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A Pilot Study of Reduced Intensity Conditioning (RI) with Busulfan (Bu), Fludarabine (Flu), and Alemtuzumab Followed by Allogeneic Stem Cell Transplantation (AlloSCT) to Induce Sustained Mixed Donor Chimerism in Patients With Symptomatic Sickle Cell Disease (SCD)

Year: 2009

Type: article

Abstract: SCD can be cured by HLA matched family donor AlloSCT (Walters et al, NEJM, 1996). Patients undergoing myeloablative AlloSCT are at risk for many complications post SCT including death, graft versus host disease (GVHD), and life threatening infections, thus making RIC regimens an attractive alternative. Having an unaffected, HLA-matched identical sibling is another major obstacle for most SCD patients to proceed to AlloSCT(Bhatia et al,BMT,2008). Umbilical cord blood (UCB) has been proven to be an excellent alternate donor source that can safely reconstitute hematopoiesis after AlloSCT(Cairo et al,BBMT,2008). In this study, we report the results of RIC and AlloSCT from matched family and UCB donors in 14 patients (12M:2F) with symptomatic SCD (HbSS = 8, HbSC = 3, HbSßThal = 3). Conditioning was Bu (4mg/kg x 4d ≤ 4 yrs and 12.8mg/ kg x 4d > 4 yrs), Flu (30mg/m2 x 6d), and Alemtuzumab (2mg/m2 x 1d, 6mg/m2 x 2d, and 20mg/m2 x 2d). Median age was 6.15 yrs(1.5–16). Donor sources: 6-6/6 HLA-matched sibling bone marrow (BM), 2-6/6 sibling UCB, 3-4/6 and 3-5/6 unrelated UCB. Bone marrow recipients received median cell doses of 5.4±3.5 × 108 TNC/kg and 4.98±1.8 × 106 CD34/kg while cord blood recipients received median cell doses of 4.1±2.0 × 107 TNC/kg and 2.2±1.8 × 105 CD34/kg. All received tacrolimus and mycophenolate mofetil as GVHD prophylaxis and phenytoin or keppra as seizure prophylaxis for 180 days post SCT. Median neutrophil and platelet recovery was day 27(0–47) and day 43(0–86), respectively. One patient had primary graft failure at day +60 post SCT. Median whole blood donor chimerism on days 30, 60, 100, and 180 was 95%(9–100), 90%(61–99), 90%(60–99), and 91%(88–98), respectively. Median CD71 chimerism on days 30, 60, 100, and 180 was 98%(17–99), 88%(1–99), 90%(71–99), and 92%(80–96), respectively. Hb electrophoresis demonstrated median %HbS levels of 1.1±0.1, 0±0.1, and 1.0±0.1 on days 30, 60, and 100 respectively. Of evaluable patients, Grades II-IV acute GVHD was seen in 4/13(30.7%) patients and chronic extensive GVHD was seen in 1/9(11.1%) patients. Three patients developed CMV pre-engraftment (CMV pneumonitis (n = 2), CMV viremia (n = 1)) and one developed CMV viremia post engraftment. OS is 100% (longest follow up 1491 days). In summary, RIC and AlloSCT in patients with SCD using both related and unrelated donors has been shown to be well tolerated and effective in inducing a high degree of sustained mixed donor chimerism.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2008.12.072