Effective donor lymphohematopoietic reconstitution after haploidentical CD34+-selected hematopoietic stem cell transplantation in children with refractory severe aplastic anemia

Abstract

Summary:Peritransplant toxicity and a delay in effective immune reconstitution have limited the utility of alternate donor transplantation for children with refractory severe aplastic anemia. We have assessed the effectiveness of infusing large numbers of highly purified haploidentical CD34 þ cells after immunoablative conditioning in three patients who had failed intensive immunosuppression, lacked unrelated donors, and had active or recent serious infections. One patient rejected the first infusion, but engrafted after a second infusion from the same donor. This patient died 4 months after hematopoietic stem cell transplantation with no evidence of lymphoid reconstitution. Two patients experienced mixed chimerism requiring treatment with antibodies and/or donor lymphocyte infusion. Both currently survive more than 1 year after transplantation with normal blood counts, 100% donor engraftment, effective lymphoid reconstitution, and no chronic graft-versus-host disease. We observed functional thymopoiesis as measured by lymphocyte immunophenotyping, T cell receptor excision circles and T cell receptor Vb spectratyping complexity analysis. Further study is required to validate the initial promise of these preliminary observations.

A novel protocol for haploidentical hematopoietic SCT without in vitro T-cell depletion in the treatment of severe acquired aplastic anemia

“…Both currently survive more than 1 year after transplantation with normal blood counts, 100% donor engraftment, effective lymphoid reconstitution and no chronic GVHD. 4 Passweg et al report that among 66 cases with 1 locus mismatched relative donor HSCT and 20 cases with 41 mismatched relative donor HSCT, one-third of the cases received purified CD34 þ cells. The reported rates of 100-day graft failure were 21 and 25%, 1-year failure rates were 26 and 25%, aGVHD rates were 35 and 15%, cGVHD rates were 18-19 and 23%, 1-and 3-year OS rates were 49 and 35%, respectively.…”

“…[1][2][3] In immunoseppressive therapy (IST)-refractory patients, large doses of highly purified CD34 þ -selected hematopoietic stem cells from haploidentical donors after an intensified immunoablative conditioning regimen can result in stable engraftment without increasing GVHD, but there is not enough data to show that better survival is achieved. 4,5 Reported results of mismatched relative donor transplantation for SAA are somewhat heterogeneous, and most series are limited by the small numbers of patients and the fact that cases may receive different conditioning and GVHD prophylaxis regimens. [1][2][3][4][5] Information at the level of detail required for decision-making, such as outcome of transplants from a mismatched related donor as upfront or salvage treatment with information on the degree of HLA matching, is lacking.…”

“…4,5 Reported results of mismatched relative donor transplantation for SAA are somewhat heterogeneous, and most series are limited by the small numbers of patients and the fact that cases may receive different conditioning and GVHD prophylaxis regimens. [1][2][3][4][5] Information at the level of detail required for decision-making, such as outcome of transplants from a mismatched related donor as upfront or salvage treatment with information on the degree of HLA matching, is lacking. A novel approach to HLA-mismatched/haploidentical blood and marrow transplantation without in vitro T-cell depletion has been developed by Peking University researchers and gives robust recovery and excellent survival rates for the treatment of malignant hematological disease, [6][7][8] but it is undetermined if a similar procedure is suitable for patients with SAA.…”

Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study

“…3,[6][7][8][9][10] Higher risk HSCT for those who lack a histocompatible donor often include umbilical cord blood and haploidentical donor as a source of HSCs (HSCs). [11][12][13][14][15][16][17][18][19] The use of haploidentical donors has some advantages compared with matched unrelated donors (MUD) and cord blood units, as a donor is more widely and readily available usually within the family, abbreviating the time for stem cell collection and infusion into the recipient. 18 However, past reports of haploidentical HSCT as therapy in SAA have encountered important limitations with graft failure and risk of severe graft-versus host disease (GVHD).…”

“…18 However, past reports of haploidentical HSCT as therapy in SAA have encountered important limitations with graft failure and risk of severe graft-versus host disease (GVHD). [11][12][13][14][15][16][17][18]20,21 Recently, the use of post-transplant cyclophosphamide (Cy) has permitted transplantation across major HLA barriers for patients receiving BM from a haploidentical donor. [22][23][24][25][26] The use of posttransplant Cy has several advantages compared with traditional methods of ex vivo T-cell depletion, which include lower complexity and cost, and improved immune reconstitution permitting a more widespread adoption of this transplant procedure.…”