Children constitute an important subset of patients undergoing BMT. Despite differences in diagnoses, organ function and immune reconstitution capability, children are often considered together with adults in studies of GVHD, and reports of the effect of age on incidence of GVHD have been inconsistent (4
). Some reports have described a reduced risk of GVHD in younger patients, while in other reports this has not been seen. The small number of children receiving BMT relative to adults has limited studies focused specifically on children. We examined a large database to examine the incidence, risk factors and outcome of GVHD in children to determine whether children with GVHD have similar risk factors and outcomes as adults, and to examine temporal trends in outcomes of unrelated donor transplants in children.
Our analysis showed that T-cell depletion for GVHD prophylaxis significantly reduced risk of GVHD, as might be expected. In addition, year of transplant was a significant risk factor, with lower risk of GVHD in more recent transplants. Perhaps unexpectedly, risk of GVHD was not increased by an allele or antigen mismatch at a single HLA locus, in contrast to findings in adult studies (20
). This may indicate greater tolerance of modest degrees of HLA disparity in pediatric transplant recipients compared with adults, or greater success of GVHD prophylaxis in controlling alloreactivity. It should be noted, however, that survival was reduced in recipients of marrow with an allele or antigen mismatched bone marrow, perhaps indicating inferior immune reconstitution in this circumstance, despite lack of a measurable excess of GVHD.
Our analysis of risk factors for chronic GVHD failed to identify any important risk factors, aside form a marginal increase in risk with multiparous female donors, as described by others (26
). Of note, HLA mismatch did not increase risk of chronic GVHD in agreement with our findings in acute GVHD, and risk was not decreased by T-cell depletion of the graft. It should be noted that the overall incidence of chronic GVHD was significant, with approximately one third of children affected, including even the youngest children, and efforts should be made to provide effective treatments for all chronic GVHD for all ages.
Our study showed a marked reduction in relapse in children with ALL who developed grades III/IV acute GVHD. These data are perhaps surprising as clinical experience of quite limited responses to donor lymphocyte infusions in ALL suggest that any graft-versus-leukemia effect in ALL might be modest (reviewed in 34
). However, data from previous non-pediatric registry studies of sibling and URD BMT support the observation of a reduced relapse rate in cases with ALL who develop GVHD (35
). Horowitz et al analyzed 2,254 sibling donor transplants performed in children and adults with early stage leukemia (ALL or AML in CR1 and CML in first chronic phase) reported to the International Bone Marrow Transplant Registry (IBMTR) (35
). This study included 439 ALL cases and showed an almost 3-fold reduction in risk of relapse associated with acute GVHD, but no effect of chronic GVHD. Similarly, a low relapse rate, attributed to graft-versus-leukemia, has been described in a report of 127 adults receiving URD BMT for high risk ALL, facilitated by the NMDP (36
). It is unclear, and perhaps equally surprising that a reduction of relapse was not seen in children with AML. It is possible that competing mortality from severe GVHD has obscured any benefit from GVHD, or that small sample size has rendered a biologically meaningful effect statistically insignificant. Future studies will address this question again as additional transplant data are accrued.
The data in our study show a significant effect of grades III/IV acute GVHD on mortality, with an almost doubled risk of death in children with acute GVHD, demonstrating that current treatments for acute GVHD are inadequate. In contrast, grade II GVHD had only a minor effect on survival. Performance of randomized controlled trials to optimize treatment of acute GVHD is an essential step in improving survival for children receiving URD BMT.
Our analysis has identified some striking temporal changes in outcome of URD BMT for children with leukemia. The risk of acute GVHD is reduced in more recent transplants (1999-2003) compared with those performed prior to 1999, even when T-cell depletion and HLA-match are included in the multivariate model. These data may indicate greater success in optimizing use of calcineurin inhibitors, and or methotrexate as GVHD prophylaxis in recent years. In contrast to this improvement in outcome, risk of relapse is increased in children transplanted in the more recent era and the increased risk is most notable in children with AML. This may reflect the use of increasingly intense chemotherapy in the primary treatment of children with AML. Of note, 35% of children with AML were transplanted with advanced disease compared with 11% of children with ALL. In addition, criteria for selection of children with leukemia for transplantation change frequently, based on improvements in identification of genetic characteristics that alter risk of relapse, for example and improvements in the effectiveness of chemotherapy. Notably, the era of transplant was not a significant risk factor for overall survival, perhaps indicating that recent reductions in GVHD are counterbalanced by the increase in relapse, illustrating the dynamic nature of leukemia patient populations as chemotherapy outcomes continue to evolve.
This study is a registry analysis and so is limited by the heterogeneity of treatment regimes and clinical practices at different institutions. The strength of the study is the size of the population, allowing analyses of subsets that could not be examined in single institution studies.
In summary, this study is the largest single analysis of GVHD in URD BMT in children to date. We have identified important temporal changes in clinical outcomes that will merit continued observation as chemotherapy and transplant strategies both continue to improve. In addition we have shown a significant effect of GVHD in reducing relapse in children with ALL, but not AML. However, overall, acute GVHD has a significant negative effect on survival, demonstrating the need for further improvements in both GVHD prophylaxis and the treatment of acute GVHD.