Graft-versus-leukaemia effect in children: chronic GVHD has a significant impact on relapse and survival

Abstract

Summary:To examine whether graft-versus-host-disease (GVHD) is associated with a graft-versus-leukaemia (GVL) effect that also influences the outcome of allogeneic stem cell transplantation (SCT) in childhood acute leukaemia, we evaluated all consecutive (n ¼ 169) children who had undergone SCT for ALL and AML at our centre. Median followup was 7 years. The 5-year probability of chronic GVHD was 34%. Median time to relapse was 24 months in children with chronic GVHD and 6 months in those without. The corresponding 5-year probabilities of relapse were 30 and 45% (P ¼ 0.01). The 5-year probability of survival was 54%. Patients with chronic GVHD had a significantly better survival, 77 vs 51% (P ¼ 0.01). In a Cox regression model, chronic GVHD independently decreased the risk of relapse (RR 0.44) and further predicted an increased chance of relapse-free survival (RR 1.7) and survival (RR 2.6). The impact of chronic GVHD on survival was most apparent in late-stage disease and in ALL. Acute GVHD was not an independent predictor for relapse or death in this study. This study is in support of a GVL effect in childhood leukaemia related to chronic GVHD, reducing the risk of relapse and improving survival. Bone Marrow Transplantation (2003) 31, 175-181. doi:10.1038/sj.bmt.1703808 Keywords: bone marrow transplantation; children graft-versus-host disease; graft-versus-leukaemia; relapse survivalThe major cause of failure after haematopoietic stem cell transplantation (SCT) in childhood leukaemia is relapse of disease, followed by transplant-related causes such as graftversus-host disease (GVHD), treatment toxicity and infections. 1,2 The original concept of SCT was to enable complete eradication of malignant cells by a maximum dose of chemoradiotherapy, bypassing the otherwise dose-limiting bone marrow aplasia with a salvaging autologous or allogeneic graft. In addition, now a well-established belief in the immunotherapeuthic potential of the allogeneic graft has evolved, usually described as the graft-versus-leukaemia (GVL) effect. This antileukaemia effect was first postulated in the 1950s by Barnes 3 and later reported in humans by Weiden et al 4 in 1979. Acute and chronic GVHD were presented as favourable in decreasing the risk of relapse.This was later confirmed in an IBMTR study in 1990, 5 which further supported the existence of a GVL effect by reporting a higher probability of relapse in patients receiving T-cell-depleted (TCD) or syngeneic grafts. Several recent studies, including those on the effect of donor lymphocyte infusions (DLI), have strengthened this concept. [6][7][8][9] However, treatment of relapses post-SCT with DLI has been considerably less successful for acute leukaemias than in CML. 9 In a previous study, comparing the outcomes of MUD and sibling graft recipients, we found a significant difference in occurrence of relapse between children who did or did not develop chronic GVHD. 2 We decided to further investigate this issue in the entire group of children transplanted for acute leukaemias at our c...

Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission

“…A select number of studies have shown an impact of acute 10, 34, 35 or cGvHD 11, 36 on relapse after related or unrelated bone marrow HSCT for pediatric acute leukemia. Pulsipher et al observed that aGvHD and pre-transplant MRD, independently and in combination, influenced the risk of relapse after HSCT for pediatric ALL after controlling for graft source and other variables 9 .…”

“…It is well established that the GvL effect, likely due to immune surveillance provided by donor NK- and T-cells, is important in eradicating leukemia after allogeneic HSCT 2–5 , although the GvL effect in ALL may be weaker than in other malignancies 6–8 . Select clinical reports have demonstrated lower rates of relapse in pediatric patients with ALL who experience graft-versus-host disease (GvHD) after HSCT, providing indirect evidence of GvL actions in this disease 9–11 .…”

T‐cell‐replete haploidentical stem cell transplantation is highly efficacious for relapsed and refractory childhood acute leukaemia

“…The role of aGVHD in ALL has been less clearly defined than the generally accepted notion that the GVL effect plays an important role in the treatment of AML. Many recent publications (Zecca et al , ; Gustafsson Jernberg et al , ; Nordlander et al , ) have reported the effects of GVHD and GVL on remission rates and OS for acute leukaemic relapse after SCT in both adult and paediatric populations. This indicates that the GVL effect may also improve the ALL survival rate.…”

Chronic graft versus host disease

“…The incidence of chronic GvHD is lower in children but remains significant. A review of the experience of a single centre, which evaluated patients transplanted for leukaemia using several different regimens for GvHD prophylaxis, had a chronic GvHD rate of 34% (Gustafsson Jernberg et al , 2003). A recent evaluation of GvHD following matched sibling or one antigen mismatched‐related transplantation by the Children's Cancer Group, in which GvHD prophylaxis was uniform, reported a chronic GvHD rate of 21·2% with 7·3% of the patients with limited disease and the remaining 14% demonstrating extensive disease (Neudorf et al , 2004).…”

“…Efforts to modulate the immune system frequently result in GvHD that may improve disease‐free survival (DFS) but result in chronic GvHD. Long‐term follow‐up of adults and children increasingly demonstrate a possible role for chronic GvHD in improving DFS, especially in high‐risk malignancies, but may not improve event‐free survival (EFS) secondary to complications of GvHD and its treatment (Cutler et al , 2001; Gustafsson Jernberg et al , 2003; Neudorf et al , 2004). The recent publication by the Children's Cancer Group demonstrated the benefit of acute GvHD in relapse‐free survival (Neudorf et al , 2004), while the role of chronic GvHD in children has been reported from Sweden (Gustafsson Jernberg et al , 2003).…”