Stem cell transplantation of sibling donors compared with specific immunosuppressive therapy for acquired severe aplastic anemia

Acquired severe aplastic anemia is rare. Stem cells from the bone marrow usually replace naturally dying blood cells in the peripheral blood. Severe aplastic anemia is probably caused by an irregular, attacking immune response against these blood producing stem cells within the body. If supplies are not maintained, functional blood cells are lacking and infections, bleeding, and exhaustion will occur. Patients may experience paleness, weakness, fatigue, and shortness of breath. Disease progression is associated with severe infections, which are a major cause of death.

The transplantation of stem cells from a human leukocyte antigen (HLA)-matched sibling donor without prior therapy (first-line therapy) is a treatment option for newly diagnosed patients with severe aplastic anemia. An HLA-matched sibling donor, a brother or a sister, serves as a donor of stem cells that carry identical (matched) genetic characteristics to the HLA genes. The harvested cells are transfused intravenously and produce new blood cells. Problems may arise when the cells do not settle down sufficiently to produce blood cells (graft failure) or if the donor immune cells recognize body cells of the recipient as foreign and attack them (graft-versus-host disease). Both problems may lead to early death.

The application of the drugs ciclosporin and/or antithymocyte or antilymphocyte globulin as immunosuppressive therapy without prior therapy (i.e. as first-line therapy) is an alternative to transplantation and can be used for patients where no HLA-matched sibling donor is found. Immunosuppressive therapy means the drugs suppress reactions of the immune system. The aim is to reduce abnormal immune reactions. Problems may arise when patients do not respond well or show no response at all.

We identified three studies meeting our quality criteria for inclusion in the review. All had methodological limitations meaning that we could not draw firm conclusions. With respect to the primary outcomes, they showed ambiguous results for overall mortality when comparing treatment arms: one study favored transplantation and two studies favored treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin. Treatment-related mortality, that is death caused by complications of the treatment, was considerable for patients in the transplantation arm. Treatment failure, that is no response to treatment, was substantial for patients in the ciclosporin and/or antithymocyte or antilymphocyte globulin arm. Graft failure was reported for 3% to 16% and graft-versus-host-disease for 26% to 51% of the transplanted patients. Because the data are scarce and biased it is not possible to determine which treatment is better - transplantation for HLA-matched sibling donors or ciclosporin and/or antithymocyte or antilymphocyte globulin for patients that do not have such a sibling.

Several reasons make it highly probable that there will not be any good evidence comparing these interventions in the future. One reason is that randomized controlled trials are unlikely to be conducted due to ethical constraints and strong patient and clinician preferences. Studies with 'Mendelian randomization' could provide some good evidence in theory, however, in practice they are difficult to conduct properly and have been disappointing. 'Mendelian randomization' means the view that nature itself has already 'randomized' the paternal and maternal part of a gene given that donor and recipient are siblings. Another reason is that the outcome of transplantation has improved considerably. This is true for matched donor transplantation including both related and unrelated donors. It means that ciclosporin and/or antithymocyte or antilymphocyte globulin may not be a first treatment choice if a matched sibling or even a matched unrelated donor is available.

Authors' conclusions: 

There are insufficient and biased data that do not allow any conclusions to be made about the comparative effectiveness of first-line allogeneic hematopoietic stem cell transplantation of an HLA-matched sibling donor and first-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin (as first-line immunosuppressive therapy). We are unable to make firm recommendations regarding the choice of intervention for treatment of acquired severe aplastic anemia.

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Background: 

Acquired severe aplastic anemia is a rare and potentially fatal disease, which is characterized by hypocellular bone marrow and pancytopenia. The major signs and symptoms are severe infections, bleeding, and exhaustion. First-line allogeneic hematopoietic stem cell transplantation (HSCT) of a human leukocyte antigen (HLA)-matched sibling donor (MSD) is a treatment for newly diagnosed patients with severe aplastic anemia. First-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin (as first-line immunosuppressive therapy) is an alternative to MSD-HSCT and is indicated for patients where no MSD is found.

Objectives: 

To evaluate the effectiveness and adverse events of first-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared to first-line immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin in patients with acquired severe aplastic anemia.

Search strategy: 

We searched the electronic databases MEDLINE (Ovid), EMBASE (Ovid), and The Cochrane Library CENTRAL (Wiley) for published articles from 1946 to 22 April 2013. Further searches included trial registries, reference lists of recent reviews, and author contacts.

Selection criteria: 

The following prospective study designs were eligible for inclusion: randomized controlled trials (RCTs) and non-randomized controlled trials if the allocation of patients to treatment groups was consistent with 'Mendelian randomization'. We included participants with newly diagnosed severe aplastic anemia who received MSD-HSCT or immunosuppressive therapy without prior HSCT or immunosuppressive therapy, and with a minimum of five participants per treatment group. We did not apply limits on publication year or languages.

Data collection and analysis: 

Two review authors abstracted the data on study and patient characteristics and assessed the risk of bias independently. We resolved differences by discussion or by appeal to a third review author. The primary outcome was overall mortality. Secondary outcomes were treatment-related mortality, graft failure, no response to first-line immunosuppressive therapy, graft-versus-host-disease (GVHD), relapse after initial successful treatment, secondary clonal and malignant disease, health-related quality of life, and performance score.

Main results: 

We identified three trials that met the inclusion criteria. None of these trials was a RCT. 302 participants are included in this review. The three included studies were prospectively conducted and had features consistent with the principle of 'Mendelian randomization' as defined in the present review. All studies had a high risk of bias due to the study design. All studies were conducted more than 10 years ago and may not be applicable to the standard of care of today. Primary and secondary outcome data showed no statistically significant difference between treatment groups. We present results for first-line allogeneic hematopoietic stem cell transplantation of an HLA-matched sibling donor, which we denote as the MSD-HSCT group, versus first-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin, which we denote as the immunosuppressive therapy group in the following section.

The pooled hazard ratio for overall mortality for the MSD-HSCT group versus the immunosuppressive therapy group was 0.95 (95% confidence interval 0.43 to 2.12, P = 0.90, low quality evidence). Therefore, overall mortality was not statistically significantly different between the groups. Treatment-related mortality ranged from 20% to 42% for the MSD-HSCT group and was not reported for the immunosuppressive therapy group (very low quality evidence). The authors reported graft failure from 3% to 16% for the MSD-HSCT group and GVHD from 26% to 51% (both endpoints not applicable for the immunosuppressive therapy group, very low quality evidence). The authors did not report any data on response and relapse for the MSD-HSCT group. For the immunosuppressive therapy group, the studies reported no response from 15% (not time point stated) to 64% (three months) and relapse in one of eight responders after immunosuppressive therapy at 5.5 years (very low quality evidence). The authors reported secondary clonal disease or malignancies for the MSD-HSCT group versus the immunosuppressive therapy group in 1 of 34 versus 0 of 22 patients in one study and in 0 of 28 versus 4 of 86 patients in the other study (low quality evidence). None of the included studies addressed health-related quality of life. The percentage of the evaluated patients with a Karnofsky performance status score in the range of 71% to 100% was 92% in the MSD-HSCT group and 46% in the immunosuppressive therapy group.

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