Allogeneic peripheral blood stem cell transplantation from two- or three-loci-mismatched related donors in adult Japanese patients with high-risk hematologic malignancies

Abstract

Summary:With the increasing frequency of haploidentical transplantation, it is becoming more important to establish the degree of HLA mismatch that can be accepted. We retrospectively analyzed clinical data of 50 adult Japanese patients with high-risk hematologic malignancies who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from two-or three-loci-mismatched related donors with HLA class I and II gene disparities in the graft-versus-host direction. They were treated at 20 transplant centers between 1996 and 2002. In all, 18 patients received unmanipulated PBSC, while 32 received purified CD34 þ blood cells. Conventional (n ¼ 31) or reduced-intensity (n ¼ 19) conditioning regimens were used. Of the 39 patients (78%) who survived for X28 days after transplant, 37 (95%) achieved neutrophil engraftment, while graft failure and rejection occurred in two of 39 (5%) and three of 37 (8%) patients, respectively. Stepwise Cox regression analysis revealed a significantly lower incidence of grades II-IV acute GVHD in patients receiving purified CD34 þ cells (hazard ratio 0.32; 95% CI 0.12-0.84; P ¼ 0.022). By 1 year post transplant, 28 patients (56%) had died of transplantrelated problems, including infectious complications (30%). Although the number of patients is small, our data suggest that transplant-related problems, particularly infectious complications, are major obstacles to the success of this therapy.

Feasibility of HLA-haploidentical hematopoietic stem cell transplantation between noninherited maternal antigen (NIMA)-mismatched family members linked with long-term fetomaternal microchimerism

“…Additionally, it is less likely that these favorable results might be attributable to the relative homogeneity of the histocompatibility antigens among the Japanese populations, because the Japanese nationwide analyses of T cell-replete HLA-2-loci-or HLA-3-loci-mismatched SCT without considering NIMA complementarity also revealed a higher incidence of severe aGVHD and inferior survival rates as have been previously reported from the non-Japanese centers. 37,38 To date, several population studies have provided evidence in favor of the presence of the tolerogenic "NIMA effect," including the suppression of humoral immune responses, 15 superior graft survival of kidney transplants from an HLA-haploidentical sibling or cadaveric donor, 16,17 and low rates of aGVHD in umbilical cord or bone marrow transplantation from an NIMA-mismatched sibling. 18,39 In addition, although pregnancy can induce longpersisting primed cytotoxic T cells specific for fetal alloantigens of paternal origin, 40,41 peripheral blood lymphocytes (PBLs) obtained from mothers were reported to exhibit a markedly depressed proliferative response to PBLs of their infants but not to those of their husbands at 6 months after delivery, 42 suggesting that the postpartum maternal immune system can preserve IPA-specific protective mechanisms at least for a certain period of time.…”

Comparative Study of the Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation from Human Leukocyte Antigen-Haploidentical Related and Unrelated Donors in the Treatment of Leukemia

“…Indeed, through an enhanced preconditioning regimen and a strengthened intensity of inhibition of the host immune response, GVHD can be alleviated, graft rejection can be reduced, and the success rate of haploidentical HSCT can be improved [14,15,16,17]. …”

Conditioning Regimen of Melphalan, Fludarabine and Total Body Irradiation in Unmanipulated HLA Haploidentical Stem Cell Transplantation Based on Feto-maternal Tolerance

“…According to a nationwide survey, all patients with graft failure had received purified CD34 + selected cells from two-to three-antigen mismatched family donors (1,2). In the survey, as additional immunosuppression, anti-thymocyte antibodies (ATG) were given in all of the patients receiving the conventional conditioning regimen and unmanipulated PBSCs (2). The inclusion of ATG in conditioning regimens contributes to reducing the incidence of graft-versus-host disease because it exerts an in vivo T cell depletion of the donorderived inoculum (4).…”

“…GVHD prophylaxis consisted of 0.03 mg/kg per day of tacrolimus given by continuous infusion, and short term methotrexate (10 mg/m 2 administered intravenously on days 1 and 6 mg/ m 2 on days 3 and 6). The donor was given filgrastim at a dose of 300 g/m 2 or lenograstim at a dose of 10 g/kg subcutaneously for 6 days. Peripheral blood stem cells (PBSCs) were collected from day 4 to 6 using a continuous blood cell separator.…”

“…Hematopoietic stem cell transplantation from haploidentical family donors has given an alternative choice for patients with hematological malignancies, but carries a high risk of transplant-related mortality (1,2). T cell depletion eliminated severe graft-versus-host disease (GVHD), but increased the risk of graft failure and infectious complications due to delayed immune reconstitution.…”