Follicular Lymphoma (Non-Hodgkin Lymphoma) Treatment Protocols

Treatment protocols for follicular lymphoma (FL) are provided below, including general recommendations and an algorithm, treatment by stage, and second-line treatment.

General treatment recommendations for FL

The oncologist managing patients with FL faces several challenges, as controversies do exist regarding the following:

• The best time to start therapy
• How to navigate treatment options
• Balancing the efficacy and toxicities in the treatment-decision algorithm
• The end point to which the success of the individual treatment should be measured

Some clinical scenarios with more straightforward decisions do exist (eg, patients with stage I or II; FL grade 1 or 2 patients with advanced disease [stages III and IV]). Nevertheless, definitions of the best time to initiate therapy continue to divide physicians.

The Groupe d’Etude des Lymphomes Folliculaires (GELF) and the British National Lymphoma Investigation (BNLI) proposed and used defined criteria for patients in whom immediate therapy is necessary. ^{[1, 2]}

GELF criteria are as follows ^[1] :

• High tumor bulk (see definition below)
• Presence of systemic symptoms
• Eastern Cooperative Oncology Group (ECOG) performance status >1
• Serum lactate dehydrogenase (LDH) or beta2-microglobulin level above normal values

High tumor bulk is defined with the following parameters:

• A tumor > 7 cm in diameter
• Three nodes in three distinct areas, each > 3 cm in diameter
• Symptomatic spleen enlargement
• Organ compression
• Ascites or pleural effusion

BNLI criteria are as follows ^[2] :

• Rapid, generalized disease progression in the preceding 3 mo
• Life-threatening organ involvement
• Renal infiltration
• Bone lesions
• Presence of systemic symptoms: Hemoglobin < 10 g/dL or WBC < 1.5 × 10 ⁹/L or platelet count < 100 × 10 ⁹/L; related to bone marrow involvement

General treatment algorithm for FL

Diagnosis of FL involves the following:

• Perform staging studies and determine FLIPI (Follicular Lymphoma International Prognostic Index) score ^[3]
• Assess therapeutic risk-to-benefit ratio for each patient
• Establish therapy end points (ie, palliation, best response, durable remission, or molecular remission)

Stage I/II

Treatment options are as follows:

• Involved-field radiotherapy (IFRT)
• Clinical trials
• Watch and wait

Advanced-stage (stages III-IV or bulky stage II) – asymptomatic

Treatment options are as follows:

• Clinical trial with correlative science studies (ie, rituximab plus other biologic agents or small molecules, and/or other monoclonal antibodies or immunotoxins)
• Rituximab chemotherapy
• Watch and wait

Advanced-stage (stages III-IV or bulky stage II) – any GELF or BNLI risk factors or high-risk FLIPI score

Treatment options are as follows::

• Clinical trial evaluating novel upfront immunochemotherapy approaches with or without postinduction therapy (rituximab maintenance, radioimmunotherapy [RIT], or bone marrow transplantation [BMT]), with correlative science studies

• If not on clinical trial: Rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) or other anthracycline-containing regimens (preferred for FL grade 3) or rituximab plus bendamustine (FL grades 1-2)

• Rituximab plus fludarabine or rituximab plus cyclophosphamide, vincristine, and prednisone (CVP); if not eligible for anthracyclines

Relapse

In all cases of relapse, check the following:

• Lymphoid tissue for gene profiling and proteomic analysis
• Biomarkers of disease
• Availability of preclinical studies with novel agents

For relapse where the duration of remission is at least 1 y, therapeutic options include the following:

• Clinical trial with correlative science studies
• Rituximab chemotherapy with or without rituximab maintenance
• Rituximab re-treatment (if used initially)
• RIT
• High-dose chemotherapy and autologous stem cell transplantation (SCT) if two relapses have occurred

For relapse where the duration of remission is < 1 y, therapeutic options include the following:

• Clinical trial with correlative science studies
• Salvage therapy followed by autologous SCT or allogeneic SCT, if eligible
• Rituximab chemotherapy with or without rituximab maintenance
• RIT

Treatment recommendations for early-stage FL

Stage I or II, World Health Organization (WHO) FL grade 1 or 2 ^[4]

Recommendations are as follows:

• IFRT is the treatment of choice for early-stage disease
• Radiation doses of 24-30 Gy have been used (36 Gy only if bulky) to involved sites
• Radiation therapy is preferred for limited-stage FLs; however, if significant toxicity is expected from radiotherapy, initial observation may be more appropriate

First-line treatment recommendations include using rituximab alone, as follows ^[4] :

• Rituximab 375 mg/m ² IV on days 1, 8, 15, and 22; repeat for one additional cycle ^[5]
• Enrollment in a clinical trial evaluating rituximab with or without biologic agents

Treatment recommendations for advanced-stage FL

Stage III-IV or bulky stage II ^[4] :

First-line treatment recommendations are as follows:

• Rituximab 375 mg/m² IV weekly for 4 wk with or without four additional doses given every week or every 2 mo (preferred extended schedule of rituximab administration) ^[5]  or

• Rituximab and fludarabine ^[6] : Rituximab 375 mg/m² IV on day 1 plus fludarabine 25 mg/m² IV on days 3-5; repeat every 28 d for six cycles (prophylactic trimethoprim-sulfamethoxazole, acyclovir, and fluconazole necessary) or

• R-B regimen (rituximab and bendamustine) ^{[7, 8]} : Rituximab 375 mg/m² IV on day 1 plus bendamustine 90 mg/m² IV on days 1 and 2; repeat every 28 d for six cycles or

• R-CHOP regimen ^[9] : Rituximab 375 mg/m² IV on day 1 pluscyclophosphamide 750 mg/m² IV on day 1 or 3 plusdoxorubicin 50 mg/m² IV on day 1 or 3 plusvincristine 1.4 mg/m² (dose cap at 2 mg) IV on day 1 or 3 plusprednisone 40 mg/m² PO on days 1-5 or 3-8; every 21 d for six cycles or

• R-CHOP regimen ^[10] : CHOP chemotherapy (see above) given at 21-d intervals for six cycles in combination with six doses of rituximab 375 mg/m² IV administered on day 8 (ie, before CHOP) and day 1 of the first cycle of CHOP, on day 1 of cycles three and five of CHOP, and two additional doses on days 28 and 35 after the last cycle of CHOP or

• R-CVP regimen ^[11] : Rituximab 375 mg/m² IV on day 1 plus cyclophosphamide 750 mg/m² IV on day 1 plus vincristine 1.4 mg/m² (dose cap at 2 mg) IV on day 1 plus prednisone 40 mg/m² PO on days 1-5; every 21 d for six cycles or

• R-FND regimen (rituximab, fludarabine, mitoxantrone, and dexamethasone) ^[12] : Rituximab 375 mg/m² IV on day 1 plus fludarabine 25 mg/m² IV on days 1-3 plusmitoxantrone 10 mg/m² IV on day 1 plus dexamethasone 20 mg PO or IV on days 1-5; every 4 wk for eight cycles (prophylactic trimethoprim-sulfamethoxazole, acyclovir, and fluconazole necessary)

After first-line treatment, the following are recommended:

• Observation
• Maintenance rituximab ^[13] : 375 mg/m ² IV every 8 wk for 2 y

Second-line and subsequent treatments

Treatment options include the following:

• Rituximab 375 mg/m ² IV weekly for 4wk
• Any rituximab chemotherapy regimen described in the first-line treatment setting that was not used before
• Idelalisib 150 mg PO BID is a phosphoinositide 3-kinase (PI3K) delta inhibitor that has been granted accelerated approval by the US Food and Drug Administration (FDA) (ie, confirmatory clinical trials in progress) for relapsed FL in patients who have received at least two prior systemic therapies ^[14]
• Copanlisib 60 mg IV on days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (21 days on and 7 days off). Continue treatment until disease progression or unacceptable toxicity. Copanlisib is another PI3K delta inhibitor granted accelerated approval by the FDA for relapsed FL in patients who have received at least two prior systemic therapies. ^[15]
• Rituximab 375 mg/m2 IV qWeek in Cycle 1 (Days 1, 8, 15 and 22) on Day 1 of every 28 day cycle from Cycles 2-5  in combination with lenalidomide 20 mg PO qDay on Days 1-22 every 28 days up to 12 cycles ^[16]
• Radioimmunotherapy (only if adequate bone marrow function, < 25% bone marrow involvement by lymphoma, and nonbulky adenopathy)
• Consider high-dose chemotherapy and autologous SCT if third relapse
• Consider allogeneic SCT if the duration of response after first-line therapy was < 1 y

Therapeutic options following second-line treatment are as follows:

• Observation
• Rituximab 375 mg/m ² IV every 8 wk for four additional doses ^[17] or
• Rituximab 375 mg/m ² IV weekly for 4 wk every 6 mo for 2 y ^[18] or
• Rituximab 375 mg/m ² IV weekly for 4 wk every 3 mo and 6 mo following completion of reinduction therapy ^[19] or
• Rituximab 375 mg/m ² IV every 3 mo for 2 y ^[20]

Obinutuzumab

Obinutuzumab is indicated for FL that is refractory to, or relapses after, a rituximab-containing regimen. ^[21]

Obinutuzumab is administered with bendamustine for six 28-day cycles:

• Cycle 1: Obinutuzumab 1000 mg IV on days 1, 8, and 15 plus bendamustine 90 mg/m ²/day IV on days 1 and 2
• Cycles 2-6: Obinutuzumab 1000 mg IV on day 1 plus bendamustine 90 mg/m ²/day IV on days 1 and 2
• Monotherapy:  Patients who achieve stable disease, complete response, or partial response in the first six cycles should continue on obinutuzumab 1000 mg IV every 2 months for 2 years

Duvelisib

Duvelisib is indicated for recurrent or relapsed FL after at least 2 prior systemic therapies ^[22] :

• Initial dose: 25 mg PO BID; modify dosage for toxicity 

Mosunetuzumab 

Mosunetuzumab is indicated for recurrent or relapsed FL after at least 2 prior systemic therapies ^[23]  :

• Cycle 1: 1 mg IV on Day 1; 2 mg IV on Day 8; and 60 mg IV on Day 15
• Cycle 2: 60 mg IV on Day 1 
• Cycle 3 and thereafter: 30 mg IV on Day 1
• Administer eight cycles, unless patients experience unacceptable toxicity or disease progression
• Partial response or stable disease after eight cycles: May continue with nine additional treatment cycles (17 cycles total) 

Tazemetostat

Tazemetostat is indicated for relapsed or refractory FL in patients whose tumors are positive for an EZH2 mutation and who have received at least 2 prior systemic therapies. It is also indicated for relapsed or refractory FL in patients who have no satisfactory alternative treatment options:

• 800 mg PO BID; continue until disease progression or unacceptable toxicity ^[24]

Umbralisib

Umbralisib is indicated for relapsed or refractory FL in patients who have received at least 3 prior systemic therapies:

• 800 mg PO once daily with food; continue until disease progression or unacceptable toxicity ^[25]