New stem cell transplant approach offers potential sickle cell cure
Preparation, criteria changes show promising results in Phase 2 trial
Most people with sickle cell disease (SCD) who received a new type of stem cell transplant in a clinical trial were free of disease-related clinical events after two years, according to a study.
The scientists said the findings demonstrate that the approach, which uses a lower-intensity conditioning regimen to prepare the bone marrow for the transplant and changes traditional criteria for who can be a donor, is a potential sickle cell cure and a valid alternative to gene therapies, with advantages including lower cost and better accessibility.
“Our results … are every bit as good as or better than what you see with gene therapy,” Richard Jones, MD, professor at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and study author, said in a university news story.
The study, “Haploidentical Bone Marrow Transplantation for Sickle Cell Disease,” was published in The New England Journal of Medicine Evidence.
SCD is caused when genetic mutations lead red blood cells to take on a sickle-like shape. These abnormal cells are prone to getting trapped in blood vessels, blocking blood flow, and are also destroyed more easily than healthy red blood cells. Patients experience a range of SCD symptoms, including the sudden pain episodes known as vaso-occlusive crises, and the disease can ultimately lead to substantial organ damage.
Haploidentical approach as sickle cell cure
A stem cell transplant provides a patient with hematopoietic stem cells (blood cell precursors) harvested from a healthy donor. These cells, once introduced into the patient’s bone marrow, give rise to healthy blood cells that don’t carry the SCD-causing mutation.
It’s been thought that donors should be fully matched to patients in certain immune markers called human leukocyte antigens (HLA). That was to minimize the risk of graft-versus-host disease (GVHD), a serious transplant complication in which donor cells recognize the patient’s body as foreign and start attacking it.
But researchers are working on a new approach to transplant, called haploidentical bone marrow transplantation, in which the donor is a relative of the patient but is only half-matched to them in terms of HLA markers. This could make it easier for patients to find appropriate donors and facilitate the transplant process.
Prior to a transplant, a patient undergoes a conditioning regimen of low-dose chemotherapy and radiation to help make room for the new cells in the bone marrow and prevent the body from rejecting them. After the transplant, the patient takes immune-suppressing medications for up to a year to prevent GVHD.
In the Phase 2 trial (NCT03263559), 42 adults with severe SCD received the transplant and were followed for a median of 37 months, or a little over three years.
Results showed that 95% of the patients were alive after two years. Moreover, 88% hadn’t experienced any disease-related clinical events, essentially equating to a cure.
Three people experienced graft failure, where the transplanted cells are not taking hold in the bone marrow and producing new healthy blood cells as they should, and 22.4% experienced chronic GVHD in the first two years. Four people died, including two due to early infectious complications.
According to researchers, observed adverse events “were those anticipated from this procedure.”
One-time gene therapies also offer a potential cure for SCD. Two have recently been approved in the U.S.: Lyfgenia (lovotibeglogene autotemcel) and Casgevy (exagamglogene autotemcel).
Each of these treatments works differently to enable the body to produce healthier red blood cells, but they both involve collecting a patient’s own hematopoietic stem cells, making genetic modifications to them in the lab, and then returning them via a stem cell transplant after a round of chemotherapy.
While gene therapies have garnered significant interest, the researchers said their new transplant approach has advantages. Many SCD patients might not be eligible for gene therapy because it requires aggressive chemotherapy, but most would be able to receive the transplant, which uses a less aggressive regimen, they said.
“Many people — and maybe most adults — aren’t eligible for gene therapy because of the requirement for high dose chemotherapy that people with end organ damage can’t receive,” Jones said.
The risk of certain long-term side effects, including organ damage and leukemia, a blood cancer, are likely also higher with gene therapy, according to Jones.
Transplantation is also less costly, requiring substantially shorter hospital stays and fewer transfusions. According to a recent review study, the estimated cost of gene therapy is around $2 million to $3 million, whereas a transplant is expected to cost, on average, just shy of $500,000.
The clinical trial was supported by the Blood and Marrow Transplant Clinical Trials Network and grants from the National Institutes of Health.
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