Can stage 3 follicular non-Hodgkin's lymphoma be treated with Rituximab (rituximab) alone without lenalidomide?

Treatment of Stage 3 Follicular Lymphoma with Rituximab Monotherapy

Rituximab monotherapy alone (without lenalidomide) is an acceptable treatment option for stage 3 follicular lymphoma, but only in highly selected patients with low tumor burden, low-risk profile, or contraindications to chemotherapy. For most patients requiring treatment, rituximab combined with chemotherapy (such as bendamustine or CHOP) remains the standard approach to achieve optimal progression-free and overall survival 1.

When Rituximab Monotherapy Is Appropriate

Low tumor burden or low-risk patients:

• Rituximab monotherapy is explicitly recommended by ESMO guidelines as an alternative for patients with a low-risk profile or when conventional chemotherapy is contraindicated 1.
• In a first-line trial of 49 patients with low tumor burden follicular lymphoma, rituximab monotherapy achieved 73% overall response rate (26% complete response), with 57% achieving molecular remission 2.
• This approach is suitable when patients lack high tumor burden criteria: no bulky disease >7 cm, fewer than 3 nodes >3 cm in distinct areas, no cytopenias, no elevated LDH or beta-2 microglobulin, and no B symptoms 1.

Watch-and-wait remains an option:

• For asymptomatic stage 3 patients without high tumor burden, observation ("watch and wait") is still the standard approach, as early treatment initiation does not improve overall survival 1.
• Treatment should only be initiated when symptoms develop, including B symptoms (fever >38°C, drenching night sweats, >10% weight loss), hematopoietic impairment, bulky disease, vital organ compression, or rapid progression 1.

Why Rituximab Plus Chemotherapy Is Preferred

Superior outcomes with chemoimmunotherapy:

• Multiple prospective trials and meta-analyses confirm that rituximab combined with chemotherapy (R-CHOP, R-bendamustine, R-CVP) significantly improves overall response rates, progression-free survival, and overall survival compared to chemotherapy alone 1.
• The StiL trial demonstrated that bendamustine-rituximab achieved median PFS of 69.5 months versus 31.2 months with R-CHOP, with similar overall survival but less toxicity 1.
• If complete remission and long progression-free survival are treatment goals, rituximab combined with chemotherapy should be used 1.

Rituximab maintenance after induction:

• Following any induction regimen, rituximab maintenance every 2 months for 2 years improves progression-free survival (median 10.5 years versus 4.1 years, P < 0.0001), though without overall survival benefit 1, 3.
• This maintenance strategy is recommended for patients achieving at least partial response 3.

Lenalidomide-Rituximab as an Alternative (Not Required)

Lenalidomide is not necessary but offers an alternative:

• The RELEVANCE trial demonstrated that lenalidomide-rituximab (R²) achieved similar efficacy to rituximab-chemotherapy in previously untreated follicular lymphoma, with 3-year progression-free survival of 77% versus 78% 4.
• Complete response rates at 120 weeks were comparable: 48% with R² versus 53% with rituximab-chemotherapy 4.
• The safety profiles differ: R² causes more cutaneous reactions (7% grade 3-4) and less neutropenia (32% versus 50% grade 3-4) compared to rituximab-chemotherapy 4, 5.

Lenalidomide-rituximab is particularly useful when:

• Chemotherapy is contraindicated or refused by the patient 1.
• The patient has relapsed/refractory disease, where lenalidomide-rituximab has shown superior efficacy to rituximab monotherapy 6.

Clinical Algorithm for Stage 3 Follicular Lymphoma

1. Assess tumor burden and symptoms 1:

   • If asymptomatic with low tumor burden → Consider watch-and-wait
   • If symptomatic or high tumor burden → Proceed to treatment

2. Select treatment based on patient fitness 1:

   • Fit patients requiring treatment → Rituximab + chemotherapy (bendamustine or CHOP) followed by rituximab maintenance 1
   • Low-risk or chemotherapy-contraindicated → Rituximab monotherapy or lenalidomide-rituximab 1, 4
   • Elderly or frail patients → Consider abbreviated chemoimmunotherapy or rituximab monotherapy 1

3. Consolidation/maintenance 1, 3:

   • Rituximab maintenance every 2 months for 2 years for responders
   • Begin 8 weeks after last induction treatment

Important Caveats

Hepatitis B screening is mandatory:

• All patients receiving rituximab require hepatitis B serology screening (HBsAg and anti-core antibody) 1.
• Prophylactic antiviral medication is strongly recommended for positive serology, continuing up to 2 years beyond last rituximab exposure 1.

Biopsy confirmation at relapse:

• Always obtain repeat biopsy at suspected relapse to exclude transformation to aggressive lymphoma, which requires different treatment 1.

Rituximab monotherapy limitations:

• While rituximab alone is effective and well-tolerated, it achieves lower complete response rates and shorter progression-free survival compared to combination approaches 1, 2.
• Most patients will eventually require more intensive therapy if disease progresses 2.