Maintenance rituximab

In the PRIMA study (NCT00140582), 1,018 patients with high-risk, previously untreated, symptomatic disease achieved complete response or partial response after induction therapy with immunochemotherapy (usually R-CHOP). Patients were then randomly assigned to 2 years of maintenance rituximab versus no maintenance.[44][Level of evidence B1]

In the PRIMA study (NCT00140582), 1,018 patients with high-risk, previously untreated, symptomatic disease achieved complete response or partial response after induction therapy with immunochemotherapy (usually R-CHOP). Patients were then randomly assigned to 2 years of maintenance rituximab versus no maintenance.[44][Level of evidence B1]

With a median follow-up of 9.0 years, median PFS favored rituximab maintenance (10.5 years) compared with observation (4.1 years) (HR, 0.61; 95% CI, 0.52−0.73; P < .001), but with no difference in OS.

In the United Kingdom/International Study (NCT00112931), 379 previously untreated patients with asymptomatic, low-burden disease were randomly assigned to watchful waiting versus rituximab induction only versus rituximab induction followed by 2 years of rituximab maintenance.[45][Level of evidence A3]

In the United Kingdom/International Study (NCT00112931), 379 previously untreated patients with asymptomatic, low-burden disease were randomly assigned to watchful waiting versus rituximab induction only versus rituximab induction followed by 2 years of rituximab maintenance.[45][Level of evidence A3]

Although OS and histological transformation rates were not different at 3 years, maintenance rituximab was favored based on quality-of-life studies (Mental Adjustment to Cancer Scale P = .0004 at 7 months; Illness Coping Score P = .0012 at 7 months) and time-to-initiation of new treatment by 3 years (54% for watchful waiting vs. 12% for rituximab maintenance [HR, 0.21; 95% CI, 0.14–0.31; P < .0001]).[45][Level of evidence A3]

In the United Kingdom/International Study (NCT00112931), 379 previously untreated patients with asymptomatic, low-burden disease were randomly assigned to watchful waiting versus rituximab induction only versus rituximab induction followed by 2 years of rituximab maintenance.[45][Level of evidence A3]

This study suggested that for some patients, watch and wait resulted in watch and worry.[46] However, from the perspective of OS and histological transformation rates, no benefit could be seen with rituximab maintenance.

In the RESORT study (NCT00075946), 289 previously untreated patients with asymptomatic, low-burden disease were randomly assigned to receive rituximab induction alone, with a re-treatment strategy that used rituximab at relapse versus rituximab induction plus maintenance rituximab every 13 weeks until treatment failure.[47][Level of evidence B3]These three randomized trials in previously untreated patients showed no advantage for the use of rituximab maintenance versus observation and reinduction of therapy at the time of relapse. The trials suggest a benefit for maintenance rituximab after reinduction for relapsed disease. Many questions remain about rituximab maintenance, particularly about truncating therapy at 2 years and long-term safety and efficacy. A trial extending rituximab maintenance to 5 years showed similar EFS or OS versus 1 year of maintenance after induction therapy with rituximab in previously untreated patients.[48][Level of evidence A1]

In the RESORT study (NCT00075946), 289 previously untreated patients with asymptomatic, low-burden disease were randomly assigned to receive rituximab induction alone, with a re-treatment strategy that used rituximab at relapse versus rituximab induction plus maintenance rituximab every 13 weeks until treatment failure.[47][Level of evidence B3]These three randomized trials in previously untreated patients showed no advantage for the use of rituximab maintenance versus observation and reinduction of therapy at the time of relapse. The trials suggest a benefit for maintenance rituximab after reinduction for relapsed disease. Many questions remain about rituximab maintenance, particularly about truncating therapy at 2 years and long-term safety and efficacy. A trial extending rituximab maintenance to 5 years showed similar EFS or OS versus 1 year of maintenance after induction therapy with rituximab in previously untreated patients.[48][Level of evidence A1]

With a median follow-up of 8.7 years, the 7-year rate for freedom from cytotoxic chemotherapy or radiation therapy was 83% for patients who received maintenance rituximab and 63% for patients who received induction alone (HR, 2.37; 95% CI, 1.5–3.8; P = .0001). There was no difference in the 10-year OS rate (83% vs. 84%; nonsignificant P = .5972). A re-treatment strategy achieved comparable disease control using significantly fewer doses of rituximab.

In the RESORT study (NCT00075946), 289 previously untreated patients with asymptomatic, low-burden disease were randomly assigned to receive rituximab induction alone, with a re-treatment strategy that used rituximab at relapse versus rituximab induction plus maintenance rituximab every 13 weeks until treatment failure.[47][Level of evidence B3]These three randomized trials in previously untreated patients showed no advantage for the use of rituximab maintenance versus observation and reinduction of therapy at the time of relapse. The trials suggest a benefit for maintenance rituximab after reinduction for relapsed disease. Many questions remain about rituximab maintenance, particularly about truncating therapy at 2 years and long-term safety and efficacy. A trial extending rituximab maintenance to 5 years showed similar EFS or OS versus 1 year of maintenance after induction therapy with rituximab in previously untreated patients.[48][Level of evidence A1]

Maintenance rituximab induces prolonged B-cell depletion, but morbidity from infections was not evaluated after 2015, when the full protocol data stopped (12 years after the study began).

The FOLL12 study (NCT02063685) included 807 patients with previously untreated high-tumor burden follicular lymphoma. Patients received rituximab plus chemotherapy induction and were randomly assigned to either standard rituximab maintenance (every 8 weeks for 2 years) or to postinduction treatment (monitoring, rituximab maintenance, or radioimmunotherapy) based on their complete metabolic response and measurable residual disease (MRD)–negative status.[49]

The FOLL12 study (NCT02063685) included 807 patients with previously untreated high-tumor burden follicular lymphoma. Patients received rituximab plus chemotherapy induction and were randomly assigned to either standard rituximab maintenance (every 8 weeks for 2 years) or to postinduction treatment (monitoring, rituximab maintenance, or radioimmunotherapy) based on their complete metabolic response and measurable residual disease (MRD)–negative status.[49]

With a median follow-up of 53 months, the 3-year PFS rate was 86% for patients who received standard maintenance and 72% for patients who received response-based treatment (P < .001). The 3-year OS rate was the same in both groups (98% vs. 97%; P = .238).[49][Level of evidence B1]

The FOLL12 study (NCT02063685) included 807 patients with previously untreated high-tumor burden follicular lymphoma. Patients received rituximab plus chemotherapy induction and were randomly assigned to either standard rituximab maintenance (every 8 weeks for 2 years) or to postinduction treatment (monitoring, rituximab maintenance, or radioimmunotherapy) based on their complete metabolic response and measurable residual disease (MRD)–negative status.[49]

This trial does not support the use of an end-of-treatment PET-CT scan to guide the use of maintenance rituximab.

A prospective trial included 202 patients with previously untreated low-tumor burden follicular lymphoma. Patients were randomly assigned to receive either four weekly doses of IV rituximab (standard dose, 375 mg/m2) or one dose of IV rituximab followed by three weekly doses of SQ rituximab (1,400 mg) and maintenance doses in months 3, 5, 7, and 9.[19]

A prospective trial included 202 patients with previously untreated low-tumor burden follicular lymphoma. Patients were randomly assigned to receive either four weekly doses of IV rituximab (standard dose, 375 mg/m2) or one dose of IV rituximab followed by three weekly doses of SQ rituximab (1,400 mg) and maintenance doses in months 3, 5, 7, and 9.[19]

With a median follow-up of 50.2 months, the 4-year PFS rate was 58.1% (95% CI, 47.5%–67.4%) for patients in the SQ arm who received maintenance therapy, and 41.2% (95% CI, 30.6%–51.6%) (HR, 0.585; 0.939–0.871; P = .0076) for the patients in the IV arm who did not receive maintenance therapy.[19][Level of evidence B1]

A prospective trial included 202 patients with previously untreated low-tumor burden follicular lymphoma. Patients were randomly assigned to receive either four weekly doses of IV rituximab (standard dose, 375 mg/m2) or one dose of IV rituximab followed by three weekly doses of SQ rituximab (1,400 mg) and maintenance doses in months 3, 5, 7, and 9.[19]

There was no difference in OS or time-to-next treatment.

Outside the context of clinical trials, the use of MRD testing has not been shown to be predictive in directing therapy for patients with follicular lymphoma. In retrospective analyses of two randomized prospective trials, while MRD negativity was prognostic of outcome, maintenance rituximab or obinutuzumab prolonged PFS the most among patients with MRD-negative disease.[49,50][Level of evidence C2] Stopping maintenance rituximab or obinutuzumab was not indicated in patients with MRD-negative disease, negating any possible change in therapy based on that status.

In a prospective randomized trial of 465 patients with relapsed follicular lymphoma, responders to R-CHOP or CHOP were further randomly assigned to receive rituximab maintenance (1 dose every 3 months for 2 years) or no maintenance.[51][Level of evidence B1]

In a prospective randomized trial of 465 patients with relapsed follicular lymphoma, responders to R-CHOP or CHOP were further randomly assigned to receive rituximab maintenance (1 dose every 3 months for 2 years) or no maintenance.[51][Level of evidence B1]

At a median follow-up of 6 years, rituximab maintenance was better for median PFS (44 months vs. 16 months, P < .001) and borderline for 5-year OS (74% vs. 64%, P = .07).

In a prospective randomized trial of 465 patients with relapsed follicular lymphoma, responders to R-CHOP or CHOP were further randomly assigned to receive rituximab maintenance (1 dose every 3 months for 2 years) or no maintenance.[51][Level of evidence B1]

This benefit for maintenance was evident even for patients who received rituximab during induction therapy. Most patients in both arms received extensive rituximab during postprotocol salvage treatment.

In a prospective randomized trial of 280 patients with relapsed follicular lymphoma, responders to chemotherapy and autologous stem cell transplant consolidation were randomly assigned to receive four doses of rituximab maintenance or no maintenance.[52][Level of evidence B1]

In a prospective randomized trial of 280 patients with relapsed follicular lymphoma, responders to chemotherapy and autologous stem cell transplant consolidation were randomly assigned to receive four doses of rituximab maintenance or no maintenance.[52][Level of evidence B1]

With an 8.3-year median follow-up, the 10-year PFS rates favored maintenance (54% vs. 37% [HR, 0.66; 95% CI, 0.47–0.91; P = .012]), but there was no difference in OS.

A meta-analysis of nine randomized clinical trials with a total of 2,586 patients with follicular lymphoma, most of whom had relapsed disease, compared rituximab maintenance with no maintenance and showed improved OS for rituximab maintenance in previously treated patients (HRdeath, 0.72; 95% CI, 0.57–0.91).[53][Level of evidence A1]