Unrelated donor marrow transplantation in children with severe aplastic anaemia using cyclophosphamide, anti‐thymocyte globulin and total body irradiation

Summary:Both increased graft rejection and increased graft vs host disease (GVHD) remain obstacles to success for unrelated donor (URD) BMT for patients with SAA. Partial T cell depletion (PTCD) may decrease the risk of severe GVHD, while still maintaining sufficient donor T lymphocytes to ensure engraftment. We report on 12 patients with SAA who underwent PTCD URD BMT. All patients had failed medical therapy or relapsed following initial responses, and were transfusion dependent. The median age was 6 years, and there were five males. Donors were matched for four patients, and mismatched for eight. All patients received total body irradiation with either Ara-C or thiotepa and cyclophosphamide. PTCD was accomplished using monoclonal antibody T10B9 or OKT3 and complement. All patients engrafted, with a median time of 18 days to ANC 4500. Only one patient had greater than grade II acute GVHD; two patients had limited and one patient extensive chronic GVHD. Nine patients are alive and transfusion independent at a median months post BMT. Three patients died from infection or renal failure. This series suggests that an aggressive immunosuppressive conditioning regimen with PTCD results in successful engraftment and minimal GVHD in pediatric patients with SAA, even with HLA mismatched donors.

Section: Discussionsupporting

confidence: 77%

Unrelated donor bone marrow transplantation for children with severe aplastic anemia: minimal GVHD and durable engraftment with partial T cell depletion

Bunin

Aplenc

Iannone

et al. 2005

“…31 In vivo or ex vivo T-cell depletion can effectively reduce the incidence and severity of GvHD, 1,10 but it may significantly delay T-cell reconstitution. 11,12 A number of different in vivo [32][33][34][35] and ex vivo 8 strategies have been used to deplete T cells from the graft. In our study, T cells were rigorously depleted (reduced by a factor of 10 3 -10 5 ) by positive selection of CD34 + hematopoietic progenitor cells with the CliniMACS-system.…”

Section: Discussionmentioning

confidence: 99%

A prospective comparison of immune reconstitution in pediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated donors vs recipients of unmanipulated bone marrow from related donors

Eyrich

Leiler

Lang

et al. 2003

Summary:Positively selected CD34 + hematopoietic stem cells from unrelated donors (UD-HSCT) have been successfully transplanted, but little is known about immune reconstitution in this setting. Here we report a prospective comparison of immune reconstitution in recipients of UD-HSCT and of unmanipulated bone marrow from matched sibling donors (MSD-BMT). T-cell reconstitution occurred more than 100 days later in the UD-HSCT than in the MSD-BMT group. The first T cells after UD-HSCT were almost exclusively CD45RO + HLA-DR + , whereas early-emerging T cells after MSD-BMT more frequently expressed CD62L, CD28, and CD25. In both groups, numbers of CD45RA + naive T cells increased after 180 days. After UD-HSCT, the T-cell-receptor (TCR)-repertoire was severely skewed and showed significantly reduced diversity during the first year, but only minor abnormalities were seen after MSD-BMT. TCR-diversity increased simultaneously with the number of naive T cells. In both groups, we observed transient expansions of cd T cells. B cells were reconstituted more rapidly in UD-HSCT than in MSD-BMT recipients, whereas the rapidity of NK-cell reconstitution was similar in the two groups. In summary, T-cell reconstitution was slower after UD-HSCT than after MSD-BMT because of the delayed recovery of early memory-type T cells with reduced TCR-diversity, whereas naive T-, NK-, and B cells were reconstituted similarly in the two groups.

“…13 Intensification of the preparative regimen by the addition of irradiation, either as limited field or total body irradiation to CY, has been advocated to minimize graft rejection. [5][6][7] The outcome of irradiation-based, alternative donor BMT has been variable. 4,8,9 Recent reports of unrelated donor BMT have been somewhat better.…”

Section: Discussionmentioning

confidence: 99%

“…A number of authors reported the inclusion of irradiation in the conditioning regimen. [5][6][7] While the rate of engraftment appeared to have increased, improvement in transplant outcome has been less impressive. [1][2][3][4]8,9 In addition, the shortand long-term side-effects of irradiation are of concern, especially in the pediatric age group.…”

mentioning

confidence: 99%

A fludarabine-based conditioning regimen for severe aplastic anemia

Chan

Worth

et al. 2001

Summary:Graft rejection is a common problem after alternative donor transplantation for patients with refractory severe aplastic anemia (SAA). Intensification of the conditioning regimen, with the inclusion of irradiation, has often been advocated to combat this problem. With this approach engraftment rate improved, but the incidence of transplant-related complications is also increased, resulting in little change in the overall outcome. We investigated the use of the combination of fludarabine, cyclophosphamide and anti-thymocyte globulin as the conditioning regimen in five multiply-transfused SAA patients. Three patients received an HLA one-antigen disparate related donor transplant, while two patients were given marrow from matched, unrelated donors. The regimen was well tolerated, with only grade I toxicity encountered. With a median follow-up of 9 months, all patients are alive with complete donor chimerism. We conclude that fludarabine may be used in place of irradiation to augment the conditioning regimen of cyclophosphamide and anti-thymocyte globulin for alternative donor transplantation in children with SAA. Bone Marrow Transplantation (2001) 27, 125-128.