Late effects of myeloablative bone marrow transplantation (BMT) in sickle cell disease (SCD)

To the editor:

We are greatly encouraged to read the report by Bernaudin et al,¹  showing excellent outcomes for children and adolescents receiving myeloablative allogeneic bone marrow transplantation (BMT) for sickle cell disease (SCD). Approximately 200 children worldwide have undergone BMT after myeloablative conditioning with busulfan and cyclophosphamide, with or without antithymocyte globulin, with a follow-up period approaching 10 years.^1-3  With this experience, outcome has improved with an event free survival of 95% in the most recent patient cohort, and children undergoing BMT can now reasonably expect to be cured of SCD.

The reports to date contain valuable information including rates of engraftment, graft rejection, graft-versus-host disease (GVHD), and cerebral vascular complications; however, details regarding the late effects of BMT in this population are lacking (Table 1). While some complications are well known,⁴  patients with SCD may be more susceptible to or more burdened by such complications given the legacy of organ damage from their underlying disease. For example, the authors describe that 11% of patients experienced “mild forms” of chronic GVHD, and that 2.4% had extensive chronic GVHD. The mild forms were not described, nor was organ involvement delineated. Because SCD and busulfan may lead to pulmonary toxicity, a more detailed description of chronic GVHD, potentially including objective measures such as pulmonary function tests, would be helpful to assess the risk of developing late pulmonary complications. The authors also reported that “2 years after transplantation, the mean height was unchanged.” Did the children grow normally as in other reports?^5-7  In addition, busulfan is toxic to gonadal tissue, and hypergonadotropic hypogonadism is very frequent after myeloablative BMT.^6,8  This cause of primary amenorrhea (ovarian failure) is assumed in the prepubertal girls reported, but no data on LH, FSH, or estrogen levels were provided. In boys, the Sertoli cells (responsible for spermatogenesis) are more easily damaged than Leydig cells (responsible for testosterone production), thus having normal testosterone, LH, and FSH levels does not ensure normal gonadal function.^6,8  In fact, testicular size and semen analysis better predict gonadal function and fertility potential. There are also incomplete descriptions of treatment related outcomes, such as cataracts and secondary malignancy, or other long-term outcomes for which underlying SCD could alter the long-term consequences, such as renal and neurocognitive function.

As clinicians begin to recommend myeloablative BMT to children with SCD more routinely in the absence of current major complications based upon these encouraging results, long-term outcome data will be an essential part of the decision-making process. Perhaps the assembled experience of those involved in BMT for SCD could be combined to make such outcomes available to the clinicians, and ultimately, the affected patients.