Unrelated bone marrow transplantation in children: outcome and a comparison with sibling donor grafting

Summary:The optimal total body irradiation (TBI) regimen for unrelated donor bone marrow transplant (UD-BMT) is unknown.In the present study we analyze the outcomes of two different TBI regimens used in our center for patients with leukemia undergoing an UD-BMT. Between January 1994 and August 2001, 99 consecutive UD-BMT patients entered this comparative study. The conditioning regimen consisted of cyclophosphamide, 120 mg/kg followed by TBI on days ؊3, ؊2 and ؊1. Forty-six patients received TBI 12 Gy (2 Gy, twice a day) in six fractions (HF-TBI) and 53 patients received TBI 9.90 Gy (3.30 Gy per day) fractionated over 3 days (F-TBI). End-points were transplanted-related mortality (TRM), leukemia relapse rate (LRR) and overall survival (OS). At median follow-up of 22 months (58 months for HF-TBI and 17 for F-TBI, respectively), 60 patients were alive (32 in HF-TBI sub-group and 28 in F-TBI one). The actuarial 5-year TRM was 31% for HF-TBI and 41% for F-TBI (P = 0.1), whereas the 5-year LRR was 13% for HF-TBI and 31% for F-TBI (P = 0.04). The actuarial 5-year OS was 68% for patients treated with HF-TBI and 51% for those treated with F-TBI (P = 0.02). At multivariate analysis F-TBI schedule emerged as an adverse predictor for OS (P = 0.04) and LRR (P = 0.03). These data indicate that a lower total dose of TBI appears significantly less effective in leukemia eradication and associated with worse overall survival when compared with a higher dose of radiation. Allogeneic hemopoietic stem cell transplant (HSCT) is an established treatment modality for a variety of congenital and acquired disorders of the hemopoietic system. 1 Being an HLA-genotypically identical sibling (SIB-HSCT) available for less than 30% of the potential transplant candidates, the use of alternative donors has been increasingly explored; 2 nowadays, HSCT from unrelated donors (UD-BMT) has become a steady approach and many patients have achieved complete immunologic tolerance and long survival. 3,4 However, compared with SIB-HSCT, transplant from unrelated donors is associated with a high incidence of graft-versus-host disease (GVHD), morbidity and mortality. [5][6] Total body irradiation (TBI) is included in the vast majority of conditioning regimens to be used in SIB and UD-BMT, although busulfan-based conditioning regimens have been extensively reported. 7 The aims of TBI are to destroy the host marrow to allow repopulation with donor marrow cells, to achieve immunosuppression in order to prevent graft rejection and to eradicate leukemia cell population. 8 TBI is generally delivered with a fractionated or hyperfractionated regimen in an attempt to increase the therapeutic ratio between disease cell killing and normal tissue toxicity. 9 Clinical studies have confirmed the therapeutic efficacy of once-a-day or multiple daily fractionated TBI regimens with lower risk of radiation-induced toxicity compared to single dose TBI. 8,10 However, the optimal regimen of TBI with regard to total dose, number and type of fractionation remains controversial. 11...

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

Low-dose fractionated total body irradiation (TBI) adversely affects prognosis of patients with leukemia receiving an HLA-matched allogeneic bone marrow transplant from an unrelated donor (UD-BMT)

Corvò

Lamparelli

Bruno

et al. 2002

“…However, severe graft-versus-host disease (GVHD) increases morbidity and mortality for haematopoietic transplantation from alternative donors when compared to HLA-matched siblings. [1][2][3][4] Pre-graft serotherapy directed against lymphocytes has been demonstrated to reduce the risk of severe GVHD. [5][6][7] Different types of pre-graft serotherapy have been used including monoclonal antibodies such as OKT3, or Campath 1G anti-CD52, or rabbit or horse polyclonal antibodies directed against thymocytes or T lymphocytes.…”

mentioning

confidence: 99%

Immune reconstitution after haematopoietic transplantation with two different doses of pre-graft antithymocyte globulin

Duval

Pédron

Rohrlich

et al. 2002

Summary:Antithymocyte globulin is widely used before haematopoietic transplantation with HLA-matched unrelated donors or mismatched relatives to prevent rejection and graft-versus-host disease (GVHD). However, optimal dosage is still under debate. Thirty-one consecutive children, mainly with haematological malignancies, were transplanted in a single institution with such donors, selected by HLA-A -B compatibility by serology and DRB1* by DNA typing. Antithymocyte globulin (Thymoglobuline; Sangstat) was infused at days ؊3, ؊2, ؊1. Total dosage varied: 16 patients received a median of 7.5 mg/kg (2.5 to 10.5: low-dose group), and 15 a median of 15.5 mg/kg (14.4 to 19.4: high-dose group). Post-transplant GVHD prophylaxis consisted of cyclosporine, short-course methotrexate and steroids. CD3 + , CD4 + and CD19 + cell reconstitution was slower in the high-dose group. Median time to reach 100 CD4 + cells was 8 months vs 4 months (P = 0.03). Median time to normal CD19 + cells was 16 months vs 8 months (P = 0.01). CD16 + CD56 + and CD8 + cell reconstitution was similar. Nine patients in the high-dose group and two in the low-dose group experienced life-threatening opportunistic infections (P = 0.009). Although obtained from a limited number of patients, our data suggest that a higher pre-graft dose of antithymocyte globulin may negatively influence immune reconstitution.

“…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 centre. The aim of the present study was thus to examine whether a GVL effect also is present in the paediatric setting and to relate it to the occurrence of GVHD.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Jernberg

Remberger

Ringdén

et al. 2003

Self Cite

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...