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573 Restoring Iron Homeostasis in Pts Who Achieved Transfusion Independence after Treatment with Betibeglogene Autotemcel Gene Therapy: Results from up to 7 Years of Follow-up

Program: Oral and Poster Abstracts
Type: Oral
Session: 112. Thalassemia and Globin Gene Regulation
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Adults, Hematopoiesis, Clinical Research, Thalassemia, Hemoglobinopathies, Diseases, Gene Therapy, Pediatric, Therapies, Biological Processes, Young Adults, Study Population
Monday, December 13, 2021: 11:00 AM

Alexis A. Thompson, MD, MPH1,2, Franco Locatelli, MD, PhD3, Evangelia Yannaki, MD4*, Mark C. Walters, MD5, John B. Porter, MD, FRCP, FRCPath6*, Suradej Hongeng, MD7, Andreas E. Kulozik, MD, PhD8*, Martin G. Sauer, MD9, Adrian J. Thrasher, MBBS, PhD, FMedSci10*, Isabelle Thuret, MD11*, Ashutosh Lal, MD5, Marina Cavazzana, MD, PhD12,13,14, John E.J. Rasko, BSc (Med), MBBS (Hons), PhD, MAICD, FFSc (RCPA), FRCPA, FRACP, FAHMS15,16,17*, Lin Du18*, Richard A. Colvin, MD, PhD18* and Janet L. Kwiatkowski, MD, MSCE19,20

1Hematology Section, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
2Department of Pediatrics (Hematology, Oncology, and Stem Cell Transplantation), Northwestern University, Feinberg School of Medicine, Chicago, IL
3Department of Hematology/Oncology, IRCCS Bambino Gesù Children’s Hospital, Sapienza, University of Rome, Rome, Italy
4Gene and Cell Therapy Center, Hematology-HCT Unit, G. Papanikolaou Hospital, Thessaloniki, Greece
5Division of Hematology, UCSF Benioff Children's Hospital Oakland, Oakland, CA
6Haematology Department, University College London Hospitals, London, United Kingdom
7Mahidol University, Ramathibodi Hospital, Bangkok, Thailand
8Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL), and Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany
9Department of Hematology and Oncology, Medizinische Hochschule Hannover, Hannover, Germany
10UCL Great Ormond Street Institute of Child Health, London, United Kingdom
11Pediatric Hematology, Hôpital de la Timone, Marseille, France
12Biotherapy Department and Clinical Investigation Center, Assistance Publique Hopitaux de Paris, Inserm, Paris, France
13Université de Paris, Paris, France
14University of Paris, Imagine Institute, Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France
15The University of Sydney, Sydney, Australia
16Centenary Institute, Camperdown, Australia
17Royal Prince Alfred Hospital, Camperdown, Australia
18bluebird bio, Inc., Cambridge, MA
19Division of Hematology, Children's Hospital of Philadephia, Philadelphia, PA
20Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA

Introduction: Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease requiring lifelong, regular packed red blood cell (pRBC) transfusions and iron chelation treatment. Betibeglogene autotemcel (beti-cel) is a one-time ex vivo gene therapy that addresses the underlying cause of TDT to potentially enable lifelong, stable production of modified adult hemoglobin (Hb) sufficient to achieve transfusion independence (TI). Patients (pts) with TDT (N=63) were treated with beti-cel in 2 completed phase 1/2 studies (HGB-204, HGB-205) and 2 ongoing phase 3 studies (HGB-207, HGB-212). After 2 y of follow-up, pts could enroll in a long-term follow-up study (LTF-303 [NCT02633943]) for up to an additional 13 y. We report results from LTF-303 in pts with up to 7 y of follow-up.

Methods: Pts underwent single-agent, pharmacokinetic-adjusted busulfan myeloablation and were infused with autologous CD34+ cells transduced with BB305 lentiviral vector. The phase 3 studies used a refined transduction process compared with the phase 1/2 studies. LTF-303 assessments included transfusion status, Hb, iron overload, and safety. Around the time of beti-cel infusion, pts stopped iron chelation; however, chelation could be resumed post-infusion at the physician’s discretion. A subanalysis was conducted to assess iron status in pts who restarted then stopped chelation. Pts who achieved TI and had a minimum of 9 mo of follow-up after discontinuation of chelation were included in the subanalysis to assess iron parameters while off chelation. Data are reported as median (min–max) unless otherwise stated.

Results: As of March 9, 2021, LTF-303 enrolled 51 pts (phase 1/2: 22 pts; phase 3: 29 pts), of which 55% were female; the median age was 19 (7–35) y. Post-infusion follow-up was 44.2 (22.9–86.5 mo; 1 pt had their Month 24 visit at 22.9 mo). TI (weighted average Hb ≥9 g/dL without pRBC transfusions for ≥12 mo) was achieved in 15/22 (68%) pts treated in the phase 1/2 studies and in 25/29 (86%) pts treated in the phase 3 studies (all during parent study); at last follow-up, all pts had remained TI for 32.2 (13.1–84.1) mo. Median (Q1, Q3) gene therapy–derived Hb (HbAT87Q) in pts treated in the phase 1/2 studies who achieved TI was stable over time: 7.3 (5.4–8.4) g/dL at Month 24 (n=15) and 7.6 (6.6–9.3) g/dL at Month 72 (n=7). Median (Q1, Q3) HbAT87Q in pts treated in the phase 3 studies was also stable: 9.1 (8.5–10.3) g/dL at Month 24 (n=24) and 9.9 (9.8–10.0) g/dL at Month 42 (n=2). HbAT87Q helped to sustain total Hb. Total Hb was a median (Q1, Q3) of 10.0 (9.7–11.8) g/dL at Month 24 and 10.5 (10.3–12.1) g/dL at Month 72 in phase 1/2 studies and 12.1 (10.8–13.1) g/dL at Month 24 and 12.2 (11.7–12.8) g/dL at Month 42 in phase 3 studies.

Pts who achieved TI (n=40) experienced reductions in iron burden over time; all pts had normal cardiac T2* levels at last follow-up and liver iron concentration (LIC) and serum ferritin were positively and strongly correlated at Months 24, 36, and 48 (Table). The subanalysis showed iron reduction in response to chelation and stabilization of iron markers after chelation was discontinued (Figure). Of the 15 pts who achieved TI in phase 1/2 studies, 10 (67%) restarted and then stopped iron chelation 25 (12–56) mo after beti-cel infusion; the 5 remaining pts continued on chelation. Of the 25 pts who achieved TI in phase 3 studies, 18 (72%) stopped iron chelation 29 (6–47) mo after beti-cel infusion; 11 (44%) pts never restarted and 7 (28%) restarted and then stopped again. Two pts in the subanalysis treated in a phase 1/2 study also received phlebotomy for approximately 20 and 56 mo post-infusion.

Serious AEs occurring after 2 y in LTF-303 were reported in 8 pts (diabetic ketoacidosis, gonadotropic insufficiency, ectopic pregnancy, fetal death, cholelithiasis, gallbladder wall thickening/polyp, bacteremia with neutropenia, pulmonary embolism, and major depression; each n=1). No beti-cel–related AEs were observed beyond 2 y post-infusion. No deaths, replication-competent lentivirus, insertional oncogenesis, or malignancies were reported. Insertion site analysis indicated sustained polyclonal hematopoiesis.

Conclusions: Beti-cel is a potentially curative gene therapy for pts with TDT through the ability to achieve TI with near-normal Hb levels. Sustained levels of HbAT87Q and effective restoration of iron homeostasis over time reduced iron management burden in pts treated with beti-cel.

Disclosures: Thompson: Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Global Blood Therapeutics: Current equity holder in publicly-traded company. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Yannaki: Novartis: Speakers Bureau; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; SANDOZ: Speakers Bureau; Gilead: Speakers Bureau. Walters: Vertex pharmaceuticals: Consultancy; Ensoma, Inc.: Consultancy; BioLabs, Inc: Consultancy; AllCells, Inc: Consultancy. Porter: Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kulozik: Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioMedX: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thuret: Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board. Lal: Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Insight Magnetics: Research Funding; Chiesi: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio, Inc.: Research Funding; Agios Pharmaceuticals: Consultancy; Terumo Corporations: Research Funding; Novartis: Research Funding; La Jolla Pharmaceutical Company: Research Funding. Cavazzana: Smart Immune: Other: co-founder. Rasko: Australian Government: Membership on an entity's Board of Directors or advisory committees; Cynata: Honoraria, Speakers Bureau; Genea: Current equity holder in publicly-traded company; Cure the Future Foundation: Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Gene Technology Technical Advisory Board: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Speakers Bureau; NHMRC Mitochondrial Donation Expert Working Committee: Membership on an entity's Board of Directors or advisory committees; Australian Cancer Research: Membership on an entity's Board of Directors or advisory committees; FSHD Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer Inc: Honoraria, Speakers Bureau; Glaxo-Smith-Kline: Honoraria, Speakers Bureau; Spark: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; bluebird bio: Honoraria, Speakers Bureau. Du: bluebird bio, Inc.: Current Employment, Other: bluebird bio, Inc.: Employee, Ownership Interest and Salary. Colvin: bluebird bio, Inc.: Current Employment, Other: Employee, Ownership Interest and Salary. Kwiatkowski: Agios: Consultancy; Bioverativ: Research Funding; Imara: Consultancy, Research Funding; bluebird bio,Inc.: Consultancy, Research Funding; Sangamo: Research Funding; Silence Therapeutics: Consultancy; Bristol Myers Squibb: Consultancy; Apopharma: Research Funding; Celgene: Consultancy.

*signifies non-member of ASH