Recent Decrease in Acute GVHD and Increased Relapse in Children with Leukemia Receiving Unrelated Donor Bone Marrow Transplants.

Unrelated donor (URD) BMT is an effective treatment for leukemia in children, but significant morbidity and mortality occur as a result of acute graft versus host disease (GVHD). In addition, relapse is a major cause of treatment failure in children with otherwise successful transplants. We used the database of the Center for International Blood & Marrow Transplant Research (CIBMTR) to determine whether improved HLA typing and prophylaxis have changed incidence and risk factors for acute GVHD, and the impact of GVHD on treatment-related mortality and relapse. We analyzed outcomes of 638 myeloablative URD BMT performed between 1990 and 2003 for the treatment of AML, ALL, CML or MDS. Peripheral blood stem cell and cord blood recipients were excluded as risk factors for GVHD might differ. All recipients were <18 years of age, and had available high resolution HLA typing for HLA A, B, C and DRB1. Overall, 45% of children developed aGVHD grades II–IV, and 27% aGVHD grades III–IV. The data showed that risk of aGVHD was significantly higher in recipients of T-replete compared with T-depleted grafts (OR 3.12, 95%CI 2.02–4.83; p< 0.0001). Survival was reduced in children with grades II–IV aGVHD compared to those without (OR 1.96, 95% CI 1.46–2.62; p<0.0001). However, the occurrence of aGVHD reduced risk of relapse in children with ALL (OR 0.36 95% CI 0.17–0.75, p=0.004) but not in children with AML (OR 1.23, 95% CI 0.50–2.98; p=0.65). Outcomes have changed significantly over time. The risk of aGVHD was higher in children transplanted in earlier years (1990–1998, n=365) compared to 1999–2003 (n= 220) (OR 1.93 95%CI 1.27–2.91; p=0.002), suggesting that current prophylactic regimens may be more effective. In contrast to this recent improvement in risk of GVHD, risk of relapse was lower in children transplanted 1990–1998 compared with 1999–2003 (OR 0.47, 95% CI 0.28–0.78; p=0.004), possibly reflecting changes in the patient population currently referred for transplant, or perhaps a reduced graft versus leukemia effect with better control of GVHD. As more intense risk adapted chemotherapy has improved outcomes of upfront treatment of leukemia, children who are referred for transplant may have more resistant disease, increasing the difficulty of controlling disease with standard irradiation and chemotherapy preparative regimens. Overall survival of children with URD BMT has not changed over time, although it is possible that current results reflect treatment of children with more resistant disease compared with 10 years ago.