OUTCOMES IN PATIENTS TREATED WITH LENTIGLOBIN FOR SICKLE CELL DISEASE (SCD) GENE THERAPY: UPDATED RESULTS FROM THE PHASE 1/2 HGB-206 GROUP C STUDY
Author(s): ,
Julie Kanter
Affiliations:
Division of Hematology & Oncology,University of Alabama at Birmingham,Birmingham,United States
,
John F. Tisdale
Affiliations:
Sickle Cell Branch, NHLBI/NIDDK,National Institutes of Health,Bethesda,United States
,
Markus Y. Mapara
Affiliations:
Adult Blood and Marrow Transplantation Program,Columbia University Medical Center,New York,United States
,
Janet L. Kwiatkowski
Affiliations:
Division of Hematology,Children's Hospital of Philadelphia,Philadelphia,United States; Department of Pediatrics,Perelman School of Medicine, University of Pennsylvania,Philadelphia,United States
,
Lakshmanan Krishnamurti
Affiliations:
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University,Atlanta,United States
,
Manfred Schmidt
Affiliations:
GeneWerk GmbH,Heidelberg,Germany
,
Melissa Bonner
Affiliations:
bluebird bio, Inc.,Cambridge,United States
,
Francis J. Pierciey, Jr.
Affiliations:
bluebird bio, Inc.,Cambridge,United States
,
Wenmei Huang
Affiliations:
bluebird bio, Inc.,Cambridge,United States
,
Jean-Antoine Ribeil
Affiliations:
bluebird bio, Inc.,Cambridge,United States
,
Alexis A. Thompson
Affiliations:
Hematology Section,Ann & Robert H. Lurie Children's Hospital of Chicago,Chicago,United States;Department of Pediatrics,Northwestern University, Feinberg School of Medicine,Chicago,United States
Mark C. Walters
Affiliations:
Division of Hematology/Oncology,UCSF Benioff Children's Hospital,Oakland,United States
EHA Library. Kanter J. 06/12/20; 295102; S282
Julie Kanter
Julie Kanter
Contributions
Abstract

Abstract: S282

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Immunotherapy - Clinical

Background
The ongoing Phase 1/2 HGB-206 Study (NCT02140554) is evaluating the safety and efficacy of LentiGlobin for SCD gene therapy, which contains autologous CD34+ cells transduced with BB305 lentiviral vector (LVV), encoding a human β-globin gene with the anti-sickling T87Q substitution (βA-T87Q). An initial 7 patients (Group A) were treated with LentiGlobin produced using bone marrow–harvested hematopoietic stem cells (HSCs). The protocol was then modified by including pre-harvest red blood cell (RBC) transfusions, increasing the total busulfan exposure, and using a refined LentiGlobin manufacturing process (Group B, n=2). Next, HSC collection via plerixafor mobilization/apheresis was instituted (Group C). Group C data are discussed here.

Aims
Update safety and efficacy data for LentiGlobin in adolescent and adult HGB-206 Group C patients.

Methods
Patients (≥12 and ≤50 years) with SCD and severe vaso-occlusive events, including acute episodes of pain and acute chest syndrome (ACS), were enrolled. CD34+ cells collected by plerixafor mobilization/apheresis were transduced with BB305 LVV. LentiGlobin was infused following myeloablative busulfan conditioning. Patients were monitored for adverse events (AEs), laboratory parameters, and SCD manifestations. Data are shown as median (min–max).

Results
As of 26 August 2019, 30 Group C patients (25 [12–38] years old) had initiated cell collection. Seventeen patients were treated with LentiGlobin with a follow-up of 10.9 (0.9–20.7) months; neutrophil and platelet engraftment were achieved at 20 (15–26) days and 28 (17–136) days, respectively.

All patients stopped red blood cell (RBC) transfusions within 90 days post-treatment. In 12 patients with ≥6 months of follow-up, median HbS was ≤60% of total Hb; total Hb at last visit was 11.2 (9.3–15.2) g/dL, with HbAT87Q contribution of 5.0 (2.7–9.0) g/dL and HbS of 5.8 (5.1–7.3) g/dL. At last visit, ≥70% of RBCs from these 12 patients contained βA-T87Q. In 9 patients with ≥6 months of follow-up and a history of vaso-occlusive crisis (VOCs) or ACS, the annualized ACS+VOC rate was 4.0 (2.0–14.0) in the 2 years prior to treatment. One non-serious Grade 2 VOC occurred ~3.5 months after LentiGlobin infusion, resulting in a 99% (95% confidence interval, 92.5–99%) reduction in the annualized VOC+ACS rate post-treatment (Figure 1); no ACS or serious VOCs were observed in these patients post-treatment. At last visit post-treatment, lactate dehydrogenase was 213 (180–362) U/L, reticulocyte count was 167 (45–352) ×109/L, and total bilirubin was 22 (5–38) µmol/L (all for n=17); these hemolysis markers were reduced compared to baseline by a median of 41% (n=16), 43% (n=17), and 58% (n=17), respectively, and trending toward normalization.

The most common non-hematologic Grade ≥3 AEs post-treatment were febrile neutropenia (n=10) and stomatitis (n=9). Serious AEs reported in ≥2 patients post-treatment were nausea and vomiting. As of the data cutoff, there have been no events of LentiGlobin-related AEs or graft failure, vector-mediated replication-competent lentivirus, or clonal dominance. 

Conclusion
The safety profile of LentiGlobin for SCD gene therapy remains consistent with single-agent busulfan conditioning and underlying SCD. At ≥6 months post-treatment, HGB-206 Group C patients maintained median total Hb at ≥10 g/dL with stable, nearly pancellular, HbAT87Q expression and reduction of median HbS contribution to ≤60%. Absence of ACS and serious VOCs, and reduction in hemolysis suggest suppression of sickle-related complications. Longer follow-up and data on additional patients will be presented.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): Autologous hematopoietic stem cell transplantation, Gene therapy, Sickle cell disease

Abstract: S282

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Immunotherapy - Clinical

Background
The ongoing Phase 1/2 HGB-206 Study (NCT02140554) is evaluating the safety and efficacy of LentiGlobin for SCD gene therapy, which contains autologous CD34+ cells transduced with BB305 lentiviral vector (LVV), encoding a human β-globin gene with the anti-sickling T87Q substitution (βA-T87Q). An initial 7 patients (Group A) were treated with LentiGlobin produced using bone marrow–harvested hematopoietic stem cells (HSCs). The protocol was then modified by including pre-harvest red blood cell (RBC) transfusions, increasing the total busulfan exposure, and using a refined LentiGlobin manufacturing process (Group B, n=2). Next, HSC collection via plerixafor mobilization/apheresis was instituted (Group C). Group C data are discussed here.

Aims
Update safety and efficacy data for LentiGlobin in adolescent and adult HGB-206 Group C patients.

Methods
Patients (≥12 and ≤50 years) with SCD and severe vaso-occlusive events, including acute episodes of pain and acute chest syndrome (ACS), were enrolled. CD34+ cells collected by plerixafor mobilization/apheresis were transduced with BB305 LVV. LentiGlobin was infused following myeloablative busulfan conditioning. Patients were monitored for adverse events (AEs), laboratory parameters, and SCD manifestations. Data are shown as median (min–max).

Results
As of 26 August 2019, 30 Group C patients (25 [12–38] years old) had initiated cell collection. Seventeen patients were treated with LentiGlobin with a follow-up of 10.9 (0.9–20.7) months; neutrophil and platelet engraftment were achieved at 20 (15–26) days and 28 (17–136) days, respectively.

All patients stopped red blood cell (RBC) transfusions within 90 days post-treatment. In 12 patients with ≥6 months of follow-up, median HbS was ≤60% of total Hb; total Hb at last visit was 11.2 (9.3–15.2) g/dL, with HbAT87Q contribution of 5.0 (2.7–9.0) g/dL and HbS of 5.8 (5.1–7.3) g/dL. At last visit, ≥70% of RBCs from these 12 patients contained βA-T87Q. In 9 patients with ≥6 months of follow-up and a history of vaso-occlusive crisis (VOCs) or ACS, the annualized ACS+VOC rate was 4.0 (2.0–14.0) in the 2 years prior to treatment. One non-serious Grade 2 VOC occurred ~3.5 months after LentiGlobin infusion, resulting in a 99% (95% confidence interval, 92.5–99%) reduction in the annualized VOC+ACS rate post-treatment (Figure 1); no ACS or serious VOCs were observed in these patients post-treatment. At last visit post-treatment, lactate dehydrogenase was 213 (180–362) U/L, reticulocyte count was 167 (45–352) ×109/L, and total bilirubin was 22 (5–38) µmol/L (all for n=17); these hemolysis markers were reduced compared to baseline by a median of 41% (n=16), 43% (n=17), and 58% (n=17), respectively, and trending toward normalization.

The most common non-hematologic Grade ≥3 AEs post-treatment were febrile neutropenia (n=10) and stomatitis (n=9). Serious AEs reported in ≥2 patients post-treatment were nausea and vomiting. As of the data cutoff, there have been no events of LentiGlobin-related AEs or graft failure, vector-mediated replication-competent lentivirus, or clonal dominance. 

Conclusion
The safety profile of LentiGlobin for SCD gene therapy remains consistent with single-agent busulfan conditioning and underlying SCD. At ≥6 months post-treatment, HGB-206 Group C patients maintained median total Hb at ≥10 g/dL with stable, nearly pancellular, HbAT87Q expression and reduction of median HbS contribution to ≤60%. Absence of ACS and serious VOCs, and reduction in hemolysis suggest suppression of sickle-related complications. Longer follow-up and data on additional patients will be presented.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): Autologous hematopoietic stem cell transplantation, Gene therapy, Sickle cell disease

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