Dr Haydar Frangoul (Sarah Cannon Research Institute, USA) presented gene therapy approaches for 2 haemoglobinopathies caused by mutations: SCD and TDT [1]. SCD is an inherited disorder of haemoglobin affecting 270,000 infants born yearly worldwide, leading to chronic haemolysis and vaso-occlusive crises (VOCs). Patients with SCD have a lower life expectancy (median 48 years) [2]. Current therapy includes supportive care, transfusion, and biologicals. Allogeneic stem cell transplantation is the only curative therapy; however, most of the patients lack an HLA-identical donor. β-thalassaemia affects 40,000 infants born each year, approximately half of them being classified as transfusion-dependent. Patients suffer from iron overload, thrombosis, skeletal, and cardiopulmonary symptoms. Current therapy includes red blood cell transfusions, iron chelation therapy, and luspatercept. Allogeneic bone marrow transplant from HLA-identical siblings is the only curative therapy.
There are 2 approaches to gene therapy: gene editing and gene addition [1]. An example of gene addition in haemoglobinopathies is a lentiviral vector encoding a modified β-globin gene including an anti-sickling mutation. Dr Frangoul presented 2 case reports, with both patients expressing ≤50% of the transduced β-globin after >1-year post-treatment [3,4]. In a phase 1/2 study (NCT02140554) including 32 patients with SCD, LentiGlobin treatment effectively prevented vaso-occlusive events [5].
Dr Frangoul also presented a gene-editing approach to increase foetal haemoglobin (HbF) production. In patients with SCD and TDT, symptoms occur when haemoglobin is switched from foetal to adult. In patients with persistence of HbF, fewer or no symptoms of SCD or TDT are present, suggesting HbF could be a treatment option. A CRISPR-Cas9 gene-editing tool (CTX001) was used to target BCL11A to decrease the expression of BCL11A protein and increase the expression of HbF [6]. Patients’ blood stem cells were collected and CRISPR-Cas9-edited. Patients received chemotherapy to facilitate engraftment, infused with CTX001 and followed up for Hb production, HbF expression, transfusion requirements (TDT; NCT03655678), and VOCs (SCD; NCT03745287).
Preliminary results of the first 7 TDT patients in this study showed a clinically meaningful expression of HbF. Increased total haemoglobin was achieved early and maintained, and all patients became transfusion independent (median follow-up 8.9 months). CTX001 was also used in 3 SCD patients and the first results after a median follow-up period of 7.8 months were presented at the EHA 2021 Virtual Congress. HbF represented 31–47% after 3 months with a trend towards an increase at later time points. A pancellular HbF expression of almost 100% was observed with follow-up times ≥4 months. All patients had detectable haptoglobin and improved LDH, indicating no evidence of haemolysis, and were VOC-free. All patients treated to date demonstrated increased total haemoglobin and HbF [7].
Despite encouraging results, gene therapy approaches still have limitations. Recently, cases of myelodysplastic syndrome and acute myeloid leukaemia after receiving LentiGlobin were reported (NCT02140554; NCT04293185). Follow-up times are still short and there is a need for high-dose chemotherapy to facilitate engraftment.
Dr Frangoul concluded that “gene therapy approaches can offer an alternative to allogeneic stem cell transplantation especially for patients who lack an HLA-identical donor.” Data for gene addition and gene editing approaches are promising. Additional follow-up is required to determine the long-term safety and persistence of gene-modified cells in the marrow.
- Frangoul H. Gene therapy approaches to treatment of haemoglobinopathies. P210-1, EHA 2021 Virtual Congress, 9–17 June.
- DeBaun MR, et al. Blood 2019;133(6):615–7.
- Cavazzana-Calvo M, et al. Nature 2010;467(7313):313–22.
- Ribeil JA, et al. N Engl J Med 2017;376(9):848–55.
- Kanter J, et al. Abstract 365, ASH 2020, 7–10 December.
- Frangoul H, et al. N Engl J Med 2021;384(3):252–60.
- Grupp S, et al. EP736, EHA 2021 Virtual Congress, 9–17 June.
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Table of Contents: EHA 2021
Featured articles
Lymphoma
Immuno-oncology agents are effective in treating classic Hodgkin’s lymphoma
MATRix with ASCT: best long-term survival for primary CNS lymphoma
Naratuximab emtansine + rituximab safe and effective in diffuse large B-cell lymphoma
The journey ahead for CAR T-cell therapy in r/r follicular lymphoma
ZUMA-5 vs SCHOLAR-5: Axicabtagene ciloleucel significantly improves FL outcome
Promising chemo-free treatment options in r/r DLBCL
Leukaemia
Sabatolimab achieved durable responses in patients with high-risk MDS and AML
Final analysis of EURO-SKI: primary endpoints met in chronic myeloid leukaemia
Favourable outcomes with zanubrutinib versus ibrutinib in patients with r/r CLL
Oral azacitidine improves overall survival in patients with acute myeloid leukaemia
Reduced-intensity conditioning ASCT is effective in older patients with AML
ELEVATE-TN: Acalabrutinib shows long-term efficacy in chronic lymphocytic leukaemia
ELEVATE-RR: Acalabrutinib demonstrates similar efficacy and better safety versus ibrutinib
Fixed 12 cycles and MRD-guided venetoclax consolidation effective in CLL
GLOW: Ibrutinib + venetoclax showed superior PFS as first-line CLL treatment
Myeloma and Myelofibrosis
Novel targets in myelofibrosis: overview of emergent therapies
Immune therapy of multiple myeloma
MAIA results confirm superior efficacy of daratumumab with standard-of-care
ANDROMEDA: Addition of daratumumab showed superior efficacy in patients with AL amyloidosis
Thrombotic and Thrombocytopenic Disorders including COVID-19 related
Acquired TTP: new treatments and updated guidelines
Maternal screening to prevent foetal and neonatal alloimmune thrombocytopenia
Fostamatinib effectively increased platelet counts in immune thrombocytopenic purpura
Physiopathology of coagulopathy in haematological malignancies and COVID-19
Haemostatic abnormalities are associated with mortality in COVID-19
Mechanisms of COVID-19 vaccine-induced thrombotic thrombocytopenia
COVID-19 vaccine-induced immune thrombotic thrombocytopenia: discovery and diagnosis
Haemoglobinopathies
Luspatercept improved anaemia in patients with non-transfusion-dependent β-thalassaemia
Personalising treatment for sickle cell disease
Gene therapy: A promising approach for hereditary haemoglobinopathies
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