Cyclosporin A-induced graft-versus-host disease following autologous bone marrow and stem cell transplantation in hematological malignancies of childhood

Abstract

Summary:Cyclosporin A (CsA) can induce graft-versus-host disease (GVHD) following autologous bone marrow transplantation (ABMT) and autologous peripheral blood stem cell transplantation (APBSCT) in adults. We investigated whether GVHD can be induced following ABMT and APBSCT in childhood, and which cells are involved in the pathogenesis of this syndrome. We conducted a prospective study of 20 children and adolescents with hematological malignancies receiving CsA after ABMT and APBSCT. Skin biopsies were obtained on day 21 after transplantation or in the event of a rash. Immunophenotypic analysis of peripheral blood lymphocytes was performed on days 14, 21, 28 and 60 after transplantation. Clinical GVHD of the skin, confirmed by histological criteria, occurred in five patients. Five patients had no clinical GVHD but had acute GVHD alterations on routine skin biopsy. In all 10 patients with a positive skin biopsy for GVHD, CD4 + lymphocytes were the predominant cells in the epidermis. Immunophenotypic analysis of peripheral blood lymphocytes revealed a significantly increased CD4/CD8 ratio in patients with a positive skin biopsy (P Ͻ 0.01). Our findings indicate that it is possible to induce acute GVHD following ABMT and APBSCT in childhood. In addition, CD4 + lymphocytes play an important role in the pathogenesis of CsA-induced GVHD. Keywords: cyclosporin A; graft-versus-host disease; bone marrow transplantation; hematopoietic stem cell transplantation Despite the increased morbidity and mortality in patients with graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT), GVHD is associated with a clinically significant antitumor effect. 1,2 It has been shown that mature T cells from the donor contaminating the bone marrow inoculum are responsible for the development of GVHD. 3 T cell depletion of donor marrow for allogeneic BMT leads to a markedly reduced incidence of GVHD in the marrow recipients. Unfortunately, T cell depletion is also associated with an increased incidence of marrow graft failure and an increase in relapse rate. 4 The procedure-related toxicity is lower after autologous bone marrow transplantation (ABMT) than after allogeneic BMT. In contrast, the higher relapse rates after autologous and syngeneic BMT than after allogeneic BMT are at least partly due to the absence of graft-versus-tumor effect associated with GVHD. 5,6 A syndrome that clinically resembles acute GVHD has been observed spontaneously in 8% of patients receiving autologous or syngeneic BMT. 7 This syndrome appears to involve only the skin, is generally mild, and is self-limiting. Due to the rarity of this phenomenon, it has not been possible to determine its effects on leukemic relapse rates.In ABMT, further significant dose escalation with the current conditioning protocols is limited due to unacceptable toxicity. Therefore, interest has focused on methods stimulating immunologically mediated antitumor activity. In animal models, GVHD was induced by treatment with cyclosporin A (CsA) in rats or mice un...

Autologous bone marrow transplantation for childhood acute lymphoblastic leukemia: a novel combined approach consisting of ex vivo marrow purging, modulation of multi-drug resistance, induction of autograft vs leukemia effect, and post-transplant immuno- and chemotherapy (PTIC)

“…Recently, the results of a study on CsA-induced aGVHD following ABMT in childhood malignancies suggested that aGVHD can be safely and reproducibly induced by 1.5 mg/kg/day of CsA administered intravenously for 28 days. 16,29,30 Our results confirm this finding since CsA was well tolerated and no grade III/IVtoxicity was reported with the use of CsA. Furthermore, hematopoietic recovery was not delayed by the administration of CsA during the first 28 days post-myeloablation and ABMT.…”

“…As has been previously demonstrated in animal and human clinical studies, an autologous GVHDlike reaction (aGVHD) may be induced by CsA. 16,29 Of our 24 patients, eight developed a skin rash, three were biopsied and one was positive for aGVHD. The other seven rashes were consistent with grade II clinical skin aGVHD.…”

“…13,14 Additionally, recent data suggest the use of posttransplant immuno-or chemotherapy may reduce the risk of post-BMT leukemia relapse. [15][16][17] It has been demonstrated that it is possible to induce acute GVHD following ABMT in children with cyclosporin A (CsA). 16 Alphainterferon (␣-IFN) is also able to induce autologous GVHD and has been shown to enhance autologous GVHD induced by cyclosporin.…”

“…[15][16][17] It has been demonstrated that it is possible to induce acute GVHD following ABMT in children with cyclosporin A (CsA). 16 Alphainterferon (␣-IFN) is also able to induce autologous GVHD and has been shown to enhance autologous GVHD induced by cyclosporin. 17 To reduce the relapse rate post ABMT for poor-risk childhood ALL, we piloted the use of CsA, CsA and ␣-IFN, and CSA, ␣-IFN, and chemotherapy post-ABMT.…”

Clinical course and predictive factors for cyclosporin‐induced autologous graft‐versus‐host disease after autologous haematopoietic stem cell transplantation

“…Although histocompatibility differences are thought to initiate the anti‐host response of the graft, a syndrome with pathology identical to GVHD can occur after autologous bone marrow transplantation (BMT) (Thien et al , 1981). This syndrome, termed autologous or syngeneic GVHD, occurs spontaneously in 5–10% of patients receiving an autologous or syngeneic HSCT (Hood et al , 1987; Byrne et al , 1997) and may be induced by the administration of cyclosporin A (CyA) after autologous HSCT in animals (Glazier et al , 1983; Bryson et al , 1989) and humans (Jones et al , 1989; Talbot et al , 1990; Carella et al , 1991; Kennedy et al , 1993; Yeager et al , 1993; Pati et al , 1996; Giralt et al , 1997; Gruhn et al , 1998). This syndrome has notable anti‐tumour activity in animal studies (Geller et al , 1989; Charak et al , 1992a; Bryson et al , 1999) and there is also some indication of an anti‐tumour effect in humans (Byrne et al , 1997).…”