April 18, 2018
3 min read

Gene therapy reduces need for transfusions in beta-thalassemia

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Alexis Thompson
Alexis A. Thompson

LentiGlobin BB305 gene therapy reduced or eliminated the need for monthly transfusions among patients with transfusion-dependent beta-thalassemia, according to results from two phase 1/phase 2 clinical trials.

“These study results exceeded our expectations with clinical benefit for nearly all patients and suggest that gene therapy may be an effective treatment for thalassemia in the future,” Alexis A. Thompson, MD, MPH, head of hematology and director of the comprehensive thalassemia program at Ann & Robert H. Lurie Children’s Hospital of Chicago, said in a press release.

Patients with transfusion-dependent beta-thalassemia — the most severe form of the disease — require long-term red cell transfusions for survival; however, risk for transfusion-related iron toxicity and infections remains high. Allogeneic hematopoietic stem cell transplantation serves as a possible curative option for beta-thalassemia, but use is limited by high risk for graft rejection, graft-versus-host disease and other toxicities.

Previous research showed a patient with severe beta-thalassemia discontinued transfusions for more than 6 years once they achieved sustainable beta-globin expression after gene therapy with LentiGlobin BB305 (Bluebird Bio).

The FDA granted breakthrough therapy designation to the gene therapy product for the treatment of transfusion-dependent patients with beta-thalassemia major in 2015.

Researchers evaluated the safety and efficacy of LentiGlobin BB305 among 22 patients aged 12 to 35 years with severe beta-thalassemia enrolled in the HGB-204 and HGB-205 studies — two nonrandomized, open-label trials initiated at various clinical sites in 2013.

All patients were transfusion dependent and had various beta-thalassemia genotypes. Red cell infusions began at a median age of 3.5 years among patients in the HGB-204 study and when aged younger than 3 years among patients in the HGB-205 study.

Researchers retrieved autologous CD34-positive cells from the patients, which were then transduced ex vivo with LentiGlobin BB305 vector — encoded adult hemoglobin with a T87Q amino acid substitution (HbAT87Q) — and reinfused after patients underwent IV myeloablative busulfan conditioning.

In the HGB-205 study, patients underwent red cell hypertransfusion at least 3 months prior to stem cell mobilization and harvesting to ensure a hemoglobin level of at least 11 g/dL to enrich the hematopoietic stem cells in the harvested CD34-positive cells.

Hematopoietic engraftment and kinetics, transplantation-related mortality at 100 days, OS, adverse events, vector-derived replication-competent lentivirus detection and analysis of vector insertion sites served as safety endpoints in the two studies. Efficacy endpoints included quantification of vector-derived HbAT87Q in peripheral blood after transfusion and discontinued red cell transfusions.

After a 2-year primary study period, 13 patients enrolled in the long-term LTF-303 follow-up study for close monitoring.

A median of 26 months (range, 15-42) after infusion of the gene therapy, 12 of 13 patients with non-beta0/beta0 genotype stopped red cell transfusions. These patients had a median HbAT87Q level of 6 g/dL (range, 3.4-10) and median total hemoglobin of 11.2 g/dL (range, 8.2-13.7).

Among nine patients with beta0/beta0 genotype or homozygosity for IVS1-110 mutation, six had a median HbAT87Q level of 4.2 g/dL (range, 0.4-8.7) and continued transfusions. However, these patients had a 74% (range 7-100) median reduction in the annual number of transfusions and a 73% (range, 19-100) median reduction in annual transfusion volume. The other three patients discontinued red cell transfusions.

Researchers observed a correlation between blood HbAT87Q levels and blood vector copy number levels (r2 = 0.75; P < .001). However, age, genotype and splenectomy status did not appear to correlate with gene expression.

Dyserythropoiesis appeared corrected for all patients with normal hemoglobin levels.

Five mild treatment-related adverse events and nine serious adverse events — including liver disease attributed to busulfan conditioning — occurred among patients in the HGB-204 study. No serious adverse events were considered treatment related among patients in the HGB-205 study.

“[Although] these gene therapy trials were the largest for thalassemia to date, we need to evaluate effectiveness in a much larger population,” Thompson said in the release.

Beta-thalassemia serves as one of the first examples of how gene therapy can be applied to a large population of patients who largely reside in developing countries, Alessandra Biffi, MD, director of the gene therapy program at Dana-Farber Cancer Institute, wrote in a related editorial.

“These results are of great importance considering the widespread prevalence of the betaE/beta0 genotype and the major effect of reducing the transfusion needs of patients with beta0/beta0 genotype on their overall quality of life and long-term prognosis,” Biffi wrote. “Large-scale feasibility and cost management of this potentially curative treatment, as well as of the other gene therapies being developed for beta-thalassemia, present excited challenges for the gene therapy community.”

Important determinants of benefit for researchers to consider when studying a wider population in the future include sufficient autologous hematopoietic stem cells and high-quality clinical-grade vector, and manufacturing capability for transduced cells, Biffi wrote. – by Melinda Stevens


Disclosure: Bluebird Bio funded this study. Please see the full study for a list of all authors’ relevant financial disclosures. Biffi reports no relevant financial disclosures.