Gene therapy appears to reduce sickle cell disease-related complications
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LentiGlobin gene therapy led to reductions in sickle cell disease-related complications and hemolysis, according to results of a phase 1/phase 2 trial presented at the virtual American Society of Gene and Cell Therapy Annual Meeting.
The agent also had an acceptable safety profile consistent with that of myeloablative single-agent busulfan conditioning, according to the investigators.
LentiGlobin (bluebird bio) is an autologous CD34+ gene therapy derived from hematopoietic stem cells encoding beta-globin with the antisickling T87Q substitution. Researchers are studying the therapy among patients with severe sickle cell disease in the open-label, multicenter HGB-206 trial. The study has evolved into three cohorts “to incorporate improvements in patient management, product manufacturing and target cell collection,” John F. Tisdale, MD, senior investigator in the molecular and clinical hematology branch at the NHLBI, said during a presentation.
Tisdale and colleagues presented data from cohort 3 of the HGB-206 study, which has completed enrollment. Patients in cohort 3 (n = 17) had a history of severe vaso-occlusive events and acute chest syndrome and failed or could not tolerate hydroxyurea.
Investigators collected CD34+ hematopoietic stem cells by apheresis after plerixafor mobilization. They then transduced the cells with the BB305 lentiviral vector to manufacture the LentiGlobin gene therapy, which patients received as an IV infusion after myeloablative busulfan conditioning.
The weighted average of hemoglobin AT87Q level greater than or equal to 30% of total hemoglobin at 6 months after infusion served as the primary study outcome. Secondary outcomes included a greater than 75% reduction in severe vaso-occlusive events at 24 months after infusion.
Thirteen patients in group C received LentiGlobin, with median follow-up of 10.9 months (range, 0.9-20.7).
All but one patient in the study had neutrophil and platelet engraftment as of the data cutoff date.
Results for eight patients in cohort C with at least 6 months of follow-up showed a median hemoglobin S level of 50% or less of total hemoglobin. Total hemoglobin at baseline among these patients was 11.5 g/dL (range, 10.2-15), with a baseline hemoglobin AT87Q level of 5.3 g/dL (range, 4.5-8.8).
Patients in cohort C demonstrated sustained expression of treatment-derived hemoglobin. Median total unsupported hemoglobin at last visit was greater than 10 g/dL among patients with at least 6 months of follow-up.
Three-quarters of these patients reported previous vaso-occlusive events or acute chest syndrome. The annualized composite rate of vaso-occlusive events plus acute chest syndrome was zero (range, 0-1) after treatment with LentiGlobin compared with four (range, 2-14) before treatment. One patient experienced a nonserious vaso-occlusive event at 3.5 months after infusion.
“This represents a 99% reduction in the annualized rate of [vaso-occlusive events],” Tisdale said.
Markers of hemolysis also decreased after patients received the gene therapy.
The most frequent grade 3 or higher nonhematologic adverse events after gene therapy infusion included febrile neutropenia (n = 10) and stomatitis (n = 9).
There were no cases of adverse events related to the gene therapy or graft failure.
“Longer follow-up for durability and safety in this study is needed, and data from additional studies will help us further assess the clinical impact of this treatment for sickle cell disease,” Tisdale concluded.
Perspective
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Ifeyinwa Osunkwo, MD, MPH
Manipulation of one’s own stem cells (ie, gene therapy) to achieve curative status and circumvent the need for post-transplant graft-versus-host disease prophylaxis is a desired therapeutic approach for individuals living with severe sickle cell disease. This is because only 17% of affected individuals will have an eligible matched sibling donor.
The donor pool for patients with sickle cell disease has expanded with the inclusion of haploidentical siblings or parents. However, what happens to patients who have neither an available sibling nor a parent to serve as a donor source, or those with other end-organ contraindications to allogeneic transplant?
Tisdale and colleagues report updated data on the clinical safety and efficacy of the LentiGlobin CD34+ anti sickling hemoglobin product (beta A-T87Q) in ameliorating both the pain and hemolysis associated with severe sickle cell disease while achieving median hemoglobin S level of 50% or less. Mobilization with plerixafor followed by stem cell collection via apheresis showed acceptable yield of CD34+ stem cells, and transduction of lentiviral product provided the appropriate cell dose for engraftment.
Patients with at least 6 months of follow-up had reductions in annualized acute vaso-occlusive complications (pain and acute chest syndrome), which approached zero. Even more exciting, nearly half of their hemoglobin (without transfusions) was composed of the novel hemoglobin product, demonstrating persistence of the infused gene product over time.
Toxicity was mild to moderate, and there were no reports of graft failure or complications related to the presence of the novel hemoglobin product.
Longer-term follow-up is needed to confirm sustained levels of gene product; however, the clinical benefit at more than 6 months of follow-up is clearly evident, making this curative therapeutic strategy quite promising for adults with severe sickle cell disease.
Levine Cancer Institute at Atrium Health
The University of North Carolina at Chapel Hill
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Tisdale JF, et al. Abstract 1298. Presented at: ASGCT Annual Meeting; May 11-15, 2020 (virtual meeting).
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