Unmanipulated HLA 2–3 Antigen-Mismatched (Haploidentical) Stem Cell Transplantation Using Nonmyeloablative Conditioning

Abstract

The major problems in human leukocyte antigen (HLA)-mismatched stem cell transplantation (SCT) are graft failure and graft-versus-host disease (GVHD). Less-intensive regimens should be associated with a lower release of inflammatory cytokines and possibly less GVHD. The objective of this study was to investigate whether HLA-haploidentical SCT can be performed using nonmyeloablative conditioning and pharmacologic GVHD prophylaxis, including glucocorticoids. Using conditioning consisting of fludarabine, busulfan, and anti-T-lymphocyte globulin and GVHD prophylaxis consisting of tacrolimus and methylprednisolone (1 mg/kg/day), 26 patients who had hematologic malignancies in an advanced stage or with a poor prognosis underwent transplantation using peripheral blood stem cells from an HLA-haploidentical donor (2-3 antigen mismatches in the graft-versus-host [GVH] direction) without T-cell depletion. All patients except for 1 achieved donor-type engraftment. Rapid hematologic engraftment was achieved (neutrophils > 0.5 x 10(9)/L on day 12 and platelets > 20 x 10(9)/L on day 12), with full donor chimerism achieved by day 14. Fifteen patients did not develop acute GVHD clinically, and only 5 patients developed grade II GVHD. The recovery of CD4+ T cells was delayed compared with that of CD8+ T cells. Sixteen of the 26 patients are alive in complete remission. Four died of transplantation-related causes, and 6 died of progressive disease. These data suggest that nonmyeloablative conditioning, GVHD prophylaxis consisting of tacrolimus and methylprednisolone, and early therapeutic intervention for the GVH reaction allow stable engraftment and effectively suppress GVHD in HLA 2-3 antigen-mismatched SCT.

Donor-derived HLA antibody production in patients undergoing SCT from HLA antibody-positive donors

“…Institutional protocols for SCT from HLA 2 --3 antigen-mismatched donors either with myeloablative or with reduced-intensity conditioning have been described previously. 13,14 None of the patients received T-cell-depleted graft. Of note, GVHD prophylaxis for HLA 2 --3 antigen-mismatched SCT was intensified by using a combination of tacrolimus, methotrexate, mycophenolate mofetil (15 mg/kg per day), and methylprednisolone (2 mg/kg per day) for myeloablative SCT, and tacrolimus and methylprednisolone (1 mg/kg per day) for reduced-intensity SCT.…”

Salvage haploidentical transplantation for graft failure using reduced-intensity conditioning

“…GVHD prophylaxis and treatment GVHD prophylaxis and treatment followed the institutional haplo-RIC protocol, which has been detailed elsewhere. 18 Briefly, GVHD prophylaxis consisted of continuous i.v. infusion of tacrolimus with target levels of 10-12 ng/mL and methylprednisolone 1 mg per kg per day.…”

“…The methodology used for cell separation and chimerism analysis has been detailed elsewhere. 18,19 Briefly, T cells were enriched by a negative selection system (RosetteSep; StemCell, Vancouver, Canada) to a purity of 495%, and granulocytes were recovered from the Ficollred blood cell interface with a purity of 499%. Chimerism analysis involved quantitative PCR of informative STRs in the recipient and donor.…”

Prophylactic and therapeutic treatment of graft-versus-host disease in Japan

“…Nonetheless, they demonstrated high engraftment rates and low incidences of acute GVHD after HLA-haploidentical donor transplantation with the RIC regimen including ATG and GVHD prophylaxis consisting of Tac and mPSL [102] or with the MAC regimen not including ATG and GVHD prophylaxis consisting of Tac, MTX, mPSL, and MMF [103]. Ikegame et al [104] reported the feasibility of HLA-haploidentical transplantation using non-ATG-containing preconditioning followed by standard GVHD prophylaxis consisting of CsA and sMTX or MMF for HLA-homozygous patients from heterozygous donors.…”