Transplantation in Sickle Cell Disease: Who, When, and How

In 2020, one of the hottest debates in sickle cell disease (SCD) asks the question, “What are the indications for transplantation?” It is clearly a data-free zone. SCD is a serious public health problem around the world, killing nearly half a million people annually. In 2010 there were more than 300,000 newborns with SCD.¹  In the United States, SCD is the most common inherited blood disease affecting nearly 100,000 children and adults. Therefore, there are many more patients with SCD than with acute myeloid leukemia, a disease for which precise indications for transplantation do exist. The annual cost for medical care for patients with SCD in the United States exceeds $1 billion. For adults with SCD, the average annual cost of medical care exceeds $35,000 USD per year.²  And while survival of patients with SCD has improved in developed countries owing to improved supportive care, use of blood transfusions, prophylactic antibiotics, and drug therapy with hydroxyurea, none of these interventions are curative. Despite these advancements, most adults and many children develop a chronic debilitating condition, leaving more than 30 percent of adults on disability and more than 50 percent of patients unemployed.³  Median survival is shortened by more than two decades, and quality of life is severely impacted due to complications such as chronic pain, narcotic dependence, stroke, renal failure, thrombosis, pulmonary hypertension, blindness, priapism, and infection.

Allogeneic bone marrow transplantation (ABMT) can cure SCD. In 1984, Dr. F Leonard Johnson and colleagues reported a successful BMT of a child with leukemia and SCD who was cured of both disorders.⁴  As of 2013, there were 1,238 BMTs for SCD reported to the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation-Eurocord.⁵  This was followed by several reports of myeloablative ABMT from matched sibling donors for children with SCD.^6,7  These data firmly established that SCD is a potentially curable disease following myeloablative ABMT from a healthy human leukocyte antigen (HLA) –matched sibling donor. However, BMT is seldom used for these patients owing to perceived toxicity and lack of suitable donors. The medical problems described above make some of these patients unsuitable for aggressive therapy such as transplantation. Moreover, BMT is only available in developed countries; however, these countries also have obstacles that limit the availability of BMT to only small percentage of patients, such as donor availability, transplant related morbidity and mortality, and engraftment difficulty in patients with SCD.^8,9  The past decade has witnessed dramatic improvements in increasing safety and expanding the donor pool for patients in need of BMT. However, despite the fact that BMT is more available than before, particularly given the availability of nonmyeloablative conditioning,^8,10,11  there is no consensus among hematologists as to the indications for BMT in patients with SCD.

It is important to remember that patients with SCD are interested in BMT, so we must present them with a rational, evidence-based set of indications for the procedure. Drs. Suparno Chakrabarti and David Bareford surveyed 30 adult patients with SCD about their feelings toward receiving a reduced intensity BMT for the management of their disease.¹²  Sixty-two percent were willing to accept a 10 percent transplant-related mortality, and a third of patients, could accept even a 30 percent transplant-related mortality rate. Most patients (62%) were willing to accept a 10 percent risk of graft failure, 50 percent were willing to accept infertility, but only 20 percent considered chronic graft-versus-host disease acceptable. In fact, 60 percent of those surveyed would consider joining a clinical trial of reduced intensity BMT. If patients are willing to try this intervention despite its potential toxicities, it is up to us, the transplant community, to develop sensible guidelines that can be applied to patient care.

Indications for BMT in patients with SCD are evolving, and clearly there is no consensus on them.⁹  The majority of the published series reports on highly symptomatic SCD with advanced disease.^{7,10,11,13-15}  Until recently, virtually all BMT in SCD was performed in children using myeloablative conditioning and matched-related sibling donors. This meant that parents of patients with SCD were often put in the difficult position of making the final decision. Now that nonmyeloablative conditioning regimens and HLA-haploidentical donors are showing success in children and adults with SCD, the indications continue to evolve, and adult patients are now able to sign consent forms.^8,10,11  Most pediatric hematologists agree that stroke or silent cerebral infarction is an absolute indication for children with SCD, especially given recent data showing that red cell exchange transfusions are not as effective as previously thought in preventing secondary vascular events.¹⁶  Recurrent acute chest syndrome (ACS) or frequent vaso-occlusive crisis despite hydroxyurea with good drug adherence are also considered by some to be good indications for BMT in children. Others feel that all symptomatic children with SCD should be transplanted as soon as possible if they have a fully matched HLA-sibling donor; however, this is not universally accepted given variable clinical trajectories. In adult patients, common indications have included cerebrovascular disease, recurrent vaso-occlusive crisis despite hydroxyurea, osteonecrosis, red cell alloimmunization, and recurrent ACS.^8,10,11  While pulmonary hypertension is a known cause for morbidity and mortality in these patients, there is no agreement as to whether or not patients with this condition should proceed to transplantation, and at least in one study, such individuals were excluded.^10,11  Some degree of renal dysfunction should not be seen as a reason to avoid transplantation (given the use of nephrotoxic drugs such as calcineurin inhibitors or fludarabine); however, data on patients receiving transplants for this indication on renal replacement therapy are limited.¹⁷  The indications for BMT in children and adults with SCD will continue to evolve as the availability of alternative donors, engraftment rates, and safety of BMT increases.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) currently has open studies evaluating the role of ABMT in patients with SCD. Given the national relevance of the BMT CTN, it is important to look into their eligibility for such studies. BMT CTN 1507 is a study of reduced intensity conditioning using haploidentical donors. BMT CTN 1503 compares BMT to standard non-BMT care for adolescents and young adults with SCD. Both studies have similar enrollment criteria. Regarding SCD-specific manifestations in children, they are looking for children with a neurological event (stroke or abnormal MRI) or abnormal transcranial Doppler ultrasonography. For adults, besides the neurological event, it is required that they have two or more episodes of ACS in the prior two years, history of three or more episodes of pain crises per year in the preceding two years, transfusion dependence, or a tricuspid valve regurgitant jet velocity of 2.7 m/sec or greater. Patients also need to be eligible for BMT by standard criteria (e.g., good cardiac, pulmonary, and renal functions). These indications are similar but not identical to others used on previous studies.

ASH has developed clinical practice guidelines on SCD. A panel on transplantation is working on clarifying some of the issues related to indications. I suspect that now that BMT is becoming more prevalent due to the use of alternative donors, consensus will develop so we will be able to tell our patients who, when, and how.