Early initial therapy of advanced follicular lymphoma: the need for vigilance

Data from several recent studies have shown that the overall survival for patients with low grade follicular lymphoma has improved over the last two decades [1–3 ]. Although some studies have attributed this to improved salvage therapy, and supportive care, it is widely believed that this is mainly due to the introduction of anti-CD20 monoclonal antibody-based therapies. Evidence from prospective, randomized clinical trials has confirmed that these agents, particularly rituximab, in combination with chemotherapy improve progression-free survival and overall survival compared with chemotherapy alone in the front-line and the relapsed settings [4,5]. Additionally, recent studies have shown that maintenance rituximab can improve progression-free and overall survival rates, also in the front-line and relapsed settings [6,7].

The results of these studies have the potential to change the paradigm for initial therapy of low grade follicular lymphoma. The rationale for a ‘watchful waiting’ approach as initial management was based upon the observation that available therapies could not affect the natural history of follicular lymphoma. As data emerge which suggest that current therapy can, in fact, impact survival, the watch and wait approach may no longer be the standard approach for the asymptomatic patient with low volume disease and no cytopenias. Even for patients with low risk disease, who are asymptomatic and do not fulfill standard criteria for ‘requiring’ therapy, there are now preliminary data from Europe to suggest that single-agent rituximab may improve progression-free survival [8].

As the trend toward early intervention for these patients gathers momentum, it raises major questions about the optimal initial regimen. Relatively intensive chemo-immunotherapy regimens typically produce higher response rates and longer progression-free survival duration than less intensive, single-agent regimens, but are associated with more short-term toxicity and, in some cases, the potential for long-term complications which can be life-threatening. The benefits of intensive induction therapy on overall survival are unclear, and there are no data at present to suggest that intensive therapy needs to be used as the first-line treatment to be most effective—it is still not clear where intensive chemo-immunotherapy regimens should be placed in the treatment algorithm for this disease.

In this issue of Leukemia and Lymphoma, Tomás et al. have investigated the use of a fludarabine-based, rituximab-containing induction regimen followed by rituximab maintenance therapy in previously untreated patients with advanced follicular lymphoma [9]. Seventy-five patients were entered onto a prospective phase II study in which the planned treatment was six cycles of fludarabine, cyclophosphamide, and rituximab, followed by maintenance rituximab given at 6-month intervals for a total of 2 years of therapy. The complete response rate was high at 89%, and the 5-year overall, progression-free, and event-free survival rates were 77%, 93%, and 72%, respectively. Although the response rate was high, this benefit was offset by an extremely high treatment-related mortality—10 patients died from causes directly attributable to therapy, most commonly infection or secondary myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Furthermore, the regimen was associated with very significant short-term toxicity, particularly hematologic to the extent that only eight of 75 patients actually completed all of the planned therapy on this study. As the authors conclude, this regimen is too toxic for use in the first-line therapy of follicular lymphoma. It adds to the existing literature which suggests that fludarabine-based first-line regimens should be used with caution in this disease, and that the subsequent use of maintenance rituximab may compound this problem. For example, the Eastern Cooperative Oncology Group/Cancer and Leukemia Group B (ECOG/CALGB) E1496 study included an initial randomization to fludarabine/cyclophosphamide (FC) versus cyclophosphamide/vincristine/prednisone (CVP), with a second randomization to maintenance rituximab or no further therapy in this patient population [10]. The FC arm of this study was closed due to a high rate of toxicity and toxic deaths, and it was notable that four further therapy-related deaths occurred in patients randomized to rituximab maintenance after FC induction. Other studies have also highlighted potential long-term complications of fludarabine therapy, including late infections, secondary AML/MDS, and impaired marrow function, resulting in difficulty in mobilizing peripheral blood progenitor cells for autologous stem cell transplant [11–13 ]. Recent data have also suggested that the prolonged use of rituximab is associated with an increased risk for late infectious complications [14,15].

A review of previous studies of fludarabine-based first-line therapy suggest that the profound early and late toxicities may be, at least in part, dose related, although as several treatment options exist for these patients, purine analogs should probably be relatively low on the list of preferred regimens. It also suggests that close long-term observation will be required for patients receiving bendamustine-based regimens as first-line therapy. The recently presented randomized trial from the Study group for Indolent Lymphomas (StiL) in Germany demonstrated a progression-free survival advantage for the combination of bendamustine and rituximab (BR) in a randomized comparison with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-rituximab in patients with indolent B-cell lymphomas [16]. The BR regimen was associated with significantly less short-term toxicity. As a result, this regimen has been widely adopted, and is being included in large-scale randomized studies in the USA and Europe. In view of the purine analog-like properties of this drug, concerns about the potential for late marrow toxicity will require prolonged and careful follow-up of patients entered into randomized trials.

The report from Tomás et al. highlights a fundamental challenge for those involved in advancing our understanding of the treatment of this disease. The natural history of the disease is long, options for treatment are expanding, and new treatments are likely to be more rationally targeted against disease-specific pathways. Any short-term benefits from an early intensive approach may be lost over time because of late side effects, or simply ‘washed out’ because of the activity of second-line or subsequent therapies. Overall, the most important priorities for patients with these conditions will likely remain duration and quality of survival. Late toxicities must remain an important endpoint in all studies of first-line therapy for this disease, especially as the trend for treating asymptomatic patients continues.

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal