Graftversushost Disease

Most reports show that GvHD is a major cause of morbidity and mortality after reduced-intensity or nonmyeloablative conditioning regimens.7'9'34'3941 In the EBMT lymphoma study, grade II-IV acute GvHD was seen in 29% of in vivo T-cell-depleted HCT recipients, versus 58% of T-cell-replete HCT recipients (P = 0.03).46 In multivariate analysis, both T-cell depletion of grafts and grafts from sibling donors were associated with lower GvHD incidences.46 In a French study that used a conditioning regimen of fludarabine, busulfan, and ATG, the cumulative incidence of grade II-IV acute GvHD was 36%, and the 2-year cumulative incidence of chronic GvHD was 43%.50 In multi-variate analysis, a lower incidence of acute GvHD was significantly associated with higher ATG doses infused during conditioning (P = 0.0005), whereas the use of G-PBMC instead of marrow as the stem cell source was the only risk factor for the development of chronic GvHD (P = 0.0007). Not surprisingly, the relapse rates were much lower in patients who experienced GvHD than in those without it, suggesting potent GvT effects.

We recently compared GvHD in 44 nonmyeloablative and 52 age-matched conventional HCT recipients (ablative group).51 HCT included grafts from both related and unrelated donors who were at least sero-logically matched for HLA-A, -B, and -C, and allele-level matched for HLA-DRB1 and -DQB1. The median patient age was 56 years in the nonmyeloablative group versus 54 years in the ablative group. Postgrafting immunosuppression was MMF and CSP in the nonmyeloablative group, and MTX plus CSP (n = 48) or MMF plus CSP (n = 4) in the ablative group. Grades II-IV and III-IV acute GvHD to day 100 were lower among unrelated recipients in the nonmyeloab-lative group than among those in the ablative group (P = 0.01 and 0.01, respectively). Peaks of skin and gastrointestinal morbidities occurred between 6 and 12 months in the nonmyeloablative group and during the first month in the ablative group. Interestingly, 7 of 10 nonmyeloablative HCT recipients who required steroid treatment for cutaneous GvHD after day +80 had acute inflammatory changes similar to those seen in acute GvHD ("late onset acute GvHD"). These observations emphasized that a new GvHD classification that is based on criteria emphasizing the quality of target organ involvement rather than temporal presentation would be required to assess GvHD after non-myeloablative HCT. The median time to initiation of corticosteroids was 3.0 months in the nonmyeloablative group versus 0.9 months (P <0.001) in the ablative group. Significantly smaller proportions of non-myeloablative compared to ablative recipients required steroids during each of the first 3 months after HCT (month 1, P <0.001; month 2, P <0.001; month 3, P = 0.02). However, differences in steroid requirements between the nonmyeloablative and the ablative groups were no longer significant beyond the first 3 months after HCT. The 15-month cumulative incidence of death with manifestations of GvHD under treatment was 24% in the nonmyeloablative group versus 35% not significant (NS) in the ablative group. One-year overall survival was 68% in the nonablative group versus 50% (P = 0.04) in the ablative group.

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