What is the role of stem-cell transplantation for follicular non-hodgkin lymphoma in the rituximab era?

Defining the best treatment for follicular lymphoma (FL) is still a challenge, partly because the available treatment options are often associated with prolonged overall survival (OS) as a result of the long natural history of this disease. Many clinical studies have used progression-free survival (PFS) as their end point but suffer from insufficient follow-up or lack of statistical power to assess OS, which is the indisputably best end point. Until the introduction of rituximab, standard chemotherapy (varying from low-dose oral chlorambucil to intensive multidrug schedules) was effective in producing responses but did not result in a survival benefit. The introduction of autologous peripheral-blood stem-cell transplantation with its inherent low morbidity and mortality in comparison with autologous bone marrow transplantation resulted in three trials applying high-dose therapy as first-line treatment for FL. All these studies showed an improvement of antitumor efficacy, but none had a significant impact on OS. This is most likely the result of the inability to select patients who might benefit most from this procedure or, again, insufficient follow-up. Patients who experience relapse, especially early relapse, have shown that they have a lymphoma with a clinically less benign behavior. In this patient population, several phase II studies suggested an improved survival, which was confirmed by the only randomized study in relapsed FL that showed a significantly improved OS in patients who underwent transplantation as compared with standard chemotherapy. Several authors have described a relatively high incidence of myelodysplasia, attributed to the high-dose therapy. However, this may also be the result of extensive pretreatment, suggesting that high-dose therapy might be of greater benefit earlier in the treatment course, as opposed to after multiple relapses. After the introduction of rituximab, several groups chose to investigate whether OS was improved with the incorporation of rituximab in standard-dose, first-line treatment of FL. The general conclusion is that PFS was improved in all, but OS was prolonged in only some, of these trials. Likewise, incorporating rituximab into highdose chemotherapy as part of first-line therapy resulted in better PFS but an OS benefit was observed in only one such trial. In the article that accompanies this editorial, Pettengel et al describe the results of the randomized European Group for Blood and Marrow Transplantation (EBMT) LYM-1 study. Rituximab-naive patients with relapsed chemosensitive FL were randomly assigned to analyze the efficacy of in vivo purging and maintenance therapy with rituximab in combination with high-dose therapy and autologous stem-cell transplantation. In 7 years, 280 patients were included. The authors conclude that in vivo purging did not improve outcome; however, maintenance therapy did improve PFS, but not OS at the time of this report. This study was not designed to assess the value of high-dose therapy because all patients received this treatment, which the authors considered standard therapy in relapsed FL. Although an important observation, it is important to realize that the patients in the EBMT LYM-1 study all were rituximab naive, which limits conclusions on current applicability. In addition, from the French Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) study, we have learned that the results of high-dose therapy in patients with diffuse large B-cell lymphoma who experience relapse after first-line rituximab-containing therapy are significantly inferior, especially in the situation of an early relapse. Whether this is also the case in FL is an open question, but data from another French study in FL may be reassuring that this is not necessarily the case in FL. We can conclude that high-dose therapy changes the natural behavior of FL in relapsed disease and, probably, also in first-line therapy if PFS is a convincing end point. However, it is not clear that PFS is the best end point in FL. How can we improve the outlook for patients with FL? One approach is to wait for the current studies to mature and report OS data. Alternative options are new and more effective monoclonal antibodies or monoclonals conjugated to either radionuclides or toxins. Currently, there are no randomized data in support of these expensive options. Is allogeneic transplantation the panacea? Although complicated by a high treatment-related mortality (TRM), myeloablative transplants resulted in convincing evidence of cure in patients for whom other intensive therapies had failed. With the introduction of nonmyeloablative transplants, the decreased TRM resulted in better outcomes, even in patients who had previously undergone autograft. The high TRM after allografting in comparison with autografting limits its role in first-line salvage. It remains to be seen whether tandem transplantation combining the efficacy of highdose therapy with the immunological graft versus lymphoma effect will lead to the desired more favorable outcome. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 13 MAY 1 2013