Gene therapy reduces transfusion dependence in patients with beta-thalassemia major

Issue: January 10, 2016

ORLANDO, Fla. — The infusion of a lentiviral vector containing an engineered beta^A-T87Q-globin gene effectively reduced or eliminated the transfusion needs of patients with beta-thalassemia major without leading to severe adverse events, according to updated results from the Northstar Study presented at the ASH Annual Meeting and Exposition.

“Beta-thalassemia major is a hereditary disease that causes a defect in making hemoglobin,” Mark C. Walters, MD, program director for blood and marrow transplantation and the cord blood program at University of California, San Francisco’s Benioff Children’s Hospital in Oakland, California, said during a press conference. “These individuals are generally diagnosed in the first year of life, and need to start red blood cell transfusions for this disorder. These transfusions are lifelong and administered monthly, but they contain more iron than can be eliminated naturally, so patients must also receive a medicine to leech excess iron from the body.”

Researchers developed the gene therapy drug product, LentiGlobin BB305 (Bluebird Bio), which uses a non-communicable virus to deliver a fully functioning HBB gene to the patient’s blood-producing stem cells. Earlier reports from the Northstar study indicated the therapy exhibited a favorable safety profile and lead to beta^A-T87Q-globin production in patients.

The analysis included 13 patients (women, n = 11; median age, 21 years; range, 16-35) with transfusion-dependent beta-thalassemia, including five patients with the beta⁰/beta⁰ genotype, three with the beta⁰/beta^E genotype, one with the beta⁰/beta⁺ genotype, and one with the heterozygous beta⁰genotype. Prior to the analysis, the patients had received a median of 170 mL/kg (range, 137-233) a year of transfused red blood cells.

The researchers mobilized hematopoietic stem cells from the patients using granulocyte colony–stimulating factor (G-CSF) and plerixafor (Mobozil, Genzyme). Researchers then selected CD34-positive cells and transduced them with LentiGlobin BB305 lentiviral vector to create the drug product.

Prior to infusion, the patients underwent myeloablation with busulfan.

The patients received a median of 8.1 x 10⁶CD34-positive cells/kg (range, 5.2 to 14 x 10⁶/kg) with a median vector copy number of 0.7 (range, 0.3-1.5 copies/diploid genome).

The researchers then monitored patients for hematologic recovery, vector copy number, beta^A-T87Q-globin expression, adverse events and transfusion requirements following infusion.

All patients engrafted following infusion, with a median time to engraftment of 17 days for neutrophils (range, 13-29) and 30 days for platelets (range, 17-35).

Researchers noted the safety profile on the trial appeared consistent with that of autologous stem cell transplantation. After a median follow-up of 198 days (range, 65-492), no grade 3 or higher adverse events have occurred, and there has been no evidence of clonal dominance post-infusion.

Further, all patients have detectable vector-derived hemoglobin A^T87Q, with a median peak level of 5.4 g/dL (range, 2.4-8.9) at 3 months or longer post-infusion.

Seven patients (beta⁰/beta⁰, n = 3; beta⁰/beta^E, n = 3; beta⁰/beta⁺, n = 1; heterozygous beta⁰, n = 1) have been monitored for at least 6 months post-infusion. These patients produced a median hemoglobin A^T87Q of 5.2 g/dL (range, 1.9-8.2), with total hemoglobin ranging from 8.5 g/dL to 11.1 g/dL at their most recent visit.

One of these seven patients (beta⁰/beta⁰ genotype) remains transfusion dependent and two patients (beta⁰/beta⁰) have received a single red blood cell transfusion. The other four patients have remained transfusion-free for more than 90 days (median transfusion independence, 287 days; range, 171-396).

“All patients enrolled in the trial experienced a clinical benefit, and in some cases, their transfusions have stopped,” Walters said. “This appears to be a safe treatment, in that all patients recovered completely after infusion. To date, these analyses show no evidence of activation of the cancer-causing gene in the stem cells infused.”

Walters stated that these findings represent a significant advance in the treatment of beta-thalassemia.

“Compared with a bone marrow transplant, which is the only curative treatment that has been proved, this appears to be safer,” Walters said. “None of these patients have had a life-threatening complication. Because the treatment uses the patients’ own stem cells, this bypasses the need to find a healthy bone marrow donor. Thus, it should be more broadly available to patients with this disease.” – by Cameron Kelsall

Reference:

Walters MC, et al. Abstract 201. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Disclosure: Walters reports a leadership position with ViaCord and All Cells Inc. Please see the abstract for a list of all other researchers’ relevant financial disclosures.