Response: Late effects of myeloablative stem cell transplantation or late effects of sickle cell disease itself?

We thank Dr Fitzhugh and colleagues for their careful reading of our paper. We agree with the authors that the 95% chance of cure reported for stem cell transplantation (SCT) in the most recent patient cohorts will elicit its recommendation to more patients and families. Therefore, documented data on post-SCT quality of life, long-term effects, and potential sequelae, possibly via a registry, will become important when weighing the risks and benefits of the procedure. Nevertheless, sickle cell disease (SCD) itself results in decreased quality of life, frequent organ injury, and long-term sequelae in patients who have not received transplants. Thus, it is our opinion that only a careful prospective comparison of these parameters between patients who receive transplants and patients treated with transfusion or hydroxyurea could potentially reveal the real benefits of transplantation.

The authors raised several issues that we would like to clarify with supporting data. We reported extensive chronic graft-versus-host disease (GVHD) in 2 patients (2.4%). It affected the lungs (obliterative bronchiolitis) for one patient and the digestive tract for the other and was ultimately responsible for their death at 12 months after transplantation. The mild forms of GVHD observed in 9 patients (11%) involved skin [4 patients], skin and digestive tract [2 patients], liver [2 patients] and, skin and liver [1 patient]. Seven of the 11 patients still have symptoms; that is, irregular pigmentation [2 patients], hepatic GVHD [1 patient], sicca syndrome and/or jugal lichen planus [4 patients].

Indeed, SCT and busulfan may lead to pulmonary toxicity. Transitory obstructive airway disease was observed in 7 cases between 3 months and 9 months post-SCT, but it was reversed by administration of combined inhaled steroids and bronchodilatators,¹  except in the severe obliterative bronchiolitis described above. Pre- and post-SCT pulmonary function tests were available in 26 patients and showed a stabilization of total lung capacity (82.7% post- vs 82.5% pre-SCT) and an improvement of carbon monoxide diffusing capacity (DLCO)/alveolar volume (AV) (92.2% post- vs 83.6% pre-SCT). Although not significant, these data should be given some consideration as it has been shown that 90% of SCD adult patients have abnormal pulmonary function with a progressive severe restrictive syndrome.² 

The authors' comments made us realize that the following sentence “Two years after transplantation the mean height was unchanged” needed clarification. Height and weight determinations were converted to the number of standard deviations from the age- and sex-adjusted norms to give height and weight standard deviation scores (SDS). We meant to say that “mean height SDS” were unchanged, indicating that the children in our series grew normally after transplantation, as reported in other cohorts.

Of the 33 girls who were prepubertal at the time of transplantation, 3 are no longer followed at our Center and 13 are still too young to evaluate their puberty status. Among the 17 assessable girls, 12 had high levels of FSH and LH with low estradiol levels and received oestroprogestative treatment for puberty induction, whereas 5 of 17 had spontaneous puberty with regular menstruations and normal estradiol, FSH, and LH levels. However, one of them had secondary ovarian failure at the age of 21 years. The girls who had spontaneous puberty were significantly (P = .002) younger at time of transplantation (mean 5.9 ± 2.6 years, range 2.2-8.3 years) than the girls who required hormonal treatment for puberty induction (mean 10.1 ± 2.1 years, range 6.1-12.9 years).

As mentioned by the authors, Sertoli cells responsible for spermatogenesis are more easily damaged than Leydig cells and testicular size and semen analysis better predict gonadal function and fertility potential. Unfortunately, we did not perform any post-SCT semen analysis. We agree that it would be important to do such studies but we think that it would also be critical to compare these results to those obtained in SCD patients who did not receive transplants and who frequently have oligoazoospermia.^3,4 

Finally, neither cataract nor any secondary malignancies were observed in this series. In particular, no Epstein-Barr virus (EBV)–induced lymphoproliferative syndrome was observed in patients prepared with antithymocyte globulin (ATG).

In conclusion, while we noted a propensity to seizures in the early post-SCT period in these patients, we have not observed a greater susceptibility to other complications and it is our opinion that they are not at an increased risk of late effects, despite the legacy of organ damage from their underlying disease. Current conditioning regimens do not include total body irradiation (TBI) or pretransplantation chemotherapy, thereby reducing to a minimum the risk of transplant-related long-term effects such as cataract, growth failure, secondary malignancy, and EBV-induced posttransplantation lymphoproliferative disorder (PTLD). We have not observed any specific lung disease in our series and we believe that current data suggest that sickle vascular disease stops when engraftment occurs. The major problems that remain are the risks of ovarian failure and infertility. Clearly, these need further investigations and development of innovative solutions.