Unanswered Questions in Follicular Lymphoma

In this issue of ONCOLOGY, David Maloney presents the evidence for rituximab (Rituxan) maintenance in patients with follicular lymphoma. Rituximab maintenance refers to the use of prolonged treatment with rituximab alone after a response to initial therapy. However, it includes many types of administration (for example, one injection every 2 or 3 months, or four infusions every 6 months) for different durations (most frequently 2 years) in different settings (first-line or relapse), and after different treatments have induced the initial response (rituximab alone, chemotherapy without rituximab, rituximab/chemotherapy combination, or autologous transplant).

Studies exist in all these settings, and all such investigations are designed differently; none may be considered confirmatory. However, all studies have shown the same results: a statistically lower relapse rate in patients receiving rituximab maintenance therapy and, thus, a prolongation of progression-free and overall survival.

Unconfirmed Benefit

Although these studies have shown a statistically significant advantage in terms of survival, most of them are not relevant to the current treatment of follicular lymphoma. Most patients are now treated with R-CHOP, a combination of rituximab and CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone), allowing high complete response rates and longer progression-free survival than any other available treatment (even if the superiority of R-CHOP over R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] was not proven in a prospective randomized study).

None of the studies presented in the article by Dr. Maloney have looked at the benefit of rituximab maintenance in patients treated with first-line R-CHOP. This is precisely the objective of the European Primary Rituximab and Maintenance (PRIMA) study, which is closed for accrual with 1,200 patients given R-CHOP or R-CVP and more than 1,000 of them randomized between observation and rituximab maintenance for 2 years. However, the median follow-up after randomization is currently too short, and no analysis has yet been presented.

In his review, Dr. Maloney writes, "Given the above data [showing a statistically significant benefit in relapsing patients treated with R-CHOP] it would seem reasonable to conclude that the results should be similar [in first-line patients treated with R-CHOP]." This has not been demonstrated. We may assume that patients achieving a complete response with R-CHOP in the first-line setting have less refractory disease and a deeper response than relapsing patients, as demonstrated by a much longer median progression-free survival than the one observed after R-CHOP at time of relapse. Because of this deeper response, the demonstration of the benefit of rituximab maintenance may require a longer period of observation or may never be seen in the whole population of patients.

A benefit in patients with more aggressive disease or in those who did not reach a complete response after induction also seems probable but has not been demonstrated. In fact, only one study has been presented in first-line patients treated with R-CHOP and then randomized between observation and rituximab maintenance, and that study was conducted in patients with diffuse large B-cell lymphoma. These investigators concluded that there was no benefit from rituximab maintenance.

Magnitude of Benefit

Thus, while it may seem logical that rituximab maintenance benefits follicular lymphoma patients treated with first-line R-CHOP, the magnitude of this benefit is totally unknown. Based on these assumptions, Dr. Maloney recommends that rituximab maintenance "should be considered," especially in high-risk patients. Even if this strategy is associated with a benefit during the first years after treatment, I am not certain that we may consider it standard treatment-that is, treatment implemented by several randomized studies.

We must consider the duration of this benefit, the response at time of disease progression in patients receiving maintenance therapy, and the overall survival benefit. Curiously, none of the phase II or randomized studies that have looked at rituximab maintenance present any data for patients progressing after such therapy. Patients may be refractory to rituximab retreatment and progress more rapidly, may need chemotherapy in place of immunotherapy, and thus, may have a poorer quality of life and a shorter overall survival.

We know that nearly all patients treated with rituximab maintenance at the time of relapse have progressed, with a longer time to progression than patients not receiving maintenance therapy. We urgently need a cohort analysis of these patients, looking at response rates after a salvage regimen (with or without rituximab) and at the duration of this response. This and survival data for patients randomized in these studies will confirm or nullify the hypothesis of a large benefit for patients treated with rituximab maintenance.

Rituximab Maintenance vs Retreatment

From the studies presented by Dr. Maloney, we know that there is a benefit in terms of progression-free and overall survival for some patients treated at time of first/second relapse. The picture has become clearer, and this treatment can be recommended. We still need to watch for the appearance of resistance to rituximab, and long-term follow-up of the patients included in these studies is certainly recommended.

However, we do not yet know the difference between rituximab maintenance and rituximab retreatment in terms of overall survival and quality of life. If patients treated with maintenance more frequently develop disease that is refractory to later rituximab therapy, then a strategy of retreatment without maintenance may be better for those in whom cure is not possible. In this regard, the results of the RESORT study, being conducted by the Eastern Cooperative Oncology Group (ECOG), are much anticipated.

Given that rituximab has proven activity in all B-cell lymphomas, the demonstration of a benefit in progression-free and overall survival for maintenance therapy in patients with follicular lymphoma will surely translate to other B-cell lymphomas. Studies that are better defined than the ECOG study will have to address diffuse large B-cell lymphoma, particularly for patients with a high risk of relapse. Maintenance therapy has already proven active for relapse prevention in mantle cell lymphoma.

Conclusions

In conclusion, preliminary data support the use of rituximab maintenance in patients with relapsing follicular lymphoma. However, data showing a benefit from one infusion of monoclonal antibody combined with a radionuclide (iodine-131 or yttrium-90) will have to be compared with rituximab maintenance in this setting. If other chemotherapy drugs or small targeted agents added to R-CHOP succeed in curing patients or in delaying relapse for more than 10 years, maintenance therapy may be less interesting.

Rituximab maintenance is currently the best we have for follicular lymphoma because we do not cure these patients and they regularly relapse. However, improving the cure rate with initial treatment (as has been achieved in diffuse large B-cell lymphoma) is a direction that has not been explored in this setting and may prove to be a better option than maintenance.

-Bertrand Coiffier, MD

Financial Disclosure:Dr. Coiffier is a member of the speakers bureau for Genentech and Roche and is also on the advisory board for Roche.