Reason for request

First assessment

Key points

Unfavourable opinion for reimbursement in the treatment of adult patients with transfusion-dependent anaemia associated with beta-thalassaemia.

Role in the care pathway?

The objectives of treatment of patients with transfusion-dependent β-thalassaemia are, in particular, to improve life expectancy, morbidity and quality of life via:

  • correction of anaemia with a chronic transfusion regime in order to ensure normal growth and activity and reduce manifestations of dyserythropoiesis,
  • identification of an HLA-matched family donor and assessment of the feasibility of HSCT, with this preferably being proposed in early childhood,
  • prevention of long-term transfusion complications, primarily cardiac, hepatic and endocrine complications related to iron overload,
  • detection at a pre-symptomatic stage and early treatment of organ damage related to iron overload by intensification of iron-chelating therapy and symptomatic treatment if necessary,
  • treatment of other complications of the disease.

Until recently, haematopoietic stem cell transplantation (HCSCT) was the only available curative treatment for transfusion-dependent β-thalassaemia. It is recommended that this be proposed at an early age, or before the development of complications related to iron overload, for all patients with an HLA-matched related donor. In France HSCT is only discussed in exceptional cases in patients without a compatible related donor but with an HLA-matched unrelated donor and if it is impossible to continue transfusion (allo-immunisation) or iron-chelating therapy. This practice remains marginal due to non-optimal results.

For patients without an HLA-matched related donor unable to undergo allogeneic HSCT (75% based on the laws of genetics), the proprietary medicinal product ZYNTEGLO (betibeglogene autotemcel) was granted a conditional marketing authorisation on 29 May 2019 in patients 12 years and older who do not have a β0/β0 genotype. In its opinion of 18 March 2020, the Committee issued a favourable opinion for its reimbursement only in patients under 35 years of age. However, the MA for this proprietary medicinal product was temporarily suspended in March 2021 due to a potential risk of leukaemia and myelodysplastic syndrome demonstrated with another medicinal product using the same viral vector.

In patients without an HLA-matched related donor, on the date of the present decision, management is therefore based primarily on symptomatic treatment with regular and frequent life-long red blood cell (RBC) transfusions. However, transfusions lead to iron overload in the long term, which is life-threatening as a result of cardiac damage, and causes significant morbidity due to iron deposits in the liver and glands. It should be noted that hydroxyurea, a cytotoxic agent triggering the production of HbF, is also widely used in clinical practice (off-label) in transfusion-dependent (primarily intermediate) or transfusion-independent patients. Although its efficacy has only been assessed in observational studies and in heterogeneous populations, a certain number of studies have demonstrated a clear advantage of using this agent, in terms of a reduction in transfusion burden, an increase in haemoglobin levels, and a reduction in ineffective erythropoiesis markers and morbidity.

Role of the medicinal product in the care pathway


  • demonstration of the superiority of luspatercept compared to placebo in the BELIEVE study in terms of responder patients with an at least 33% reduction in transfusion burden at W24 (primary endpoint) but with a size effect deemed to be modest (only 21.4% responder patients versus 4.5% in the placebo group; OR = 5.79; CI95% [2.24; 14.97]; p < 0.0001);
  • the debatable clinical relevance of this endpoint compared to other more clinically relevant endpoints, such as transfusion independence, hepatic and myocardial iron concentrations and quality of life, assessed in an exploratory manner;
  • uncertainties concerning the transposability of the results to clinical practice, mainly due to inclusion of young patients and patients with major and intermediate beta-thalassaemia with different clinical progressions and transfusion burdens, making it impossible to determine with any certainty the expected benefit of the medicinal product in each of the two groups;
  • the absence of comparison with hydroxyurea, which constitutes the reference treatment, primarily in patients with intermediate β-thalassaemia, representing the majority of patients in the study, whereas direct comparison with this medicinal product would have been possible;
  • the absence of long-term safety data despite the fact that the treatment is liable to be administered in the long term;

REBLOZYL (luspatercept) has no role in the care pathway for patients with transfusion-dependent anaemia associated with beta-thalassaemia.



Clinical Benefit


The Committee deems that the clinical benefit of REBLOZYL (luspatercept) is insufficient to justify its public funding cover in the treatment of adult patients with transfusion-dependent anaemia associated with beta-thalassaemia.


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