Intensive graft-versus-host disease prophylaxis is required after unrelated-donor nonmyeloablative stem cell transplantation

Abstract

Summary:Nonmyeloablative stem cell transplantation (NST) harnesses the graft-versus-tumor effect while minimizing regimen-related toxicity, and can result in donor chimerism and remission. Acute graft-versus-host disease (GVHD) and infections are major complications after sibling NST. Toxicity of unrelated-donor (UD) NST and the most appropriate GVHD prophylaxis in this setting remain poorly defined. We describe 25 patients who received UD-NST conditioned with fludarabine and cyclophosphamide. The first six patients received cyclosporine (Cs) and mycophenolate mofetil (MMF) (n ¼ 5) or methotrexate (MTX) (n ¼ 1) as GVHD prophylaxis (group 1) and all developed grade III-IV acute GVHD. The next 19 patients received the same conditioning regimen with the addition of alemtuzumab, and all received Cs/MTX post-transplant. Engraftment and donor chimerism were achieved in all but one evaluable patient. In all, 15 patients died: five of six deaths in group 1 were attributable to acute GVHD, while deaths in group 2 were due to infection or progressive disease (P ¼ 0.05). The combination of Cs/MMF is inadequate GVHD prophylaxis for UD-NST. The use of Cs, MTX, and alemtuzumab eliminated severe acute GVHD; its impact on response merits further study. Bone Marrow Transplantation (2005) 35, 921-926.

Sirolimus, Tacrolimus, and Low-Dose Methotrexate as Graft-versus-Host Disease Prophylaxis in Related and Unrelated Donor Reduced-Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation

“…19 Reports have suggested that cyclosporine and MMF may not be sufficient to prevent GVHD in unrelated donors. 20 Rates for developing acute GVHD after RIC transplantation using tacrolimus or cyclosporine and methotrexate range from 12%–36% for patients with related and unrelated donors 21,22 Incorporation of alemtuzumab as GVHD prophylaxis is associated with a low incidence of acute and chronic GVHD 4 , however, many patients have persistent or progressive disease after transplantation suggesting that some element of the GVL effect has been compromised.…”

The Role of T Cells in Hematopoietic Stem Cell Engraftment

“…Alemtuzumab is a monoclonal antibody against CD52, an antigen present on T cells as well as B cells and other antigenpresenting cells. It has been used both for ex vivo T cell depletion of stem cell grafts and has been administered directly to patients as part of conditioning regimens for alloHSCT [43,44,45]. Anti-CD52 therapy has been shown to reduce the risk of acute GVHD, although in one study engraftment was delayed, which may be due to the relatively long half-life of the antibody and thus a donor T cell−depleting effect.…”

“…Anti-CD52 therapy has been shown to reduce the risk of acute GVHD, although in one study engraftment was delayed, which may be due to the relatively long half-life of the antibody and thus a donor T cell−depleting effect. In a more recent study of recipients of nonmyeloablative alloHSCT (see below), engraftment was achieved for all but one patient receiving alemtuzumab [44,45]. Because host antigenpresenting cells are also known to be critical to GVHD induction, alemtuzumab may work by blocking this key activation event [46].…”

Donor leukocyte infusions for the treatment of relapsed acute leukemia after allogeneic stem cell transplantation

“…However, relapse rates tend to be high due to patient selection and the reduced intensity conditioning therapy, or in some cases the use of serotherapy (for example, alemtuzumab or antithymocyte globulin) resulting in in vivo T-cell depletion. 31,32 In these attenuated conditioning regimens, DLI has become increasingly important to maximize the GVL effect. [32][33][34][35][36][37] In addition, DLI is typically employed after NST when complete lymphohematopoietic chimerism is not achieved.…”