Is there still a place for myeloablative regimen to transplant young adults with sickle cell disease?

To the editor:

We have read with great interest the comprehensive and detailed review on hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD) published by Hsieh et al in a recent issue of the journal.¹ 

As emphasized by the authors, allogeneic HSCT is currently the only available curative treatment for SCD, but is clearly underutilized. Although it is now considered by many teams as the “standard of care” for symptomatic children with an HLA identical sibling, the experience in adults remains very limited.

In their paper, the authors claim that the development of a SCD-specific transplant regimen based on nonmyeloablative conditioning, along with the use of peripheral blood donor cells and long-term immunosuppression will provide stable mixed chimerism without rejection or GVHD.²  This innovative approach is proposed with the implicit rationale that classic transplantation regimens used for hematologic malignancies are too toxic and dangerous for SCD adult patients who have accumulated organ failures and comorbidities before transplant.

We believe that classic myeloablative HSCT regimen has still a place for young adults with severe SCD, and in this context, we wish to report the French experience in 15 patients older than 16 years of age (Table 1) who have received geno-identical HSCT after a full-dose conditioning regimen, 4 of them having been reported previously.³ 

All patients received the same BU-CY-ATG regimen³  and GVHD prophylaxis with short-methotrexate and cyclosporine. Only 1 death was observed in a patient with severe cerebral vasculopathy and Moya-Moya who suffered of massive cerebral hemorrhage at day 32 posttranplant despite a successful engraftment. Seven patients experienced grade 2 and one grade 3 acute-GVHD, quickly resolved with prednisone. Other complications included seizures, pericarditis, hemorrhagic cystitis, a successfully evacuated sub-dural hematoma and an episode of prolonged but ultimately resolved thrombopenia. Only 2 patients experienced moderate chronic-GVHD. With a median follow-up of 3.4 years (range = 1-16.1), overall disease-free survival was 93.3% ± 0.12. All survivors currently enjoy a normal quality of life without immunosuppression. Chimerism at 1 year was full-donor in 12 patients and mixed but > 75% donor in 2 patients.

Although limited, this experience is the largest so far, and demonstrates that full myeloablative transplantation has an acceptable toxicity in selected young adults with SCD. In fact, we did not observe any unusual complications because of accumulated organ failures such as veno-occlusive disease or renal failure. The post-HSCT period had more complex events than in younger patients but remained manageable. As opposed to nonmyeloablative transplantation, full-dose regimen carries much less risk of rejection, does not necessitate prolonged immunosuppressive treatment, and allows the establishment of a stable donor chimerism. Of note, ABO incompatibility is not a major obstacle to transplantation and modern management can prevent infertility, even in females as recently demonstrated in the litterature.⁴ 

In conclusion, we think that innovative nonmyeloablative protocols are crucial for the future of HSCT for older SCD patients with organ failure, but there is still a place for myeloablative regimens for young SCD adults who experience more severe disease with aging.