Risk factors for chronic graft-versus-host disease after allogeneic stem cell transplantation in children

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...

Section: Discussionsupporting

confidence: 81%

“…2,11,30,31,33,34 The beneficial effect of chronic GVHD was evident in ALL as well as in AML patients (Figures 1 and 3). This is an important observation in a perspective, where the role of a GVL effect has been questioned along with the uncertain efficacy of DLI in acute leukaemias, in contrast to the situation in CML.…”

Section: Discussionmentioning

confidence: 97%

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

Jernberg

Remberger

Ringdén

et al. 2003

“…1,5 Chronic GvHD has been identified as an important predictor of late treatment-related mortality. 6 Therefore, the reported rates of chronic GvHD after allogeneic HSCT (X55%) 7 are unacceptably high, especially in pediatric patients, whose post transplantation life expectancy is longer. One strategy used to reduce the incidence of GvHD is transplantation of positively selected CD34 + PBSC with concomitant depletion of T cells by a factor of 10 3 -10 5 .…”

mentioning

confidence: 99%

A prospective comparison of immune reconstitution in pediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated donors vs recipients of unmanipulated bone marrow from related donors

Eyrich

Leiler

Lang

et al. 2003

Summary:Positively selected CD34 + hematopoietic stem cells from unrelated donors (UD-HSCT) have been successfully transplanted, but little is known about immune reconstitution in this setting. Here we report a prospective comparison of immune reconstitution in recipients of UD-HSCT and of unmanipulated bone marrow from matched sibling donors (MSD-BMT). T-cell reconstitution occurred more than 100 days later in the UD-HSCT than in the MSD-BMT group. The first T cells after UD-HSCT were almost exclusively CD45RO + HLA-DR + , whereas early-emerging T cells after MSD-BMT more frequently expressed CD62L, CD28, and CD25. In both groups, numbers of CD45RA + naive T cells increased after 180 days. After UD-HSCT, the T-cell-receptor (TCR)-repertoire was severely skewed and showed significantly reduced diversity during the first year, but only minor abnormalities were seen after MSD-BMT. TCR-diversity increased simultaneously with the number of naive T cells. In both groups, we observed transient expansions of cd T cells. B cells were reconstituted more rapidly in UD-HSCT than in MSD-BMT recipients, whereas the rapidity of NK-cell reconstitution was similar in the two groups. In summary, T-cell reconstitution was slower after UD-HSCT than after MSD-BMT because of the delayed recovery of early memory-type T cells with reduced TCR-diversity, whereas naive T-, NK-, and B cells were reconstituted similarly in the two groups.

“…19 In general, male donors are superior to female donors, because female to male transplantation has been associated with decreased survival in some studies. [15][16][17] However, our study showed that donor parity was not associated with the duration of systemic IST, GSS and OS. Underlying disease, degree of HLA mismatch, nature of the conditioning regimen and whether the donor was sibling or not were not related to the duration of systemic IST, GSS and OS.…”

Section: Discussionmentioning

confidence: 70%

“…Duration of IST was only significantly associated with the difference between grade I or II and III. The new chronic GVHD grade, a prior history of acute GVHD, 14 risk of transplantation, serum bilirubin level more than 1.5 mg/dl at diagnosis and date of diagnosis of chronic GVHD (oday 150 versus 4day 150) [15][16][17] were significantly associated with both GSS and OS.…”

Section: Discussionmentioning

confidence: 99%

New clinical grading system for chronic GVHD predicts duration of systemic immunosuppressive treatment and GVHD-specific and overall survival

Jung

et al. 2007

We investigated outcomes according to a new clinical grading system for chronic graft-versus-host disease (chronic GVHD) in 38 patients who developed chronic GVHD after an allogeneic hematopoietic stem cell transplantation. We categorized the patients into three grade groups, namely, grade I, grade II and grade III, according to the presence of three risk factors: extensive skin involvement, thrombocytopenia (TP) and progressive type of onset. Sixteen patients were classified into grade 1, 19 into grade II and three into grade III. The probability of withdrawal of systemic immunosuppression (IST) at 1, 2 and 3 years was 61, 76 and 87%, respectively. Patients with grades 2 or 3 chronic GVHD had prolonged duration of systemic IST compared to grade 1 (P ¼ 0.043). The probability of GVHD-specific survival (GSS) at 5 years was 52%. Twenty-two of 38 patients with chronic GVHD were still alive and the estimated 3-year overall survival (OS) rate was 60%, whereas that for the group with chronic GVHD grade I and grade II þ III was 64 and 48% (Po0.05). Multivariate analysis showed that prior occurrence of acute GVHD, chronic GVHD grade, serum bilirubin over 1.5 mg/dl, date of diagnosis of chronic GVHD (oday 150 versus 4day 150) and transplantation-risk factor were independent prognostic factors for GSS and OS.