Treatment of High-Risk Acute Leukemia with T-Cell–Depleted Stem Cells from Related Donors with One Fully Mismatched HLA Haplotype

Abstract

The main limitations of transplantation of bone marrow from donors who are matched with the recipient for only one HLA haplotype GVHD and graft failure - can be overcome. Since most patients have a relative with one haplotype mismatch, advances in this method will increase the availability of hematopoietic-cell transplantation as curative therapy for acute leukemia.

Outcome of alloanergized haploidentical bone marrow transplantation after ex vivo costimulatory blockade: results of 2 phase 1 studies

“…Steroid-refractory aGVHD only occurred in 2 patients (9%), despite a median T-cell dose 2 logs greater than the dose (8-20 ϫ 10 4 /kg) at which 30% of children undergoing nsTCD haploidentical HSCT were observed to develop steroid-refractory GVHD and 3 logs above a published threshold dose below which severe aGVHD was reliably prevented in the haploidentical setting. 34,35 AGVHD did not occur more often in those patients receiving CD3 ϩ , CD4 ϩ , or CD8 ϩ T cell doses above median levels, and although alloreactive precursor frequency data were available on a relatively small proportion of patients, we also did not see an association between residual in vitro CD4 ϩ alloresponses and aGVHD occurrence. A potential explanation for this observation might be that residual alloresponses after alloanergization are mediated in vivo by CD28 Ϫ donor T cells (which are predominantly CD8 ϩ ), ␥␦ T cells, or successfully alloanergized CD4 ϩ donor T cells that had their anergic state temporarily reversed by high levels of cytokines in vivo.…”

Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers

“…However, for patients lacking an HLA-identical donor and for those with progressive disease, the use of haploidentical family donors is increasingly considered to be a suitable alternative. 1,2 In the traditional protocol pioneered by the Perugia group, 3 vigorous T-cell depletion and high numbers of CD34 þ cells are required to cross the HLA barrier, avoiding severe GVHD.…”

Preservation of Immune Repertoire by Selective Depletion of Haploidentical Grafts

“…An interesting development in the field was the introduction of the megadose concept to overcome the HLA barrier and the use of mobilized peripheral stem cells (PBSCs) instead of bone marrow as the stem cell source [4]. The positive selection of CD34 1 stem cells was introduced as an efficient large-scale clinical indirect method for T cell depletion and a number of clinical studies using peripheral CD34 1 stem cells were performed in adults and children [4,25].…”

“…The positive selection of CD34 1 stem cells was introduced as an efficient large-scale clinical indirect method for T cell depletion and a number of clinical studies using peripheral CD34 1 stem cells were performed in adults and children [4,25]. Although CD34 1 positive selection methods have widely been used to indirectly deplete T and B cells from mobilized peripheral stem cell grafts, negative T cell-depletion strategies might offer some advantages in overcoming the HLA barrier with RIC while maintaining an effective graft-versus-malignancy effect.…”

“…However, it soon became apparent that donor T cells play an important role in preventing graft rejection by eliminating or inactivating recipient alloactive cells that remain functionally active after the pretransplant conditioning. Graft rejection, resulting from the paucity of T cells in the graft, became the main obstacle to success; but by the late 1990s this complication largely was overcome in children by administration of very intensive immunosuppressive regimens, and in adults by transplantation of very large numbers of hematopoietic stem cells found in mobilized peripheral blood (PB) [3,4].…”