Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene Autotemcel Gene Therapy for Non–β0/β0 Genotype β-Thalassemia. New England Journal of Medicine. 2021;386(5): 415-27.
Clinical Question
Is betibeglogene autotemcel (beti-cel) effective and safe in inducing transfusion independence in non-β0/β0 genotype beta thalassemia?
Background
Beta thalassemia is an inherited, autosomal recessive disorder causing decreased or absent production of the beta globin chain. The resulting imbalance between alpha and beta globin production causes oxidative stress and impaired red blood cell development and survival, with subsequent ineffective erythropoiesis, hemolysis, and anemia. At the time of this study, the only curative therapy for beta thalassemia was allogeneic hematopoietic stem cell transplant (HSCT). However, use of allogeneic HSCT was limited by availability of donors and due to the risks of transplant related-mortality, graft failure, and graft-vs-host disease. Early phase studies using the BB305 lentiviral vector-based gene therapy, which encodes a modified beta globin gene with threonine-to-glutamine substitution at position 87, showed achievement of transfusion independence, especially in patients with non-β0/β0 genotypes. However, most post-therapy hemoglobin levels did not normalize, despite achieving transfusion independence. Furthermore, post-gene therapy hemoglobin levels appeared to correlate with lentiviral vector copy numbers. Thus, the manufacturing process was refined to increase transduction of hematopoietic stem cells with the lentiviral vector and increase post-therapy vector copy numbers with the goal of increasing post-therapy hemoglobin levels and likelihood of achieving transfusion independence. This phase 3 study was designed to test the efficacy of the improved beti-cel gene therapy in inducing transfusion independence in an expanded cohort of pediatric and adult patients with non-β0/β0 genotypes.
Guidelines
The 2025 Thalassemia International Federation guidelines recommend the following:
- Gene therapy is an optimal therapeutic option for patients ≥14 years or those who do not have an HLA-identical family donor
- Initial consideration of patients for gene therapy should be based on the eligibility criteria used in the supporting studies for regulatory approval
- Patients with at least one of the following should be considered for treatment, ideally within 24 months, provided there is expertise with gene therapy:
- Age 35-45Moderate-to-severe iron overload (Liver Iron Concentration (LIC) > 7 and <15 mg/g dry liver weight and mT2* < 20 and >15 ms)Rare erythrocyte phenotype or history of alloimmunization causing concern for future availability of packed red blood cell (pRBC) transfusion
- Proven intolerance to iron chelation with likely rapid worsening of iron overload1
Study Design
- Single-group, open-label, international phase 3 study (HGB-207)
- N = 23
- Follow-up period: 2 years
- All patients underwent gene therapy with beti-cel
- Primary outcome: proportion of patients achieving transfusion independence
- Defined as the weighted average hemoglobin ≥9 g/dl starting 60 days after last transfusion in patients who had not received pRBC transfusions for ≥12 months
- Key secondary outcomes:
- Efficacy outcomes:
- Duration of transfusion independence
- Average total hemoglobin after beti-cel infusion
- Median gene-therapy derived HbAT87Q after beti-cel infusion
- Transfusion reduction
- Treatments to reduce iron levels after infusion
- Change in iron burden
- Efficacy outcomes:
Populations
- Inclusion Criteria
- Age ≤50 years
- Transfusion dependent: ≥100 ml/kg/year of pRBC transfusion or ≥8 pRBC transfusions/year in the 2 years prior to enrollment
- Clinically stable with Karnofsky performance status ≥80 for patients ≥16 years of age or Lansky performance status ≥80 if <16 years of age, and eligible for hematopoietic stem cell transplant
- Treated and followed for ≥2 years in a specialized center with detailed records on pRBC transfusions, inpatient hospitalizations, and iron chelation
- Key exclusion criteria:
- β0/β0 genotype, including IVS-I-110 mutation
- Advanced liver disease
- Evidence of severe iron overload, including cardiac T2*-weighted MRI <10 msec
- Presence of known, available HLA-matched family donor
- Baseline characteristics
- N = 23
- 32 patients provided consent
- 3 ineligible due to advanced liver disease, 1 due to low cardiac T2*-weighted MRI, 1 due to β0/β0 genotype, 3 withdrew consent. 1 discontinued treatment due to pregnancy.
- 32 patients provided consent
- Included both pediatrics and adults
- Age 12-50: 15 patients
- Age <12: 8 patients
- β0/β+ genotype was most common—12/23 (52%)
- βE/β0 6/23 (26%)
- β+/β+ 5/23 (22%)
- Median number of pRBC transfusions ≤2 years before enrollment: 16
- Weighted average nadir hemoglobin level before transfusion: 9.6 g/dl
- N = 23
Intervention
- Staring ≥30 days prior to mobilization and apheresis, patients were hypertransfused to hemoglobin ≥11 g/dl to suppress stress erythropoiesis during stem cell collection.
- Patients then underwent peripheral blood hematopoietic stem cell collection. Collected CD34+ stem cells were transduced ex vivo with the BB305 lentiviral vector.
- BB305 lentiviral vector contains erythroid-specific promoter and enhancer elements to limit transgene expression to primarily erythroid lineages
- Iron chelation was stopped ≥7 days prior to conditioning
- Prophylaxis for hepatic veno-occlusive disease/sinusoidal obstructive syndrome and seizure was started prior to conditioning
- Patients underwent myeloablative conditioning with busulfan (dose adjusted based on pharmacokinetic analysis) over 4 days. After a minimum 48 hours washout period, beti-cel was infused into the patients.
- Target dose ≥5.0 x106 CD34+ cells/kg
Outcomes
- Primary Outcomes: 20/22 (91%) patients achieved transfusion independence after beti-cel infusion
- 14/15 (93%) in ages 12-50
- 6/7 (86%) in age <12
- Secondary Outcomes:
- Transfusion independence was durable with median duration 20.4 months (range 16.7-21.6)
- Average total hemoglobin during transfusion independence was 11.7 g/dl (range 9.5-12.8), made primarily of gene therapy-derived HbAT87Q (median level at 12 months 8.6 g/dl, range 5.2-10.6)
- The two patients without transfusion independence had a 67.4% and 22.7% reduction in transfusion volume from 6 months to last follow up (48.2 and 27.2 months, respectively)
- After beti-cel, only 3/20 (15%) did not start iron chelation and/or therapeutic phlebotomy to reduce iron levels.
- While median cardiac T2*-weighted MRI measurements and median liver iron concentrations did not change significantly change over 24 months of follow up, 3 patients had normal liver iron concentration at 36 months
- Safety:
- 100% engraftment
- 100% overall survival at last follow-up
- Few adverse events were attributed to beti-cel infusion, with the only serious event including grade 3 thrombocytopenia.
- Most adverse events were typical of busulfan-based myeloablative conditioning, including cytopenias, stomatitis, febrile neutropenia, and hepatic veno-occlusive disease. 3/23 (13%) grade 4 hepatic veno-occlusive disease were reported, which resolved after defibrotide.
- There was no detection of replication-competent lentivirus, insertional oncogenesis, or clonal predominance/malignancy.
Commentary:
In this HGB-207 study, beti-cel gene therapy resulted in transfusion independence in 91% of patients with non-β0/β0 genotype, transfusion dependent beta thalassemia. This response was durable with a median duration of 20.4 months and an average total hemoglobin level of 11.7 g/dl. While adverse effects were noted, they were primarily typical of busulfan myeloablative conditioning and there were no reports of cancer. Although there were no significant changes in cardiac and liver iron burden throughout most of the study, three patients were reported to have normalized liver iron concentrations at 36 months. The impact of beti-cel on iron overload may be better assessed in subsequent long-term follow-up studies as the natural history of clinical improvement from iron overload can take years in the absence of targeted therapy such as iron chelation or therapeutic phlebotomy.
This study is limited by its small sample size and short follow-up period. Long-term follow-up data are needed to support the durability of improved hemoglobin levels and freedom from transfusion for this potentially curative therapy. Similarly, long-term data are needed to fully assess the risk of oncogenesis from lentiviral insertion causing oncogene activation or tumor suppressor gene inactivation. While lentiviral vectors have lower risks of insertional oncogenesis than previously used γ-retroviral vectors, the risk of subsequent clonal predominance and malignancy remain and need to be better characterized.
Despite its limitations, this study showed that Beti-cel led to significant rates of transfusion independence in non-β0/β0 transfusion dependent beta thalassemia patients, via a mechanism that offers potential for curative treatment. Based on this and a subsequent study in β0/β0 genotype beta thalassemia, beti-cel was approved as the first gene therapy for transfusion dependent beta thalassemia and has broadened the pool of patients eligible for curative therapies, including those who had not been candidates for allogeneic HSCT.
References
- Musallam KM, Cappellini MD, Porter JB, et al. TIF Guidelines for the Management of Transfusion‐Dependent Β‐Thalassemia. HemaSphere. 2025;9(3):e70095. ↩︎
Ann Kim, MD is a hematology fellow at Beth Israel Deaconess Medical Center in the ASH Hematology-Focused Fellowship Training Program. She completed medical school at Case Western Reserve University, followed by internal medicine residency at Johns Hopkins. Her interests broadly include classical hematology, with a focus on hemostasis and thrombosis.
