A modified bone marrow transplant procedure for sickle cell disease (SCD) co-developed at Vanderbilt University Medical Center, Johns Hopkins University School of Medicine and the University of California, San Francisco, can cure the disease, a new study has found.
Of 38 adults with severe SCD who participated in the study, more than 97% no longer required immunosuppressive therapy one year after the transplant, the researchers reported Feb. 25 in the journal NEJM Evidence. The two-year survival rate was 95%.
“The findings are significant and have implications for enhancing the care of patients with sickle cell disease,” said Adetola Kassim, MD, MS, professor of Medicine, clinical director of VUMC’s Adult Stem Cell Transplant Program, and co-first author of the paper with Mark Walters, MD, of UCSF.
Results of the Phase 2 study, conducted at VUMC and 18 other U.S. centers between 2017 and 2021, echoed the findings of the previously published study — the Vanderbilt-led Global Haploidentical BMT Learning Collaborative — which highlighted a novel conditioning regimen for related HLA-haploidentical bone marrow transplantation (BMT).
“Our earlier clinical trial, published in the journal Blood last year, showed that we can cure SCD in children and adults,” said Michael DeBaun, MD, MPH, the J.C. Peterson, MD, Chair and professor of Pediatrics at VUMC, and director of the Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease.
The new trial, conducted through the National Institutes of Health (NIH)-supported Blood and Marrow Transplant Clinical Trials Network, “is a direct extension of our previous study,” DeBaun said. “The results are just as good, if not better, than gene therapy or gene editing therapy.”
More SCD patients with complicating medical conditions should be able to qualify for curative therapy because the new regimen has fewer toxic side effects and is about one-fifth the cost of myeloablative gene therapy, said DeBaun, senior co-author of the paper with Johns Hopkins’ Robert Brodsky, MD, who trained at VUMC.
Results of an NIH-supported curative therapy trial in children, also co-led by DeBaun, Kassim, Brodsky, and Walters, are expected to be published later this year.
Sickle cell disease is an inherited disorder that results in abnormal hemoglobin, the oxygen-carrying molecule in red blood cells. Cells with abnormal hemoglobin adopt a sickle shape and tend to clump together easily, leading to severe pain; damage to the heart, lungs and kidneys; and increased mortality.
Current curative treatment options for SCD include allogeneic hematopoietic stem cell transplants (when a patient receives health stem cells most often from a related donor) and autologous genome-modification therapies (when a patient’s own cells are modified).
For this population, finding human leukocyte antigen (HLA) fully matched donors, whether related or unrelated, presents challenges, and many adult patients are unable to tolerate the myeloablative treatment associated with HLA-matched related donors or the recently FDA-approved gene therapies aimed at curing SCD.
The haploidentical transplant protocol developed at Johns Hopkins requires only a half HLA match from a related family member. The immunosuppressive drug cyclophosphamide is given post-transplant to prevent graft-versus-host disease. The protocol also does not require myeloablation (toxic chemotherapy). However, an early study from Johns Hopkins reported a graft failure rate of 40%.
In 2012, DeBaun and Kassim, with colleagues from France and the United Kingdom, established the Global Haploidentical BMT Learning Collaborative to evaluate the effect of adding the cancer drug thiotepa to the Johns Hopkins’ approach.
The 10-year international trial, which involved 32 children and 38 adults, demonstrated a two-year overall survival rate exceeding 94%, with no significant difference in overall survival between children and adults.
In the current study, adults with SCD underwent pre-transplant treatments with the Vanderbilt regimen. The results were comparable to those reported by the Vanderbilt consortium, demonstrating durable, two-year graft survival (engraftment) and an overall patient survival rate of 95%.
Both trials validate a new standard of care for curative therapy for adults with SCD, said Kassim and DeBaun. Unlike gene therapy, these results will not require FDA approval.
SCD affects approximately 100,000 individuals in the United States and millions worldwide.
The haploidentical protocol can be implemented immediately in most bone marrow transplant centers across the United States, Europe and the Middle East, as the haploidentical transplant with posttransplant cyclophosphamide procedure is already widely utilized for various bone marrow transplant treatments.
The study received support from grants U10HL069294 and U24HL138660 provided by the National Heart, Lung, and Blood Institute and the National Cancer Institute of the NIH to the Blood and Marrow Transplant Clinical Trials Network.
