Follicular Lymphoma: Pharmacologic Management

Follicular lymphoma is caused by genetic alterations to B cells located in the follicular zone of a lymph node that have a t(14,18) chromosomal translocation.^1,2 Follicular lymphoma makes up approximately 20% of all non-Hodgkin lymphoma diagnoses and is the second-most common type of slow-growing lymphoid malignancy in western countries.^1,2 

The prognosis for patients with follicular lymphoma is usually favorable, with length of survival influenced by stage of disease at diagnosis.¹ According to the National Cancer Institute, the average 5-year survival rate for patients with follicular lymphoma is 90.6%,³ and more than 80% of diagnosed individuals live more than 10 years following diagnosis.¹ The median age at diagnosis of follicular lymphoma ranges from 60 to 65 years.¹

Treatment of follicular lymphoma is highly individualized, and choice of treatment is based on disease grading and staging, individual health risk, and patient age. 

Characterizing Follicular Lymphoma Risk

Because treatment for follicular lymphoma is so specialized, it is important to understand all the specific characteristics of the cancer and the individual. Diagnosis is made through a combination of imaging and biopsy. Positron emission tomography (PET) and computed tomographic (CT) imaging is usually performed to determine the size and number of sites involved. Biopsy followed by an extensive molecular workup that includes immunohistochemistry and flow cytometry are also used to confirm the molecular identity of the tumor.⁴

Grade, stage, and other specific diagnostic criteria can be useful in determining prognosis and treatment course for patients with follicular lymphoma.

Grade

Follicular lymphoma is graded using histology. The severity of grading is based on the number of large cancerous cells (centroblasts) per microscopic high-power field (HPF).⁵ Histologic grading for follicular lymphoma is as follows:⁴

Grade 1: 0 to 5 centroblasts/HPF

Grade 2: 6 to 15 centroblasts/HPF

Grade 3A: >15 centroblasts/HPF with centrocytes

Grade 3B: >15 centroblasts/HPF with sheets of centrocytes

Stage

The stage of follicular lymphoma contributes to identifying the appropriate treatment regimen. Staging criteria are ubiquitous for all B-cell lymphomas,⁴ except tumor size criteria for bulky disease may change based on the specific type of lymphoma. 

Stage I:  One lymph node is involved.

Stage II: More than one lymph node is involved on the same anatomical side of the diaphragm.

Stage II bulky: Stage II but with a tumor measuring ≥7 cm.

Stage III: Lymph nodes are either on both sides of the diaphragm or above the diaphragm and have spread to the spleen.

Stage IV: The cancer has spread beyond the lymph nodes to other organs.

Stages III and IV follicular lymphoma are considered advanced but may have an overall good prognosis. Stage II can be described as contiguous if the lymph nodes affected are overlapping or nearby each other in the same anatomical space.

Other Diagnostic Criteria

Two other assessments that are used in decision-making for the treatment of follicular lymphoma are the Follicular Lymphoma International Prognostic Index (FLIPI) and the Groupe d’Etude des Lymphomes Folliculaire (GELF) criteria.

FLIPI

FLIPI is a set of criteria used to categorize patients into 3 risk groups — high (>3 factors), intermediate (2 factors), and low (0-1 factor) — based on the number of factors present. These factors include^4,5:

• Older than 60 years of age;
• Cancer stage III or IV;
• Presence of at least 5 affected lymph nodes;
• Hemoglobin levels below 12 g/dL; and
• Serum lactate dehydrogenase (LDH) levels above the upper limit of normal.

These criteria are more useful for predicting prognosis rather than preferred treatment for follicular lymphoma.

GELF

The GELF criteria are used as a diagnostic tool for treatment-decision making based on a binary system: patients either meet at least 1 criterion of the GELF assessment or they do not. The GELF criteria include⁴:

• >3 lymph nodes affected with a diameter measuring >3 cm;
• Tumor measuring >7 cm;
• Displaying B symptoms (night sweats, fever, weight loss);
• Spleen enlargement;
• Fluid buildup in the lungs or peritoneal cavity;
• <1.0 x 10⁹ leukocytes/L and/or <100 x 10⁹ platelets/L; and
• Leukemia. 

Follicular Lymphoma Treatment Types

Treatments for follicular lymphoma include watchful waiting, radiation, chemotherapy, immunotherapy, and targeted therapy. First-line therapies usually include combination regimens.

Chemotherapy

Chemotherapy may be used at any stage during treatment of follicular lymphoma. First-line therapy recommendations include these treatments in combination with anti-CD20 monoclonal antibody therapies.^4,6,7

The following are chemotherapy agents for the treatment of follicular lymphoma:

• Bendamustine hydrochloride
• Chlorambucil
• Cyclophosphamide

Immunotherapy Including CD20-Targeted Monoclonal Antibody Therapy

CD20-targeted immunotherapy is the first-line treatment option for follicular lymphoma. These are monoclonal antibody treatments that target CD20, an extracellular protein expressed by tumorigenic cells. These antibodies can effectively target the tumor cells for degradation. Rituximab and obinutuzumab are the preferred first-line treatments in many cases of follicular lymphoma. 

The following are immunotherapy agents for the treatment of follicular lymphoma^4,6,7:

• Ibritumomab tiuxetan
• Obinutuzumab
• Rituximab
• Lenalidomide

Targeted Therapy

Targeted therapies for follicular lymphoma consist of molecular inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and a bispecific T-cell engager therapy. Axicabtagene ciloleucel and tisagenlecleucel are CAR T-cell therapies approved for use in patients with follicular lymphoma. These are usually second- or third-line therapies.^4,6,7

The following are targeted therapy agents for the treatment of follicular lymphoma^4,6,7:

• Tazemetostat hydrobromide
• Copanlisib hydrochloride
• Axicabtagene ciloleucel
• Tisagenlecleucel
• Mosunetuzumab-axgb

Combination Regimens

First-line therapy recommendations for follicular lymphoma usually include a combination of monoclonal antibody therapies and chemotherapies.⁵ 

The following are combination treatment regimens for follicular lymphoma^4,6,7:

• Bendamustine with obinutuzumab or rituximab
• Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)
• Cyclophosphamide, vincristine, and prednisone (CVP)
• CHOP with obinutuzumab or rituximab
• CVP with obinutuzumab or rituximab
• Lenalidomide with rituximab
• Chlorambucil with rituximab

When To Use Different Treatments for Follicular Lymphoma

All recommendations provided are for grades 1 and 2 of follicular lymphoma. As grades 3A and grade 3B follicular lymphoma closely resemble other B-cell lymphomas, treatment recommendations are the same as for those other lymphomas. However, diffuse large B-cell lymphoma (DLBCL) and large B-cell lymphoma (LBCL) are treated differently. Treatment for grade 3B follicular lymphoma is the same as that for DLBCL and will be mentioned briefly later in this review. However, as noted, the scope of this review is to provide an overview of treatment for patients with follicular lymphoma grades 1 and 2.

Chemotherapy is typically given in combination with anti-CD20 monoclonal antibodies. Table 1 reviews the dosage, administration, and recommended use for chemotherapy for follicular lymphoma.

Table 1. Management Guidelines for Chemotherapy for Follicular Lymphoma

Drug	Dosage	Administration	Treatment Duration	Recommended Use
Bendamustine hydrochloride	120 mg/m2 on days 1 and 2 of 3-wk cycle	IV infusion over 60 min	Up to eight 3-wk cycles	Given with obinutuzumab or rituximab; first-line therapy; stages I and II follicular lymphoma; stages III and IV follicular lymphoma if GELF indications are present
Chlorambucil*	0.1-0.2 mg/kg/d	Oral tablets	3-6 wk	Can be given with or without rituximab; first- and second-line therapy for the elderly or those not physically strong;  stages I and II follicular lymphoma; stages III and IV follicular lymphoma if GELF indications are present
Cyclophosphamide*	1-5 mg/kg/d	Oral capsules		Can be given with or without rituximab; first- and second-line therapy for the elderly or those not physically strong; stages I and II follicular lymphoma; stages III and IV follicular lymphoma if GELF indications are present; also part of CHOP and CVP regimens (see Table 4)

GELF = Groupe d’Etude des Lymphomes; IV = intravenous; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP = cyclophosphamide, vincristine, and prednisone.

*Off-label use for follicular lymphoma but recommended by the NCCN in certain circumstances.

From FDA-approved prescribing information and NCCN.^4,8-10

CD20-targeted monoclonal antibodies are first-line treatments for follicular lymphoma. Table 2 reviews the dosage, administration, and recommended use for CD20-targeted therapies and immunotherapies in this setting.

Table 2. Management Guidelines for CD20-Targeted Therapy and Immunotherapy for Follicular Lymphoma

Drug	Dose	Administration	Treatment Duration	Recommended Use
Ibritumomab tiuxetan	If platelets > 150,000/mm3, administer 0.4 mCi/kg 4 h after rituximab infusion If platelets are between 100,000 and 149,000/mm3, administer 0.3 mCi/kg 4 h after rituximab infusion	IV infusion	6-12 wk; given 4 h after rituximab on days 7, 8, or 9 after rituximab was also given on day 1	Given with rituximab; second-line therapy used in stages III and IV and stage II bulky follicular lymphoma; may be recommended for elderly or physically weak
Obinutuzumab	1000 mg	IV infusion	Every 2 mo up to 2 y for maintenance therapy	First-line when used as maintenance therapy; second-line as a single agent; rituximab-refractory; used with other therapies for stages III and IV and stage II bulky follicular lymphoma
Rituximab	375 mg/m2 weekly	IV infusion	4 doses administered every 8-12 wk up to 2 y in extended dosing or maintenance therapy	Preferred first-line therapy in elderly or physically weak when used alone; often used with chemotherapy regimens and other immunotherapies, as well as following radiation; stages III and IV and stage II bulky follicular lymphoma
Lenalidomide	20 mg/d for days 1-21 of 28-d cycle	Oral capsules	Up to 12 28-d cycles	Usually taken with rituximab

IV = intravenous.

From FDA-approved prescribing information and NCCN.^4,11-14

Targeted therapies are only recommended as second- or third-line treatment for follicular lymphoma. Treatment with 2 or more other systemic therapies is usually recommended first. CAR T-cell therapies are newer treatments, so data on their effects are limited. Preliminary studies suggest that CAR T-cell therapies may be useful in recurrent follicular lymphoma.¹⁵ Table 3 reviews the dosage, administration, and recommended use for targeted therapies in this setting.

Table 3. Management Guidelines for Targeted Therapy for Follicular Lymphoma

Drug	Dose	Administration	Timeline of Treatment	Recommended Use
Tazemetostat hydrobromide	800 mg twice daily	Oral tablets	Until disease worsens or intolerable toxicity	Second-line therapy for elderly or physically weak; third-line for stages III and IV and stage II bulky follicular lymphoma*; recommended following use of 2 other systemic therapies for patients who have no other treatment options
Copanlisib hydrochloride	60 mg on days 1, 8, and 15 of 28-d cycle	IV infusion over 1 h	Until disease worsens or intolerable toxicity	Third-line therapy; recommended following use of 2 other systemic therapies in fit patients
Axicabtagene ciloleucel	2 x 106 CAR-positive viable T cells/kg	IV infusion	Single dose	Third-line therapy; recommended following use of 2 other systemic therapies in fit patients
Tisagenlecleucel	0.6-6.0 x 106 CAR-positive viable T cells/kg	IV infusion	Single dose	Third-line therapy; indicated following use of 2 other systemic therapies
Mosunetuzumab-axgb	1 mg on day 1, 2 mg on day 8, and 60 mg on day 15 of the first cycle; 60 mg on day 1 of the second cycle; and 30 mg on day 1 of the third cycle and any subsequent cycles	IV infusion	Three 15-day cycles	Third-line therapy; indicated following use of 2 other systemic therapies

CAR = chimeric antigen receptor; IV = intravenous. 

*Prescription label recommends EZH2 [enhancer of zeste homolog 2] confirmation in certain cases, but NCCN does not.

From FDA-approved prescribing information and NCCN.^4,16-20

Combination regimens are typically first-line treatment options in the treatment of follicular lymphoma. Table 4 reviews the dosage, administration, and recommended use for combination regimens for managing this condition.

Table 4. Management Guidelines for Combination Regimens for Follicular Lymphoma

Drug	Dosing Schedule	Treatment Duration	Recommended Use
Bendamustine with obinutuzumab or rituximab	Rituximab 375 mg/m2 on day 1 of 4-wk cycle; obinutuzumab 1000 mg on days 1, 8, and 15 of a 4-wk cycle; bendamustine 90 mg/m2 on days 1 and 2 of a 4-wk cycle for either antibody treatment	Six 4-wk cycles	Preferred first-line therapy for stages III and IV and stage II bulky follicular lymphoma
CHOP	On the first day, IV infusion of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/2 with oral prednisone 100 mg/m2 administered on days 1-5	Six 21-d cycles	Only recommended with obinutuzumab or rituximab
CVP	On the first day, IV infusion of cyclophosphamide 750 mg/m2 and vincristine 1.4 mg/2 with 100 mg/m2 of oral prednisone administered on days 1-5	Eight 21-d cycles	Only recommended with obinutuzumab or rituximab
CHOP with obinutuzumab or rituximab	Obinutuzumab 1000 mg on days 1, 8, and 15 with CHOP in 21-day cycle OR  CHOP with rituximab 375 mg/m2 on day 0 of 21-day cycle	Six 21- d cycles of CHOP with obinutuzumab OR   Rituximab followed by 2 cycles of obinutuzumab or rituximab alone	Preferred first-line therapy for stages III and IV and stage II bulky follicular lymphoma
CVP with obinutuzumab or rituximab	CVP with obinutuzumab 1000 mg on days 1, 8, and 15 in 21-day cycle OR CVP with rituximab 375 mg/m2 on day 0 of 21-day cycle	Eight 21-d cycles	Preferred first-line therapy for stages III and IV and stage II bulky follicular lymphoma
Lenalidomide with rituximab	Lenalidomide 20 mg/d on days 2-22 of first 6 cycles and rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2-6	Six 28-d cycles and then possible modifications for 12 additional cycles based on response	First-line therapy for stages III and IV and stage II bulky follicular lymphoma
Chlorambucil with rituximab	Chlorambucil 6 mg/m2/d for weeks 1-6, 9, 10, 13, 14, 17, 18, 19, 21, and 22, and rituximab 375 mg/m2 on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 19	22 wk	First-line therapy for elderly or physically weak, as well as stages III and IV and stage II bulky follicular lymphoma

CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CVP = cyclophosphamide, vincristine, prednisone;

From NCCN and clinical trials.^4,21-24

Monitoring Side Effects of Follicular Lymphoma Treatments

Because there is generally good evidence to support the use of a variety of chemotherapies and different regimens, recommendations need to be individualized.

In one study comparing bendamustine, CHOP, and CVP with anti-CD20 monoclonal antibody therapies (GALLIUM; ClinicalTrials.gov Identifier: NCT01332968), bendamustine showed higher rates of infections and greater numbers of fatal events than CHOP or CVP regimens.²⁵ In this same study, CHOP treatment was shown to induce neutropenia faster than other treatments, but it did not lead to more infections.²⁵ Overall, CHOP or CVP may be better treatments than bendamustine for elderly or physically weak patients.

Table 5. Side Effect Profiles for Chemotherapy for Follicular Lymphoma

Drug	Most Common Adverse Events	Side Effects Necessitating Treatment Discontinuation or Modification	Drug-Drug Interactions	Special Populations
Bendamustine hydrochloride	Nausea, tiredness, low lymphocyte count, low leukocyte count, anemia, low neutrophil count, low platelet count, vomiting, diarrhea, fever, constipation, weight loss, cough low body weight, rash, headache, difficulty breathing, inflammation of the oral mucosa	Low neutrophil and platelet count, infection, PML, anaphylaxis, tumor lysis syndrome, severe skin reactions, liver toxicity, new malignancies	CYP1A2 inhibitors and inducers	Can lead to miscarriage and birth defects; not recommended during pregnancy; breastfeeding is not advised until 1 wk after final dose; female patients should use contraception for 6 mo after last dose; male patients should use contraception for 3 mo after last dose; may affect fertility in male patients; not advised for patients with pre-existing kidney and liver dysfunction
Chlorambucil	Bone marrow suppression, anemia, low leukocytes, low neutrophils, low platelets, low red and white blood cells, vomiting nausea, diarrhea, inflammation of the oral mucosa, neurologic symptoms, skin reactions	Kidney toxicity, seizures, severe neurologic reactions, new malignancies, jaundice, fever, peripheral nerve damage, lung disease, anaphylaxis, severe skin reactions, pulmonary fibrosis	None indicated	Can cause fetal harm; not recommended during pregnancy; contraception is advised during administration; may cause infertility in male  patients
Cyclophosphamide	Low neutrophil count, fever caused by low neutrophil count, hair loss, nausea, vomiting, diarrhea	Bone marrow suppression leading to infections, kidney and urinary tract toxicity, lung toxicity, new malignancies, veno-occlusive liver disease, cardiac toxicity	Protease and ACE inhibitors, natalizumab, thiazide diuretics, zidovudine, paclitaxel, anthracyclines, cytarabine, trastuzumab, pentostatin, amiodarone, G-CSF, GM-CSF, indomethacin, amphotericin B, azathioprine, busulfan, etanercept, metronidazole, coumarins, cyclosporine, tamoxifen, depolarizing muscle relaxants	May cause fetal harm; not recommended during pregnancy; breastfeeding is not advised until 1 wk after final dose; female patients should use contraception for 1 y after last dose; male patients should use contraception for 4 mo after last dose; may affect fertility in male and female patients; reproductive harm is a greater risk in pediatric population; may have more risks for individuals with pre-existing kidney and liver issues

ACE = angiotensin-converting enzyme; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; PML = progressive multifocal leukoencephalopathy.

From FDA-approved prescribing information and NCCN.^4,8-10

Obinutuzumab and rituximab are first-line therapies in the treatment of follicular lymphoma, and choosing between them is patient-specific. Obinutuzumab treatment has been associated with a longer time until disease recurrence, but there are no data to suggest that it improves overall survivability.²²

Rituximab generally has fewer severe adverse events. Specifically, obinutuzumab has been shown to have higher rates of infusion-related reactions, secondary malignancies, cardiac issues, low neutrophil and platelet counts, and fatal reactions.²²

Table 6. Side Effect Profiles for CD20-Targeted Immunotherapy for Follicular Lymphoma

Drug	Most Common Adverse Events	Side Effects Necessitating Treatment Discontinuation or Modification	Drug-Drug Interactions	Special Populations
Ibritumomab tiuxetan	Low counts of certain blood cells,  tiredness, cold symptoms, cough, nausea, diarrhea, stomach pain, weakness, fever	Severe infusion-related reactions, decreased platelet and neutrophil counts, severe skin and mucosal reactions, secondary malignancies	None indicated	May cause fetal harm; not recommended during pregnancy; breastfeeding is not advised until 6 mo after final dose; contraception should be used for 1 y after last dose in male and female patients; may affect fertility in male and female patients
Obinutuzumab	Infusion-related reactions, tiredness, low neutrophil count, upper respiratory tract infections, diarrhea, cough, muscle pain	Severe infusion-related reactions, hypersensitivity reactions, tumor lysis syndrome, infection, low neutrophil count, low platelet count, DIC	Immunizations should not be given at the same time	May cause fetal harm; not recommended during pregnancy; breastfeeding is not advised until 6 mo after final dose; female patients should use contraception for 6 mo after last dose; geriatric population may have higher rates of adverse events
Rituximab	Infusion-related reactions, low lymphocyte counts, fever, chills, infection, weakness	Severe infusion-related reactions, severe mucocutaneous reaction, HBV reactivation, PML	Cisplatin	May cause fetal harm; not recommended during pregnancy; breastfeeding is not advised until 6 mo after final dose; female patients should use contraception for 1 y after last dose; may not be advisable in patients > 70 y
Lenalidomide	Low neutrophil count, low platelet count, low leukocyte count, anemia, diarrhea, fever, constipation, nausea, tiredness, cough, upper respiratory tract infection, skin rash	Low neutrophil count, low platelet count, blood clots	Digoxin; erythropoietin-stimulating agents, therapies with estrogen	May cause fetal harm; not recommended during pregnancy; breastfeeding is not advised; contraception is recommended for 4 wk prior to start and 4 wk following last dose of medication; geriatric population may have more adverse events; patients on dialysis should have dose adjusted based on creatinine clearance value

DIC = disseminated intravascular coagulation; HBV = hepatitis B virus; PML = progressive multifocal leukoencephalopathy.

From FDA-approved prescribing information and NCCN.^4,11-14

Tazemetostat, copanlisib, and mosunetuzumab-axgb have specific drug interactions to consider during use. Axicabtagene ciloleucel and tisagenlecleucel — the CAR T-cell therapies — pose the risk of developing cytokine release syndrome (CRS), which is a condition in which cytokines are released in bulk into the bloodstream. This may result in rash, headache, fever, nausea, increased heart rate, and difficulty breathing.²⁶

Table 7 reviews the side effect profiles for targeted therapies used in the treatment of follicular lymphoma.

Table 7. Side Effect Profiles for Targeted Therapy for Follicular Lymphoma

Drug	Most Common Adverse Events	Side Effects Necessitating Treatment Discontinuation or Modification	Drug–Drug Interactions	Special Populations
Tazemetostat hydrobromide	Tiredness, upper respiratory tract infection, stomach pain, nausea, muscle pain	Low neutrophil count, low platelet count, anemia, secondary malignancies	Strong and moderate CYP3A inhibitors and inducers	May cause fetal harm; not recommended during pregnancy; breastfeeding is not advised until 1 wk after final dose; female patients should use contraception for 6 mo after last dose; male patients should use contraception for 3 mo after last dose
Copanlisib hydrochloride	Hyperglycemia,  diarrhea, weakness, hypertension, low leukocyte count, low neutrophil count, low platelet count, nausea, lower respiratory tract infections	Infections, hyperglycemia, hypertension, noninfectious pneumonitis, low neutrophil count, severe skin reactions	CYP3A inhibitors and induces	May cause fetal harm; not recommended during pregnancy; breastfeeding is not advised until 1 mo after final dose; female and male patients should use contraception for 1 mo after last the dose; may affect fertility; geriatric populations may experience increased adverse events
Axicabtagene ciloleucel	CRS, fever, hypotension, encephalopathy, tiredness, headache, increased heart rate, low neutrophil count, fever caused by low neutrophil count, diarrhea, musculoskeletal pain, infections, low leukocyte count, low lymphocyte count, chills, anemia, low platelets, decreased hunger, low serum phosphate levels	Hypersensitivity reactions, severe infections, prolonged reduction in blood cell counts, low serum antibody levels, secondary malignancies, toxic neurologic reactions	None indicated	May cause fetal harm; not recommended during pregnancy; breastfeeding is not advised during use
Tisagenlecleucel	CRS, infections, headache, tiredness, musculoskeletal pain, low neutrophil count, low leukocyte count	CRS, toxic neurologic reactions, hypersensitivity reactions, severe infections, prolonged reduction in blood cell counts, low serum antibody levels, secondary malignancies	False positive results on HIV nucleic acid tests	May cause fetal harm; not recommended during pregnancy; breastfeeding is not advised during use
Mosunetuzumab-axgb	CRS, skin rash, tiredness, fever, headache, decreased lymphocyte count, decreased serum phosphate levels, hyperglycemia, decreased neutrophil count, elevated uric acid, decreased leukocyte count,  decreased hemoglobin, decreased platelet count	CRS, toxic neurologic reactions, severe infections, cytopenias, reduction blood cells, tumor flare reaction	CYP450 substrates	May cause fetal harm; not recommended during pregnancy; breastfeeding is not advised until 3 mo after final dose; female and male patients should use contraception for 3 mo after last the dose

CRS = cytokine release syndrome.

From FDA-approved prescribing information and NCCN.^4,16-20

Follicular Lymphoma Treatment Guidelines

There has been much debate regarding the preferred guidelines for the treatment of follicular lymphoma. The age, physical health, previous treatment status, and severity of illness for each patient all play a role in identifying individualized treatment recommendations.

The following recommendations are based on the National Comprehensive Cancer Network (NCCN) consensus. Recommendations provided are for grades 1 and 2 follicular lymphoma. As grades 3A and 3B follicular lymphoma have features similar to DLBCL, they are treated as such. 

First, the preferred first-line and second-line treatments will be reviewed. Second, stage-specific treatment recommendations for follicular lymphoma will be covered. Lastly, a brief review of the DLBCL treatment strategy will be provided.⁴

Preferred Treatment Regimens for Follicular Lymphoma

First-line treatment regimens usually include a combination of chemotherapy and anti-CD20 monoclonal antibody therapy. The following are preferred first-line regimens for the treatment of follicular lymphoma:

• Bendamustine with obinutuzumab or rituximab
• CHOP with obinutuzumab or rituximab
• CVP with obinutuzumab or rituximab
• Lenalidomide with rituximab

For elderly patients or physically weak patients, rituximab is the preferred first-line therapy. In situations for which extended dosing is recommended, rituximab or obinutuzumab may be used.

Second-line preferred treatment recommendations are the same as first-line treatments; however, if the patient has already received bendamustine, it is recommended they receive a different chemotherapy. It is also recommended that the patient use a different immunotherapy than previously used.

Maintenance therapy with rituximab is only a preferred recommendation when the patient has a high tumor burden and their primary treatment was either rituximab with CHOP or rituximab with CVP.

Stage I and Contiguous Stage II Follicular Lymphoma

In the early stages of the disease, involved-site radiation treatment (ISRT) is the preferred treatment.

ISRT with anti-CD20 monoclonal antibody therapy with or without chemotherapy has been shown to slow the rate of recurrence but does not change overall survival rates.

For patients with bulky, intra-abdominal disease, anti-CD20 monoclonal antibodies with or without chemotherapy may be recommended.

Watchful waiting may also be recommended for individuals who may not be good candidates for ISRT.

Bulky Disease and Noncontiguous Stage II Follicular Lymphoma

For stage I and contiguous stage II tumors with a diameter greater than 7 cm and noncontiguous stage II tumors, first-line anti-CD20 monoclonal antibody therapy with or without chemotherapy is recommended.

Stages III and IV Follicular Lymphoma

When treating advanced disease, clinicians should patients for:

• GELF criteria;
• Bulky disease;
• Aggressive or continuous tumor progression; or
• Serious organ function threat.

If none of these criteria are met, watchful waiting is recommended. If any of these criteria are met, first-line anti-CD20 monoclonal antibody therapy with or without chemotherapy regimens is recommended.

Diffuse Large B-Cell Lymphoma Treatment Recommendations

Stage I and II DLBCL are treated based on whether they are considered bulky (tumor measures greater ≥7.5 cm) or nonbulky (tumor measures <7.5 cm). Patients with nonbulky DLBCL should receive 3 cycles of CHOP with rituximab. Patients with bulky DLBCL should receive 6 cycles of CHOP with rituximab with or without ISRT.

Patients with advanced stages of DLBCL are recommended to have CHOP with rituximab or Pola-R-CHP (polatuzumab vedotin-piiq, rituximab, cyclophosphamide, doxorubicin, prednisone). There are other recommendations based on specific health conditions, old age, and frailty.

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Author Bio

Hannah Actor-Engel, PhD, earned a Bachelor of Science degree in Neural Science at New York University, and she received her PhD in Neuroscience at the University of Colorado. She is a multidisciplinary neuroscientist who is passionate about scientific communication and improving global health through biomedical research.