Between 1991 and 2000, 59 children with symptomatic sickle cell disease (SCD) were enrolled in a multicenter investigation of myeloablative HLA-identical sibling bone marrow transplantation (BMT). Patients had stroke (N=30) or other significant central nervous system disease (CNS) (N=1), recurrent episodes of acute chest syndrome (ACS) (N=20), or recurrent painful episodes (N=8) before study entry. Currently, 55 patients survive, and 50 survive free of sickle cell disease. Four patients died of complications of graft-versus-host disease (GVHD)(N=3) or intracranial hemorrhage (N=1). Five patients had graft rejection accompanied by return of SCD. With a median follow-up of 5.2 years, the Kaplan-Meier probabilities of survival and event-free survival are 93% and 85%, respectively. To investigate the toxicity of transplantation and to assess its impact on the natural history of SCD, long-term follow-up evaluations of the CNS, pulmonary function, and gonadal function were performed. As reported previously, engrafted patients with stroke had no subsequent stroke events after BMT, and cerebral MRI and MRA exams demonstrated stable or improved appearance. One patient with graft rejection experienced a second stroke when the Hb S fraction reached 60% after BMT. Forty-three of 55 surviving (78%) patients had pulmonary function testing (PFT) performed at least 1 year after BMT, and 24 were tested 3 or more years after BMT. Seven of the 12 who lacked follow-up testing had normal baseline testing. Of the 43 with follow-up exams, 30 had stable, and 8 had improved PFTs. Five had worsened pulmonary function, 4 with restrictive changes, and 1 with obstructive changes. Three of the 4 with progression of restrictive changes had a history of ACS before BMT. One patient with a history of ACS died of pulmonary complications caused by graft-versus-host disease. Currently, 24 males and 19 females treated by BMT are >14 years of age. Of these, 15 males (63%) and 14 (74%) females had post-BMT gonadal function studies performed. Eleven of 15 males had normal LH and FSH levels, however, a normal testosterone level was observed only in 4. In contrast, 9 of 14 females had elevated gonadotropin and decreased estradiol levels that mimicked a post-menopausal state. Six females had primary or secondary amenorrhea. In summary, patients with stable engraftment of donor cells had cessation of clinical complications of SCD after BMT. In addition, most had stabilization or improvement in sub-clinical markers of disease. However, a limited number of patients who had progression of PFT abnormalities also had a history of ACS before BMT. In addition, gonadal toxicity was observed commonly in females after BMT. Together, these data confirm that BMT is a suitable intervention for patients with severe sickle cell disease, however efforts to reduce the toxicity of BMT should be pursued.

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