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REBLOZYL (luspatercept) (syndrome myélodysplasique - SMD)

Opinions on drugs - Posted on Aug 05 2021

Reason for request

First assessment

Key points

Favourable opinion for reimbursement in the treatment of adult patients with transfusion-dependent anaemia due to very low, low and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, without 5q deletion, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.

Unfavourable opinion for reimbursement in the treatment of adult patients with transfusion-dependent anaemia due to very low, low and intermediate-risk myelodysplastic MDS with ring sideroblasts, with 5q deletion, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.

What therapeutic improvement?

Therapeutic improvement in the management of the disease.

Role in the care pathway?

The therapeutic management of patients with low-risk MDS is primarily based on the correction of cytopenias - mainly anaemia - which have a major impact on patients and may require repeated red cell concentrate transfusions.

When cytopenia is moderate or asymptomatic, no treatment may be favoured.

In the event of symptomatic anaemia, first-line treatment is based on high-dose recombinant EPO alone or in combination with G-CSF in patients with ≤10 g/dl Hb and poor clinical tolerance to this anaemia, even if they are not transfused. A treatment response is observed within three months; in the event of inefficacy after this period, treatment should be stopped. It should be noted that only the epoietin alfa EPREX and its biosimilar BINOCRIT have a specific MA in this indication in monotherapy (without G-CSF).

In the event of failure of EPO:

  • Red cell concentrate (RCC) transfusions should be used following the failure of EPO and in the absence of other therapeutic alternatives. They are associated with a deterioration in quality of life, serious complications (particularly cardiovascular) and toxicity due to iron overload.
  • Lenalidomide (REVLIMID) is indicated only in adult patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q (del 5q) cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
  • Other therapeutic options are cited by the national and European guidelines in specific populations but do not have a validated MA in France at present.

It should be noted that allogeneic haematopoietic stem cell transplantation (HSCT) is currently the only curative treatment, reserved for patients with high-risk MDS, with an HSC donor and aged less than 65-70 years.

Role of REBLOZYL (luspatercept) in the care pathway:

Within the reimbursement scope (without 5q deletion in the event of an inadequate response to or ineligibility for EPO therapy)

In view of:

  • demonstration of the efficacy of REBLOZYL (luspatercept) compared to placebo for the endpoint of short-term achievement of transfusion independence at 24 and 48 weeks (with a small sample of patients remaining in the placebo group (n=12) for this last analysis), in patients not having responded to EPO, with transfusion-dependent anaemia and without 5q deletion,
  • the comparison conducted versus placebo in a context in which the great majority of patients included (n=218/229; 95%) had previously received an erythropoiesis-stimulating agent, almost all of whom (n= 213/218; 98%) were refractory, which is therefore acceptable,
  • the non-inclusion of patients presenting MDS associated with a chromosomal 5q deletion in the same study,

REBLOZYL (luspatercept) is a second-line treatment following an inadequate response to erythropoietin-based treatment or in the event of ineligibility for this treatment, in adult patients with transfusion-dependent anaemia due to very low, low and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, without 5q deletion.

Within the scope included in the MA but not retained for reimbursement:

In other patients within the scope of the MA indication for myelodysplastic syndrome (corresponding to patients with 5q deletion), these patients not having been included in the MEDALIST study, and consequently in the absence of data in this subpopulation eligible for lenalidomide, REBLOZYL (luspatercept) has no role in the care pathway.

It is highlighted that, in accordance with the SPC, subcutaneous injections of REBLOZYL (luspatercept) every three weeks should be administered by a healthcare professional. The recommended maximum volume of medicinal product per injection site is 1.2 mL. If more than 1.2 mL is required, the total volume should be divided and administered across separate sites.


Clinical Benefit
Substantial

The Committee deems that the clinical benefit of REBLOZYL (luspatercept) is substantial in the treatment of adult patients with transfusion-dependent anaemia due to very low, low and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, without 5q deletion, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.
Insufficient

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 due to very low, low and intermediate-risk myelodysplastic MDS with ring sideroblasts, with 5q deletion, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.

 

Clinical Added Value
minor

Considering:

  • demonstration of the superiority of luspatercept compared to placebo assessed in a randomised, double-blind study in RCC transfusion-dependent patients with very low, low or intermediate-risk MDS with ring sideroblasts, without 5q deletion, predominantly refractory (93%) to erythropoiesis-stimulating agents for the percentages of patients achieving red cell concentrate transfusion independence:
    • ≥ 8 consecutive weeks during the initial 24-week treatment phase (primary endpoint), with a moderate effect size: 9% in the luspatercept group versus 13.2% in the placebo group, i.e., an absolute difference of 24.6% ((OR = 5.1; CI95% [2.3; 11.3]; p< 0.0001),
    • ≥ 12 consecutive weeks:
      • throughout the 48-week treatment period (ranked secondary endpoint): 33.3% versus8%, i.e., an absolute difference of 21.4% between the two groups (OR=4.0; CI95% [1.8; 8.9]; p=0.0003,
      • during the initial 24-week treatment phase (ranked secondary endpoint): 28.1% versus9%, i.e., an absolute difference of 20.0% between the two groups (OR = 5.1; CI95% [2.0; 12.8]; p=0.0002),
    • the clinical relevance of achieving transfusion independence in this population with an unsatisfactory response to/ineligible for EPOs and with a severely impaired quality of life, as reported by patient associations,

and despite:

  • the absence of robust comparative data versus placebo for the response duration (unranked secondary endpoint) and changes in haemoglobin levels,
  • the absence of robust quality of life data, which is regrettable in this disease,
  • uncertainties concerning the long-term maintenance of efficacy, with an ad hoc analysis at a median follow-up of 26 months having reported a luspatercept discontinuation rate of 44% of patients treated due to lack of efficacy,
  • the safety profile observed after a median treatment follow-up limited to around 12.7 months,

the Committee considers that REBLOZYL (luspatercept) provides a minor clinical added value (CAV IV) in the therapeutic strategy for the treatment of adult patients with transfusion-dependent anaemia due to very low, low and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, without 5q deletion, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.

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