Recent trials have demonstrated improvements in progression-free and overall survival with the inclusion of the chimeric anti-CD20 monoclonal antibody rituximab (Rituxan) in chemotherapy regimens for treatment-naive and relapsed patients with advanced-stage follicular non-Hodgkin's lymphoma (NHL). As rituximab therapy has significant single-agent activity in follicular NHL, is generally well tolerated, and has no dose-limiting or significant hematologic toxicity, a number of approaches evaluating maintenance therapy with extended dosing of rituximab are being tested. Trials have demonstrated prolonged progression-free survival in patients treated with maintenance rituximab using a variety of schedules following treatment with single-agent rituximab, induction or salvage chemotherapy, or salvage therapy with rituximab and chemotherapy combinations. Small increases in neutropenia and infections have been reported with extended rituximab use. Ongoing trials are evaluating the optimal use of rituximab (maintenance vs retreatment) and the benefit of rituximab maintenance following treatment of therapy-naive patients treated with rituximab-containing chemoimmunotherapy induction regimens. This article discusses the risks and benefits of maintenance rituximab for follicular NHL.
Immunotherapy with the chimeric anti-CD20 monoclonal rituximab (Rituxan) has rapidly gained acceptance in both initial and salvage therapy for patients with follicular lymphoma (FL). Chemoimmunotherapy with regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone), R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), or R-MCP (rituximab, mitoxantrone, chlorambucil [Leukeran], prednisone) have been associated with improved outcomes, including longer duration of remissions and improvements in overall survival (OS).[1-3]
Several factors have contributed to this remarkable success. These include significant single-agent activity with acceptable infusion-related toxicity and, most critically, a lack of significant overlapping toxicity when rituximab is administered simultaneously or following conventional chemotherapy. This favorable benefit-to-risk ratio has led to studies using extended rituximab dosing as maintenance therapy following a variety of induction treatments. Nearly all such studies have demonstrated a benefit to maintenance therapy. This review will address the principles of maintenance therapy and the current data concerning the risks and benefits of the use of maintenance therapy with rituximab for patients with FL.
Defining 'Maintenance' Therapy
One of the difficulties in addressing this issue is a lack of definition of what constitutes "maintenance" therapy. In practice, there are two situations included in this category. In one case, rituximab is given as maintenance following an induction treatment regimen containing rituximab. This would include treatment with single-agent rituximab or the use of a rituximab-containing immunochemotherapeutic regimen. In the other situation, prolonged rituximab therapy is given following initial treatment with regimens not containing rituximab. This can also be thought of as sequential therapy. In this latter situation it is perhaps not as surprising that treatment with rituximab following chemotherapy would be better than chemotherapy alone as rituximab produces high levels of single-agent activity (50%–70%) in patients with de novo or relapsed FL.
Principles of Maintenance Therapy
Several principles contribute to the effectiveness of maintenance therapy. Obviously, maintenance treatment is neither necessary nor effective in patients cured by the primary treatment. In fact, the more effective the primary treatment is, the more difficult it may be to prove the effectiveness of a maintenance strategy. Effective treatments lead to a reduced frequency of—or a delay in time until—relapse, and may require larger studies or longer duration of maintenance and follow-up to prove benefit. Conversely, the effects of maintenance therapy with an active agent may be easier to demonstrate when a high frequency and rate of events are observed following the induction therapy.
In follicular non-Hodgkin's lymphoma (NHL), which is not currently considered curable by initial therapy, an increased rate/frequency of relapse is observed in a number of situations. These include the treatment of patients at higher risk (ie, higher Follicular Lymphoma International Prognostic Index [FLIPI] scores at diagnosis), treatment of relapsed patients (shorter expected subsequent remission rate and duration), and the use of less effective treatment regimens (lower response rates, complete response [CR] rates, and duration of remission).
A second important concept is that the disease must initially be, and must remain, sensitive to the agents given for maintenance. Thus, treatment of a population already resistant to the maintenance therapy is not beneficial and only exposes patients to the continued risks of the therapy.
Development of Resistance to Rituximab
It is clear that resistance to rituximab may be present at the time of initial therapy or may develop following rituximab exposure. In our initial trials with rituximab for relapsed indolent NHL, 48% of patients had a documented response (partial response [PR] plus CR) to treatment with infusions of 375 mg/m2 weekly for four doses, with a median time to progression for responding patients of approximately 1 year.[4,5] Thus, at least 50% of these relapsed patients had some level of resistance to initial therapy with this regimen.
Furthermore, in a follow-up study, patients with a documented PR or CR to rituximab were then retreated upon disease progression with a second course of rituximab. All of these patients had previously responded with at least a PR or CR lasting more than 6 months, but only 40% had a documented response (PR or CR) to retreatment. Thus, 60% of these patients developed some level of resistance to retreatment following prior therapy with rituximab. However, it is also true that only a minority of patients actually developed progressive disease on therapy and many had some response (defined as less than a PR, but not progression) to retreatment. Thus, there may still be some benefit in these situations.
In most cases, the mechanism of resistance to rituximab is poorly understood. Occasionally, this appears to be due to loss of the CD20 antigen,[7,8] but more often, antigen expression appears to persist, implying that the resistance must be due to either the loss of direct effects (cell signaling, growth inhibition, apoptosis) or to acquired resistance to the immune effector functions of antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). In the context of a discussion on maintenance therapy, the question is: When during the course of therapy did this acquired resistance develop? Unfortunately, little information is currently available to help answer this question.
Patients with progressive disease while receiving rituximab maintenance, by definition, will be rituximab-refractory/resistant. It is reasonable to assume (but not proven) that patients refractory to rituximab therapy are unlikely to derive substantial benefit from rituximab maintenance therapy. As discussed below, it is not known how treatment with maintenance rituximab will influence the emergence of rituximab-resistant clones, nor what the clinical implications of this would be on subsequent therapy.
Maintenance Therapy After Single-Agent Rituximab
Our initial experience with single-agent rituximab for relapsed FL using a single dose and the weekly dose × 4 schedules did not identify a maximally tolerated dose or dose-limiting toxicity.[10,11] Further dose escalation was initially limited by drug availability. A subsequent study utilized eight weekly infusions for patients with relapsed FL, producing a similar response rate and duration of response to the weekly × 4 doses.
Recent studies have clearly demonstrated that giving additional rituximab on an extended schedule can prolong remission durations. A phase II study evaluated treatment with repeated courses of rituximab (375 mg/m2 weekly × 4), given at 6-month intervals for up to 2 years, to patients with stable or responding disease at 3 months following an initial course of rituximab. Patients in this study had not received any prior therapy and had FL or small lymphocytic lymphoma. The time to disease progression was more than 34 months for the patients with FL, which is longer than reported outcomes of a single course of rituximab in patients with low tumor bulk. Continued improvement in response was observed throughout the maintenance treatments.
A randomized study by the Swiss Group for Clinical Cancer Research (SAKK) provided more conclusive evidence. This trial evaluated patients with FL who were treated with four doses of rituximab on the usual weekly schedule.[15,16] Patients with at least stable disease were then randomized to observation vs an additional infusion of rituximab (375 mg/m2) at months 3, 5, 7, and 9. The extended schedule resulted in prolongation of time to progression, both for patients without prior chemotherapy and for relapsed patients. Interestingly, there was no greater improvement in the response rate (PR, CR, or conversion of PR to CR) in the maintenance group compared with the observation group, with both arms demonstrating improvement following the initial evaluation time at 12 weeks from the start of treatment.
In this randomized study, the benefit of maintenance was limited to patients with a documented response (PR or CR) to the initial rituximab treatment. An advantage of using maintenance rituximab following initial treatment with rituximab is that one can judge the response to the initial rituximab and restrict the administration of maintenance to those who are sensitive to rituximab and who will receive the most benefit. This may make such an approach even more cost-effective.
1. 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.
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. 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.
4. Maloney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90:2188-2195, 1997.
5. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998.
6. Davis TA, Grillo-Lopez AJ, White CA, et al: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: Safety and efficacy of re-treatment. J Clin Oncol 18:3135-3143, 2000.
7. Alvaro-Naranjo T, Jaen-Martinez J, Guma-Padro J, et al: CD20-negative DLBCL transformation after rituximab treatment in follicular lymphoma: A new case report and review of the literature. Ann Hematol 82:585-588, 2003.
8. Haidar JH, Shamseddine A, Salem Z, et al: Loss of CD20 expression in relapsed lymphomas after rituximab therapy. Eur J Haematol 70:330-332, 2003.
9. Jazirehi AR, Vega MI, Bonavida B: Development of rituximab-resistant lymphoma clones with altered cell signaling and cross-resistance to chemotherapy. Cancer Res 67:1270-1281, 2007.
10. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al: IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol 15:3266-3274, 1997.
11. Maloney DG, Liles TM, Czerwinski DK, et al: Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84:2457-2466, 1994.
12. Piro LD, White CA, Grillo-Lopez AJ, et al: Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 10:655-661, 1999.
13. Hainsworth JD, Litchy S, Burris HA 3rd, et al: Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol 20:4261-4267, 2002.
14. Colombat P, Salles G, Brousse N, et al: Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: Clinical and molecular evaluation. Blood 97:101-106, 2001.
15. Ghielmini M, Rufibach K, Salles G, et al: Single agent rituximab in patients with follicular or mantle cell lymphoma: Clinical and biological factors that are predictive of response and event-free survival as well as the effect of rituximab on the immune system: A study of the Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 16:1675-1682, 2005.
16. 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.
17. Hainsworth JD, Litchy S, Shaffer DW, et al: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment 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.
18. 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), 2005.
19. Hochster H, Weller E, Gascoyne R, et al: Cyclophosphamide and fludarabine (CF) in anvanced indolent lymphoma: Results from the ECOG/CALGB intergroup E1496 trial (abstract 8004). J Clin Oncol 25(18S):442s, 2007.
20. Forstpointner R, Dreyling M, Repp R, et al: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104:3064-3071, 2004.
21. 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.
22. van Oers MH, Klasa R, Marcus RE, et al: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood 108:3295-3301, 2006.
23. Cabanillas F, Liboy I, Pavia O, et al: High incidence of non-neutropenic infections induced by rituximab plus fludarabine and associated with hypogammaglobulinemia: A frequently unrecognized and easily treatable complication. Ann Oncol 17:1424-1427, 2006.
24. Bearden CM, Agarwal A, Book BK, et al: Rituximab inhibits the in vivo primary and secondary antibody response to a neoantigen, bacteriophage phiX174. Am J Transplant 5:50-57, 2005.
25. Gonzalez-Stawinski GV, Yu PB, Love SD, et al: Hapten-induced primary and memory humoral responses are inhibited by the infusion of anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab). Clin Immunol 98:175-179, 2001.
26. van der Kolk LE, Baars JW, Prins MH, et al: Rituximab treatment results in impaired secondary humoral immune responsiveness. Blood 100:2257-2259, 2002.
27. Freim Wahl SG, Folvik MR, Torp SH: Progressive multifocal leukoencephalopathy in a lymphoma patient with complete remission after treatment with cytostatics and rituximab: Case report and review of the literature. Clin Neuropathol 26:68-73, 2007.
28. Perceau G, Diris N, Estines O, et al: Late lethal hepatitis B virus reactivation after rituximab treatment of low-grade cutaneous B-cell lymphoma. Br J Dermatol 155:1053-1056, 2006.
29. Maturi B, Mikhael JR, Dunlop WCN, et al: Maintenance therapy with rituximab for follicular lymphoma is cost-effective—a Canadian perspective (abstract 343). Blood 108(11), 2006.
30. Gordan LN, Grow WB, Pusateri A, Douglas V, Mendenhall NP, Lynch JW: Phase II trial of individualized rituximab dosing for patients with CD20-positive lymphoproliferative disorders. J Clin Oncol 23:1096-1102, 2005.