Allogeneic hematopoietic stem-cell transplantation, also known as allogeneic bone marrow transplant, which uses healthy blood stem cells from a donor to replace bone marrow that’s not producing enough healthy blood cells, is a potentially curative treatment for sickle cell disease (SCD). However, due to a lack of suitable donors or the inability to tolerate the intensive chemotherapy required as part of the treatment this approach may not be feasible for most patients diagnosed with the disease.
Results from a new study, funded by the National Heart, Lung and Blood Institute (NHLBI) and the National Cancer Institute (NCI) and presented as a Late Breaking Abstract during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 9 – 12, 2023 in San Diego, CA, adults living with severe sickle cell disease saw good outcomes from a modified transplantation procedure that broadens the potential donor pool and includes a gentler conditioning regimen, suggesting a less toxic approach could allow a much broader array of people to benefit from the treatment.
“This is a pragmatic approach for adults with sickle cell disease, and the results are fantastic,” said Adetola A. Kassim, MBBS, MS, professor of medicine at Vanderbilt University Medical Center, the study’s lead author.
“It actually beat our expectations. This study has clearly shown that you can take selected adult patients with significant comorbidities to transplant, and hopefully change the trajectory of their disease.”
The trial is the largest multi-center study to date to test the modified approach in adults with sickle cell disease.
An inherited blood disorder
Sickle cell disease is an inherited blood disorder in which red blood cells become hard, sticky, and misshapen (in the form of a ‘sickle’), diminishing their ability to carry oxygen (which causes chronic anemia).
The condition causes episodes of severe and debilitating pain, called vaso-occlusive crises, as well as damage to tissues and organs that accrue over time and can lead to early death.
Although the exact number of people living with sickle cell disease in the United States is unknown, the Centers for Disease Control and Prevention (CDC) estimates that the disease affects approximately 100,000 Americans, with about 1 out of every 365 Black or African-American births and about 1 out of every 16,300 Hispanic-American births diagnosed with the disease. 
A stem cell transplant can cure the disease by removing the stem cells that produce misshapen blood cells and replacing them with stem cells from a donor that will make healthy blood cells.
The standard transplantation procedure for sickle cell disease requires that the donor be a sibling with a high degree of genetic similarity and that the recipient be healthy enough to tolerate a high-intensity chemotherapy regimen as part of the procedure. In the modified procedure used for the study, called related, reduced intensity haploidentical bone marrow transplantation, the donor only needs to be ‘half-matched‘ genetically to the recipient, broadening the pool of potential donors to include not only siblings but parents, children, cousins, aunts, and uncles.
While fewer than one-quarter of people with sickle cell disease have a matched sibling who could potentially serve as a donor, about 90% have a relative who could serve as a half-matched donor. In addition, because it uses a lower-intensity conditioning regimen, the modified approach is more easily tolerated by people with health problems such as organ damage, a complication of sickle cell disease that becomes more common with age.
A broader group of people
As a result of these modifications, a much broader group of people living with sickle cell disease could be eligible for reduced intensity haploidentical bone marrow transplantation than for conventional matched-donor transplantation, including older individuals, those with more comorbidities, and those without a matched sibling donor.
For the study, researchers enrolled 54 individuals living with sickle cell disease with a history of stroke or reduced heart functioning, pain episodes, or frequent blood transfusions. Forty-two participants ultimately underwent the modified stem cell transplantation procedure. At two years, the overall rate of survival following the transplant was 95% and the estimated rate of event-free survival (defined as survival without graft failure or a second infusion of stem cells) was 88%.
At 100 days following the transplant, 4.8% of patients experienced a primary graft failure and 4.8% experienced adverse events of grade three or higher. Infections were common; 78.6% of patients experienced at least one hospital admission following their transplant, most due to infections. Two participants died within the first year after the transplant, one from organ failure and one from fluid buildup in the lungs associated with COVID-19 infection.
Most participants experienced significant improvements in markers of healthy blood functioning, a reduction in pain episodes and fatigue, and improved heart and lung functioning. Overall, researchers said that the results suggest the modified procedure can achieve results that are comparable to conventional stem cell transplantation and are tolerable even for people with health conditions that would make them ineligible for a conventional transplant.
Ongoing and future studies
In future studies, the researchers plan to focus on opportunities to reduce rates of infection, enhance supportive care, and preserve fertility among people undergoing the procedure. They also plan to continue to follow trial participants to track long-term outcomes.
“Some of these patients are really thriving and now getting back into the community,” Kassim said.
“We hope that long-term follow-up will be able to quantify the added value of curing patients of sickle cell disease.”
Kassim added that most patients were off immunosuppression therapy at both the one and two-year post-transplant timepoints with no significant chronic graft-versus-host disease (cGvHD), providing evidence that the study’s cyclophosphamide-based post-transplant regimen helped to reduce the risk of this serious complication.
Researchers noted that for many people, the feasibility of this treatment will depend not only on the availability of family donors, but on costs and insurance coverage, the ability to take time off work and even temporarily relocate to undergo the procedure, and the availability of family and caregiver support.
Haploidentical Bone Marrow Transplantation in Sickle Cell Patients (BMTCTN1507) – ClinicalTrials.gov ID: NCT03263559
 Kassim AA, MBBS, Walters MC, Eapen M, Ritzau N, Smith M, Solh MM, McKinney C, Nieder M, Ross M, Kent M, Abusin G, Mallhi KK, Galvez Silva J, Shaughnessy P, Kanter J, Haines H, Farah RJ, Khaled Y, Abraham A, Bollard CM, Cooke KR, De La Fuente J, Hanna R, Horowitz MM, Jordan LC, Krishnamurti L, Leifere E, Mahadeo KM, Shenoy S, Ritzau NM, DeBaun MR, and Brodsky RA. LBA-4 Reduced Intensity Haploidentical Bone Marrow Transplantation in Adults with Severe Sickle Cell Disease: BMT CTN 1507. Presented on Tuesday, December 12, 2023, 9:00 AM-10:30 AM during the 65th annual meeting of the American Society for Hematology, held December 9 – 12, 2023. [Abstract]
 Sickle Cell Disease. Data & Statistics on Sickle Cell Disease, July 6, 2023. Online National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. Last accessed on December 10, 2023.
Featured image: Doctor talking to African American patient. Phot courtesy: © 2016 – 2023 Fotolia/Adobe. Used with permission.