Anti-CD25 monoclonal antibody (basiliximab) for prevention of graft-versus-host disease after haploidentical bone marrow transplantation for hematological malignancies

Haploidentical hematopoietic SCT (haplo-HSCT) is to be established in patients with acquired severe aplastic anemia (SAA) refractory to immunosuppressive therapy and lacking HLA-matched related or unrelated donors. Graft failure (GF) and GVHD have been major obstacles to HSCT. A total of 17 children and adolescents with SAA underwent haplo-HSCT in our center. The conditioning regimen consisted of BU, fludarabine, CY and anti-thymocyte globulin. All patients received cyclosporine, short-term MTX, mycophenolate mofetil and basiliximab for GVHD prophylaxis. Mesenchymal stem cells derived from unrelated umbilical cord were infused on day 1. Neutrophil engraftment was achieved in all 17 patients in a median time of 16 days (range 9-25 days). The median time of platelet engraftment was 22 days (range 9-95 days) in 16 patients. The cumulative incidence (CI) of II-IV acute GVHD (aGVHD) at day +100 was 30.53 ± 11.12% and III-IV aGVHD occurred in only one patient. The CI of chronic GVHD was 21.25 ± 13.31%. Secondary GF with autologous hematopoiesis recovery occurred in one patient. The OS was 71.60 ± 17.00% at a median follow-up of 362 (36-1321) days. These limited promising data suggest that haplo-HSCT is feasible as a salvage therapy for children and adolescents with refractory SAA who lack matched donors.

Section: Discussionmentioning

confidence: 99%

Good outcome of haploidentical hematopoietic SCT as a salvage therapy in children and adolescents with acquired severe aplastic anemia

Wang

Zheng

Yan

et al. 2014

“…[70][71][72] First, over the years in the HLA matched setting, the addition of broadly active immunosuppressants or lymphocyte depletion has yet to limit the GVHD problem compared with standard calcineurininhibitor/MTX prophylaxis, without the consequence of higher relapse/progression rates. Second, patients referred to our institution for NMAT were of advanced age or with comorbid conditions and intermediate to poor cytogenetics, but not in florid relapse; therefore, a potent, welltolerated therapy for older recipients with high-risk features and low tumor burden is needed.…”

Section: Discussionmentioning

confidence: 99%

Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia

Nelson

Schwartz

et al. 2010

A total of 50 consecutive patients (median age, 57.5 years) with AML (n ¼ 30) or myelodysplasia (MDS, n ¼ 20) underwent HLA matched related donor (MRD, n ¼ 27) or unrelated donor (MUD, n ¼ 23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n ¼ 19) ± mycophenolate mofetil (n ¼ 31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan-Meier analysis, year 1-4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P ¼ 0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.

“…Two kinds of recipient mice, (B6 Â bm1) F 1 or (B6 Â bm12) F 1 , were used to develop CD8T-celldependent acute GVHD (CD8-GVHD) or CD4T-celldependent acute GVHD (CD4-GVHD), respectively. 5,6 CD4 or CD8T cells were prepared from B6 splenocytes with anti-CD4-or anti-CD8-conjugated magnetic beads, respectively. Each type of acute GVHD was induced by adaptive transfer of CD8 or CD4T cells to irradiated recipient mice.…”

Section: Suppressive Effect Of Nk026680 On Allogeneic T-cell Responsesmentioning

confidence: 99%

“…[1][2][3] Then, allogeneic donor T cells primarily recognize major histocompatibility complex (MHC) antigens on host DCs, and subsequently activate and proliferate in the presence of DC-derived accessory signals and cytokines. Currently proposed or practiced prophylaxis for acute GVHD includes use of a monoclonal antibody to CD52, 4 CD25, 5,6 cytotoxic T-lymphocyte antigen-4 7 or tumor necrosis factor-alpha (TNFa) 8 all of which are DC-specific antigens and/or take part in T-cell activation in the antigen presentation stage. Currently increasing studies for the development of immunosuppressive drugs have been evaluating DC function as a pharmacological target for prevention of acute GVHD.…”

Section: Introductionmentioning

confidence: 99%

NK026680, a novel compound suppressive of dendritic cell function, ameliorates mortality in acute lethal graft-versus-host reaction in mice

Saiga

Toyoda

Tokunaka

et al. 2005

A role for dendritic cells (DCs) has been emphasized in the onset of acute graft-versus-host disease (GVHD). We have made efforts to develop a new strategy for suppression of DC functions with a chemical compound in the treatment of acute GVHD. We here describe the immunological characterization of the new chemical compound NK026680. It was found that NK026680 significantly suppressed (1) expression of CD83, CD86, and major histocompatibility complex (MHC) class I and II antigens on human monocyte-derived DCs, (2) excretion of interleukin-12p40 on activation of monocyte-derived DCs, (3) allogeneic responses of human and mouse T cells and (4) mortality in mice with acute GVHD evoked across MHC class I or II. The beneficial effect of NK026680 administered orally was without any recognizable adverse effects. Early intervention in acute GVHD was required for this effect, indicating that an early event in acute GVHD is a critical target of NK026680. We propose the use of NK026680 as a prophylactic for acute GVHD.