Early Sickle Mortality Prevention

Dr. Fitzhugh is exploring new avenues of hematopoietic cell transplantation (HCT) for sickle cell disease (SCD), while also studying the long-term health effects of curative therapies for SCD.

Currently, HCT offers the only real cure for patients with SCD, though the transplantation procedure can only be applied to select people and carries its own health risks. One risk is that traditional stem cell transplants involve high-dose chemotherapy, which many adults with SCD cannot tolerate due to pre-existing organ damage. Dr. Fitzhugh and her team have been developing an alternative approach where patients receive agents that focus on eradicating the immune system and making space in the bone marrow while avoiding high-dose chemotherapy. Dr. Fitzhugh has demonstrated the efficacy of this non-myeloablative procedure in both mice and human volunteers and is currently participating in a long-term follow-up study with patients to see if they remain free of SCD.

Dr. Fitzhugh is also conducting a half-matched protocol to increase the number of people eligible for HCT. The current procedure requires a fully HLA-matched sibling donor, and less than 15% of patients with SCD would qualify. Through a half-matched donor protocol, 90% of patients have parents, children, and siblings who could serve as stem cell donors. However, the immune system barriers and potential complications are greater. Dr. Fitzhugh is currently examining the feasibility of this approach in a clinical pilot study that includes patients with compromised organ function.

Dr. Fitzhugh is also interested in learning more about the long-term health effects of curative therapies in patients with SCD. Her team has shown in small studies that heart morphology improves, tricuspid regurgitant jet velocity decreases, and kidney function remains normal after non-myeloablative HCT with follow-up of up to 3 years. Dr. Fitzhugh is collaborating with investigators to study the impact of curative therapies on organ function and also leads an NIH study to deeply phenotype major organs in patients with SCD who undergo HCT or receive standard treatment.

Lastly, myelodysplastic syndrome and acute myeloid leukemia incidence is higher than expected after graft rejection and gene therapy for SCD. Dr. Fitzhugh and her team have shown that TP53 mutations found at the time of myeloid malignancy diagnosis were present at baseline in a few patients. Further, the incidence of myeloid malignancies is higher after graft failure and mixed donor/recipient chimerism. They are now interested in exploring genetic risk factors for myeloid malignancy development after curative therapies for SCD. The goal of the clinical HCT protocols is full donor chimerism and not mixed chimerism. Altogether, Dr. Fitzhugh’s group seeks to develop a personalized approach to curative therapies for SCD.