Abstract: Our search strategies led to 3046 potentially relevant references. Of these, five RCTs involving 1093 patients were included; four trials in previously untreated patients and one trial in relapsed patients. Overall, the quality of the five trials is judged to be moderate. All trials were reported as randomised and judged to be open-label studies, because usually trials evaluating stem cell transplantation are not blinded. Due to the small number of studies in each analysis (four or less), the quantification of heterogeneity was not reliable and not evaluated in further detail. A potential source of bias are uncertainties in the HR calculation. For OS, the HR had to be calculated for three trials from survival curves, for PFS for two trials. We found a statistically significant increased PFS in previously untreated FL patients in the HDT + ASCT arm (HR = 0.42 (95% confidence interval (CI) 0.33 to 0.54; P < 0.00001). However, this effect is not transferred into a statistically significant OS advantage (HR = 0.97; 95% 0.76 to 1.24; P = 0.81). The subgroup of trials adding rituximab to both intervention arms (one trial) confirms these results and the trial had to be stopped early after an interim analysis due to a statistically significant PFS advantage in the HDT + ASCT arm (PFS: HR = 0.36; 95% CI 0.23 to 0.55; OS: HR = 0.88; 95% CI 0.40 to 1.92). In the four trials in previously untreated patients there are no statistically significant differences between HDT + ASCT and the control-arm in terms of TRM (RR = 1.28; 95% CI 0.25 to 6.61; P = 0.77), secondary acute myeloid leukaemia/myelodysplastic syndromes (RR = 2.87; 95% CI 0.7 to 11.75; P = 0.14) or solid cancers (RR = 1.20; 95% CI 0.25 to 5.77; P = 0.82). Adverse events were rarely reported and were observed more frequently in patients undergoing HDT + ASCT (mostly infections and haematological toxicity). For patients with relapsed FL, there is some evidence (one trial, N = 70) that HDT + ASCT is advantageous in terms of PFS and OS (PFS: HR = 0.30; 95% CI 0.15 to 0.61; OS: HR = 0.40; 95% CI 0.18 to 0.89). For this trial, no results were reported for TRM, adverse events or secondary cancers. In summary, the currently available evidence suggests a strong PFS benefit for HDT + ASCT compared with chemotherapy or immuno-chemotherapy in previously untreated patients with FL. No statistically significant differences in terms of OS, TRM and secondary cancers were detected. These effects are confirmed in a subgroup analysis (one trial) adding rituximab to both treatment arms. Further trials evaluating this approach are needed to determine this effect more precisely in the era of rituximab. Moreover, longer follow-up data are necessary to find out whether the PFS advantage will translate into an OS advantage in previously untreated patients with FL. There is evidence that HDT + ASCT is advantageous in patients with relapsed FL.

Plain-language summary: With this assumption, we assessed the role of high-dose therapy followed by autologous stem cell transplantation in the treatment of follicular lymphoma in adults. We included five trials with 1093 patients in the main analyses. As a result, the meta-analyses for previously untreated patients (four trials) show no statistical significant differences in terms of survival, treatment-related mortality or secondary malignancies between the patients treated with high-dose therapy followed by autologous stem cell transplantation and those treated with chemotherapy only. However, progression-free survival (tumour control), was significantly improved by the high-dose chemotherapy and stem cell transplantation. Adverse events are more common in patients treated with high-dose therapy followed by autologous stem cell transplantation. There is an advantage of the high-dose chemotherapy and stem cell transplantation for patients with a relapse of the disease, both in survival and in tumour control (one trial). No data on adverse events are reported in this trial.