ATGAM (horse anti-human T lymphocyte immunoglobulin (eATG))

Key points

Favourable opinion for reimbursement in adults and children aged 2 years and older for the treatment of acquired moderate to severe aplastic anaemia of known or suspected immunologic aetiology in patients who are unsuitable for haematopoietic stem cell transplantation (HSCT) or for whom a suitable HSC donor is not available. 

What therapeutic improvement?

Therapeutic improvement compared to THYMOGLOBULINE in the treatment of the disease.

Role in the care pathway?

The therapeutic management of aplastic anaemia depends on the severity of the aplasia, its cause and the patient’s age. Severe aplastic anaemia or a moderate form requiring repeated transfusions is an indication for specific treatment.

In severe forms, it is a therapeutic emergency. Management requires either haematopoietic stem cell transplantation or immunosuppressive therapy using anti-lymphocyte serum (ATGAM) combined with ciclosporin and supportive care. The choice between haematopoietic stem cell transplantation and intensive immunosuppressive therapy depends on age, comorbidities and the availability of a donor.

Haematopoietic stem cell transplantation is the reference treatment in the event of an HLA-matched family donor in patients under 40 years of age, and makes it possible to achieve a cure in over 80% of cases of severe acquired aplastic anaemia. It is the only curative treatment.

For patients ineligible for a transplant (due to their age, the absence of a compatible donor and/or concomitant diseases), the reference first-line treatment is based on the combination of anti-lymphocyte serum (ATGAM) and ciclosporin. However, the mean time to haematologic response following this treatment is long, at around 3 months, and can be as long as 6 months. It should be noted that in elderly patients, this treatment is only used if there are no cardiovascular or renal comorbidities or an excessively high risk of loss of autonomy related to a prolonged hospitalisation.

In practice, in subjects over 65 years old or with comorbidities, the proprietary medicinal product REVOLADE (eltrombopag) can be used in combination with ciclosporin or as monotherapy (off-label). However, given the lack of robust data, this treatment cannot be routinely proposed as first-line treatment.

Supportive care (red cell and platelet transfusions, anti-infective treatments) should be combined with first-line treatments.

THYMOGLOBULINE has an MA in aplastic anaemia. In its opinion of 17 January 2007, the Committee granted a substantial clinical benefit for THYMOGLOBULINE and considered that it provided no clinical added value. Since the publication of the results of the study by Scheinberg et al. (2011) (randomised, single-centre, open-label study), which demonstrated the superiority of ATGAM (eATG) compared to THYMOGLOBULINE in terms of haematologic response, THYMOGLOBULINE is no longer recommended as first-line treatment and ATGAM (eATG) has become the standard treatment.

In patients in whom immunosuppressive therapy has failed or in early relapse, an allogeneic transplant may be discussed for subjects under 30 years of age (and up to 40 years of age depending on the patient’s general condition) with a compatible 10/10 phenotypically-identical HLA-matched donor and patients of over 40 years of age with an HLA-matched related donor. In patients over 50 years of age, an allogeneic transplant will only be offered on a case-by-case basis if the other possible treatments have failed. A second immunosuppressive treatment with THYMOGLOBULINE and ciclosporin can be proposed in patients over 30 years of age in relapse without an HLA-matched related donor, or under 30 years of age without a 10/10 phenotypically-identical donor. Combination with eltrombopag may be proposed in this situation. In the Committee’s decision of 7 September 2016 relative to REVOLADE (eltrombopag), the Transparency Committee considered that REVOLADE (eltrombopag) is a non-curative treatment with a limited role in adults refractory to immunosuppressive therapy or heavily pretreated and unable to have an allogeneic transplant. In the absence of survival data, this drug cannot lead to a cure as it does not contribute to the allogeneic transplantation rationale or to induction of immunosuppression capable of reducing the primary autoimmune factor of this disease.

Graft failure within 30 days following transplantation or graft rejection within 6 months following transplantation (exceptional but possible in the longer term) are not uncommon in the event of aplastic anaemia due to the autoimmune nature of acquired aplastic anaemia as well as the multiple transfusions received before transplantation, irrespective of the type of aplasia. In these cases, a second transplant is possible, depending on the patient’s general condition and haematological status (residual haematopoiesis or severe pancytopenia). Other treatments can also be used (off-label), such as alemtuzumab, particularly in the event of significant toxicity of ciclosporin, as well as androgens. Since the published data is extremely limited, androgens should be reserved for refractory or relapsed forms not eligible for any other treatment.

Finally, it should be noted that a recent multicentre, phase 3 study [RACE study] evaluated the efficacy of adding REVOLADE (eltrombopag) to the ATGAM (eATG) + ciclosporin combination, in the treatment of severe aplastic anaemia (currently off-label).

Role of ATGAM in the care pathway:

The ATGAM (eATG) plus ciclosporin combination is the reference treatment to be used as first-line therapy in the context of standard immunosuppressive therapy in adults and children aged 2 years and older for the treatment of acquired  moderate to severe aplastic anaemia of known or suspected immunologic aetiology in patients who are unsuitable for haematopoietic stem cell transplantation (HSCT) or for whom a suitable HSC donor is not available.