Severe aplastic anaemia: Reliable evaluation of unrelated donor stem cell transplantation currently not possible

It is so far unclear whether and which patients with acquired severe aplastic anaemia can benefit from unrelated donor stem cell transplantation. There is a lack of sufficiently verified data from studies that compare stem cell transplantation with the treatment alternative immunosuppression. For reasons of patient safety and to fill knowledge gaps as quickly as possible, this type of stem cell transplantation should currently only be applied within the framework of appropriate clinical trials. In order to implement such trials, the establishment of a disease registry would be helpful. This is the conclusion of a final report by the German Institute for Quality and Efficiency in Health Care (IQWiG) published on the Internet on 23 April 2007.

Cause of disease often unclear

Aplastic anaemia is an extremely rare disease: it affects about 2 per million people every year in Europe and the United States. In these patients, failure to produce cells in the bone marrow results in a lack of blood cells for circulation. Without treatment, severe aplastic anaemia is usually fatal. Although several potential triggers are known (e.g. drugs, viruses and toxins, radiation), in most cases the specific cause remains unclear. It is assumed that an autoimmune reaction is directed against blood-producing stem cells. Stem cells are the origin of a number of cells that, among other things, ensure vital functions such as oxygen transport, protection against infections, and blood coagulation. Besides the acquired form, there is also an inherited form of the disease.

Therapy alternatives have different risks

Blood transfusions can only temporarily compensate the lack of blood cells (supportive therapy).

Two long-term treatment options are currently available. Immunosuppressive drug therapy aims to suppress autoimmune reactions against blood-producing stem cells. Most patients cannot be permanently cured with this treatment method - some do not respond to treatment, others experience recurrence of the disease. The long-term, often lifelong treatment with immunosuppressive drugs can lead to substantial adverse effects.

Stem cell transplantation is an alternative. At first, the deficient bone marrow of the patient is destroyed (conditioning) and replaced by healthy stem cells of a donor, which migrate to the bone marrow. If stem cells from a related donor are transplanted, the chances of curing the disease are good. However, only about 30% of affected patients find a suitable related donor.

In principle, stem cell transplantation is a risky intervention, as there is a considerable risk of dying as a consequence of the intervention, depending, among other things, on the type of donor. There are indications that the chances of success depend on the match between the immunological characteristics of the donor and recipient cells. The donor cells may also "attack” the recipient's organs (graft-versus-host disease).

The Federal Joint Committee commissioned the German Institute for Quality and Efficiency in Health Care to compare the benefits of unrelated donor stem cell transplantation with immunosuppressive therapy in patients with acquired severe aplastic anaemia. The evaluation of related donor stem cell transplantation did not form part of the commission.

Lack of data from comparative studies

Despite an extensive systematic literature search, no direct comparative studies were available that were fully published and interpretable with sufficient certainty, even though various study types were considered by IQWiG, for example, non-randomised clinical studies and data from registries. The only requirement was the inclusion of a control group. One comparative study was identified including nearly 60 patients in whom a first course of immunosuppressive therapy had failed: 25 of these patients then underwent unrelated donor stem cell transplantation, and 29 underwent a second course of immunosuppressive therapy. However, these results have not yet been fully published. As soon as the data are fully published, they could be considered in a new evaluation.

Different definitions of a "refractory” situation

As a reaction to the comments submitted on the preliminary report, IQWiG also searched for and evaluated studies in which patients underwent unrelated donor stem cell transplantation as a final option after unsuccessful immunosuppressive therapy. The studies were considered in the evaluation even if they did not include a control group. The additional assessment of these studies showed highly inconsistent results - reported survival rates varied considerably.

Moreover, no consistent definition was provided in the studies with regard to how much longer additional attempts with immunosuppressive therapy were reasonable and from which point onwards a "refractory” situation could be assumed where there was no alternative to transplantation. Therefore, the data from these studies cannot be generalised.

However, IQWiG considers it to be justified to offer unrelated donor stem cell transplantation as a last treatment alternative to patients for whom immunosuppressive therapy is no longer a treatment option, and for whom there is no suitable related donor available. The prerequisite for offering this intervention to patients in such a desperate situation is to inform patients sufficiently about the uncertain evidence base.

IQWiG advocates an international disease registry

In view of the lack of national and international evidence and the considerable therapy-related risks, IQWiG calls upon experts to improve the state of evidence as soon as possible by conducting comparative studies. Due to the small number of cases, these studies must be conducted on a multinational level. The necessary structures would be relatively simple to establish: a disease registry is required in which, ideally, data on all courses of disease in patients with aplastic anaemia are collected and documented, independently of whatever therapy was used.

The fact that comparative studies are quite possible is shown by the comparisons between immunosuppressive therapy and related donor stem cell transplantation in patients with severe aplastic anaemia. In the last 5 years alone, 7 papers have been published, reporting on a total of several thousand patients.

Procedure of report production

On 24 July 2006, IQWiG published the preliminary report on the Internet for discussion.

A total of 33 substantial comments were received, including 62 references to study publications. Most publications (42) had already been identified by IQWiG in its literature search. The remaining 20 publications did not fulfil the inclusion criteria. An oral debate did not take place, as the comments submitted did not leave any important questions open. The written comments are attached to the final report. IQWiG discusses the arguments presented in the written comments in detail in the "Discussion” section (pp. 41-50). By revising the preliminary report, IQWiG followed the requirements outlined in its methods paper. It did not withdraw the preliminary report.

Contact: info@iqwig.de