Journal Club – Thalassemia

Kwiatkowski JL, Walters MC, Hongeng S et al. Betibeglogene autotemcel gene therapy in patients with transfusion-dependent, severe genotype β -thalassaemia (HGB-212): a non-randomised, multicentre, single-arm, open-label, single-dose, phase 3 trial

Clinical Question

Does betibeglogene autotemcel gene therapy lead to more transfusion independence in patients with a severe genotype β -thalassaemia?

Background

Betibeglogene autotemcel gene therapy (Beti-cel) adds copies of a modified β-globin geneinto hematopoietic stem cells via autologous CD34+ cells transduced with a lentiviral vector. Beti-cel had been studied in a phase 3 trial of transfusion dependent beta-thalassemia patients with a non-β⁰/β⁰ genotype, showing promising results, with a rate of transfusion independence of 91%. This study was the first phase 3 trial of a lentiviral vector-based gene therapy enrolling patients with a more severe genotype, including β⁰/β⁰, β⁰/β^+IVS-I-110, or β^+IVS-I-110/β^+IVS-I-110. Of note, the IVS-I-110 mutation, although it is classified as a β⁺ mutation, leads to almost completely absent β-globin production when present in two copies or paired with β⁰, conferring a similar severe phenotype to β⁰/β⁰.

Guidelines

Current guidelines, including the 2021 Thalassemia International Federation Guidelines for the Management of Transfusion-dependent Thalassemia continue to emphasize regular transfusions and iron chelation for transfusion-dependent patients. Those guidelines comment on how for years the only curative treatment has been allogeneic stem cell transplant but do comment on gene therapy.

They discuss how gene therapy in thalassemia can be achieved by either (1) gene addition via insertion of a healthy copy of the gene using viral vectors; or via (2) gene editing via a directed mutation that repairs the gene in situ or induces a disease-modifying effect.

Those guidelines however predate the publication of this study.

Study Design

• Non-randomized, multicenter, single-arm and open label
• Centers included: France, Germany, Greece, Italy, the UK and the USA
• Patients underwent a hypertransfusion regimen to achieve a hemoglobin level of 11 g/dL 60 days prior to stem cell mobilization
• Follow-up: 24 months
• Outcomes
  • Primary: transfusion-independence (TI) – hemoglobin 9 g/dL or above without any pRBC transfusions for 12 months
  • Secondary: duration of TI, time from beti-cel infusion to TI, and other characterization of patients who achieved TI

Populations

N = 18: patients aged 50 years or younger, clinically stable transfusion-dependent thalassemia, eligible to undergo hematopoietic stem cell transplant

• Inclusion Criteria
  • Transfusion history of at least 100 mL/kg per year of packed red blood cells (pRBC) OR at least eight transfusions of pRBCs per year in the 2 years before enrollment.
• Key exclusion criteria:
  • Non-β⁰/β⁰ genotype (β^+IVS-I-110 was considered to be equivalent to β⁰).
  • Clinically significant infection
  • WBC < 3 x 10⁹/L, and/or platelet count < 100 x 10⁹/L, or a bleeding disorder
  • Prior or current malignancy, or immediate family member with a familial cancer syndrome
  • Prior HSCT
• Baseline characteristics
  • Non-β⁰/β⁰ genotype (β^+IVS-I-110 was considered to be equivalent to β⁰).

Interventions

• Betibeglogene autotemcel (beti-cel) – autologous CD34+ hematopoietic stem cells transduced with BB305 lentiviral vector encoding modified β-globin gene at a dose of 5·0 × 106 CD34+ cells/kg or above
• Conditioning regimen: Busulfan-based, pharmacokinetic-adjusted myeloablative conditioning
• Follow-up visits occurred every month for the first 12 months after beti-cel infusion, then at months 14, 15, 16, 18, 20, 22, and 24.
• Long-term follow-up study enrollment was offered (total of 15 years)

Outcomes

• Primary Outcome: 
  • Transfusion independence (TI): 89% (16/18 patients) reached transfusion independence (95% CI: 65.3-98.6).
  • Two patients did not achieve independence (patients A and B). Patient A had no reduction in the number of transfusions and patient B had a 96·6% reduction in the number of transfusions.
• Secondary Outcomes:
  • All 16 patients who achieved TI maintained it through last follow-up.
  • Hemolysis markers normalized or remained normal in patients who reached TI.
  • Soluble transferrin receptor levels did not change significantly.
  • 11 patients with TI resumed iron chelation after beti-cel. Of those, 5 discontinued chelation at a median of 14 months.
• Safety:
  • No serious adverse events attributed to beti-cel itself. All events were consistent with busulfan-based myeloablative conditioning and stem cell transplant.
  • There were no cases of graft failure, graft-versus-host disease, or secondary malignancy.

Commentary and Intepretation:

Patients with severe genotype β-thalassemia are bound to a life of recurrent blood transfusion and iron chelation. Those patients with a biallelic loss of function in the β globin gene require transfusions every 2 to 6 weeks, which inevitably leads to transfusion-associated complication, increasing morbidity and mortality. Allogeneic stem-cell transplantation (allo-SCT) is a potentially curative approach for patients with transfusion dependent thalassemia, and one of the few alternatives. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands, can decrease transfusion requirements to some extent.

This paper was designed to be a multicenter, single-arm, open label phase 3 addressing the efficacy and safety of an ex-vivo modified autologous stem cell transplant called betibeglogene autotemcel (beti-cel) in patients with severe genotype β thalassemia, with the primary outcome being transfusion independence. Transfusion independence was defined as weighted average hemoglobin ≥9 g/dL without transfusions for at least 12 months.

Four of five adult patients (aged ≥18 years) and 12 of 13 pediatric patients achieved transfusion independence with beti-cel. The study has a median follow-up of 47.9 months, providing evidence of durability, with all 16 patients who achieved transfusion independence maintaining it through last follow-up. It will be important to see the results of the 15-year follow-up (ongoing study).

The authors comment on how allo-SCT has been considered the only potentially cure, but best outcomes are in younger than 14-year-old patients, with a sibling donor. Despite the small sample size, the results of this trial indicate that beti-cel can be a potentially curative option for patients with severe β-thalassemia genotypes who are older or who lack matched sibling donors. Nearly 90% of patients achieved transfusion independence, a rate comparable to that seen with allo-SCT in this population.

There are clearly obstacles that still need to be overcome, including cost and accessibility (only done at highly specialized hematology centers), especially considering that β-thalassemia is endemic in many low-income countries.