📘 TLDR Heme / Onc - Journal Club (#049)

In this issue:

💊 Our H/O study of the month: Betibeglogene Autotemcel (beti-cel) Gene Therapy in Patients With Transfusion-Dependent, Severe Genotype β-Thalassaemia: Results from the HGB-212 (Northstar-3) Study

STUDY OF THE MONTH

Beti-cel Gene Therapy in Patients with Transfusion-Dependent, Severe Genotype β-Thalassaemia

Results from the HGB-212 (Northstar-3) Study

Study link: Northstar-3 (preprint in The Lancet; April 25, 2024)

💊 Study Importance

• Prior to this study, hematopoietic stem cell transplant (HSCT) was the only potentially curative therapy for transfusion-dependent (TDT) β-Thalassemia.
• Smaller early-phase trials have explored gene therapy in thalassemia, albeit with smaller sample sizes, exclusion of severe β0/β0 genotype, or failure to achieve transfusion independence (TI).
  • This is the first phase III trial of a lentiviral vector-based gene therapy for TDT β-thalassemia that enrolled patients with severe genotypes (β0/β0, β0/IVS-I-110, or IVS-I-110/IVS-I-110).
• You’ll find details related to this study below. For a more comprehensive catalog of recent practice-changing trials in Hematology and Oncology, head over to Pathway! 

🧠 Ask Pathway AI:

1. What are the indications for blood transfusion in thalassemia? 
2. What are the indications for iron chelation therapy in thalassemia?
3. How does gene therapy work in thalassemia?

🦠 Study Background:

• Patients with TDT β-thalassemia require lifelong, regular blood transfusions, usually initiated at an early age, with subsequent iron overload and its associated complications.
• Prior to gene therapy, allogeneic HSCT was the only potentially curative option for TDT. However, HSCT is associated with immunological risks (graft failure, graft-versus-host disease) and age restrictions → Need for alternatives!
• Betibeglogene autotemcel (beti-cel) is a lentiviral vector-based (BB305 vector) gene therapy that adds functional copies of a modified β-globin gene via autologous CD34+ transduced cells. 
• Encouraging results from previous early-phase studies of beti-cel prompted the conduction of this phase III trial in pediatric and adult patients.
• This phase III trial assessed the efficacy and safety of beti-cel in patients with the most severe β-thalassemia genotypes (β0/β0, β0/IVS-I-110, or IVS-I-110/IVS-I-110) (N.B. IVS-I-110 = G->A at position 110 of 1st intron of HBB)

❤️ Study Methodology:

Study Design:

• Phase III, multicenter (France, Germany, Greece, Italy, UK, and USA), single-arm, open-label trial.

Inclusion Criteria:

• Clinically stable patients with TDT aged ≤50 years, with the following transfusion history:
  • ≥100 mL/kg/year of packed red blood cells (pRBCs), or,
  • ≥8 transfusion episodes/year in the 2 years prior to enrolment
  • Genotypes: β0/β0, β0/IVS-I-110, or IVS-I-110/IVS-I-110 (HBB mutations in IVS-I-110 were considered equivalent to β0).
• Patients with non-β0/β0 genotypes, T2* cardiac MRI <10ms, other evidence of severe iron overload, and a known, available HLA-matched family donor were excluded.

Trial procedures and treatment allocation:

• All included patients were infused with beti-cel after undergoing the following procedure:
  • Peripheral-blood HSC: collection/mobilization with granulocyte colony-stimulating factor and plerixafor → apheresis and selection of CD34+ cells.
  • CD34+ cells activation: ex vivo with recombinant human cytokines, fms-like tyrosine kinase receptor 3, stem-cell factor, and thrombopoietin.
  • Washing + ex vivo transduction with BB305 lentiviral vector.
  • Myeloablative conditioning chemotherapy with busulfan → beti-cel infusion at a dose of ≥5.0 x 106 CD34+ cells/kg, after ≥48 hours post-conditioning.
• Follow-up visits: every month (through month 16) and every other month (through month 24).
• Annual assessments: cardiac and liver iron overload (T2* MRI), 12-lead ECG, bone density imaging, and quality of life assessments.

Outcomes:

• Primary endpoint: proportion (%) of patients achieving TI
  • TI = weighted average hemoglobin (Hb) ≥9 g/dL without pRBC transfusions for a continuous period of ≥12 months at any time during the study after beti-cel infusion (assessed once Hb ≥ 9 g/dL achieved without transfusion in the preceding 60 days) 
• Secondary outcomes: % of TI at 24 months, duration of TI, time from beti-cel infusion to achieving TI, (weighted) average Hb during TI, transfusion reduction, iron management, and change in iron burden over time.
• Safety evaluation: success of HSC engraftment, incidence of treatment-related mortality, and frequency and severity of clinical adverse events (AEs)

Statistical Analysis:

• Sample size: no formal sample size calculations were done, though they were estimated to see TI in ≥ 30% of patients based on data from an earlier phase trial
• Protocol-defined success: achievement of TI in 10/18 (55.6%) patients.
• Analysis: as-treated; all patients who received beti-cel infusion were included in all analyses. 

🫁 Let’s get to the Results already!

Patient enrollment and treatment receipt:

• Total patients screened: 20 and total enrolled and infused beti-cell: 18 (1 ineligible due to liver disease, 1 withdrew consent)
• Median age of 23.5 years: 8/18 patients (44.5%) <12 years
• Median follow-up duration (min-max) was 47.9 months (23.8-59.0)
• Genotypes: 12 patients (66.7%) were β0/β0, 3 were β0/IVS-I-110, and 3 IVS-I-110/IVS-I-110. Engraftment: all patients had successful neutrophil and platelet engraftment.

Transfusion independence (TI): all 18 patients were evaluated for TI at the last follow-up visit. The table below summarizes the key outcomes in terms of TI

Table 1. Summary of TI-related outcomes. TI: transfusion independence. pRBC: packed red blood cells; min: minimum; max: maximum; n=number of patients

Secondary outcomes: biomarkers of ineffective erythropoiesis and iron overload were measured at baseline, after beti-cell infusion (month 24), in all patients who achieved TI.

The table below compares and summarizes differences in key secondary outcomes:

Table 2. Summary of secondary outcomes in terms of erythropoiesis and iron overload. EPO: erythropoietin; LDH: lactate dehydrogenase; LIC: liver iron concentration.

In terms of iron chelation therapy:

• Resumed in 11/16 patients who achieved TI (at investigator’s discretion), at a median of 7.82 months
• 5/11 (31.3%) eventually discontinued chelation at a median of 14 months, though 2/5 (40%) restarted phlebotomy–with only 50% (½) discontinuing at cut-off
• 5 patients never received iron chelation with near-normal LIC (3.6 mg/g dry weight) at last follow up.
• Safety: 
  • Most observed AEs were consistent with known side effects of plerixafor mobilization, busulfan conditioning, and the HSCT procedure.
  •  Side effects attributed to beti-cell infusion as assessed by either the investigators or the study sponsor, included abdominal pain, cytopenias, immune thrombocytopenia, and liver focal nodular hyperplasia 

The table below summarizes the most common (i.e., ≥3 patients) Grade ≥3 AEs.

Table 3. Summary of common Grade ≥3 adverse events. AE: adverse event; TEAE: treatment-emergent adverse event; ALT: alanine aminotransferase. 

🔥 Discussion: 

• This trial was positive according to the protocol-specified (> 55.6% TI) definition: TI was achieved in 88.9% of patients with TDT and severe genotype. 
• Outcomes comparable to non-severe, non-β0/β0 patients in the HGB-207 study (91.3% achieved TI)
  • Beti-cel led to favorable outcomes in both adult (80% achieved TI) and pediatric patients (92.3%) with severe genotype TDT
• Most patients who achieved TI were eventually able to discontinue iron chelation and, in most patients (12/16; 75%), LIC was ≤ 5mg/g at last follow-up. 
• Importantly, no cases of insertional oncogenesis were noted (N.B. this is a theoretical risk of viral vector technology)
• Compared to HSCT:
  • No need for a donor
  • No immunologic risks associated with allogeneic HSCT
  • beti-cel offers a safer and more effective alternative to allo-HSCT

• Major limitations to this trial include the following: 
  • Open-label design, with no comparative arm for randomization → associated biases. 
  • Sponsor involvement in data collection and interpretation, namely attributing side effects.
  • Relatively small sample size and short median follow-up → ongoing trial (LTF-303) to assess long-term safety and efficacy (loss of lentiviral vector?) in this same group of patients for 13 additional years

📈 Conclusion:

• Beti-cell gene therapy showed clinical benefit in patients with TDT with severe genotypes, with high rates of TI achieved.
• Therapy appears to be safe with a profile consistent with the known effects of HSC mobilization
• This is the first potentially curative gene therapy option to receive FDA approval in adults and pediatric patients with TDT β-thalassemia with severe genotypes.
• However, costs (~ $ 2.8 million USD) associated with this novel, advanced therapy for a disease mostly affecting people outside the U.S. pose a real challenge to routine clinical use!!

Longer follow up for safety and efficacy data is warranted. Potential comparative efficacy and cost-benefit analysis data between lentiviral gene therapy and FDA-approved CRISPR-based gene therapy may be helpful.

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