The bone marrow transplant process, co-developed by investigators at the Johns Hopkins Kimmel Cancer Centre, is safe and therapeutic for adults with sickle cell disease, according to results from trials completed at Johns Hopkins and completed at around 20 additional cancer centres nationwide and London. Therapies available at multiple US medical centers may be present in gene therapy products recently approved for sickle cell disease, and are costly alternatives, the authors say.
During this type of implantation, called low-intensity haplotime identical bone marrow transplants, bone marrow is given by a “semi-matched” donor, such as a patient's parent, sibling, child, nie, ne, aunt, uncle, or Cousin. This means that proteins that aid the functioning of the body's immune system, as well as proteins present in the donor's bone marrow cells, will adapt at least half of these proteins on the recipient's cells and will not attack the recipient's body after implantation.
Prior to implantation, patients are treated with low-dose chemotherapy and given full-body irradiation. After implantation, they are administered cyclophosphamide (a drug that prevents graft-versus-host disease in which immune cells in the donor bone marrow attack a new host) and other drugs for up to 1 year.
Of the 42 people with severe sickle cell disease treated during the trial, 95% are alive two years after transplant, with 88% being cured and not experiencing disease-related events. These results will be published in the February 25th issue of the New England Journal of Medicine Evidence. The initial results were presented at the American Society of Hematology Annual Meeting in December 2023.
The test shows very high engraftment and very high stiffness of donor cells, the authors say.
“Our outcomes with allografts are as good or even more than what we see in gene therapy,” says Richard Jones, MD, professor of oncology, director of the blood bone marrow transplant program at Kimmel Cancer Center and co-director of the hematological malignant drug program. Most people with sickle cell disease are eligible for transplants, and will cost a portion of the price of gene therapy, he says.
“Many people, and perhaps most adults, are not necessarily eligible for gene therapy due to the requirements for high-dose chemotherapy that people with organ damage cannot receive,” says Jones. “The risk of long-term side effects will also be higher in gene therapy, both with organ damage and the risk of leukemia.”
A common misconception in the medical field is that the transplant of sickle cell disease requires a perfectly consistent donor, which can result in severe graft-versus-host disease and high mortality.
Transplantation is a much more expensive option for medical centers and patients, says Brodsky. In the case of transplants, patients are in the hospital for about 8 days, as opposed to 6-8 weeks for gene therapy. He also says, “The median transfusion for gene therapy patients is 50, but the median transfusion after haplotide bone marrow transplantation is 6. It is almost entirely outpatient,” he says.
A review paper co-authored by Jones and Brozky comparing allogeneic bone marrow transplantation and gene therapy was published in the February 25th issue of the journal Blood Advances. This paper shows that the estimated cost of gene therapy is between $2 million and $3 million, compared to about $467,747 for transplants.
The median age of participants in the Phase II trials that occurred between 2017 and 2021 was 22. 59% were male, 92% were black, and 4% were Hispanic. The average follow-up period was 37 months. Serious side effects were rare, including three graft disorders, moderate to severe graft-versus-host disease (22%) and two deaths at the first year after implantation (one since Covid-19).
According to the Centers for Disease Control and Prevention, sickle cell disease – red blood cells tend to form like larvae instead of discs, affecting about 100,000 Americans (mostly black people).
The clinical trials were supported and sponsored by the Blood and Bone Marrow Transplant Clinical Trial Network. National Institutes of Health; National Heart, Lung and Blood Institute and The National Cancer Institute (Grants U10HL069294 and U24HL138660).
The other center that took part in the trial was Vanderbilt University Medical Center in Nashville, Tennessee. University of California, San Francisco School of Medicine. Wisconsin Medical University, Milwaukee. Northside Hospital in Atlanta. Children's Hospital Colorado; H. Lee Moffit Cancer Center in Tampa, Florida. Roswell Park General Comprehensive Cancer Center in Buffalo, New York. Atrium Health Levine Children's Hospital in Charlotte, North Carolina. University of Michigan Ann Arbor. Washington University in Seattle. Niklaus Children's Hospital in Miami. Methodist Hospital in San Antonio. University of Alabama, University of Birmingham. University of Pittsburgh Medical Center. Orlando Health Cancer Institute in Florida. Children's Hospital in Washington, DC. St. Mary's Hospital in London. Cleveland Clinic; Yale Cancer Center in New Haven, Connecticut. Duke University Medical Center in Durham, North Carolina. Washington University in St. Louis. Additional study authors were from M's Inc., Rockville, Maryland, and the National Institutes of Heart, Lung and Blood.
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