Correspondence
Stem-Cell Transplantation for Sickle Cell Disease
N Engl J Med 2010; 362:955-956March 11, 2010
- Article
To the Editor:
As described by Hsieh et al. (Dec. 10 issue),1 the use of nonmyeloablative hematopoietic stem-cell transplantation as a tolerable, curative treatment option for adults with sickle cell disease is desirable. However, given the difficulty of identifying HLA-matched sibling donors, this therapy is out of reach for all but a small minority of patients.2 In order to provide access to this potentially curative treatment for patients with sickle cell disease, the use of HLA-matched unrelated donors or alternative donor sources should be explored. Our group at the University of Chicago has successfully established a state of mixed T-cell chimerism in patients with hematologic cancers by performing alemtuzumab-based hematopoietic stem-cell transplantation using unrelated HLA-matched donors.3 Similar to the patients in the study by Hsieh et al., our patients had low rates of graft-versus-host disease (GVHD) and other treatment-related complications. Thus, exploring the use of unrelated stem-cell donors could provide a viable treatment option for an increased number of patients with sickle cell disease. However, since few black patients have HLA-identical unrelated donors, widespread application of allogeneic transplantation for sickle cell disease will depend on success in mismatched transplantation.
Alexander Dew, B.S.
Koen van Besien, M.D.
University of Chicago, Chicago, IL
kvbesien@medicine.bsd. uchicago. edu Dr. van Besien reports receiving research support from Genzyme, the manufacturer of alemtuzumab.
No other potential conflict of interest relevant to this letter was reported.
3 References1
Hsieh MM ,Kang EM ,Fitzhugh CD , et al. Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N Engl J Med 2009;361:2309-2317
Full Text | Web of Science | Medline2
Dew A ,Collins D ,Artz A , et al. Paucity of HLA-identical unrelated donors for African-Americans with hematologic malignancies: the need for new donor options. Biol Blood Marrow Transplant 2008;14:938-941
CrossRef | Web of Science | Medline3
van Besien K ,Dew A ,Lin S , et al. Patterns and kinetics of T-cell chimerism after allo transplant with alemtuzumab-based conditioning: mixed chimerism protects from GVHD, but does not portend disease recurrence. Leuk Lymphoma 2009;50:1809-1817
CrossRef | Web of Science | Medline
To the Editor:
Hsieh et al. report that long-term administration of sirolimus after nonmyeloablative stem-cell transplantation for sickle cell disease extended the duration of mixed donor–recipient hematopoietic chimerism. This represents an advance over myeloablative regimens that can cure sickle cell disease but that bring with them gonadal toxic effects.1 Although the authors appear to have identified a regimen that is safe in the short term, there is concern about long-term use of sirolimus with regard to patient safety and adherence. Furthermore, it is uncertain whether the nonmyeloablative regimen would suffice for engraftment after stem-cell transplantation from an unrelated donor, which is important because the majority of adults with severe sickle cell disease lack an HLA-matched sibling donor. Together, these constraints are very likely to limit the broader application of this regimen. It falls short of the primary goal of allogeneic transplantation for sickle cell disease, which is to establish donor–recipient tolerance in the absence of long-term immunosuppressive therapy. We believe it is important to test alternative regimens, particularly those that might prove effective in the transplantation of stem cells from an unrelated donor.
Mark C. Walters, M.D.
Children's Hospital and Research Center Oakland, Oakland, CA
mwalters@mail.cho. org Keith M. Sullivan, M.D.
Duke University Medical Center, Durham, NCNo potential conflict of interest relevant to this letter was reported.
1 ReferencesAuthor/Editor Response
Finding a cure for the entire population of patients with sickle cell disease (children and adults with and without sibling donors) remains a highly desirable, shared goal, and we believe that our results represent a significant step in that direction. However, a commitment to that goal does not imply that researchers must seek out a single transplantation regimen that can be applied in all subgroups of patients from all donor types. Our regimen was developed specifically for adult patients with a high degree of disease burden, a population that historically has been excluded from this potentially curative approach and for whom an experimental approach can be justified. We make no claim that this regimen will serve all types of patients and donor sources, and we would argue the contrary: conditioning regimens for stem-cell transplantation must at a minimum be tailored to take into account factors such as the age range, indication, previous therapy, disease burden, cell source, cell dose, and degree of matching.
The goal of weaning immunosuppression, which is achievable in most pediatric stem-cell recipients, is certainly desirable, but the avoidance of GVHD is paramount in this nonmalignant disease in which no graft-versus-tumor effect is needed. Although continued immunosuppression is not the norm for pediatric patients, adults who are undergoing stem-cell transplantation often require such therapy, principally to treat chronic GVHD.1,2 In one large series, chronic GVHD developed in 61% of patients, and about 70% were still undergoing immunosuppression at 2 years.1 In another large series, 55% of patients had chronic GVHD 2 to 5 years after transplantation, and 81% were still undergoing immunosuppression.2 Long-term immunosuppression from a single agent (sirolimus) without GVHD is superior immunologically to such immunosuppression with any GVHD and far superior to replacing sickle cell disease with chronic GVHD. Though not dictated by the protocol, two of our patients have weaned themselves from immunosuppression and maintained stable mixed chimerism, free of sickle cell disease. This observation has prompted us to amend our protocol to allow weaning in patients for whom T cells are a majority donor type.
We encourage the development of new approaches for patients who do not have a matched sibling donor. However, we would caution strongly against the reflexive application of transplantation regimens that have been developed for application in patients with hematologic cancers.
Matthew M. Hsieh, M.D.
John F. Tisdale, M.D.
National Institutes of Health, Bethesda, MD
johntis@mail.nih. gov Since publication of their article, the authors report no further potential conflict of interest.
2 References1
Stewart BL ,Storer B ,Storek J , et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood 2004;104:3501-3506
CrossRef | Web of Science | Medline2
Fraser CJ ,Bhatia S ,Ness K , et al. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood 2006;108:2867-2873
CrossRef | Web of Science | Medline
