20 Years of Experience with Hematopoietic Stem Cell Transplantation for β-Thalassemia Major.

Background: Hematopoietic stem cell transplantation (HSCT), the sole cure for β-thalassemia major (TM), is plagued by graft rejection or disease recurrence (10–30%). The risk of recurrence is influenced by age, type of allograft, presence of graft-versus-host-disease (GVHD), ferritin levels and hepatic iron overload. Complete donor hematopoiesis was believed essential for sustained marrow engraftment, but according to pre-clinical/clinical data, stable mixed chimera is also curative. We report our experience using T cell depletion (TCD) as prevention of GVHD versus fludarabine-based conditioning in unmanipulated HSCT.

Material & Methods: 35 patients (6 mo-7 yr; median 29 mo; 10 female and 25 male) with TM were transplanted (1984–95) with HLA-matched donors siblings (29), parents (2), grandparents (2), cousin (1) and aunt (1). Conditioning encompassed total lymphoid irradiation (TLI) of 2 cGy/dx4 followed by busulfan 4 mg/kg/dx4 and cyclophosphamide 50 mg/kg/dx4; TCD was performed in vitro with CAMPATH1M (21) or CAMPATH1G “in the bag” (14). No GVHD-prophylaxis was given.

Based on our results with non-myeloablative regimens, we used since 1996 fludarabine-based conditioning for TM. A total of 24 patients (2–23 yr; median 5 yr; 14 female and 10 male) were transplanted with unmanipulated inocula from HLA-matched siblings (20), matched grand-father (1), mismatched sibling (1) and MUD (2). For 21 patients conditioning consisted of fludarabine 30 mg/m²/dx6, busulfex (BU) 3.2 mg/kg/dx4; 2 patients received BU 3.2 mg/kg/dx2, and 1 patient received TBI 2 cGy/dx1 without BU. All patients received ATG (Frisenius) 10 mg/kg/dx4 and Cyclosporine from day -4 for GVHD-prophylaxis.

Results: In the TCD group, no GVHD occurred; 5 patient (14.3%) died from transplant related complications, 5 patients (14.3%) rejected the graft and in 3 patients (8.6%) recurrence of TM occurred; 11 patients (31.4%) were 100% donor, 10 patients (28.6%) had stable mixed chimera (70–96% donor); one patient had 5% of donor cells 5 years after transplant and with allogeneic HSCT from the same donor following ambulatory non-myeloablative conditioning, complete displacement of host cells was accomplished (

In the fludarabine based group no transplant related mortality occurred; 4 patients (16.7%) rejected the graft (2 patients with BUx2; 1 patient transplanted from a mismatched sibling; 1 patient with unrelated donor), but all survived with autologous rescue. All 7 patients (29.2%) suffering from acute GVHD responded to treatment. 11 patients (45.8%) had 100% donor cells; 9 patients (37.5%) had stable mixed chimera and overall survival up to 9 years after HSCT is 100%.

Conclusions: TCD is a feasible conditioning preventing completely GVHD. Unstable mixed chimera can be converted to full donor with donor lymphocyte infusion. TCD requires more intensive conditioning to prevent allograft rejection, but is associated with increased transplant related mortality.

Fludarabine based conditioning is well tolerated with minimal procedure related morbidity and no mortality. The incidence of acute GVHD was low and treatable. Low dose BU is not sufficient for consistent engraftment; mixed chimera was frequent, yet stable and associated with functionally normal hematopoiesis. With reduced intensity conditioning, age seems no longer to be contraindication for HSCT for TM.