LentiGlobin gene therapy shows promise for severe sickle cell disease

ORLANDO — LentiGlobin gene therapy led to substantial reductions of sickle hemoglobin and considerable improvement in key markers of hemolysis, according to updated results from the phase 1/phase 2 HGB-206 study presented at TCT | Transplantation & Cellular Therapy Meetings.

The safety profile of the investigational gene therapy appeared consistent with that of myeloablative single-agent busulfan conditioning. Researchers observed no cases of acute chest syndrome or serious vaso-occlusive crises among the cohort, and results also showed stable engraftment.

The open-label, multicenter HGB-206 study evaluated LentiGlobin (Bluebird Bio) for .

Mark C. Walters, MD, program director of the blood and marrow transplantation program and medical director of Jordan Family Center for BMT & Cellular Therapies Research at UCSF Benioff Children’s Hospital, presented data from Group C of the study.

The cohort included patients aged 12 to 50 years who had history of severe vaso-occlusive episodes and either failed on or were intolerant to hydroxyurea.

CD34-positive hematopoietic stem cells from mobilized peripheral blood were harvested by apheresis after plerixafor mobilization and transduced with BB305 lentiviral vector.

Patients underwent busulfan myeloablative conditioning, followed by LentiGlobin infusion via IV. Study protocol called for 2 years of follow-up, but patients were given the option to participate in a long-term 13-year follow-up study.

Key outcomes included weighted average of functional hemoglobin (anti-sickling HbA^T87Q) of at least 30% of total hemoglobin for at least 6 months after infusion, weighted average of total hemoglobin increase of at least 3 g/dL compared with baseline or total hemoglobin of at least 10 g/dL for 6 months or longer after infusion, and a 75% or greater reduction in severe vaso-occlusive episodes in the 24 months after infusion.

Researchers enrolled 49 patients. Thirty patients (median age, 25 years; range, 12-38; 18 males) underwent plerixafor mobilization and apheresis. All had the ^s/ ^s genotype. Twenty-five had history of vaso-occlusive crises (median per year, 4; range, 2-15), two had history of acute chest syndrome (median per year, 1; range, 1-1), six had history of stroke and four had elevated tricuspid regurgitant jet velocity.

Walters presented data from 17 patients who underwent LentiGlobin infusion.

Patients underwent a median two mobilization cycles (range, 1-4), with a median 10.3 x 10⁶ cells/kg (range, 3.9-55.4) CD34-positive cells collected per cycle.

The drug product had a median vector copy number of 3.6 (range, 2.3-5.6), which translated to 80% of hematopoietic stem cells transduced with the lentiviral vector. The cell dose achieved its target, with a median 6.3 x 10⁶ cells/kg infused (range, 3-14).

Median follow-up was 10.9 months (range, 0.9-20.7). Median time to neutrophil engraftment was 20 days (range, 15-26) and median time to platelet engraftment was 28 days (range, 17-136).

Median duration of hospitalization was 36 days (range, 30-65).

The most common grade 3 or higher nonhematologic events included febrile neutropenia (58.8%), stomatitis (52.9%) and increased blood bilirubin (17.6%). Investigators reported two cases (11.8% each) of upper abdominal pain, increased alanine aminotransferase, increased aspartate aminotransferase, nausea and premature menopause.

Seven patients (41%) experienced at least one serious adverse events. Researchers reported two cases each of nausea (11.8%) and vomiting (11.8%). However, none of these were related to the drug product, Walters said.

Researchers reported no vaso-occlusive liver disease, graft failure or death. In addition, no deaths, no vector-mediated replication-competent lentivirus and no evidence of clonal dominance were detected.

The percentages of lentiviral vector-positive colonies from peripheral blood mononuclear cells were 79.2% at 9 months and 81.5% at 12 months, suggesting stable engraftment of transduced cells.

An analysis of hemoglobin fractions at least 6 months after LentiGlobin treatment showed median hemoglobin S of 60% or less, and median anti-sickling HbA^T87Q levels of 40% or more. Among patients who had had least 6 months of follow-up, total hemoglobin ranged from 9.3 g/dL to 15.2 g/dL at their last visit, and total HbA^T87Q ranged from 2.7 g/dL to 9 g/dL.

Results also showed considerable improvement in key markers of hemolysis in the months after infusion. Reticulocyte counts, lactate dehydrogenase and total serum bilirubin all fell to near normal-levels, Walters said.

No acute chest syndrome or serious vaso-occlusive crises occurred during follow-up (reduction of annualized rate, 99%; 95% CI, 92.5-100). One patient developed a grade 2 vaso-occlusive crises approximately 3.5 months after infusion.

“Longer follow-up for durability and safety in this study, and data from additional studies, will help further assess the clinical impact of LentiGlobin for sickle cell disease,” Walters said. – by Mark Leiser

Reference: Walters MC, et al. Abstract 2. Presented at: TCT | Transplantation & Cellular Therapy Meetings; Feb. 19-23, 2020; Orlando.

Disclosures: Walters reports consultant roles with AllCells Inc., Editas and Trucode. Please see the abstract for all other authors’ relevant financial disclosures.