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

Abstract

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...

Prospective phase II trial to evaluate the complications and kinetics of chimerism induction following allogeneic hematopoietic stem cell transplantation with fludarabine and busulfan

“…In this prospective study, we showed that a combination of fludarabine (180 mg/m 2 ) and oral busulfan (8 mg/kg), despite the omission of antithymocyte globulin from the original regimen by Slavin et al [6], can be successfully used to help prepare patients older than 50 years with hematological malignancies for HSCT from an HLA-matched related donor: All patients achieved sustained engraftment without graft failure, only an insignificant occurrence of RRT and treatment-related complications were seen, and PS and dietary intake were well maintained, which agrees with published observational studies on RIST with fludarabine and busulfan [16,22,23].…”

“…G-CSF mobilized peripheral blood stem cells may have been associated with an increased incidence of GvHD, particularly in its chronic form [34,35]. Conditioning regimen excluded antithymocyte globulin was also a possible explanation of this finding [23]. Most importantly, patients undergoing RIST are usually older than those undergoing CIST, which leads to a higher risk for GvHD [36,37].…”

Reduced-toxicity conditioning with fludarabine and treosulfan prior to allogeneic stem cell transplantation in multiple myeloma

“…[8][9] The nucleoside analogue fludarabine has already been incorporated into a variety of reduced-intensity or nonmyeloablative conditioning regimens. [10][11][12] The substance is characterized by high activity against lymphoid neoplasms and has a favorable toxicity profile. 13 Its immunosuppressive effects, particularly on T-cell activity, makes the substance suitable as part of a RIC regimen before allogeneic SCT.…”

In vivo T-cell depletion with low-dose ATG is effective in reducing cGVHD after peripheral blood stem cell myeloablative sibling transplants in CML: results from a prospective phase II study

“…3 With regard to family donors, instead, ATG-F has been used with bone marrow, 6 while in peripheral blood SCT, it has been almost exclusively associated with reducedintensity conditioning (RIC). 8 No data, however, are available for myeloablative, HLAidentical sibling PBSC transplants. We prospectively planned a prospective phase II study on the use of ATG- Table 1 Patients' characteristics and outcome F for the prophylaxis of GVHD after PBSC sibling transplants in CML.…”