Summary:Graft failure, regimen-related toxicity and graft-versus-host disease (GVHD) are the critical barriers to unrelated donor transplants for aplastic anaemia (AA). We investigated the use of a novel conditioning regimen consisting of alemtuzumab (humanized CD52 antibody), fludarabine and cyclophosphamide in seven patients with AA, who underwent bone marrow transplant procedure using matched unrelated donors. The aetiology of AA was acquired (n ¼ 3), Fanconi's (n ¼ 3) and congenital (n ¼ 1). Median age was 13 years (range 8-35). All the donors were fully matched for HLA class I and II antigens using high-resolution typing. All the patients engrafted at a median of 18 days (range 13-35). Two patients died of transplant-related complications: one of adenovirus disease and the other developed extensive chronic GVHD of skin followed by cytomegalovirus (CMV) disease. Three patients developed Grade II acute GVHD disease (GVHD); none had Grade III-IV acute GVHD. Of the six evaluable patients, only one developed chronic GVHD. We conclude that this conditioning regimen for unrelated donor transplants for AA is sufficiently immunosuppressive to allow stable engraftment and appears to have a favourable impact on the incidence and severity of GVHD, warranting further investigation. The long-term survival of aplastic anaemia (AA) with bone marrow transplantation (BMT) using HLA-identical family donors has improved over the years and is in the range of 75-90%. 1-3 However, in comparison, the survival of patients transplanted from unrelated donors has only been in the range of 20-50%. 2,4-6 Main causes of transplantation failure in unrelated donor transplants in patients with AA (acquired as well as Fanconi's anaemia) are a high-incidence of graft failure, toxicities related to conditioning regimen and graftversus-host disease (GVHD). 5,6 To improve the outcome of unrelated donor transplants, a multidimensional approach using strategies addressing all the above issues is needed.The optimum conditioning regimen for unrelated donor transplants in AA is not known. Excellent long-term outcomes have been reported with cyclophosphamide (CY) and antithymocyte globulin (ATG) in the conditioning of acquired AA patients using HLA-identical family donors. 3 However, a similar approach with unrelated donors resulted in a high-incidence of graft failure. 7 Irradiation containing regimens result in better engraftment, but add substantial regimen-related toxicity and more GVHD resulting in no improvement in survival. [8][9][10][11] The role of low-dose total body irradiation (TBI, 200-300 cGy) in acquired AA has also been investigated and recommended as a measure to reduce graft rejection. 12,13 Even with low-dose of TBI, fatal pulmonary toxicity such as diffuse alveolar damage has been observed. 12 Alemtuzumab (Campath-1H) is a humanized IgG1 anti-CD52 monoclonal antibody (MoAb) and effectively depletes lymphocytes. In a pilot study, we previously reported a low incidence of GVHD in marrow transplants from HLA-identical sibling donors u...

Between August 1989 and November 2003, 33 patients at our center with acquired aplastic anemia underwent bone marrow transplantation (BMT) from HLA-identical sibling donors with cyclophosphamide and in vivo anti-CD52 monoclonal antibodies (MoAb) for conditioning. The median age at BMT was 17 years (range, 4-46 years). Before BMT, 58% were heavily transfused (>50 transfusions), and 42% had previously experienced treatment failure with antithymocyte globulin-based immunosuppressive therapy. Unmanipulated bone marrow was used as the source of stem cells in all patients except 1. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine alone in 19 (58%) patients; 14 received anti-CD52 MoAb in addition to cyclosporine. The conditioning regimen was well tolerated without significant acute toxicity. Graft failure was seen in 8 patients (primary, n = 4; secondary, n = 4). Of those whose grafts failed, 4 survived long-term (complete autologous recovery, n = 2; rescue with previously stored marrow, n = 1; second allograft, n = 1). The cumulative incidence of graft failure and grade II to IV acute and chronic GVHD was 24%, 14%, and 4%, respectively. None developed extensive chronic GVHD. With a median follow-up of 59 months, the 5-year survival was 81% (95% confidence interval, 68%-96%). No unexpected early or late infectious or noninfectious complications were observed. We conclude that the conditioning regimen containing cyclophosphamide and anti-CD52 MoAb is well tolerated and effective for acquired aplastic anemia with HLA-matched sibling donors. The favorable effect on the incidence and severity of GVHD is noteworthy in this study and warrants further investigation.

The precise effects of CD34 þ cell dose on the outcome of allogeneic transplantation for aplastic anaemia (AA) are not known. Previous studies have used the total mononuclear cell count to quantify stem cell dose. We evaluated the effects of CD34 þ cell dose on the clinical and haematological end points of transplantation. The transplant variables and outcome parameters on 46 patients with acquired AA were assessed by comparing low vs high CD34 þ cell doses. Infusion of less than 2 Â 10 6 /kg of CD34 þ cells was associated with an increased incidence of graft failures (P ¼ 0.03), higher incidence of bacterial infections (P ¼ 0.006) and a delay in the engraftment of neutrophils (P ¼ 0.046). The latter was found to be an effect of stem cell source (non-PBSC) rather than the CD34 þ count. Other parameters, such as plt engraftment (P ¼ 0.63), red cell (P ¼ 0.94) and plt (P ¼ 0.31) transfusion independence, chimerism, acute and chronic GVHD (P ¼ 1.0) and OS (P ¼ 0.57), were not significantly influenced by the CD34 þ cell dose. These findings are different to the published studies on the relevance of CD34 þ cell dose in allogeneic transplantation for haematological cancers.

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We report the outcome of nine unrelated bone marrow transplants performed for acquired severe aplastic anaemia at a single centre. Six patients received transplants from fully matched donors. Three donor/recipient pairs were mismatched, two at a single allele on high resolution typing. Pre-transplant conditioning consisted of cyclophosphamide and in vivo Campath-1 monoclonal antibody. One patient also received total body irradiation (TBI), and another patient with a coexisting paroxysmal nocturnal haemoglobinuria (PNH) clone received additional busulphan. Cyclosporin A was given for 12 months as prophylaxis against graft-versus-host disease (GVHD). Six of nine patients are alive and transfusion independent with a mean follow-up of 24 months (range: 1.5-94). All six patients who received fully matched transplants are alive; the three who received mismatched grafts died. Four long-term survivors developed autologous haematological recovery following rejection of their grafts. Acute GVHD grade II+ occurred in two patients. We highlight the importance of high-resolution HLA typing, including Cw matching in reducing the incidence of graft rejection and GVHD, resulting in improved survival in our patient group. This study also shows that autologous recovery with long-term survival can occur following non-irradiation conditioning regimens.