CLINICAL OUTCOMES OF LENTIGLOBIN GENE THERAPY FOR TRANSFUSION-DEPENDENT Β-THALASSAEMIA (TDT) FOLLOWING COMPLETION OF THE NORTHSTAR (HGB-204) STUDY
Author(s): ,
Mark C. Walters
Affiliations:
UCSF Benioff Children's Hospital,Oakland,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
,
John E. J. Rasko
Affiliations:
Royal Prince Alfred Hospital,Camperdown,Australia;Sydney Medical School,University of Sydney,Camperdown,Australia;Gene and Stem Cell Therapy Program,Centenary Institute,Camperdown,Australia
,
Suradej Hongeng
Affiliations:
Ramathibodi Hospital,Mahidol University,Bangkok,Thailand
,
Gary J. Schiller
Affiliations:
Hematology-Oncology,David Geffen School of Medicine at UCLA Medicine,Los Angeles,United States
,
Usanarat Anurathapan
Affiliations:
Ramathibodi Hospital,Mahidol University,Bangkok,Thailand
,
Marina Cavazzana
Affiliations:
Biotherapy Department,Hopital Necker - Enfants Malades,Paris,France;IMAGINE Institute,Université Paris Descartes,Paris,France;Biotherapy Clinical Investigation Center,Groupe Hospitalier Universitaire Ouest,Paris,France
,
P. Joy Ho
Affiliations:
Royal Prince Alfred Hospital,Camperdown,Australia;Sydney Medical School,University of Sydney,Camperdown,Australia
,
Manfred Schmidt
Affiliations:
GeneWerk GmbH,Heidelberg,Germany
,
Morris Kletzel
Affiliations:
Ann and Robert H. Lurie Children’s Hospital of Chicago,Chicago,United States;Northwestern University Feinberg School of Medicine,Chicago,United States
,
Philippe Leboulch
Affiliations:
Ramathibodi Hospital,Mahidol University,Bangkok,Thailand;Brigham & Women’s Hospital and Harvard Medical School,Boston,United States;Institute of Emerging Diseases and Innovative Therapies (iMETI),CEA, INSERM, Université Paris-Sud,Paris,France
,
Elliott Vichinsky
Affiliations:
UCSF Benioff Children's Hospital,Oakland,United States
,
Briana Deary
Affiliations:
bluebird bio, Inc.,Cambridge,United States
,
Ying Chen
Affiliations:
bluebird bio, Inc.,Cambridge,United States
,
Alexandria Petrusich
Affiliations:
bluebird bio, Inc.,Cambridge,United States
Alexis A. Thompson
Affiliations:
Ann and Robert H. Lurie Children’s Hospital of Chicago,Chicago,United States;Northwestern University Feinberg School of Medicine,Chicago,United States
EHA Library. C. Walters M. Jun 14, 2019; 267342; S141
Mark C. Walters
Mark C. Walters
Contributions
×
Abstract

Abstract: S141

Type: Oral Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 11:45 - 12:00

Location: Hall E106

Background
While regular red blood cell (RBC) transfusions extend the lifespan of patients with transfusion-dependent β-thalassaemia (TDT), iron overload and end-organ damage can result. The curative alternate, allogeneic haematopoietic stem cell (HSC) transplantation, is limited by donor availability and transplant-related risks. LentiGlobin gene therapy in TDT is under investigation as a treatment option that may overcome some of these limitations. LentiGlobin gene therapy contains autologous CD34+ cells transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β-globin with a T87Q substitution.

Aims
To evaluate the safety and efficacy of LentiGlobin gene therapy in adolescents and adults with TDT (≥ 100 mL/kg/yr of RBCs or ≥ 8 RBC transfusions/yr) in the phase 1/2 Northstar study (NCT01745120).

Methods

HSCs were mobilised with G-CSF and plerixafor and enriched CD34+ cells were transduced with the BB305 LVV. Patients received myeloablative busulfan, after which transduced HSCs were infused. Primary efficacy endpoints were sustained production of ≥ 2 g/dL of gene therapy-derived haemoglobin (Hb), HbAT87Q, between months 18-24 and transfusion independence (TI; weighted average Hb ≥ 9 g/dL without RBC transfusions for ≥ 12 months). Patients were monitored for 2 years and offered participation in the long-term follow-up study, LTF-303.

Results
Eighteen patients with TDT (median age 20 [min-max: 12-35] years) were treated in Northstar. As of 14 September 2018, median follow-up was 38.9 (29.3-48.1) months. Median time to neutrophil and platelet engraftment was 18.5 (14-30) and 39.5 (19-191) days, respectively. There was no graft failure. Grade ≥ 3 non-haematologic adverse events (AEs) in ≥ 25% of patients were stomatitis, febrile neutropenia, and pharyngeal inflammation. Serious AEs reported in ≥ 2 patients were thrombosis (n=2) and liver veno-occlusive disease (n=2), all of which resolved. The vector integration site profile in all patients remains polyclonal.

Sixteen of 18 (89%) patients met the primary endpoint of sustained production of ≥ 2 g/dL of HbAT87Q from months 18-24. Eight of 10 (80%) patients with non-β00 genotypes achieved transfusion independence with a median weighted average Hb during TI of 10.2 (min-max: 9.3-13.2 g/dL). TI has been maintained for a median of 38 (min-max: 21- 44) months. The median time to last RBC transfusion after LentiGlobin infusion was 2.0 (min-max: 0.3-5.8) months. In the 8 patients who achieved TI, median (min-max) total Hb, RBC counts, and mean corpuscular volume (MCV) were 10.8 (9.7-14.1) g/dL, 4.1 (2.8-5.8) x1012/L, and 83.0 (74.2-108.6) fL at last study visit.

Of 8 patients with β00 genotypes, 3 (38%) achieved TI for 16-21 months during any interval post-infusion. Median time to last RBC transfusion was 19.4 (min-max: 1.8-19.8) months. At last study visit, median (min-max) total Hb, RBC counts, and MCV in these 3 patients were 10.3 (9.1-10.9) g/dL, 4.2 (3.4-4.4) x1012/L, and 82.8 (78.3-83.8) fL.

Liver iron concentration as measured by magnetic resonance imaging in patients who achieved TI is shown in Figure 1. Patients re-initiated iron chelation therapy at a median of 13 (min-max: 2-16) months after infusion.

Conclusion
With up to 4 years of follow-up, we observed durable transfusion independence in 8/10 and 3/8 patients with non-β00 genotypes and β00 genotypes, respectively, and a safety profile that is consistent with myeloablative conditioning. Two ongoing Phase 3 studies, Northstar-2 and Northstar-3, are evaluating refined manufacturing of LentiGlobin with the goal to improve patient outcomes.

Session topic: 27. Thalassemias

Keyword(s): Autologous hematopoietic stem cell transplantation, Beta thalassemia, Gene therapy

By continuing to browse or by clicking “Accept Terms & all Cookies”, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies