not significant). In murine models, granulocyte colony-stimulating factor mobilized peripheral-blood stem cells have been shown to induce less GVHD than bone marrow–derived stem cells because of polarization of T cells toward the Th2 subclass, which are GVHD neutral.^34,35 The meta-regression model used in this study was considered exploratory, because only the five randomized trials reported CD3+ cell doses and could be included in the model. In several of these trials, there were only a limited number of chronic GVHD observations, which limited the statistical power of this regression. Nevertheless, the model generated biologically feasible results that merit further investigation.

The risk of malignant relapse after PBSCT was lower than after BMT in this analysis (RR = 0.81; 95% CI, 0.62 to 1.05), but this did not reach statistical significance. In chronic myelogenous leukemia, the risk of relapse has been shown to be lower after PBSCT,³² however, no attempt was made in the current study to stratify recurrence rates by either malignant disease or by indication for transplantation. In addition, no attempt was made to adjust for the influence of early mortality after transplantation on the relapse rates. The coincidental finding of a higher risk of chronic GVHD and a lower relapse rate after PBSCT has biologic plausibility as graft-versus-leukemia/graft-versus-lymphoma effects are difficult to clinically separate from GVHD.

There was insufficient data present in most of the published studies to evaluate whether the higher than expected incidence of both acute and chronic GVHD observed after PBSCT was associated with a change in treatment-related (100-day) mortality. Early mortality after PBSCT could be decreased because of faster engraftment or conversely, could be increased because of a higher than expected incidence of acute GVHD. Recently, PBSCT has been shown to be associated with lower treatment-related mortality when used in certain subtypes of leukemia.¹⁹ There was also insufficient data to evaluate whether long-term survival was affected, because this could be influenced by both lower rates of malignant relapse and higher morbidity caused by chronic GVHD.

In any meta-analysis, publication bias may skew results. There were only a few studies analyzed that reported rates of chronic GVHD after PBSCT lower or equal to those seen after BMT; however, these studies also reported higher rates of acute GVHD after PBSCT, and therefore, publication bias is unlikely. Because of the relative importance of this topic in the field of bone marrow transplantation, it seems unlikely that even negative trials would remain unpublished.

Several trials recently examined the relative economic benefits associated with PBSCT use. These trials have demonstrated decreased hospital stay and lower costs associated with the transplantation procedure.^5,6,19 However, these early economic advantages may not offset the long-term costs and morbidity associated with higher rates of extensive, chronic GVHD.³⁶ It will be important to include measures of cost and quality of life in future comparative trials to address this important issue.

Since this analysis was performed, the EBMT randomized trial has been updated¹⁰ and two new randomized trials have been reported.^37,38 The EBMT update demonstrates a significant increase in the RR of chronic GVHD (RR = 1.4, P = .037), whereas in the initial publication, there was no statistically significant relationship.^9,10 Similarly, in a randomized Norwegian trial involving 87 patients, the RR of chronic GVHD was reported to be 2.1 despite a more limited follow-up.³⁷ A large Canadian randomized trial with uniform conditioning and GVHD prophylaxis regimens demonstrated a trend toward an increased risk of chronic GVHD in the PBSCT group without a difference in the incidence of acute GVHD. In this trial, overall survival after PBSCT was superior when compared with BMT, particularly for patients with high-risk malignancies at the time of transplantation.³⁸

The results of our analysis as well as those of the forthcoming publications need to be considered strongly when choosing allogeneic stem-cell sources with patients before matched sibling transplantation. Allogeneic PBSCT seems to be associated with a greater degree of acute and chronic GVHD than BMT, however, this may be in conjunction with lower rates of relapse. Whether this increase in GVHD and decrease in relapse results in significant changes in early or late mortality is not yet evident. The ramifications of improved GVHD prophylaxis, the impact of T-cell depletion of peripheral-blood stem-cell grafts on the incidence rates of GVHD, and, ultimately, the choice of the most appropriate stem-cell graft, remain to be seen.

	ACKNOWLEDGMENTS

 
We thank the following individuals for their support and for access to their primary data for this analysis: A. Bacigalupo, MD; W. Bensinger, MD; C. de Souza, MD; C. Solano, MD; R.M. Lemoli, MD; D. Przepiorka, MD; and D. Simpson, MD.

	NOTES

 
Presented in part at the Forty-Second Annual Meeting of the American Society of Hematology, San Francisco, CA, December 1-5, 2000.

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Submitted October 23, 2000; accepted May 4, 2001.

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