UPDATE ON THE FIRST PATIENTS WITH SEVERE HEMOGLOBINOPATHIES TREATED WITH LENTIGLOBIN GENE THERAPY
Author(s): ,
Jean-Antoine Ribeil
Affiliations:
Necker Hospital,Paris,France
,
Salima Hacein-Bey-Abina
Affiliations:
Necker Hospital,Paris,France
,
Emmanuel Payen
Affiliations:
Institute of Emerging Diseases and Innovative Therapies (iMETI),CEA & University of Paris-Sud,Fontenay-aux-Roses,France
,
Elisa Magrin
Affiliations:
Necker Hospital,Paris,France
,
Alessandra Magnani
Affiliations:
Necker Hospital,Paris,France
,
Michaela Semeraro
Affiliations:
Université Paris Descartes,Paris,France
,
Laure Caccavelli
Affiliations:
Necker Hospital,Paris,France
,
Fabien Touzot
Affiliations:
Necker Hospital,Paris,France
,
Francois Lefrere
Affiliations:
Necker Hospital,Paris,France
,
Felipe Suarez
Affiliations:
Necker Hospital,Paris,France
,
Olivier Hermine
Affiliations:
Necker Hospital,Paris,France
,
Valentine Brousse
Affiliations:
Necker Hospital,Paris,France
,
Catherine Poirot
Affiliations:
Hôpital Saint Louis,Paris,France
,
Despina Moshous
Affiliations:
Necker Hospital,Paris,France
,
Philippe Bourget
Affiliations:
Necker Hospital,Paris,France
,
Wassim El-Nemer
Affiliations:
Université Paris Diderot,Paris,France
,
Pablo Bartolucci
Affiliations:
Hôpital Henri Mondor,Paris,France
,
Leslie Weber
Affiliations:
Université Paris Descartes,Paris,France
,
Herve Puy
Affiliations:
Hôpital Henri Mondor,Paris,France
,
Jean-Francois Meritet
Affiliations:
Hôpital Cochin Saint Vincent de Paul,Paris,France
,
David Grevent
Affiliations:
Necker Hospital,Paris,France
,
Yves Buezard
Affiliations:
Institute of Emerging Diseases and Innovative Therapies (iMETI),CEA & University of Paris-Sud,Fontenay-aux-Roses,France
,
Stany Chretien
Affiliations:
Institute of Emerging Diseases and Innovative Therapies (iMETI),CEA & University of Paris-Sud,Fontenay-aux-Roses,France
,
Thibaud Lefebvre
Affiliations:
Université Paris Diderot,Paris,France
,
Mohammed Asmal
Affiliations:
bluebird bio,Cambridge,United States
,
Laura Sandler
Affiliations:
bluebird bio,Cambridge,United States
,
Mariane de Montalembert
Affiliations:
Necker Hospital,Paris,France
,
Stephane Blanche
Affiliations:
Necker Hospital,Paris,France
,
Philippe Leboulch
Affiliations:
Institute of Emerging Diseases and Innovative Therapies (iMETI),CEA & University of Paris-Sud,Fontenay-aux-Roses,France
Marina Cavazzana
Affiliations:
Necker Hospital,Paris,France
(Abstract release date: May 18, 2017) EHA Learning Center. Cavazzana M. Jun 24, 2017; 181918
Marina Cavazzana
Marina Cavazzana

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Abstract
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Abstract: P631

Type: Poster Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 17:30 - 19:00

Location: Poster area (Hall 7)

Background
Insertion of an anti-sickling β-globin gene variant into hematopoietic stem cells (HSCs) could reduce or eliminate symptoms of severe sickle cell disease (SCD) and transfusion requirements in transfusion-dependent β-thalassemia (TDT). LentiGlobin Drug Product (DP) contains autologous CD34+ cells transduced with the BB305 lentiviral vector, which encodes a human β-globin gene containing a single point mutation (AT87Q) designed to confer anti-sickling properties similar to γ-globin. We recently (ASH 2016) reported 23 months of follow-up for a patient with SCD, and 12−34 months of follow-up for 4 patients with TDT.

Aims
To evaluate the safety and efficacy of LentiGlobin gene therapy for severe hemoglobinopathies. 

Methods
Patients 5−35 years old with severe SCD (e.g., ≥2 acute chest syndrome episodes or ≥2 vaso-occlusive crises [VOC] in the preceding year) or TDT (≥100 mL/kg of packed red blood cells [RBCs] per year) were enrolled. After informed consent, autologous CD34+ cells were collected and transduced with the BB305 vector. Patients underwent myeloablative conditioning with busulfan prior to infusion of transduced cells. Patients were then monitored for hematologic engraftment, vector copy number (VCN), genetically engineered hemoglobin (HbAT87Q) levels, and adverse events (AEs). Disease-specific assessments included transfusion requirements for TDT, or VOCs and hospitalizations for SCD.

Results
As of 9 September 2016, 1 patient with severe SCD (male; 13 years old) and 4 patients with TDT (2 male, 2 female; 16−19 years old) have received LentiGlobin DP in Study HGB-205. The median DP cell dose was 8.9 (range 5.6−13.6) x106 CD34+ cells/kg with a DP VCN of 1.2 (range 0.8−2.1) vector copies/diploid genome. Median post-infusion follow-up was 22.9 months (range 11.6−33.5). All subjects engrafted successfully with median time to neutrophil engraftment of 17 (range 14−38) days. Within patients, VCN in peripheral blood remained generally consistent from Month 3 (range 0.3−3.3 at last measurement). The toxicity profile was consistent with myeloablative conditioning with single-agent busulfan, with no ≥Grade 3 DP-related AEs or serious AEs and no evidence of clonal dominance reported to date.

The patient with severe SCD who, prior to study enrollment, received regular RBC transfusions, experienced no clinical symptoms or complications of SCD in the 21 months since treatment. At Month 21, his total Hb was 13.1 g/dL, with 6.2 g/dL HbAT87Q (48%) and 6.5 g/dL sickle Hb (HbS: 50%); in addition, their unconjugated bilirubin, lactate dehydrogenase and reticulocyte count had dropped by 56%, 58%, 26%, respectively, compared to screening.
Of the 4 patients with TDT, 3 have β0E genotypes and 1 is homozygous for a severe β+ mutation (IVS1 nt 110 G>A). Two of the β0E patients have completed their 2-year primary follow-up and entered a long-term follow-up study. They have been without RBC transfusions for 33 and 30 months, with total Hb of 10.9 and 13.5 g/dL, and HbAT87Q of 7.7 and 10.1 g/dL, respectively. The third patient with a β0E genotype has 12 months follow-up and has not required transfusions since 4 days post-LentiGlobin DP infusion, with total Hb 11.3 g/dL and HbAT87Q of 8.6 g/dL. The patient with the IVS1 genotype has 15 months of follow-up and has been free of transfusions for 11.6 months, with total Hb 8.3 g/dL and HbAT87Q of 6.7 g/dL.
Since September 2016, 2 more patients with severe SCD have received LentiGlobin DP. 

Conclusion
Data to date from this ongoing Phase 1/2 clinical study suggest that treatment with LentiGlobin DP elicits sustained HbAT87Q levels, which alleviate the clinical and biochemical effects of severe SCD and TDT, with safety consistent with myeloablative conditioning. Follow-up data on the 5 previously reported patients and early results from the 2 recently treated patients will be presented.

Session topic: 24. Gene therapy, cellular immunotherapy and vaccination

Keyword(s): Gene therapy, Beta thalassemia, sickle cell disease, Globin gene

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