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Follicular lymphoma arises from germinal center B cells and is the most common indolent non-Hodgkin lymphoma (1). It has a widely variable clinical course but nearly always presents as advanced disease with asymptomatic lymphadenopathy and has a long median overall survival of 8-10 years or more (2). Treatment before the onset of symptoms or organ dysfunction related to disease progression has not been proven to improve disease-specific survival or overall survival (OS), although early treatment may result in higher complete response rates and may prevent prognos- tically significant histological progression (3,4). However, the introduction of rituximab as a therapy for this disease has changed the landscape of this debate (5). When treatment is indicated, a variety of combination chemotherapeutic regimens have proven efficacy, and although some result in improvements in progression- free (PFS) and event-free survival (EFS), none are superior with respect to OS. The addition of rituximab to these regimens, how- ever, has resulted in a statistically significant improvement in OS in this disease (6-9). Response rates to chemoimmunotherapy are high, but this disease remains, for the most part, incurable and will, with rare exception, relapse. Further attempts to improve PFS and OS have included maintenance therapy with rituximab or con- solidation high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) (10-15). In this issue of the Journal, Al Khabori et al. (16) report the results of a meta-analysis exploring the efficacy and toxicity of HDC-ASCT compared with conventional-dose chemotherapy or chemoimmunotherapy in patients with untreated, advanced-stage follicular lymphoma. Four studies, including 941 patients with a median follow-up of 5-9 years, were identified that met the eligibility criteria; and data regarding OS, EFS, treatment-related mortality, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and secondary malignancies were abstracted (12-15). Only one of these studies included rituximab in both arms (15). There was no difference in OS between HDC-ASCT and con- ventionally treated patients, but EFS was statistically significantly improved following HDC-ASCT compared with conventional treatment. Treatment-related mortality and the rates of sec- ondary solid tumor malignancies were not different between the two arms. The rate of MDS/AML was somewhat higher following HDC-ASCT, although the difference was not statisti- cally significant. In these prospective randomized controlled trials, the 4- to 7-year EFS and OS ranged from 38% to 61% and 76% to 84%, respectively, and were similar whether or not rituximab was part of the therapy in each arm. An EFS benefit despite the absence of an improvement in OS is not insignificant in a disease with a long clinical course, as time off therapy may have an important impact on personal productivity and quality of life. However, the lack of OS benefit seen following HDC-ASCT in untreated patients has often been attributed, in part, to an increased rate of sec- ondary MDS/AML and solid tumors, which have been reported to be as high as 16%-21% at 10 years following total body irradiation-containing regimens (17,18). The lower rate of both secondary MDS/AML (4%) and solid tumors (5%) following HDC-ASCT observed in this meta-analysis may be a reflection of conditioning regimens, as two of the four studies did not include total body irradiation, or it may reflect abbreviated follow-up. An investigation into the efficacy of HDC-ASCT in untreated follicular lymphoma is timely in light of the recent data showing the efficacy of maintenance rituximab in the ECOG1496 and PRIMA trials (10,11). The results of the studies included in this meta-analysis are similar to the 3-year PFS of 68%-75% seen in these two trials of maintenance rituximab. Given the risk of sec- ondary MDS/AML and solid tumors following HDC-ASCT and

Follicular Lymphoma: To Treat or Not to Treat Is No Longer the Question