Session: 114. Hemoglobinopathies, Excluding Thalassemia—Clinical:Novel Treatments for Sickle Cell Disease
Hematology Disease Topics & Pathways:
sickle cell disease, Biological, Diseases, Therapies, Hemoglobinopathies, gene therapy
Sickle cell disease (SCD) is caused by abnormal sickle hemoglobin (HbS) and results in chronic hemolytic anemia, painful vaso-occlusive events (VOEs), and progressive vasculopathy that lead to significant morbidity. While acute vaso-occlusive pain is a defining clinical feature, chronic daily pain also contributes significantly to poor quality of life in many adult patients.
The ongoing Phase 1/2 HGB-206 Study (NCT02140554) evaluating safety and efficacy of LentiGlobin for SCD (bb1111) gene therapy (GT) uses a modified human β-globin gene that produces GT-derived anti-sickling hemoglobin (HbAT87Q). Data from Group C patients including red blood cell (RBC) physiology, clinical outcomes, and patient-reported pain intensity are presented here.
Patients (≥12 and ≤50 years) with SCD and stroke or severe VOEs, including acute episodes of pain and acute chest syndrome (ACS), were enrolled. CD34+ cells collected by plerixafor mobilization/apheresis were transduced with BB305 lentiviral vector. LentiGlobin was infused following myeloablative busulfan conditioning. Patients were monitored for laboratory evaluations including Hb levels and hemolysis markers, SCD-related outcomes, pain intensity using the Patient Reported Outcomes Measurement Information System (PROMIS)-57, and adverse events (AEs). Data are median (min–max) unless otherwise stated.
As of 3 March 2020, 40 Group C patients (23.5 [12–38] years) initiated cell collection; 25/40 were treated with LentiGlobin and followed for 12.1 (2.8–24.8) months. Neutrophil and platelet engraftment were achieved at 19 (12–27) days and 28 (19–136) days, respectively.
All patients stopped RBC transfusions by 90 days post-treatment. In 16 evaluable patients with ≥6 months of follow-up, total Hb at last visit was 11.5 (9.6–16.2) g/dL, with HbAT87Q contribution of 5.2 (2.7–9.4) g/dL, HbS of 6.1 (4.9–7.8) g/dL, and median HbS ≤ 60% of total Hb. Exploratory assays showed near pancellular expression of HbAT87Q ≥6 months post-treatment (N=9 patients), with ~90% of RBCs containing βA-T87Q by 18 months, and reduction in sickling propensity comparable to sickle cell trait. At last visit post-treatment, key hemolysis markers were trending towards normalization with median (quartile [Q]1–Q3) lactate dehydrogenase of 212 (201–287) U/L, reticulocyte count of 178 (146.5–236.3) ×109/L, and total bilirubin of 19 (15.4–27.4) µmol/L (all for n=25).
In 14 patients with ≥6 months of follow-up and history of vaso-occlusive crisis (VOC) or ACS, the annualized VOC+ACS rate was 4.0 (2.0–14.0) in the 2 years prior to treatment. Post-treatment, no ACS or serious VOCs were observed in these patients. One non-serious Grade 2 VOC occurred ~3.5 months after LentiGlobin infusion, resulting in a 99.5% (95% confidence interval, 92.4%–100%) mean reduction in the annualized VOC+ACS rate post-treatment (Figure 1).
Patients with PROMIS-57 pain intensity scores “worse” than the population norm at baseline reported clinically meaningful improvements in pain reduction at 12 months post-treatment (n=5). Patients with scores near or “better” than the population norm at baseline (n=5) remained stable over time (Figure 2).
The most common non-hematologic Grade ≥3 AEs post-treatment were stomatitis (n=15) and febrile neutropenia (n=11). Serious AEs reported in ≥2 patients post-treatment were nausea, opioid withdrawal syndrome, and vomiting (all for n=2); 3 patients had LentiGlobin-related nonserious Grade ≤2 AEs. There has been one death, unlikely related to LentiGlobin, >18 months post-treatment in a patient with significant baseline SCD-related cardiopulmonary disease. There have been no events of graft failure, vector-mediated replication-competent lentivirus, or clonal dominance.
LentiGlobin for SCD GT results in near pancellular βA-T87Q expression and reduced HbS expression, which impacts the pathophysiology of SCD as demonstrated by reduced RBC sickling and hemolysis and increased total Hb. Complete resolution of VOC/ACS was observed in almost all patients, with 99.5% mean reduction in the annualized VOC+ACS rate post-treatment. In addition, patients overall reported an improved pain intensity score. The safety profile post-LentiGlobin remains generally consistent with myeloablative single-agent busulfan conditioning and underlying SCD. Longer follow-up and additional patients will be presented.
Disclosures: Thompson: Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; BMS: Consultancy, Research Funding; Beam: Consultancy. Walters: AllCells, Inc: Consultancy; Veevo Biomedicine: Consultancy; Editas: Consultancy. Kwiatkowski: Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Terumo Corp: Research Funding; Sangamo: Research Funding; Celgene: Consultancy; Imara: Consultancy; Bristol Myers Squibb: Consultancy. Aygun: Patient-Centered Outsomes Research Institute: Research Funding; National Heart, Lung, and Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmidt: German Cancer Research Center, Heidelberg, Germany: Current Employment; GeneWerk GmbH, Heidelberg, Germany: Other: Equity ownership. DelCarpini: bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Pierciey: bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Miller: bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Gallagher: bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Chen: bluebird bio, Inc.: Consultancy. Goyal: bluebird bio, Inc.: Current Employment, Other: Ownership Interest and Salary. Kanter: GLG: Honoraria; Wells Fargo: Honoraria; Novartis: Consultancy; Cowen: Honoraria; Guidepoint Global: Honoraria; Medscape: Honoraria; Sanofi: Consultancy; bluebird bio, inc: Consultancy, Honoraria; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Jeffries: Honoraria; BEAM: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees.
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