Optimization of Postremission Therapy in Follicular Lymphoma: Efficacy of Rituximab Maintenance

Rituximab has been proven to be an important part of the treatment of newly diagnosed and relapsed or refractory follicular lymphoma both alone and in combination with chemotherapy. Given its tolerability, rituximab has now been investigated in the maintenance setting in an effort to further improve progression-free and overall survival in patients with follicular lymphoma.

Abstract

Rituximab has been proven to be an important part of the treatment of newly diagnosed and relapsed or refractory follicular lymphoma both alone and in combination with chemotherapy. Given its tolerability, rituximab has now been investigated in the maintenance setting in an effort to further improve progression-free and overall survival in patients with follicular lymphoma.

With the development of monoclonal antibodies and their use in combination with chemotherapy for the treatment of follicular lymphoma, median survival of patients has increased.14 Much focus has been directed to investigating rituximab in the maintenance treatment of follicular lymphoma.

Follicular Lymphoma

Follicular lymphoma is the second most common subtype of lymphoma worldwide and constitutes 22% of all non-Hodgkin's lymphomas (NHL).5 It is believed to arise from germinal center B cells and morphologically is composed of a mixture of centrocytes and centroblasts. The WHO classification grades follicular lymphoma according to the number of admixed centroblasts within the neoplastic follicles, and thus divides them into 3 subtypes6 (Table 1). Grades 1 and 2 are considered low-grade lymphomas. Grade 3a follicular lymphoma can be approached as a low-grade or more aggressive lymphoma and has been included in clinical trials for both, whereas grade 3b is generally treated as a large-cell lymphoma. The neoplastic lymphocytes in follicular lymphoma express the pan-B-cell markers CD19, CD20, CD22, and CD79a, and antigens of the germinal center, including CD10 and Bcl-6. The cytogenetic hallmark of the disease is t(14;18), which results in the juxtaposition of the bcl-2 oncogene to the immunoglobulin heavy-chain locus on chromosome 14, resulting in constitutive expression of the bcl-2 protein product.

Table 1

WHO Lymphoma Classification System

Table 1

The median age at presentation is 60 years, and men and women are equally affected. Most patients are asymptomatic at diagnosis and can present with nodal or extranodal disease. The clinical course of patients with follicular lymphoma is variable; some survive for decades and even rarely achieve spontaneous remissions, whereas others experience rapid progression to resistant disease or transformation to more aggressive histology and may die within a year. Transformation is common, occurring in 3% to 6% of patients each year, and ultimately 30% to 50% of all patients.7

The Follicular Lymphoma International Prognostic Index (FLIPI) is a 5-factor prognostic index that defines 3 prognostic risk groups8 (Tables 2 and 3). The FLIPI has been validated in the post-Rituxan era.9 A second prognostic factor model, the FLIPI2, was recently developed using prospective data from patients with newly diagnosed follicular lymphoma, more than half of whom were being treated with rituximab-containing regimens10 (Tables 2 and 3).

Table 2

Prognostic Models in Follicular Lymphoma: FLIPI and FLIPI2

Table 2
Table 3

5-Year Overall Survival According to Risk Group in FLIPI or FLIPI2

Table 3

Follicular lymphoma is generally responsive to treatment, but its clinical course is characterized by repeated relapses. The standard management for patients who have asymptomatic follicular lymphoma is to “watch and wait.” In the pre-rituximab era, multiple randomized phase III trials compared immediate treatment with chemotherapy and observation for asymptomatic patients with advanced-stage follicular lymphoma and found no difference in outcome.1113 Thus, treatment is generally delayed until symptoms, cytopenias, or impending compromise of vital organs occur. For patients with stage I or II disease, radiotherapy is the recommended approach because of the potential for long-term disease-free survival.14

Rituximab

Rituximab is a human/mouse chimeric monoclonal antibody that binds specifically to the CD20 antigen. The CD20 molecule is a 33- to 37-kDa transmembrane phosphoprotein and is an attractive target for monoclonal antibody therapy because it is expressed in almost all normal and malignant B cells but not on stem cells, and it is not shed from the cell surface or internalized after ligand (or antibody) binding. For rituximab, the mouse constant regions have been replaced by human ones, and this chimerism allows the agent to persist for long periods in circulation, effectively mobilize immune effector mechanisms, and not generate human antimouse antibody responses.15 Rituximab kills B cells through several different mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), induction of apoptosis, and sensitization to chemotherapy.

In vitro studies have shown that rituximab binds C1q and thus activates the complement cascade and subsequent generation of the membrane attack complex.16 Consumption of complement from plasma can be observed after rituximab administration.17 Facilitating complement activation has been shown to significantly increase lysis of chronic lymphocytic leukemia cells treated with rituximab.18

ADCC refers to the recruitment of natural killer cells, macrophages, and monocytes by rituximab through its binding to their Fc receptors. Clynes et al.19 observed that the protection rituximab offered in nude mice against CD20+ human tumor xenografts was largely lost in mice lacking Fc receptors, indicating that the binding of cytotoxic effector cells via Fc receptors was responsible for much of the antitumor effect. Cartron et al.20 showed that in patients with previously untreated follicular lymphoma given rituximab, outcomes were better in those who were homozygous for a mutation that allowed for stronger binding of rituximab to the Fc receptors.

Rituximab-induced apoptosis has been shown in several in vitro and in vivo studies.21,22 Rituximab also seems to act synergistically with chemotherapy. Treatment of lymphoma cell lines with rituximab has been shown to render the cells sensitive to killing by several cytotoxic agents to which they were previously resistant.23

Finally, no recent data suggest that rituximab may kill follicular lymphoma cells by eliciting a follicular lymphoma–specific T-cell response.24

Rituximab and Follicular Lymphoma

In their pivotal trial involving 166 patients, McLaughlin et al.25 proved rituximab to be an effective and tolerable agent as monotherapy in relapsed low-grade or follicular lymphoma. Patients were treated with 4 weekly doses of rituximab and achieved an overall response rate (ORR) of 48%, with a 6% complete remission rate and a median time to progression of 12.5 months in patients who experienced a response to treatment.25 Rituximab monotherapy has also been proven to be efficacious as first-line treatment in follicular lymphoma, with patients experiencing a 73% ORR and 20% complete remission rate.26

When rituximab is added to chemotherapy, the combination is active in both untreated and relapsed follicular lymphoma. Four phase III trials have compared combination rituximab and chemotherapy with chemotherapy alone in patients with previously untreated follicular lymphoma.14 In all 4 series, ORR and either median time to treatment failure or event-free survival were superior in the chemoimmunotherapy arm. Overall survival was found to be superior in the chemoimmunotherapy arm in 3 of the trials. The addition of rituximab to chemotherapy has proven to be a cost-effective treatment option.27 Furthermore, when patients with low-grade NHL who previously responded to rituximab therapy relapse and are re-treated with rituximab alone, many patients experience response, thus delaying the need for chemotherapy. In a phase II study, 60 patients whose disease responded to at least one previous course of rituximab experienced a 40% ORR when re-treated with rituximab alone on relapse.28 Time to progression after this was estimated to be 16.3 months, equivalent to that seen with their initial course of rituximab.

Rituximab Maintenance

Efforts have been made to improve progression-free and overall survivals in follicular lymphoma using maintenance therapy with cytotoxic agents such as chlorambucil, cyclophosphamide, and interferon-α alone or in combination, but no long-term benefits have been observed in terms of overall survival, and in many cases toxicity has been significant.2931 Radioimmunotherapy has been used as an adjunct with reasonable tolerability. The phase III FIT (First-Line Indolent Trial) trial randomized patients with follicular lymphoma to either observation or further treatment with 90Y-ibritumomab tiuxetan (Zevalin) after they had experienced either a partial response or a complete remission/unconfirmed complete remission with a first-line regimen.32 Among patients treated with radioimmunotherapy consolidation, median progression-free survival increased from 13.3 to 36.5 months (P < .0001) at 3.5-year follow-up, and resulted in 77% of patients with partial responses converting to complete remission/unconfirmed complete remission, with a final complete remission/unconfirmed complete remission rate of 87.4% in patients who received consolidation with Zevalin compared with 53.3% in those who were observed. Notably, only 15.6% and 13.2% of patients in the observation and radioimmunotherapy consolidation arms, respectively, received rituximab-containing induction regimens. No significant difference in overall survival was observed. Longer follow-up data for this study were presented at the 2010 American Society of Hematology conference, where the 5-year progression-free survival rate was reported to be 29% in the observation group versus 47% in the radioimmunotherapy consolidation group.33 With the advent of rituximab and its high level of activity and tolerability in follicular lymphoma, many groups have now investigated the use of rituximab alone in the maintenance setting.

Hainsworth et al.34 were among the first to study rituximab in the maintenance setting in patients with indolent B-cell NHL. In a phase II trial, after treatment with 4 weekly doses of rituximab as first-line therapy, the 92% of patients who experienced either disease regression or stable disease went on to receive maintenance rituximab delivered in 4 weekly doses every 6 months for a maximum of 4 courses. After maintenance rituximab, the ORR was 73%, with 37% of patients achieving a complete remission and 42% improving their response category after induction.34 With a minimum follow-up of 24 months and a median follow-up of 30 months, the median progression-free survival for the whole group was 34 months. Among the 38 patients with follicular lymphoma, the 2 year progression-free survival for stage II or III disease was 77%, whereas it was 47% for stage IV disease. Thus, this study showed that the addition of rituximab maintenance after a single 4-week course of rituximab led to longer progression-free survival in untreated patients with follicular lymphoma than had previously been reported.

In another trial (SAKK 35/98), patients with both previously untreated and treated follicular lymphoma who experienced response or stable disease after 4 weekly doses of rituximab were randomized to either observation or maintenance with a single infusion of rituximab every 2 months for 4 courses.35 The overall response rate became significant between the groups at 2 years, with ORRs of 45% in the rituximab maintenance group and 28% in the observation group. Complete response rates, however, did not differ significantly between the groups at 2 years (29% vs. 19%, respectively). In addition, the number of patients showing improved response in the first 2 years was similar in both arms. The median event-free survival, however, improved with the addition of rituximab maintenance, and this improvement was even more significant in the subset of chemotherapy-naïve patients. With a median follow-up of 36 months, median event-free survival was found to be 23.2 months in the rituximab maintenance arm versus 11.8 months in the observation arm (P = .024), and increased to 36 and 19 months (P = .009), respectively, in chemotherapy-naïve patients. This randomized trial was among the first to show that prolonged treatment with rituximab improved progression-free survival in patients with follicular lymphoma.

Hainsworth et al.36 went on to compare rituximab maintenance with rituximab re-treatment at disease progression in patients with indolent NHL, because both strategies were shown to be effective. Patients, all of whom were previously treated with therapies not including rituximab, underwent treatment with 4 weekly doses of rituximab. If they subsequently experienced stable or responsive disease, they were randomized to either rituximab maintenance given as 4 weekly doses every 6 months for 4 courses or rituximab re-treatment with 4 weekly doses on disease relapse. For the subset of patients with follicular lymphoma, the progression-free survival in the maintenance arm was 31 months compared with 13 months in the re-treatment group. The complete remission rate after maintenance was also significantly higher than after re-treatment on relapse (32% vs. 7%, respectively), but the duration of rituximab benefit on progression-free survival was similar between the groups (31.3 vs. 27.4 months, respectively). Importantly, the 3-year overall survival rate in the maintenance arm was 72%, whereas in the re-treatment arm it was 68% and therefore not significantly different.

In the phase III ECOG 1496 trial, Hochster et al.37 found that prolonged treatment with rituximab resulted in a significant extension of progression-free but not overall survival in a group of patients with previously untreated advanced-stage indolent lymphoma. All patients were initially treated with 6 to 8 cycles of CVP (cyclophosphamide, vincristine, and prednisone) with no rituximab, and those who experienced response or stable disease were then randomized to either observation or further treatment with rituximab given every 6 months 4 times weekly for a maximum of 4 courses. Of the 92% of patients who had either responsive or stable disease after induction with CVP, 22% of those randomized to the rituximab arm showed improved disease response over time, whereas only 9% of those who were observed after CVP showed improved response (P = .00006). In the subset of patients with follicular lymphoma, median progression-free survival from the time of either rituximab treatment initiation or observation was 4.3 versus 1.3 years, respectively (P = 9.2 × 10–8). The 3-year overall survival was 91% in patients receiving rituximab treatment and 86% in patients who were observed (P = .08). Notably, among patients with high tumor burden, overall survival at 3 years showed a strong trend favoring prolonged treatment with rituximab (hazard ratio [HR], 0.6; 95% CI, 0.3–1.0; P = .03).

To address whether rituximab maintenance was effective when remission was induced by a regimen containing both rituximab and chemotherapy, the German Low Grade Lymphoma Study Group conducted a prospective randomized trial comparing rituximab maintenance to no further treatment in patients with recurring and refractory follicular lymphoma or mantle cell lymphoma responding to salvage therapy with rituximab in combination with fludarabine, cyclophosphamide, and mitoxantrone (R-FCM). The study initially included a preceding randomization for R-FCM versus FCM alone, but this was stopped when R-FCM treatment provided a significant improvement in response rate, response duration, and overall survival over FCM alone. Subsequently, 195 patients treated with R-FCM were randomized to either observation or maintenance rituximab given as 4 weekly doses at months 3 and 9 after completion of salvage therapy. Patients with follicular lymphoma who received R-FCM as initial therapy had a significantly prolonged response when treated with rituximab maintenance compared with those who underwent observation only. The median duration of response in the rituximab maintenance group was not reached in the study, whereas the estimated median duration of response in the observation group was 26 months (P = .035).38 Thus, the antilymphoma activity of rituximab during remission did not seem to be compromised by the addition of rituximab to induction chemotherapy.

These results were confirmed by van Oers et al.39 in a similarly designed phase III trial (EORTC 20981) of patients with relapsed, resistant follicular lymphoma. Patients were initially randomized to either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP with rituximab (R-CHOP) for salvage therapy. Those who experienced response to salvage therapy underwent a second randomization to either no further treatment or rituximab maintenance in the form of a single infusion every 3 months until relapse or for a maximum of 2 years. Patients who received salvage R-CHOP had significantly higher complete remission rates (29.5% vs. 15.6%; P < .001) along with longer durations of response (median progression-free survival, 33.1 vs. 20.2 months; P < .001). Rituximab maintenance yielded longer median progression-free survival than observation, regardless of what type of salvage therapy was used. Of the patients who received R-CHOP for remission induction, median progression-free survival was 51.8 months after rituximab maintenance versus 23 months after observation (P = .004).

Notably, at a median follow-up of 33 months, rituximab maintenance significantly increased 3-year overall survival from 77.1% in the observation group to 85.1% in the rituximab maintenance group (P = .011). Unfortunately, this survival advantage was not sustained on longer follow-up at 5 years, at which point overall survival increased from 64.7% in the observation group to 74.3% in the rituximab maintenance group (P = .07).40 Although not statistically significant, subgroup analysis according to induction regimen showed a trend toward improved 5-year overall survival in the CHOP group (P = .05 in CHOP responders). With the longer median follow-up of 6 years, rituximab maintenance again yielded superior median progression-free survival over observation alone regardless of which regimen was given for remission induction therapy. Median progression-free survival in patients who experienced response to CHOP and received maintenance therapy was 3.1 years compared with 1 year in those who underwent observation (P < .001). Median progression-free survival in patients who experienced response to R-CHOP and received maintenance therapy was 4.4 years compared with 1.9 years in those who underwent observation (P = .043).

Vidal et al.41 completed a meta-analysis with the data from all of the aforementioned rituximab trials minus the long-term data from the trial by van Oers et al.39 and concluded that rituximab maintenance improved not only progression-free survival but also overall survival in patients with follicular lymphoma.41

Long-term follow-up data from the SAKK 35/98 trial has also been reported. At a median follow-up of 9.5 years, median event-free survival remained significantly superior in the rituximab maintenance group (24 vs. 13 months; P < .001), with multivariate analysis showing that the prolonged rituximab schedule was the only favorable prognostic factor for event-free survival (HR, 0.59; 95% CI, 0.39–0.88; P = .009).42 Maintenance rituximab, however, only showed benefit in patients whose disease initially responded to rituximab, because median event-free survival was not significantly different among those with stable disease who were randomized. As observed in the earlier analysis, chemotherapy-naïve patients who experienced response to induction continued to do especially well when randomized to maintenance therapy, with an 8-year remission rate of 45% (vs. 5% when randomized to observation). Notably, no significant difference was observed in overall survival between the groups (P = .0813).

The recently published PRIMA (Primary Rituximab and Maintenance) study was the first to assess the potential benefit of rituximab maintenance after first-line treatment of patients with follicular lymphoma with rituximab plus chemotherapy regimens. Patients with newly diagnosed follicular lymphoma received induction treatment with R-CVP, R-CHOP, or R-FCM according to their treatment center's preference, after which those experiencing response were randomized to either observation or maintenance rituximab given as 1 dose every 2 months for a maximum of 2 years. The 3-year progression-free survival rate was significantly higher in the rituximab maintenance group (74.9% vs. 57.6%; P < .0001).43 Median time to progression in the observation arm was estimated to be 48.3 months, whereas in the maintenance arm it had not yet been reached at the time of report. More patients experienced a complete remission or an unconfirmed complete remission after maintenance (71.5% vs. 52.2%; P = .0001), and more had an improved disease response. At median follow-up of 36 months, no significant difference in overall survival was seen between the groups (HR, 0.87; 95% CI, 0.51–1.47). The effect of rituximab maintenance did not differ among induction chemotherapy regimens according to preplanned subgroup analysis. No significant difference was seen in patient-reported quality of life measures (P = .89). If and how these results will change with longer follow-up remains to be seen.

Whether rituximab maintenance treatment is truly superior to rituximab re-treatment has not been determined. Although Hainsworth et al.36 showed significantly improved progression-free survival with rituximab maintenance, the benefit of rituximab was similar in both arms and no significant difference was seen in overall survival.

The optimal schedule and duration of rituximab maintenance are unclear. The different rituximab maintenance schedules used have been based on previous pharmacokinetic studies.44,45 The SAKK 35/03 phase III trial addresses the issue of duration of maintenance therapy with rituximab. Patients with previously untreated or relapsed/refractory follicular lymphoma who experienced response to 4 weekly doses of rituximab were randomized to 2 different maintenance rituximab schedules. Patients in arm A of the trial received a dose of maintenance rituximab every 2 months for a total of 4 doses, whereas those in arm B received a dose every 2 months for a maximum of 5 years or until progression or unacceptable toxicity. Only the safety analysis of each regimen at a median follow-up of 22.7 months has been reported, and no increased toxicity seems to accompany the extension of maintenance therapy to beyond 2 years.46 Whether this holds true with longer follow-up and what effect longer maintenance has on event-free and overall survival remains to be seen.

Toxicity

Toxicity is an obvious crucial consideration when investigating the value of using rituximab maintenance in the treatment of follicular lymphoma. Because rituximab efficiently kills both malignant and nonmalignant CD20+ cells, normal peripheral B cells are rapidly depleted after drug administration. The level of normal B lymphocytes remains low for 2 to 6 months after rituximab administration, with recovery to pretreatment levels occurring by 12 months after the last dose.47 An expected consequence of this is patients being exposed to increased risk of infection for prolonged periods. This risk of infection may be further exacerbated by the hypogammaglobulinemia that has been associated with rituximab. After rituximab administration, median levels of IgG, IgM, and IgA have been found to be lowest at 12, 6, and 9 months, respectively.47

In their meta-analysis, Vidal et al.41 found that the rate of grade 3 or 4 infection-related adverse events was significantly higher in patients receiving rituximab maintenance/consolidation therapy than in those undergoing observation (relative risk, 2.9; 95% CI, 1.21–3.27).43 In long-term follow-up of the EORTC 20981 trial, van Oers et al.40 reported that only 4 of 167 patients withdrew from maintenance treatment because of recurrent infections. Similarly, the PRIMA trial reported more grade 2 through 4 infections in their maintenance rituximab group than in their observation group (39% vs. 24%; P < .0001), with upper respiratory tract infections and urinary tract infections among the most common infections reported. Of the patients in the rituximab maintenance group, 1% had to discontinue treatment because of infection.

Rituximab is associated with an increased risk of viral infection. Reactivation of hepatitis B virus is one of the most frequently reported serious viral infections in patients treated with rituximab and has been linked to fulminant hepatic failure and death.47 In one study, hepatitis B reactivation was reported up to 170 days after the last dose of rituximab.49 Prophylactic lamivudine has successfully decreased the risk of hepatitis B virus reactivation in hepatitis B surface antigen (HepBsAg)–positive patients undergoing chemotherapy or immunotherapy, but HepBsAg-negative patients have also developed hepatitis B after treatment with rituximab-containing regimens.4951

Other commonly reported viral infections include cytomegalovirus and varicella zoster virus, whereas echovirus, influenza A, parvovirus B19, West Nile virus, BK virus, hepatitis C, herpes simplex virus, and even JC virus in association with rituximab have been seen.48 The observation that progressive multifocal leukoencephalopathy (PML) developed in patients treated with rituximab led to an FDA warning in 2006.

In 2009, Carson et al.52 reported 52 patients with lymphoid malignancies, 2 patients with lupus, 1 patient with rheumatoid arthritis, 1 patient with idiopathic autoimmune pancytopenia, and 1 patient with idiopathic thrombocytopenic purpura who all developed PML after rituximab treatment. Notably, all of the patients had been pretreated with immune suppressive therapy before receiving rituximab. Patients presented with various nonspecific neurologic symptoms, including confusion/disorientation, motor weakness/hemiparesis, poor motor coordination, speech changes, and vision changes. They had received a median of 6 doses of rituximab before PML diagnosis. The median time from first dose of rituximab to PML diagnosis was 16 months, whereas median time from last dose of rituximab to diagnosis was 5.5 months. The case-fatality rate was 90%. Of the 5 patients who survived, treatment of the PML included cytarabine alone in one patient; mirtazapine alone in another patient; a combination of cidofovir, donor lymphocyte infusion, cytarabine, and risperidone in a third patient; and nothing at all in 2 patients. All 5 patients were left with some degree of neurologic deficit.

The belief is that perhaps hematopoietic progenitor cells may be a site of JC viral latency and that these infected cells are mobilized into circulation during chemotherapy. Given the morbidity and mortality associated with PML, the role of rituximab JC virus reactivation deserves further investigation.

Pulmonary toxicity is rare but has been described in association with rituximab.53 Reversible bronchospasm can occur during the first infusion of rituximab in 10% of patients. Rarely, pulmonary infiltrates and even acute respiratory distress syndrome can occur. Delayed pulmonary damage has also been reported in the form of interstitial lung disease, bronchiolitis obliterans with organizing pneumonia, diffuse alveolar hemorrhage, pulmonary cysts, and pulmonary hypertension.

Few data exist regarding late toxicity from rituximab, but late-onset neutropenia (LON) has emerged. Rituximab-associated LON is defined by most investigators as grade III to IV neutropenia (absolute neutrophil count [ANC] < 500–1000 cells/mcL) occurring 3 to 4 weeks after the last treatment with rituximab and after the ANC has recovered to normal or near-normal.54 Several retrospective trials have been reported in recent years that have attempted to define the incidence and natural history of LON. The trials have been very heterogenous, in that study populations have included patients with different kinds of lymphomas, chronic lymphocytic leukemia, and autoimmune disease, and those who have undergone stem cell transplants. Rates of LON have mostly ranged from 3% to 27% in these trials, with median time from last rituximab dose to LON ranging from 38 to 175 days and median duration of LON episodes ranging from 5 to 77 days.54 The median number of rituximab treatments before onset of LON ranged from 2 to 8. The mechanism of LON is not completely understood. Because CD20 is not expressed on granulocytes or on stem or progenitor cells, this mechanism is not likely to be through direct cytotoxicity. Some argue that it is an immune-mediated phenomenon.55 The rates of infection during LON in these retrospective trials have ranged from 0% to 20%, and the infections do not seem to have resulted in death in any of the affected patients. Thus, the clinical significance of LON is not yet clear.

Further understanding of the risks associated with extended rituximab use will eventually become available as longer-term follow-up data are collected from the rituximab maintenance trials conducted to date. For now, rituximab maintenance does not seem to pose an unacceptable degree of risk to patients with NHL.

Conclusions

Rituximab clearly has significant activity in follicular lymphoma. It has proven to be useful in the treatment of newly diagnosed and relapsed or refractory follicular lymphoma both alone and in combination with chemotherapy. It has also been shown to be equally effective when given for a second time after patients with previously rituximab-responsive disease experience relapse. Efforts have been made for some time to improve on outcomes in follicular lymphoma by using maintenance therapy. Previously studied chemotherapy regimens have resulted in significant toxicity in the maintenance setting without improving overall survival. Radioimmunotherapy has been proven to be a safe alternative to chemotherapy in the maintenance setting, although it did not improve overall survival. In addition, it has not yet been studied extensively in patients who have received rituximab-containing induction regimens. Given its tolerability, rituximab has become another attractive option for the maintenance setting. Rituximab maintenance has been repeatedly shown in studies to provide significant improvement in disease-free survival but has yet to convincingly show significant improvement in overall survival. Toxicity data available on the extended use of rituximab in lieu of expectant observation in follicular lymphoma have been acceptable to date. Thus, experts believe that its use as maintenance to improve outcomes in patients with follicular lymphoma is appropriate.

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    • Export Citation
  • 26

    ColombatPSallesGBrousseN. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood2001;97:101106.

    • Search Google Scholar
    • Export Citation
  • 27

    LewisGMarcusREProctorSJ. The cost-effectiveness of rituximab, cyclophosphamide, vincristine, and prednisolone (RCVP) compared with CVP for the treatment of follicular non-Hodgkin’s lymphoma (NHL) in the UK [abstract]. Blood2006;108(Suppl 1):Abstract 345.

    • Search Google Scholar
    • Export Citation
  • 28

    DavisTAGrillo-LopezAJWhiteCA. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and efficacy of re-treatment. J Clin Oncol2000;18:31353143.

    • Search Google Scholar
    • Export Citation
  • 29

    RohatinerAZGregoryWMPetersonB. Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol2005;23:22152223.

    • Search Google Scholar
    • Export Citation
  • 30

    StewardWPCrowtherDMcWilliamLJ. Maintenance chlorambucil after CVP in the management of advanced stage, low-grade histologic type non-Hodgkin’s lymphoma. A randomized prospective study with an assessment of prognostic factors. Cancer1988;61:441447.

    • Search Google Scholar
    • Export Citation
  • 31

    EzdinliEZHarringtonDPKucukO. The effect of intensive intermittent maintenance therapy in advanced low-grade non-Hodgkin’s lymphoma. Cancer1987;60:156160.

    • Search Google Scholar
    • Export Citation
  • 32

    MorschhauserFRadfordJVan HoofA. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol2008;26:51565164.

    • Search Google Scholar
    • Export Citation
  • 33

    HagenbeekARadfordJVan HoofA. 90Y-Ibritumomab tiuxetan (Zevalin) consolidation of first remission in advanced-stage follicular non-Hodgkin’s lymphoma: updated results after a median follow-up of 66.2 months from the international, randomized, phase III First-Line Indolent Trial (FIT) in 414 patients [abstract]. Presented at the 52nd ASH Annual Meeting and Exposition; December 4–7, 2010; Orlando, Florida. Abstract 594.

    • Search Google Scholar
    • Export Citation
  • 34

    HainsworthJDLitchySBurrisHAIII. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin’s lymphoma. J Clin Oncol2002;20:42614267.

    • Search Google Scholar
    • Export Citation
  • 35

    GhielminiMSchmitzSFCogliattiSB. 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. Blood2004;103:44164423.

    • Search Google Scholar
    • Export Citation
  • 36

    HainsworthJDLitchySShafferDW. 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 Oncol2005;23:10881095.

    • Search Google Scholar
    • Export Citation
  • 37

    HochsterHWellerEGascoyneRD. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol2009;27:16071614.

    • Search Google Scholar
    • Export Citation
  • 38

    ForstpointnerRUnterhaltMDreylingM. 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). Blood2006;108:40034008.

    • Search Google Scholar
    • Export Citation
  • 39

    van OersMHKlasaRMarcusRE. 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. Blood2006;108:32953301.

    • Search Google Scholar
    • Export Citation
  • 40

    van OersMHVan GlabbekeMGiurgeaL. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol2010;28:28532858.

    • Search Google Scholar
    • Export Citation
  • 41

    VidalLGafter-GviliALeiboviciL. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst2009;101:248255.

    • Search Google Scholar
    • Export Citation
  • 42

    MartinelliGSchmitzSFUtigerU. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol2010;28:44804484.

    • Search Google Scholar
    • Export Citation
  • 43

    SallesGSeymourJFOffnerF. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet2011;377:4251.

    • Search Google Scholar
    • Export Citation
  • 44

    GordanLNGrowWBPusateriA. Phase II trial of individualized rituximab dosing for patients with CD20-positive lymphoproliferative disorders. J Clin Oncol2005;23:10961102.

    • Search Google Scholar
    • Export Citation
  • 45

    BerinsteinNLGrillo-LopezAJWhiteCA. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol1998;9:9951001.

    • Search Google Scholar
    • Export Citation
  • 46

    TavernaCJBassiSHitzF. First results of long-term rituximab maintenance treatment in follicular lymphoma: safety analysis of the randomized phase III trial SAKK 35/03 [abstract]. J Clin Oncol2009;27(15 Suppl):Abstract 8534.

    • Search Google Scholar
    • Export Citation
  • 47

    RaoAKellyMMusselmanM. Safety, efficacy, and immune reconstitution after rituximab therapy in pediatric patients with chronic or refractory hematologic autoimmune cytopenias. Pediatr Blood Cancer2008;50:822825.

    • Search Google Scholar
    • Export Citation
  • 48

    AksoySHarputluogluHKilickapS. Rituximab-related viral infections in lymphoma patients. Leuk Lymphoma2007;48:13071312.

  • 49

    YeoWChanTCLeungNW. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol2009;27:605611.

    • Search Google Scholar
    • Export Citation
  • 50

    PeiSNChenCHLeeCM. Reactivation of hepatitis B virus following rituximab-based regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients. Ann Hematol2010;89:255262.

    • Search Google Scholar
    • Export Citation
  • 51

    ZiakasPDKarsaliakosPMylonakisE. Effect of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in lymphoma: a meta-analysis of published clinical trials and a decision tree addressing prolonged prophylaxis and maintenance. Haematologica2009;94:9981005.

    • Search Google Scholar
    • Export Citation
  • 52

    CarsonKREvensAMRicheyEA. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood2009;113:48344840.

    • Search Google Scholar
    • Export Citation
  • 53

    KimbyE. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev2005;31:456473.

  • 54

    WolachOBaireyOLahavM. Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature. Medicine (Baltimore)2010;89:308318.

    • Search Google Scholar
    • Export Citation
  • 55

    VoogEMorschhauserFSolal-CelignyP. Neutropenia in patients treated with rituximab. N Engl J Med2003;348:26912694.

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The authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.

Correspondence: Rupali Roy, MD, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 676 North St. Clair, Suite 850, Chicago, IL 60611. E-mail: rupali-roy@md.northwestern.edu

Article Sections

References

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    McLaughlinPGrillo-LopezAJLinkBK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol1998;16:28252833.

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  • 26

    ColombatPSallesGBrousseN. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood2001;97:101106.

    • Search Google Scholar
    • Export Citation
  • 27

    LewisGMarcusREProctorSJ. The cost-effectiveness of rituximab, cyclophosphamide, vincristine, and prednisolone (RCVP) compared with CVP for the treatment of follicular non-Hodgkin’s lymphoma (NHL) in the UK [abstract]. Blood2006;108(Suppl 1):Abstract 345.

    • Search Google Scholar
    • Export Citation
  • 28

    DavisTAGrillo-LopezAJWhiteCA. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and efficacy of re-treatment. J Clin Oncol2000;18:31353143.

    • Search Google Scholar
    • Export Citation
  • 29

    RohatinerAZGregoryWMPetersonB. Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol2005;23:22152223.

    • Search Google Scholar
    • Export Citation
  • 30

    StewardWPCrowtherDMcWilliamLJ. Maintenance chlorambucil after CVP in the management of advanced stage, low-grade histologic type non-Hodgkin’s lymphoma. A randomized prospective study with an assessment of prognostic factors. Cancer1988;61:441447.

    • Search Google Scholar
    • Export Citation
  • 31

    EzdinliEZHarringtonDPKucukO. The effect of intensive intermittent maintenance therapy in advanced low-grade non-Hodgkin’s lymphoma. Cancer1987;60:156160.

    • Search Google Scholar
    • Export Citation
  • 32

    MorschhauserFRadfordJVan HoofA. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol2008;26:51565164.

    • Search Google Scholar
    • Export Citation
  • 33

    HagenbeekARadfordJVan HoofA. 90Y-Ibritumomab tiuxetan (Zevalin) consolidation of first remission in advanced-stage follicular non-Hodgkin’s lymphoma: updated results after a median follow-up of 66.2 months from the international, randomized, phase III First-Line Indolent Trial (FIT) in 414 patients [abstract]. Presented at the 52nd ASH Annual Meeting and Exposition; December 4–7, 2010; Orlando, Florida. Abstract 594.

    • Search Google Scholar
    • Export Citation
  • 34

    HainsworthJDLitchySBurrisHAIII. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin’s lymphoma. J Clin Oncol2002;20:42614267.

    • Search Google Scholar
    • Export Citation
  • 35

    GhielminiMSchmitzSFCogliattiSB. 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. Blood2004;103:44164423.

    • Search Google Scholar
    • Export Citation
  • 36

    HainsworthJDLitchySShafferDW. 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 Oncol2005;23:10881095.

    • Search Google Scholar
    • Export Citation
  • 37

    HochsterHWellerEGascoyneRD. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol2009;27:16071614.

    • Search Google Scholar
    • Export Citation
  • 38

    ForstpointnerRUnterhaltMDreylingM. 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). Blood2006;108:40034008.

    • Search Google Scholar
    • Export Citation
  • 39

    van OersMHKlasaRMarcusRE. 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. Blood2006;108:32953301.

    • Search Google Scholar
    • Export Citation
  • 40

    van OersMHVan GlabbekeMGiurgeaL. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol2010;28:28532858.

    • Search Google Scholar
    • Export Citation
  • 41

    VidalLGafter-GviliALeiboviciL. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst2009;101:248255.

    • Search Google Scholar
    • Export Citation
  • 42

    MartinelliGSchmitzSFUtigerU. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol2010;28:44804484.

    • Search Google Scholar
    • Export Citation
  • 43

    SallesGSeymourJFOffnerF. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet2011;377:4251.

    • Search Google Scholar
    • Export Citation
  • 44

    GordanLNGrowWBPusateriA. Phase II trial of individualized rituximab dosing for patients with CD20-positive lymphoproliferative disorders. J Clin Oncol2005;23:10961102.

    • Search Google Scholar
    • Export Citation
  • 45

    BerinsteinNLGrillo-LopezAJWhiteCA. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol1998;9:9951001.

    • Search Google Scholar
    • Export Citation
  • 46

    TavernaCJBassiSHitzF. First results of long-term rituximab maintenance treatment in follicular lymphoma: safety analysis of the randomized phase III trial SAKK 35/03 [abstract]. J Clin Oncol2009;27(15 Suppl):Abstract 8534.

    • Search Google Scholar
    • Export Citation
  • 47

    RaoAKellyMMusselmanM. Safety, efficacy, and immune reconstitution after rituximab therapy in pediatric patients with chronic or refractory hematologic autoimmune cytopenias. Pediatr Blood Cancer2008;50:822825.

    • Search Google Scholar
    • Export Citation
  • 48

    AksoySHarputluogluHKilickapS. Rituximab-related viral infections in lymphoma patients. Leuk Lymphoma2007;48:13071312.

  • 49

    YeoWChanTCLeungNW. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol2009;27:605611.

    • Search Google Scholar
    • Export Citation
  • 50

    PeiSNChenCHLeeCM. Reactivation of hepatitis B virus following rituximab-based regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients. Ann Hematol2010;89:255262.

    • Search Google Scholar
    • Export Citation
  • 51

    ZiakasPDKarsaliakosPMylonakisE. Effect of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in lymphoma: a meta-analysis of published clinical trials and a decision tree addressing prolonged prophylaxis and maintenance. Haematologica2009;94:9981005.

    • Search Google Scholar
    • Export Citation
  • 52

    CarsonKREvensAMRicheyEA. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood2009;113:48344840.

    • Search Google Scholar
    • Export Citation
  • 53

    KimbyE. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev2005;31:456473.

  • 54

    WolachOBaireyOLahavM. Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature. Medicine (Baltimore)2010;89:308318.

    • Search Google Scholar
    • Export Citation
  • 55

    VoogEMorschhauserFSolal-CelignyP. Neutropenia in patients treated with rituximab. N Engl J Med2003;348:26912694.

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