Treatment of Follicular Lymphoma
Treatment Strategy Based on Disease Stage and Tumor Burden
For patients with follicular lymphoma, treatment decisions depend critically on disease stage and symptom burden: early-stage disease (Stage I-II) should receive radiotherapy at 24 Gy with curative intent, while advanced-stage asymptomatic patients with low tumor burden should undergo watchful waiting, and symptomatic or high tumor burden patients require immunochemotherapy with obinutuzumab or rituximab combined with bendamustine or CHOP, followed by rituximab maintenance. 1
Early-Stage Disease (Stage I-II)
Curative Radiotherapy Approach
- Involved field radiotherapy at 24 Gy is the treatment of choice for limited-stage disease with curative potential 1, 2
- Extended field irradiation should be performed for patients with documented contiguity of involved lymph nodes treatable in the same radiotherapy field 2
- A policy of watchful waiting is not recommended in Stage I-II disease, except in patients with severe comorbidities or contraindications to therapy 2
Exception for High-Risk Stage II
- Stage II patients with high tumor burden or FLIPI score >2 should receive chemoimmunotherapy instead of radiotherapy alone 1
- Selected patients with large tumor burden may receive systemic therapy as developed for advanced stages 2
Advanced-Stage Disease (Stage III-IV)
When to Initiate Treatment
Treatment should be started only when specific criteria are met 2:
- Systemic B-symptoms
- High tumor burden (>3 lymph nodes measuring >3 cm OR single lymph node >7 cm)
- Cytopenia due to marrow involvement
- Spleen involvement (≥16 cm by CT)
- Leukemic phase
- Serous effusion (ascites or pleural effusion)
- Symptomatic or life-threatening organ involvement
- Rapid lymphoma progression
- Consistently elevated LDH levels
Asymptomatic, Low Tumor Burden Disease
- Watchful waiting remains the standard of care for asymptomatic Stage II-IV non-bulky patients 2
- Rituximab monotherapy cannot be recommended in this setting despite improved progression-free survival, as no overall survival benefit has been demonstrated 2
- This approach is supported by the lack of overall survival improvement after treatment of asymptomatic advanced-stage patients 2
Common pitfall: While rituximab monotherapy improves time to next treatment and quality of life in asymptomatic patients, the guideline panel prioritized overall survival as the critical endpoint, making watchful waiting the appropriate choice 2
Symptomatic or High Tumor Burden Disease
First-line immunochemotherapy options 1:
- Obinutuzumab or rituximab combined with bendamustine (preferred)
- Obinutuzumab or rituximab combined with CHOP
Maintenance therapy 1:
- Rituximab maintenance every 2 months for 2 years is recommended after immunochemotherapy
- This applies to patients achieving complete or partial response to rituximab-containing induction therapy 3
Relapsed/Refractory Disease
Treatment Selection Algorithm
For early relapse (<12-24 months) 1:
- Use a non-cross-resistant chemotherapy regimen
- Add rituximab if previous antibody-containing regimen achieved >6-12 months duration of remission
For rituximab-refractory disease or remissions <6 months 1:
- Obinutuzumab-bendamustine plus obinutuzumab maintenance is recommended
- This represents a switch to a different anti-CD20 antibody with demonstrated activity in rituximab-refractory cases
Maintenance after relapse therapy 1:
- Rituximab maintenance every 3 months for up to 2 years
High-Dose Therapy Consideration
- High-dose chemotherapy with autologous stem cell transplant should be considered in patients with brief first remissions after rituximab-containing regimens 1
Critical Safety Considerations
Hepatitis B Screening and Prophylaxis
This is a mandatory safety measure that cannot be overlooked 1:
- Screen all patients for HBV infection (HBsAg and anti-HBc) before initiating rituximab 3
- In patients with positive hepatitis B serology, including occult carriers (anti-HBc positive), prophylactic antiviral medication is strongly recommended up to 2 years beyond last rituximab exposure
- HBV reactivation can result in fulminant hepatitis, hepatic failure, and death 3
Infusion-Related Reactions
- Rituximab should only be administered by healthcare professionals with appropriate medical support to manage severe infusion-related reactions 3
- Fatal infusion-related reactions can occur, with approximately 80% occurring during the first infusion 3
- Premedication before each infusion is required 3
Infectious Disease Screening
- Screen for HIV and hepatitis C in addition to hepatitis B before initiating therapy 2
Staging and Monitoring Requirements
Initial Staging Workup
- CT scan of neck, thorax, abdomen, and pelvis 2
- Bone marrow biopsy (≥20 mm length from posterior iliac spine with immunohistochemistry) 2
- Complete blood count, LDH, beta-2 microglobulin, uric acid 2
- PET scan should be included for limited-stage disease at CT scan in candidates for radiotherapy, as PET upstaging changes treatment approach 2
- Calculate FLIPI score (>4 nodal sites, elevated LDH, age >60 years, Stage III-IV, hemoglobin <12 g/dL) 2
Response Assessment
- Structural imaging should be performed mid-treatment and after completion of chemotherapy 1
- PET-CT after completion of induction identifies patients with adverse prognosis, though therapeutic consequences remain undefined 1
- At suspected relapse or progression, obtain a new confirmatory biopsy 1
Follow-Up Schedule
- History and physical examination every 3 months for 2 years, every 6 months for 3 additional years, then annually 2
- Monitor for transformation to aggressive lymphoma and secondary malignancies including leukemia 2
- Blood count and LDH at 3,6,12, and 24 months, then as needed 2
- Thyroid function evaluation at 1,2, and 5 years in patients who received neck irradiation 2
- Radiological examinations at 6,12, and 24 months after treatment completion 2