Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: a matched pair analysis

Summary:It is unknown whether the addition of antithymocyte globulin (ATG) to reduced-intensity conditioning with busulfan (BU) and fludarabine (FLU) is beneficial in HLA-identical sibling transplantation. Therefore, we analyzed retrospectively data on 83 patients, who received peripheral blood stem cells from HLA-identical siblings after conditioning with either 8 mg/kg BU and 150 mg/m 2 FLU (n ¼ 45) or 8 mg/kg BU, 180 mg/m 2 FLU and 40 mg/ kg ATG (n ¼ 38). Graft-versus-host disease (GVHD) prophylaxis consisted of CSA alone (n ¼ 32) or a combination with either MTX or MMF (n ¼ 51). The median age was 52 years. Graft failure occurred in two patients after BU/FLU and in three after BU/FLU/ATG (P ¼ 0.66). After conditioning with BU/FLU, platelet recovery was significantly faster (P ¼ 0.017), and less platelet (Po0.001) and red blood cell (P ¼ 0.002) support was needed. Incidences of acute GVHD grades II and IV were 46 and 49%, respectively. Limited chronic GVHD occurred more often after BU/FLU compared to BU/FLU/ ATG (54 vs 23%, P ¼ 0.02). The overall survival, nonrelapse and relapse mortality did not differ significantly. We conclude that in peripheral blood stem cell transplantation from HLA-identical siblings after reduced-intensity conditioning with BU and FLU, ATG has no major impact on the rate of graft rejection and acute GVHD, but it reduces the incidence of limited chronic GVHD. Reduced-intensity conditioning regimens with busulfan (BU), fludarabine (FLU) and antithymocyte globulin (ATG) are increasingly used in related and unrelated hematopoietic stem cell transplantation (HSCT). 1 While the use of ATG as an additional drug for graftversus-host disease (GVHD) prophylaxis is widely accepted in unrelated transplantation, the application in HLA-identical sibling transplantation is a matter of debate. ATG-Fresenius is a polyclonal IgG antibody raised in rabbits against the Jurkat T cell line. 2 The antibody had been incorporated into dose-reduced conditioning regimens for two reasons: first, ATG given before transplantation exerts T-cell depletion of the recipient, which facilitates donor stem cell engraftment after nonmyeloablative doses of BU and FLU and second, antibody persisting in the recipient beyond transplantation exerts in vivo depletion of donor T cells, thereby possibly reducing the risk for acute and chronic GVHD. 3,4 However, ATG has considerable short-term toxicity. 5 While the efficacy of ATG to prevent GVHD and to reduce nonrelapse mortality after myeloablative HSCT has been demonstrated in several studies, the role of ATG in reduced-intensity conditioning has not been evaluated. [6][7][8][9][10] However, reduced-intensity conditioning with BU and FLU was safe even without ATG in 24 patients as shown by our group. 11 In order to assess the impact of ATG, we retrospectively compared the engraftment, incidence and severity of GVHD and survival after BU-and FLU-based reduced-intensity conditioning with or without ATG in patients who had received peripheral blood stem cell transplantation (PBSCT...

Section: Discussionmentioning

confidence: 99%

Reduced-intensity conditioning with busulfan and fludarabine with or without antithymocyte globulin in HLA-identical sibling transplantation – a retrospective analysis

Schetelig

Bornhäuser

Kiehl

et al. 2003

“…The Alberta group in Canada has gone further still, and has completed a matched pair analysis of MUD transplants receiving ATG in the conditioning regimen, with HLAidentical sibling transplants not receiving ATG. 26 In this study, all patients received the FLUBUP regimen (fludarabine, intravenous busulfan, peripheral blood allogeneic stem cells). Acute GvHD grade II was 19 vs 36% for patients receiving or not ATG, grade III-IV was 10 vs 18%.…”

Section: Comparative Nonrandomized Studiesmentioning

confidence: 99%

“…[18][19][20][21][22][23][24][25][26][27][28][29][30] One of these 23 23 Recently, the German cooperative group studied 155 patients with acute myeloid leukemia (AML) undergoing an allogeneic UD transplant: 87 received ATG as part of the conditioning regimen, whereas 68 did not. Grade III-IV acute GvHD was seen in 12% of the ATG patients vs 22% of the non-ATG patients (P ¼ 0.04) 24 (Table 1).…”

Section: Comparative Nonrandomized Studiesmentioning

confidence: 99%

Antilymphocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects

Bacigalupo

2004

109

Summary:Antilymphocyte/thymocyte globulins (ALGs/ATGs) have now been used for over 30 years in the setting of hemopoietic stem cell transplants (HSCT), with the aim of preventing graft-versus-host disease (GvHD). This is true especially for transplants from alternative donors. In this review, we will be discussing available published and unpublished data on the advantages and disadvantages of using ALG/ATG before or after an allogeneic HSCT. These studies show that ALG/ATG significantly reduce the incidence and severity of acute and chronic GvHD. Unfortunately, they also show that immune deficiency is a more prolonged and infectious complication more frequent in patients receiving ALG/ATG, suggesting the importance of aggressive monitoring of viral and fungal infections. In particular, the emerging problem of Epstein-Barr virus (EBV) infections and EBV-related lymphoproliferative disorders will be discussed, together with the use of pre-emptive therapy with rituximab. I personally believe ALG/ATG has an important role in allogeneic HSCT, especially today with the increasing use of peripheral blood transplants and the consequent high risk of chronic GvHD. ALG/ATG should be used with caution, and the negative consequences must be understood and possibly prevented. Bone Marrow Transplantation (2005) 35, 225-231.

“…2 Several previous studies have suggested suitable doses of ATG in matched unrelated transplantations. 3,4 However, to date, the optimal dose of ATG with respect to the prevention of severe GVHD following the haploidentical transplantation is unknown.…”

Section: Introductionmentioning

confidence: 99%

Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial

Wang

et al. 2013

104

131

To evaluate the effect of the different doses of antithymocyte globulin (ATG) on the incidence of acute GVHD among patients receiving hematopoietic SCT without ex vivo T-cell-depletion from haploidentical donors, 224 patients with standard-risk hematological malignancy were randomized in this study. One hundred and twelve patients received 6 mg/kg ATG, whereas the remaining patients received 10 mg/kg ATG. This study was registered at http://www.chictr.org as No. ChiCTR-TRC-11001761. The incidence of grade III-IV acute GVHD was higher in the ATG-6 group (16.1%, 95% confidence interval (CI), 9.1-23.1%) than in the ATG-10 group (4.5%, CI, 0.7-8.3%, P ¼ 0.005, 95% CI for the difference, À 19.4% to À 3.8%). EBV reactivation occurred more frequently in the ATG-10 group (25.3%, 17.1-33.5%) than in the ATG-6 group (9.6% (4.0-15.2%), P ¼ 0.001). The 1-year disease-free survival rates were 84.3% (77.3-91.3%) and 86.0% (79.2-92.8%) for the ATG-6 group and ATG-10 groups, respectively (P ¼ 0.88). In conclusion, although 6 mg/kg ATG applied in haploidentical transplantation decreased the risk of EBV reactivation compared with 10 mg/kg ATG, this treatment exposes patients to a higher risk for severe acute GVHD. INTRODUCTIONAntithymocyte globulin (ATG) has been used in the conditioning regimen to prevent severe GVHD in haploidentical hematopoietic SCT (HSCT), and our previous study presented encouraging results. 1 However, the limitations associated with the use of ATG as a regimen for in vivo T-cell depletion (TCD) include the occurrence of delayed immune reconstitution and an increased risk of severe infections, depending on the dose of ATG administered. 2 Several previous studies have suggested suitable doses of ATG in matched unrelated transplantations. 3,4 However, to date, the optimal dose of ATG with respect to the prevention of severe GVHD following the haploidentical transplantation is unknown.In our recently reported retrospective study, we reduced the total dose of ATG from the traditional 10 mg/kg in our classic regimen to 6 mg/kg for refractory/relapsed patients undergoing haploidentical HSCT. We observed that the reduction of the total dose of ATG to 6 mg/kg produced similar rates of engraftment, GVHD and survival compared with the 10 mg/kg dose of ATG. 5 Based on these findings, we set out to extend the use of 6 mg/kg ATG to standard-risk patients. Therefore, we initiated the current prospective randomized study to evaluate the effect of the two different doses of ATG in conditioning regimens on graft failure, GVHD, relapse and survival among standard-risk patients receiving haploidentical HSCT. We postulated that the use of 6 mg/kg ATG might reduce adverse events without increasing the risk of GVHD.