Criteria for Selecting Patients with Sickle Cell Anemia for Allogeneic Hematopoietic Stem Cell Transplantation

HSCT is the only available cure for SCA, and more than 500 transplants for SCA have been reported to international registries. Although usually successful and curative, the widespread use of HSCT is still limited by the lack of sufficient suitable donors and concerns about regimenrelated morbidity and mortality. HSCT is safest when an HLA-matched sibling donor is available, but only about 10 percent of transplant candidates will actually have such a donor. Current estimates place regimen-related mortality for myeloablative transplantation using an HLA-matched sibling donor at about 5 percent, with a concomitant 9 percent risk of graft rejection and a 15 percent risk of chronic graft-versus-host disease (GVHD) (Table).^4,5  There are additional late effects of transplantation not tabulated here, including infertility, endocrinopathies, premature cardiovascular disease, and possibly cancer. One can argue that SCA-related mortality during childhood (in patients cared for in comprehensive centers in developed nations) is now lower than the regimen-related mortality of HSCT, but this comparison does not integrate the lifelong risk of progressive morbidity, impaired quality of life, and early mortality due to SCA. Of course, there is no randomized comparison of transplantation versus no transplantation that accurately quantifies the relative lifetime risks of morbidity and mortality from SCA and HSCT, but life after a successful transplant — the event-free survival (EFS) of a full-sibling-donor myeloablative HSCT is approaching 90 percent (Table) — is arguably better than a life with SCA. An important caveat, however, is that the definition of EFS differs by study and often does not include chronic GVHD, which may be worse than SCA, so EFS rates that are meaningful to patients are usually lower than reported (70-80% vs. 90%, respectively).

Expert panels and professional societies provide differing sets of clinical indications for HSCT as a treatment option for SCA, but common recommendations include recurrent vaso-occlusive complications (acute chest syndrome and painful events), usually despite hydroxyurea therapy, and overt cerebrovascular disease. Other indications have been proposed and used, such as abnormal transcranial Doppler velocities and silent cerebral infarction, despite much less agreement among experts and very limited data. Some hematologists now also advocate that a diagnosis of SCA itself is an indication for HSCT, justified by the knowledge that complications of SCA are often unpredictable, and most individuals with SCA will have progressively severe morbidity and early mortality. In my clinical practice, I do not compare a fixed list of indications for HSCT with an ongoing tabulation of the number and type of SCA-related complications experienced by the patient. Rather, I initiate (or continue) the discussion of HSCT in three main clinical scenarios.

 The first usual scenario is planned. I ensure that all patients with SCA and their parents know about the possibility of cure by HSCT. I include discussion of the option of HSCT as part of the comprehensive, ongoing education about SCA starting with the very first visit after diagnosis (usually the result of newborn screening). I also recommend tissue typing of all unaffected full siblings, including those with sickle trait, to know if there is an HLA-matched donor. If there is a matched-sibling donor, I offer dedicated clinic visits for frank discussions about the risks and benefits of myeloablative HSCT compared with life with SCA, as well as the risks and benefits of hydroxyurea therapy and chronic transfusions. If there is continued interest in pursuing HSCT, then I arrange formal consultation and counseling with the HSCT team. This multi-step process does not lead to HSCT for most  patients, but they are at least aware and knowledgeable about the option, and I support them with decision-making.

The second scenario is a direct inquiry about HSCT by a patient or parent, oftentimes as a result of something heard or read about on the Internet. Recent immigrants from Africa also tend to ask commonly about transplantation.

The third scenario occurs when a patient suffers a particularly serious complication, such as overt stroke. In these instances, I follow the same general process outlined above in counseling patients and their families about HSCT.

In essence, I consider every patient with SCA (here I include both HbSS and sickle-β⁰-thalassemia) who has an HLA-matched sibling donor to be a potential candidate for myeloablative HSCT. Honest discussions about the risks, benefits, and alternatives are needed, regardless of the “severity” of a patient’s disease, and the decision to pursue HSCT is a lengthy and patient- and family-centered process. Once a decision to perform HSCT is made, I recommend that it be done during early childhood. My opinions and practices are based upon the assumption that my patient’s HSCT will be performed in a center with substantial experience in transplantation for SCA and, ideally, as part of a clinical research study. The use of alternative donors (unrelated, mismatched, or haploidentical) and stem cell sources (unrelated umbilical cord blood) for children carries a much higher risk of transplant-related morbidity, mortality, and graft rejection and should be performed only as part of a carefully designed investigational study.

Adults with SCA tolerate myeloablative conditioning regimens poorly, likely because of the cumulative burden of chronic organ injury acquired during childhood. However, there is very promising early experience with a non-myeloablative conditioning regimen (including total-body irradiation, alemtuzumab, and sirolimus) in severely affected adults with SCA that can produce stable, mixed donor-recipient chimerism that effectively cures the disease.⁶  These outcomes have been achieved without chronic GVHD or mortality and with a low rate of graft rejection. The mixed chimerism appears to persist after discontinuation of immunosuppression.⁷  In the future, adults may no longer be summarily excluded from HSCT. Until then, all transplants in adults should be performed as part of a clinical research study with the indications being dictated by the eligibility criteria of the particular study.

While the experience with adult recipients and alternative donors matures, research needs to focus on reducing transplant-associated morbidity, especially sterility, in young patients undergoing reduced-intensity conditioning regimens. Ongoing studies will continue to expand access to HSCT for both children and adults, and the next “Ask the Hematologist” question on this topic might also include the option of gene therapy.