Haploidentical bone marrow transplant provides ‘higher access’ to sickle cell disease cure
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Key takeaways:
- Two-year EFS and OS rates comparable with transplant from myeloablative matched sibling donors.
- Researchers observed durable donor engraftment at 2-years with low mortality.
Reduced-intensity haploidentical-bone marrow transplant showed durable donor engraftment at 2-years follow-up with low mortality among adults with severe sickle cell disease, according to study results.
The findings, presented at ASH Annual Meeting and Exhibition, also showed comparable 2-year EFS and OS to that observed with bone marrow transplant from a myeloablative matched sibling donor.
“These results support haploidentical-bone marrow transplant with post-transplant cyclophosphamide as a suitable and tolerable curative therapy for adults with sickle cell disease and severe end-organ toxicity, such as stroke and pulmonary hypertension,” Adetola A. Kassim, MD, MS, researcher in the department of hematology and stem cell transplant at Vanderbilt University Medical Center, said during a press briefing.
Background
Bone marrow transplant is a known curative option for sickle cell disease. However, lack of an available human leukocyte antigen (HLA)-matched family member has been an obstacle to access to this therapy, Rabi Hanna, MD, pediatric oncologist in the department of pediatric hematology oncology and blood and marrow transplantation at Cleveland Clinic Children’s, told Healio.
“Haploidentical-bone marrow transplant has been used successfully in treating malignant disorders,” he said. “We conducted this study to evaluate the safety and efficacy of haploidentical-bone marrow transplant in children and young adults with severe sickle cell disease.”
The adult arm of the multicenter phase 2 study included 54 adults (median age, 22.8 years; 59.3% men; 92.6% Black) receiving treatment across 19 sites, required to have an HLA-matched first-degree relative donor, and willing and able to donate bone marrow. Among them, 78% (n = 42) underwent transplant.
The most common indications for transplant included recurrent vaso-occlusive pain episodes (38.9%), followed by acute chest syndrome (16.8%) and overt stroke (16.7%).
“Adults with sickle cell disease continue to experience a shorter life span than pediatric patients, with a median survival among adults of 48 years — nothing has changed within the past 25 years,” Kassim said. “It is not clear to many that the heart, lung and kidney complications account for more than 50% of identifiable causes of death in this patient population. All of this is what prompted this research. We wanted to know if there is any way that we can change the disease trajectory.”
Patients underwent preconditioning with 30 mg/kg hydroxurea on day 10 to day 70. The conditioning regimen included thymoglobulin, thiotepa, fludarabine, cyclophosphamide and total body irradiation. Graft-versus-host-disease prophylaxis included post-transplant cyclophosphamide, sirolimus and mycophenolate mofetil.
The study’s primary objective included EFS at 2 years after haploidentical-bone marrow transplant. Secondary objectives included determining the impact on clinical and laboratory manifestations of sickle cell disease and other transplant outcomes at 2 years post-haploidentical bone marrow transplant.
Findings
Overall, 31% (n = 13) of patients received the 30 mg/kg dosing of hydroxyurea preconditioning.
Results showed an estimated 2-year EFS of 88% (95% CI, 73.5-94.8), with all but one qualifying event occurring within 1 year.
Researchers additionally observed a 2-year post-hydroxyurea OS of 93% (95% CI, 79.8-97.7) and a 2-year post-transplant OS of 95% (95% CI, 81.5-98.7). Primary graft failure occurred in 4.8% of patients and 2.4% experienced secondary graft failure before day 100.
Moreover, results showed a cumulative 100-day incidence of grade 2 to grade 4 acute GVHD of 26.2% (95% CI, 14-40.2) and grade 3 to grade 4 acute GVHD at day 100 of 4.8% (95% CI, 0.9-14.4).
Two deaths occurred during year 1 (one organ failure and one acute respiratory distress syndrome) and no deaths during year 2. In addition, 78.6% of patients reported at least one readmission post-bone marrow transplant due to either bacterial infection (n = 41) or viral reactivation (n = 36).
“The data showed durable donor engraftment at 2 years with low mortality, and 2-year EFS and OS are comparable to historically reported outcomes after matched sibling myeloablative bone marrow transplant,” Hanna told Healio. “These results are promising to enable higher access to this life-saving therapy for adult patients with severe sickle cell disease as the haplo-donor availability is almost universal. Additionally, the ability to get sustained engraftment with reduced intensity enables us to offer it to more patients with disease complications and severe end-organ toxicity such as stroke and pulmonary hypertension — a population typically excluded from participating in myeloablative gene-therapy and gene-editing trials.”
Further, haploidentical-bone marrow transplant resulted in decreased treatment costs, Kassim said.
“What is important is the varying costs of the three procedures,” he said. “We have to realize that 5% of patients with sickle cell disease are born in high-income countries, and the remaining 95% are born in low- to middle-income countries. The ‘sticker price’ for haploidentical-bone marrow transplant in the U.S. is $200,000 to $400,000 compared with $3 million for the FDA-approved gene therapy and $2.2 million for CRISPR — which of the three is scalable to the 95% of the population that needs treatment?”
Future research
Researchers are awaiting completion of pediatric arm of the trial, which is anticipated at the end of the 2-year follow-up.
“Curative options, including allogenic haplo-bone marrow transplant can potentially cure adult patients with severe sickle cell disease, and this study showed the safety and feasibility of almost universal donor with very promising efficacy,” Hanna said.
This is an exciting time to manage patients with sickle cell disease, Kassim said.
“We now have the approval from the FDA for two cell-based gene therapies to treat sickle cell disease,” he continued. “Now that we have a collection of curative agents, this is the time to choose which treatment to pick.”
Perspective
Back to TopMikkael A. Sekeres, MD
Where this fits in to the context of curative therapies that we're hearing about in sickle cell disease is, of course, the $1 million question — or should I say the $2 million or $3 million question. I think a lot of this speaks to availability and who is going to pay for this. It would be great to offer some sort of gene therapy to someone and have that gene therapy not have a lot of side effects and miraculously transform what is a life-shortening diagnosis into something that allows people to live a normal life span. I think it's going to take a randomized trial where some patients upfront get a bone marrow transplant and some are randomly assigned to these other newer-technology therapies and we follow them over time, looking not only at OS but complications of the therapy itself and how many patients relapse.Perspective
Back to Top
Peter Abdelmessieh, DO, MSc
Patients with severe sickle cell anemia suffer from chronic painful conditions that are not only related to disease, but also a consequence of its management. A general population study in the United States showed a median age of death of 43 years in patents with sickle cell disease, a great improvement from earlier decades but still unacceptable.
Hematopoietic cell transplantation from an HLA-identical sibling donor has been shown to be curative in the majority of patients treated. Event-free probabilities of 90% to 95% have been reported after HLA-identical sibling hematopoietic cell transplant using cord blood or marrow as the source of hematopoietic cells.
Despite these results, the application of hematopoietic cell transplant in patients with sickle cell disease is pursued infrequently due to the lack of suitable donors. Current estimates project that only 14% of patients will have an HLA-identical donor. The National Marrow Donor Program published that the likelihood of identifying a well-matched, unrelated marrow donor is 18% among African American recipients.
The use of post-transplant cyclophosphamide, pioneered by the Johns Hopkins group, has vastly increased the donor pool by proving this approach can be used for haploidentical (half-matched) donors. Therefore, any patient with a sibling or parent could potentially have a donor.
The use of haploidentical grafts along with reduced-intensity conditioning not only increases the donor options but the safety of this potentially curable procedure. Past studies that explored a reduced-intensity conditioning approach in patients with sickle cell disease were unsuccessful, resulting in patients losing graft function once immunosuppression was withdrawn. This indicates the importance of increased lymphodepletion as part of conditioning.
This study used a few altered approaches to improve outcomes. The first was the use of sirolimus instead of traditional tacrolimus, which decreased the rate of posterior reversible encephalopathy syndrome that traditionally occurs in up to 10% to 20% of patients with sickle cell disease. This protocol also increased the conditioning intensity in terms of host lymphodepletion by adding the agent thiotepia to fludarabine/cyclophosphamide along with increasing the total body radiation dose from 200 Gy to 400 Gy. It is also important to note that investigators used only bone marrow grafts in this study, which is not routinely practiced in transplant centers.
This study shows these modifications have improved outcomes and safety in patients with sickle cell diseases. If long-term follow-up continues to show the same impressive outcomes, there is hope that this approach can be applied to all transplant centers around the globe and allow more patients with severe sickle cell disease to be cured of their chronically debilitating disease.
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Kassim AA, et al. LBA-4. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
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