Abstract: 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. 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.

Plain-language summary: 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.