Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin–based reduced-intensity preparative regimen

Abstract

Reduced-intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT). RIC has been shown to allow engraftment with minimal early transplantationrelated mortality (TRM). However, in the context of RIC, predictive factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and their effect on outcome remain unknown. In this report, we analyzed the outcome of 101 high-risk patients (70 hematologic and 31 nonhematologic malignancies) who received an HLA-identical sibling allo-SCT after RIC, including fludarabine, busulfan, and antithymocyte globulin (ATG). The cumulative incidence of grade II-IV aGVHD was 36% (95% confidence interval [CI], 27%-45%), whereas the cumulative incidence of cGVHD at 2 years was 43% (95% CI, 33%-53%). In multivariate analysis, the incidence of aGVHD was significantly associated with the ATG dose infused during conditioning (P ‫؍‬ .0005), whereas peripheral blood as stem cell source was the only predictive factor for the development of cGVHD (P ‫؍‬ .0007). The 1-year cumulative incidences of disease progression or relapse in patients with (n ‫؍‬ 69) and without (n ‫؍‬ 31) GVHD (whatever its form or grade) were 30% (95% CI, 19%-41%) and 55% (95% CI, 37%-72%), respectively (P ‫؍‬ .02), suggesting that a potent graft-versus-tumor (GVT) effect can be achieved in high-risk patients following RIC. Moreover, the GVT effect was closely associated with GVHD without an increased risk of TRM (cumulative incidence of TRM, 18% [95% CI, 10%-25%]). Collectively, these results provide a framework for the refinement of RIC approaches designed to enhance the GVT effect with an acceptable risk of GVHD.

Impact of rabbit ATG-containing myeloablative conditioning regimens on the outcome of patients undergoing unrelated single-unit cord blood transplantation for hematological malignancies

“…In fact, it is because of ATG's beneficial effects in cases of HLA disparities that ATG has been recommended. 11,22,28 Although we acknowledge the limitations of our retrospective study based on a relatively small number of mostly young patients, our results suggest that the use of ATG during myeloablative conditioning of patients receiving single-unit allo-CBT should be handled cautiously outside the clinical trial setting. From our study, no conclusions can be drawn with certainty concerning patients who received nonmyeloablative conditioning and those transplanted with double-unit cord blood or with in vitro expanded cord blood.…”

“…In addition, based on our experience and various other reports, it is likely that the use of low to moderate doses (5-7 mg/kg) of ATG before allo-SCT can decrease the risk of GVHD without compromising other post-transplant outcomes. 28,29 An alternative approach to ATG administration could be the use of a fludarabine-based regimen because this chemotherapeutic agent is known to have a powerful immunosuppressive effect resulting in long-lasting engraftment; 7 however, its use in HLAmismatched transplantation needs to be established. In fact, it is because of ATG's beneficial effects in cases of HLA disparities that ATG has been recommended.…”

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

“…Early CyA withdrawal regulation to get speedy achievement of complete donor chimerism after RIST in our protocol might have influenced the increased incidence of Grade II-IV acute GvHD, which might have affected the rate of chronic GvHD [33,35,38,39]. Although severe GvHD will be unavoidable for some patients including MDS with poor prognostic factors [40,41], the balance between GvHD and GvL is a significant concern in RIST and we should seriously evaluate the type and tapering speed of immunosuppressive agents after RIST. Current findings suggested GvHD control might be improved simply by extending the duration of CyA administration.…”

The impact of graft-versus-host disease prophylaxis in reduced-intensity conditioning allogeneic stem cell transplant in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

“…[1][2][3][4] In this setting, the combination of fludarabine and 2 days of busulfan (Flu-Bu2) is a widely used RIC regimen. [1][2][3]5 Initially described in HLA identical sibling peripheral blood stem cell transplantation, Flu-Bu2 was combined with anti-T-lymphocyte globulin (ATG) (Fresenius 10 mg/kg/day) and cyclosporine A (CsA) alone for the prophylaxis of graft-versus-host-disease (GVHD). 1 However, the best GVHD prophylaxis combination in the Flu-Bu2 RIC regimen has not yet been established.…”