Autologous transplantation for follicular lymphoma? Not too soon!

Comment on Sebban et al, page 2540

In this issue of Blood, Sebban and colleagues report the final results of a randomized study for newly diagnosed advanced follicular lymphoma comparing autologous transplantation with interferon maintenance. This is the last of 3 such studies to be reported, and settles the role of autologous transplantation in advanced follicular lymphoma—for now.

Despite nearly identical eligibility criteria and the use of an anthracycline-based induction treatment in all studies, the results are quite different. The previous studies found a significant advantage to autologous stem cell transplantation (ASCT). The German Lymphoma Study Group (GLSG) reported that patients randomized to transplantation had a 64.7% progression-free survival (PFS) rate at 5 years versus 33% with conventional chemotherapy.¹  The Groupe Ouest-Est d'Etude des Leucémies aigues et autres Maladies du Sang (GOELAMS) group reported 60% PFS for those randomized to autologous transplantation versus 48% with conventional chemotherapy.²  By contrast, the Groupe d'Etude des Lymphomes de l'Adulte (GELA) study does not show a significant PFS advantage for autologous transplantation.

The authors offer several explanations for this difference, including more prolonged follow-up for the GELA study, the fact that relapsing patients may have received rituximab salvage, differences in study design, and insufficient induction treatment. More prolonged follow-up is unlikely to have a major effect on PFS curves, since with prolonged follow-up the curves for EFS continue to separate in the GLSG and GOELAMS studies (see figure). Rituximab treatment given to relapsing patients should not have affected PFS. The GLSG did not conduct an intent-to-treat analysis, but rather focused on patients undergoing the planned transplantation, which partially explains the outcomes. But the most important difference between this and the 2 previous studies may well be that in the GELA study, patients randomized to transplantation received a shortened induction treatment consisting of 4 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), whereas in the other 2 studies, they were treated until maximal response prior to proceeding to transplantation. High recurrence rates then result from incomplete disease control or from infusion of occult lymphoma cells contaminating the stem cell infusate. The principle of shortened intensive induction followed by autologous transplantation was previously tested by GELA in aggressive lymphoma and yielded inferior results in that disease as well.³  In other words, autologous transplantation may add to chemotherapy; but it should not replace conventional chemotherapy.

The overall role of ASCT in follicular lymphoma continues to be debated. It is an excellent treatment option for the management of younger patients with recurrent disease.⁴  In advanced newly diagnosed lymphoma, a survival advantage has yet to be shown; with more prolonged follow-up it may still emerge in the GLSG study.¹  An increased risk for therapy-related acute myeloid leukemia (t-AML) was observed in the GLSG and GOELAMS studies,^1,2  but this risk may be minimized by modulation of induction and mobilization therapy preceding transplantation (Sebban et al and Lenz et al⁵ ). Despite spectacular advances since the introduction of rituximab, many patients with advanced disease and a high Follicular Lymphoma International Prognostic Index (FLIPI) score have disease recurrences.⁶  For such patients, the continued study of autologous transplantation, possibly in combination with rituximab for in vivo purging, remains an important area of investigation. ▪