Marrow transplants from matched unrelated donors for aplastic anaemia using alemtuzumab, fludarabine and cyclophosphamide based conditioning

Abstract

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...

Implications of CD34+ cell dose on clinical and haematological outcome of allo-SCT for acquired aplastic anaemia

“…The superiority of the alemtuzumab-based conditioning for AA transplants in terms of decreased incidence of acute and chronic GVHD has been brought out by previous work from our centre as well as other studies from Toronto and Houston. [29][30][31][32] Most of our patients (36 out of 46; 78.3%) had donor marrow as the stem cell source, as recommended by the national guideline. 33 This is another likely explanation for the low incidence of GVHD in our analysis.…”

Graft-versus-host disease following marrow transplantation for aplastic anemia: different impact of two GVHD prevention strategies

“…8 In addition to different dosing schedules, previous studies used a high dose of anti-CD52 antibodies (75-100 mg). 8,9,13 Reducing the dose of anti-CD52 antibodies may decrease the incidence of infectious complications. Recently, a study from Sweden in patients with hematological malignancies suggested that a lower dose of alemtuzumab (30 mg) results in a lower risk of infectious complications and faster immune reconstitution.…”

“…Previous studies from St George's Hospital in London reported a favorable effect on acute and chronic GVHD in matched sibling donor and matched unrelated donor BMT for AA using in vivo anti-CD52 monoclonal antibodies (Campath-1G antibodies and alemtuzumab). 8,9 The main concerns with the use of anti-CD52 antibodies include a high risk of graft failure 8 and increased risk of infectious complications. [10][11][12] Previous observations in patients with AA also showed that the risk of graft failure was higher when in vivo anti-CD52 antibodies were administered both before and after stem cell infusion.…”

Unrelated donor search and unrelated donor transplantation in the adult aplastic anaemia patient aged 18–40 years without an HLA-identical sibling and failing immunosuppression

“…1,2 Better selection of HLA-matched donors has probably had a major role, but also significant changes in the conditioning regimen have occurred, including the use of fludarabine (FLU)-based conditioning, the addition of low-dose (2 Gy) [3][4][5][6] TBI in adults, and the use of Alemtuzumab as an alternative to ATG. [7][8][9][10] OS is currently 475%. 6,10 Results of UD transplants have improved to such an extent that treatment recommendations should be adapted: UD transplantation is now considered after failure to respond to one course of immunosuppressive therapy, and in children UD haematopoietic SCT (HSCT) may be considered as first line treatment in severe aplastic anaemia (SAA).…”

“…[14][15][16] The combination of FLU-CY and ATG is used most often for the conditioning regimen in UD HSCT for acquired AA, 5,6 although Alemtuzumab is an emerging alternative option to ATG (FCC). [7][8][9][10] Low-dose TBI, 2 or 3 Gy, was added following the Japanese and USA studies. 3,4 The dose of CY was originally set at 300 mg/ m 2 Â 4.…”