A reduced-intensity bone marrow transplant regimen developed by Johns Hopkins physicians provides durable engraftment with low rejection rates and also may preserve fertility, according to results of a new study conducted by Johns Hopkins Kimmel Cancer Center investigators.
The research, published online March 26 in Blood Advances, was supported in part by the National Institutes of Health.
"The survival rate in the long run in our study was about 95%, so we are curing the overwhelming majority of people who are transplanted, with mismatched donors," says senior study author Javier Bolaños-Meade, M.D., a professor of oncology at the Johns Hopkins University School of Medicine. "Essentially, nearly everybody who has either sickle cell disease or thalassemia, an inherited blood disorder, can be cured, because nearly everybody has a donor."
The study reports on long-term success among 43 patients with sickle cell disease, ages 5–41, who underwent bone marrow transplantation at Johns Hopkins from November 2014–January 2025. Seven had a full-matched genetic donor, and 36 had a half-matched donor such as a parent, child or sibling. Patients included 27 adults, ages 19–41, and 16 children, ages 5–17. All had more than two common complications associated with sickle cell disease such as a stroke or bone tissue death due to a lack of blood supply.
The probability of five-year overall survival was 95.5% at an average follow-up of 2.43 years, and the probability of disease-free survival at two years was 94.5%.
Only two patients (5%) experienced graft failures, and two died late after bone marrow transplant (2½ years and six years after) — one from a condition unrelated to the transplant. The incidence of severe graft-versus-host disease (GVHD) was 2.4%, and incidence of moderate GVHD was 7.3%. On average, patients were able to cease immunosuppression medications within a year (354 days); 10 adults were able to stop six months following the transplant.
The study also is believed to be the first to investigate the impact of bone marrow transplant on fertility for patients with sickle cell disease and thalassemia. Among 27 female patients studied, 12 resumed menses or had normalized hormone levels, and two had successful pregnancies within five years of their transplants. Among seven males studied, five had normalized hormone levels. All patients were offered fertility preservation before undergoing the transplant.
"There is a lot of controversy in the transplant world about how much radiation is enough to do a safe transplant but preserve fertility, and nobody knows the answer," Meade says.
This study "is a game-changer because it's the only curative approach that preserves fertility in most patients, and because the engraftment rate in children was over 90%," adds study co-author Robert Brodsky, M.D., the Johns Hopkins Family Professor of Oncology Research and director of the Division of Hematology at the school of medicine. "Previous regimens with the chemotherapy agent thiotepa had lower engraftment in children compared with adults."
The paper is the third in a series demonstrating results of a novel bone marrow transplant (BMT) regimen developed at Johns Hopkins, Meade says. In 2012, the team first reported their success with a bone marrow transplant program that allows the use of haploidentical, or half-matched, bone marrow donors such as a parent, child or sibling who is a 50% genetic match to the patient. Through their regimen, patients receive low-dose chemotherapy and total body irradiation to lower the immune response to the donor bone marrow before the transplant, and take immunosuppressive medications after to prevent GVHD. In the first study, however, about 40% of the initial group of patients experienced graft failure, meaning the transplanted cells failed to produce healthy blood cells.
Then, in 2019, investigators reported results of a clinical trial showing that by increasing total body irradiation from 200 centigray (cGy) to 400 cGy, they improved engraftment rates to 95%.
"Our BMT regimen has multiple advantages compared with others and with gene therapy, including a significant reduction in health care utilization," Brodsky says. Adult patients, for example, stayed in the hospital an average of 12 days, and 67% of patients who used opioids for pain prior to the procedure discontinued use. "BMT is at least one-fifth of the cost of gene therapy and editing trials, and it remains a more accessible option for patients with severe sickle cell disease who cannot tolerate suppression of bone marrow activity."
Sickle cell disease affects about 100,000 Americans, primarily African Americans, and 20 million people worldwide. It is a painful blood disorder in which red blood cells are shaped like crescents instead of discs, and clog blood vessels.
Study co-authors were Marti Goldenberg, Ravi Varadhan, Christopher J. Gamper, Kenneth R. Cooke, Alexander J. Ambinder, Heather J. Symons, Lydia H. Pecker and Richard J. Jones.
The work was supported by the National Institutes of Health (grants P01-CA225618, P01-CA015396, and P30-CA006973-59) and the Maryland Stem Cell Research Fund. The authors had no conflicts of interest to disclose.
