Critical Questions About Rituximab Maintenance in Lymphoma Patients

Since its introduction a decade ago, rituximab (Rituxan) has been one of the rare cancer therapeutics that has proven much better than anyone expected. The clinical development of rituximab in several B-cell malignancies has been rapid, no doubt aided by the combination of high activity, low toxicity, and ease in combining with other standard lymphoma treatments. In follicular lymphoma, rituximab has quickly become part of first-line treatment, with strong suggestions that its inclusion has finally had an impact on survival in this patient group.[1-4]

Perhaps the most interesting and unexpected benefit of rituximab in the treatment of follicular lymphoma has been its use in maintenance therapy. The efficacy of this targeted agent in chronic therapy contrasts with the well documented futility of maintenance therapy using cytotoxic agents, and raises the possibility that the strategy underlying targeted-agent therapy may be fundamentally different.

Current Data

In his characteristically concise review, Dr. Maloney has accurately presented the current clinical data regarding maintenance rituximab, much of which has appeared during the past 2 years. To date, all studies with maintenance rituximab in follicular lymphoma are consistent in showing marked prolongations of progression-free survival with minimal toxicity (rituximab given for a maximum of 2 years). These benefits have occurred whether maintenance rituximab follows single-agent rituximab, combination chemotherapy, or rituximab/chemotherapy combinations.[4-9] Several maintenance schedules have demonstrated similar benefits. While no direct comparisons of schedules have been performed, I agree with Dr. Maloney that it is currently reasonable to use the least expensive regimens (every-2-month or every-3-month administration).

Dr. Maloney also correctly highlights the two major unresolved clinical questions regarding the use of maintenance rituximab: (1) the benefit of this approach following first-line treatment with rituximab/chemotherapy combinations, and (2) the optimal duration of maintenance therapy. These are both clinically relevant questions, and are worthy of additional commentary.

Maintenance Rituximab After First-Line Rituximab/Chemotherapy

No available data from randomized trials have addressed the issue of maintenance rituximab following first-line rituximab/chemotherapy. (Although the Primary Rituximab and Maintenance [PRIMA] trial addressing this issue has completed accrual, mature results from that study cannot be expected for another 2 to 3 years.) However, maintenance rituximab produced benefits in both progression-free and overall survival when administered following R-CHOP (rituximab, cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone) in relapsed/refractory patients with follicular lymphoma.[9]

Given the results of the latter investigation and combined data from other maintenance trials, it is somewhat difficult to make a cogent argument that first-line maintenance rituximab will not also be effective. In the long history of systemic treatment for cancer, there has never been an example of a drug that works better in second-line treatment than it does in first-line treatment. The length of remission following first-line treatment with rituximab/chemotherapy combinations is mainly related to the rituximab rather than the chemotherapy component (as inferred from median progression-free survivals following chemotherapy alone vs rituximab alone in this setting). Therefore, the optimum use of rituximab in this setting should maximize the expected benefit.

As Dr. Maloney points out, the timing and duration of maintenance rituximab therapy in patients who expect a long remission following first-line treatment needs clarification. Based on the existing evidence, however, it is hard for me to avoid recommending maintenance rituximab after first-line rituximab/chemotherapy, particularly in patients with high Follicular Lymphoma International Prognostic Index (FLIPI) scores or those who achieve less than a complete remission following initial therapy.

Optimal Duration of Maintenance Rituximab

The second unresolved issue regarding maintenance rituximab therapy is the optimal duration of treatment. Although studies are ongoing, there are no available data regarding the safety and efficacy of treatment for more than 24 months. Many patients who benefit from maintenance rituximab and stop treatment after an arbitrary 24 months of therapy retain sensitivity to rituximab and respond again at the time of disease progression.[10] In such patients, it is reasonable to infer that continuation of maintenance rituximab beyond 24 months would have further prolonged their remission duration.

However, I agree with Dr. Maloney that caution is necessary in this situation, since the safety of more prolonged schedules has not been demonstrated. Given that retreatment with rituximab at progression is also an effective strategy, I currently limit maintenance rituximab to 24 months in most patients. Admittedly, I've made a few exceptions to this rule, usually when treating a patient who has enjoyed a much longer second remission duration with maintenance rituximab compared to first-line treatment (chemotherapy or rituximab/chemotherapy) without maintenance.

As we move into an era when biologics and targeted therapies are playing a greater role in cancer management, the optimal duration of treatment with these agents is an additional parameter to be addressed in clinical trials. Lymphoma investigators are to be commended for addressing the issue of maintenance rituximab in well designed clinical trials, which have generated a large amount of data in a relatively short time.

Unfortunately, the optimal duration of treatment with other important biologic agents, including trastuzumab (Herceptin) and bevacizumab (Avastin), has not been addressed with similar focus. Standard practices for use of these agents have already developed, often based on small trials or retrospective subset analyses. Since most targeted agents have more toxicity than rituximab, the precise definition of treatment duration becomes all the more important. In the future, effective (and cost-effective) use of biologic agents will require careful definition of the optimal length of treatment, in addition to the usual issues of dose, schedule, and combination therapy.

-John D. Hainsworth, MD

Financial Disclosure:Dr. Hainsworth has conducted clinical research with funding received by the Sarah Cannon Research Institute from Genentech.

References:

1. Marcus R, Imrie K, Belch A, et al: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417-1423, 2005.

2. Hiddemann W, Kneba M, Dreyling M, et al: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725-3732, 2005.

3. Herold M, Haas A, Srock S, et al: Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: An East German Study Group Hematology and Oncology Study. J Clin Oncol 25:1986-1992, 2007.

4. Hochster HS, Weller E, Gascoyne RD, et al: Maintenance rituximab after CVP results in superior clinical outcome in advanced follicular lymphoma (FL): Results of the E1496 phase III trial from the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B (abstract 349). Blood 106(11):106a, 2005.

5. Hainsworth JD, Litchy S, Burris HA, et al: Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma. J Clin Oncol 20:4261-4267, 2002.

6. Hainsworth JD, Litchy S, Shaffer DW, et al: Maximizing therapeutic benefit of rituximab: Maintenance therapy versus retreatment at progression in patients with indolent non-Hodgkin's lymphoma-a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23:1088-1095, 2005.

7. Ghielmini M, Schmitz SF, Cogliatti SB, et al: Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 103:4416-4423, 2004.

8. Forstpointner R, Unterhalt M, Dreyling M, et al: Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 108:4003-4008, 2006.

9. van Oers MH, Klasa R, Marcus RE, et al: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin's lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood 108:3295-3301, 2006.

10. Hainsworth JD, Meng C, Spigel DR, et al: Long-term followup of patients with follicular lymphoma treated with two years of maintenance rituximab: Response to rituximab retreatment at progression (abstract 4723). Blood 108:2636, 2006.