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Follicular lymphoma

Updated : April 25, 2024





Background

Follicular lymphoma (FL) is the second most prevalent kind of non-Hodgkin lymphoma and accounts for over 30% of lymphoma cases. It ranks first among non-Hodgkin lymphomas that are clinically indolent.

Follicular lymphoma is a slow-growing lymphoproliferative condition of B cells, and survival is measured in years. Based on histology, cases of follicular lymphoma are categorized in 3 stages.

Epidemiology

FL is the second most prevalent form of Non-Hodgkin Lymphoma in the United States, with around 6 cases per 100,000 people each year. The incidence of FL is greater among Caucasians than among Asians and African-Americans.

It is also more prevalent in the United States and Europe than in the rest of the world. Follicular lymphoma mainly affects older adults — with an observed median age of 55.

It is rarer in youngsters, especially in those younger than 20 years of age. It has been demonstrated that pesticide and herbicide exposure are some of the risk factors for Follicular lymphoma.

Anatomy

Pathophysiology

FL is characterized by a proliferation of malignant germinal center B cells which are mixed with nonmalignant cells such as T cells, follicular dendritic cells (FDCs), and macrophages, whose normal counterparts centroblasts and centrocytes are the predominant cell types of the germinal center reaction.

The current grading scheme is based on the relative proportion of centrocytes to centroblasts, with grade 1 FL containing only 0-5 centroblasts per high-power field and grade 3B FL characterized by dense and solid sheets of centroblasts.

Unlike many other malignancies, grading Fl does not help in making a prognosis, nor is there a consensus on the nature of grade 3B FL, as these cases frequently resemble new diffuse large B cell lymphoma (DLBCL) and possess somewhat different molecular characteristics than grades 1–3A of follicular lymphoma, for example; grade 3B FL is frequently negative for translocation of t(14;18) and variably expresses CD10).

Staining for FDC markers such as CD21 or CD23 reveals the FL’s traditional follicular development pattern. The t(14;18) (q32;q21) translocation can be detected by fluorescence in situ hybridization in 85 percent of all cases, causes overexpression of anti-apoptotic BCL2, and is considered a molecular characteristic of the disease.

This translocation is not required nor sufficient for diagnosis, as it is absent in 15% of FLs and present in 20%–30% of GCB-type DLBCLs.

Etiology

FL derives from germinal/follicular center B cells. Most cases of FL are identified due to the translocation of (14;18) (q32;q21) , which results in the overexpression of the anti-apoptotic protein BCL2.

Approximately 5% of follicular lymphomas cause BCL-6 deregulating mutations. Germinal center development requires the BCL-6 protein. BCL-6-related protein is a transcriptional repressor that controls the interleukin-4 response of B-cells.

Other genes considered to play a role in causing follicular lymphoma are related to p21, p16, and G1 arrest. Similarly, regulatory proteins such as p120, p21, p16, and CKD10, and transcription factors such Id-2 and PAX5, and cell-cell interaction related genes such as IL4RA, ILRG, and TNF are similarly increased.

MRP14 and MRP8, which are adhesion related genes, are down regulated.

Genetics

Prognostic Factors

The Follicular Lymphoma International Prognostic index determines the prognosis of the disease through identifying the number of risk factors present in the patient.

Five risk factors whose presence indicates an inferior survival rate for Follicular lymphoma are:

Age above 60 years

  • Hemoglobin under 12 g/dL
  • Serum LDH higher than normal
  • Over 4 involved nodal areas
  • Ann Arbor stage III or IV

Using these risk factors, FL patients are divided into low, intermediate, and high-risk categories.

This further helps in predicting a 5-year survival rate for these patients.

  • Patients with 0 risk factors are low risk and have an 80% 5-year survival rate;
  • Patients with 1-2 risk factors are in the intermediate risk category and have a 51% 5-year survival rate
  • Patients with 3-5 risk factors are high risk and have a 19% 5-year survival rate.

Clinical History

Physical Examination

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Medication

 

copanlisib

60

mg

Solution

Intravenous (IV)

every week

1

hr

An intermittent schedule like 21 days on and 1 week off has to be followed Continue the therapy until disease progression or unacceptable toxicity occurs



mosunetuzumab 

21-day cycle Day 1 Cycle 1: 1mg intravenous for 4 hours Day 8 Cycle 1: 2mg intravenous for 4 hours Day 1 Cycle 2: 60mg intravenous for 2 hours Day 15 Cycle 2: 60mg intravenous for 4 hours Cycle 3 and the following cycles Day 1: 30mg IV for 2 hours Restarting therapy 1mg administered last dose (Day 1 cycle 1) Week 1 and 2: Administer 2mg >2 week TO <6 weeks: administer 2 mg, then use 60 mg 2mg administered last dose (Day 8 cycle 1) Week 1 and 2: Administer 60mg >2 weeks: administer 1 mg, then use 2 mg >6 weeks: administer 1 mg and 2mg, then use 60 mg 60mg administered last dose (Day 15 cycle 1) Week 1 to <6 weeks: Administer 60mg >6 weeks: administer 1 mg and 2mg, then use 60 mg, followed by 30mg 60mg administered last dose (Day 1 cycle 2) Week 3 to <6 weeks: Administer 30mg >6 weeks: administer 1 mg and 2mg, then use 30 mg, followed by 30mg 30mg administered last dose (Cycle 3 and following cycles) Week 3 to <6 weeks: Administer 30mg >6 weeks: administer 1 mg on day 1 and 2mg on day 8, then use 30 mg on day 15, followed by 30mg on day 1 in the remaining cycles



umbralisib 

Administering a dosage of 800 mg orally daily



obinutuzumab 

Refractory or relapsed to rituximab regimen
bendamustine administered in combination for six 28-day cycles then obinutuzumab monotherapy for about two years
stage II bulky, III or IV FL Previously untreated
combined with six 28-day cycles of bendamustine, OR
two extra 21-day cycles when mixed with obinutuzumab alone after six 21-day cycles combined with CHOP, OR
Eight cycles of 21 days each combined with CVP
If a full or partial response is seen after the first 6 or 8 cycles, obinutuzumab 1000 mg as a monotherapy may be continued for up to 2 years.
Dosage regimen
Cycle 1: 1000 mg intravenous on Days 1, 8, & 15
Cycles 2 to 6 or 2 to 8: 1000 mg intravenous on Day 1
If a full or partial response is obtained, obinutuzumab 1000 mg every two months as monotherapy may be continued for about two years.
Monotherapy
1000 mg intravenous every two months for about 2 years



Dose Adjustments

Dosage Modifications
Reactions related to infusion
Grade 1 to 2

only CLL patients: After one hour, the day 1 infusion rate can be increased to 25 mg/hr, but no further.
Grade 3
An infusion rate increase can be resumed at the increment & intervals as necessary by the treatment cycle dosage after restarting at less than 50% when combined with the initial rate if no additional IRR occurs.
Only CLL: Day 1 rate of infusion can be increased to 25 mg/hr following 1 hour, but no further.
Grade 3 IRRs with FL during a 90-minute infusion: Following relief of symptoms, continue the infusion not more than the half the prior rate (the rate used when the IRR occurred) and should not exceed more than 400 mg/hr; follow-up infusions at a standard rate.
If a Grade above 3 infusion-related symptoms develops when the therapy is resumed, discontinue it permanently.
Grade 4
Stop the infusion immediately or discontinue it permanently.

rituximab-hyaluronidase 


Indicated for Follicular Lymphoma
Prior to initiating rituximab/hyaluronidase subcutaneous therapy, all patients should receive a minimum of one full dose of the rituximab intravenous infusion
Follicular lymphoma of Relapse/refractory
1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously every week for three or seven weeks after one full dose of the rituximab intravenous infusion at 1st week (total of four or eight weeks)
Retreatment: 1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously every week for three weeks after one full dose of the rituximab intravenous infusion at 1st week (total of four weeks)
Prior untreated Follicular lymphoma
1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously on the first day of a 21-day cycle in the 2-8 cycles for seven cycles, after one full dose of the rituximab intravenous infusion on the first day of 1-cycle (total of 8 cycles)
Maintenance dose after partial or complete response: 1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously every 8 weeks for 12 doses
Start 8 weeks following partial or complete response to rituximab in the combination with a chemotherapy
Follicular lymphoma non-progressing
It is used as single agent following CVP chemotherapy (cyclophosphamide, vincristine, prednisone)
After completing the six-eight cycles of CVP chemotherapy, one full dose of the rituximab intravenous infusion in 1st week, 1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously every week for three weeks (total of four weeks) in six months interval period for maximal of 16 doses
Chronic Lymphocytic Leukemia
It is used in combination with the (FC) fludarabine, cyclophosphamide with prior treated and untreated Chronic Lymphocytic Leukemia
1600 mg of rituximab /26,800 units of hyaluronidase subcutaneously on the first day of a 28-day cycle in the 2-6 cycles for a total of five cycles, after one full dose of the rituximab intravenous infusion on the first day of 1-cycle of FC (fludarabine, cyclophosphamide) (total of 6 cycles)
Diffuse Large B-Cell Lymphoma
It is used in combination with the CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) or other chemotherapy regimens which is anthracycline-based
1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously on the first day of 2-8 cycles with CHOP combination for seven cycles after one full dose of the rituximab intravenous infusion on the first day of 1-cycle of CHOP (total of 6-8 cycles)



tisagenlecleucel 

Lymphodepleting chemotherapy
3 days of fludarabine 25 mg/m2 intravenous per day
If the white blood cells count is less than or equal to 1 x 109/L within a week after the tisagenlecleucel infusion, lymphodepleting chemotherapy may not be necessary
commencing with the first dosage of fludarabine, administer cyclophosphamide 250 mg/m2 intravenous every day for 3 days
tisagenlecleucel intravenous infusion
Administer 2 to 6 days after lymphodepleting chemotherapy is finished
Dosage Modifications
Cytokine release syndrome (CRS) management
Grade 1
Mild symptoms: Fatigue, low-level fever, anorexia
Grade 2
Symptoms require and respond to moderate intervention
Grade 3
Symptoms require and respond to aggressive intervention
Grade 4
Life-threatening symptoms
Dosing Considerations
only for autologous use



axicabtagene ciloleucel 

Target dose is 2 x 106 CAR-positive viable T cells/kg body weight, not more than 2 x 108 CAR-positive viable T cells
Dosage Modifications
Cytokine release syndrome (CRS) management
For Grade 1
Symptoms: Fever, myalgia, malaise, nausea, fatigue, headache
Symptomatic treatment only
For Grade 2
Administer tocilizumab 8 mg/kg intravenously infused over one hour
Not more than 3 doses in a day
For Grade 3
Administer tocilizumab 8 mg/kg intravenously infused over one hour
Administer methylprednisolone 1 mg/kg intravenously two times a day
For Grade 4
Administer methylprednisolone 1000 mg/day intravenously for three days
Dosing Considerations
Monitor signs and symptoms of cytokine release syndrome and neurologic toxicities for minimum for 7 days following infusion



 

copanlisib

Safety and efficacy not established



 

copanlisib

Refer adult dosing



Media Gallary

References

https://pubmed.ncbi.nlm.nih.gov/26769125/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461914/

https://www.ncbi.nlm.nih.gov/books/NBK538206/

Follicular lymphoma

Updated : April 25, 2024




Follicular lymphoma (FL) is the second most prevalent kind of non-Hodgkin lymphoma and accounts for over 30% of lymphoma cases. It ranks first among non-Hodgkin lymphomas that are clinically indolent.

Follicular lymphoma is a slow-growing lymphoproliferative condition of B cells, and survival is measured in years. Based on histology, cases of follicular lymphoma are categorized in 3 stages.

FL is the second most prevalent form of Non-Hodgkin Lymphoma in the United States, with around 6 cases per 100,000 people each year. The incidence of FL is greater among Caucasians than among Asians and African-Americans.

It is also more prevalent in the United States and Europe than in the rest of the world. Follicular lymphoma mainly affects older adults — with an observed median age of 55.

It is rarer in youngsters, especially in those younger than 20 years of age. It has been demonstrated that pesticide and herbicide exposure are some of the risk factors for Follicular lymphoma.

FL is characterized by a proliferation of malignant germinal center B cells which are mixed with nonmalignant cells such as T cells, follicular dendritic cells (FDCs), and macrophages, whose normal counterparts centroblasts and centrocytes are the predominant cell types of the germinal center reaction.

The current grading scheme is based on the relative proportion of centrocytes to centroblasts, with grade 1 FL containing only 0-5 centroblasts per high-power field and grade 3B FL characterized by dense and solid sheets of centroblasts.

Unlike many other malignancies, grading Fl does not help in making a prognosis, nor is there a consensus on the nature of grade 3B FL, as these cases frequently resemble new diffuse large B cell lymphoma (DLBCL) and possess somewhat different molecular characteristics than grades 1–3A of follicular lymphoma, for example; grade 3B FL is frequently negative for translocation of t(14;18) and variably expresses CD10).

Staining for FDC markers such as CD21 or CD23 reveals the FL’s traditional follicular development pattern. The t(14;18) (q32;q21) translocation can be detected by fluorescence in situ hybridization in 85 percent of all cases, causes overexpression of anti-apoptotic BCL2, and is considered a molecular characteristic of the disease.

This translocation is not required nor sufficient for diagnosis, as it is absent in 15% of FLs and present in 20%–30% of GCB-type DLBCLs.

FL derives from germinal/follicular center B cells. Most cases of FL are identified due to the translocation of (14;18) (q32;q21) , which results in the overexpression of the anti-apoptotic protein BCL2.

Approximately 5% of follicular lymphomas cause BCL-6 deregulating mutations. Germinal center development requires the BCL-6 protein. BCL-6-related protein is a transcriptional repressor that controls the interleukin-4 response of B-cells.

Other genes considered to play a role in causing follicular lymphoma are related to p21, p16, and G1 arrest. Similarly, regulatory proteins such as p120, p21, p16, and CKD10, and transcription factors such Id-2 and PAX5, and cell-cell interaction related genes such as IL4RA, ILRG, and TNF are similarly increased.

MRP14 and MRP8, which are adhesion related genes, are down regulated.

The Follicular Lymphoma International Prognostic index determines the prognosis of the disease through identifying the number of risk factors present in the patient.

Five risk factors whose presence indicates an inferior survival rate for Follicular lymphoma are:

Age above 60 years

  • Hemoglobin under 12 g/dL
  • Serum LDH higher than normal
  • Over 4 involved nodal areas
  • Ann Arbor stage III or IV

Using these risk factors, FL patients are divided into low, intermediate, and high-risk categories.

This further helps in predicting a 5-year survival rate for these patients.

  • Patients with 0 risk factors are low risk and have an 80% 5-year survival rate;
  • Patients with 1-2 risk factors are in the intermediate risk category and have a 51% 5-year survival rate
  • Patients with 3-5 risk factors are high risk and have a 19% 5-year survival rate.

copanlisib

60

mg

Solution

Intravenous (IV)

every week

1

hr

An intermittent schedule like 21 days on and 1 week off has to be followed Continue the therapy until disease progression or unacceptable toxicity occurs



mosunetuzumab 

21-day cycle Day 1 Cycle 1: 1mg intravenous for 4 hours Day 8 Cycle 1: 2mg intravenous for 4 hours Day 1 Cycle 2: 60mg intravenous for 2 hours Day 15 Cycle 2: 60mg intravenous for 4 hours Cycle 3 and the following cycles Day 1: 30mg IV for 2 hours Restarting therapy 1mg administered last dose (Day 1 cycle 1) Week 1 and 2: Administer 2mg >2 week TO <6 weeks: administer 2 mg, then use 60 mg 2mg administered last dose (Day 8 cycle 1) Week 1 and 2: Administer 60mg >2 weeks: administer 1 mg, then use 2 mg >6 weeks: administer 1 mg and 2mg, then use 60 mg 60mg administered last dose (Day 15 cycle 1) Week 1 to <6 weeks: Administer 60mg >6 weeks: administer 1 mg and 2mg, then use 60 mg, followed by 30mg 60mg administered last dose (Day 1 cycle 2) Week 3 to <6 weeks: Administer 30mg >6 weeks: administer 1 mg and 2mg, then use 30 mg, followed by 30mg 30mg administered last dose (Cycle 3 and following cycles) Week 3 to <6 weeks: Administer 30mg >6 weeks: administer 1 mg on day 1 and 2mg on day 8, then use 30 mg on day 15, followed by 30mg on day 1 in the remaining cycles



umbralisib 

Administering a dosage of 800 mg orally daily



obinutuzumab 

Refractory or relapsed to rituximab regimen
bendamustine administered in combination for six 28-day cycles then obinutuzumab monotherapy for about two years
stage II bulky, III or IV FL Previously untreated
combined with six 28-day cycles of bendamustine, OR
two extra 21-day cycles when mixed with obinutuzumab alone after six 21-day cycles combined with CHOP, OR
Eight cycles of 21 days each combined with CVP
If a full or partial response is seen after the first 6 or 8 cycles, obinutuzumab 1000 mg as a monotherapy may be continued for up to 2 years.
Dosage regimen
Cycle 1: 1000 mg intravenous on Days 1, 8, & 15
Cycles 2 to 6 or 2 to 8: 1000 mg intravenous on Day 1
If a full or partial response is obtained, obinutuzumab 1000 mg every two months as monotherapy may be continued for about two years.
Monotherapy
1000 mg intravenous every two months for about 2 years



Dose Adjustments

Dosage Modifications
Reactions related to infusion
Grade 1 to 2

only CLL patients: After one hour, the day 1 infusion rate can be increased to 25 mg/hr, but no further.
Grade 3
An infusion rate increase can be resumed at the increment & intervals as necessary by the treatment cycle dosage after restarting at less than 50% when combined with the initial rate if no additional IRR occurs.
Only CLL: Day 1 rate of infusion can be increased to 25 mg/hr following 1 hour, but no further.
Grade 3 IRRs with FL during a 90-minute infusion: Following relief of symptoms, continue the infusion not more than the half the prior rate (the rate used when the IRR occurred) and should not exceed more than 400 mg/hr; follow-up infusions at a standard rate.
If a Grade above 3 infusion-related symptoms develops when the therapy is resumed, discontinue it permanently.
Grade 4
Stop the infusion immediately or discontinue it permanently.

rituximab-hyaluronidase 


Indicated for Follicular Lymphoma
Prior to initiating rituximab/hyaluronidase subcutaneous therapy, all patients should receive a minimum of one full dose of the rituximab intravenous infusion
Follicular lymphoma of Relapse/refractory
1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously every week for three or seven weeks after one full dose of the rituximab intravenous infusion at 1st week (total of four or eight weeks)
Retreatment: 1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously every week for three weeks after one full dose of the rituximab intravenous infusion at 1st week (total of four weeks)
Prior untreated Follicular lymphoma
1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously on the first day of a 21-day cycle in the 2-8 cycles for seven cycles, after one full dose of the rituximab intravenous infusion on the first day of 1-cycle (total of 8 cycles)
Maintenance dose after partial or complete response: 1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously every 8 weeks for 12 doses
Start 8 weeks following partial or complete response to rituximab in the combination with a chemotherapy
Follicular lymphoma non-progressing
It is used as single agent following CVP chemotherapy (cyclophosphamide, vincristine, prednisone)
After completing the six-eight cycles of CVP chemotherapy, one full dose of the rituximab intravenous infusion in 1st week, 1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously every week for three weeks (total of four weeks) in six months interval period for maximal of 16 doses
Chronic Lymphocytic Leukemia
It is used in combination with the (FC) fludarabine, cyclophosphamide with prior treated and untreated Chronic Lymphocytic Leukemia
1600 mg of rituximab /26,800 units of hyaluronidase subcutaneously on the first day of a 28-day cycle in the 2-6 cycles for a total of five cycles, after one full dose of the rituximab intravenous infusion on the first day of 1-cycle of FC (fludarabine, cyclophosphamide) (total of 6 cycles)
Diffuse Large B-Cell Lymphoma
It is used in combination with the CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) or other chemotherapy regimens which is anthracycline-based
1400 mg of rituximab /23,400 units of hyaluronidase subcutaneously on the first day of 2-8 cycles with CHOP combination for seven cycles after one full dose of the rituximab intravenous infusion on the first day of 1-cycle of CHOP (total of 6-8 cycles)



tisagenlecleucel 

Lymphodepleting chemotherapy
3 days of fludarabine 25 mg/m2 intravenous per day
If the white blood cells count is less than or equal to 1 x 109/L within a week after the tisagenlecleucel infusion, lymphodepleting chemotherapy may not be necessary
commencing with the first dosage of fludarabine, administer cyclophosphamide 250 mg/m2 intravenous every day for 3 days
tisagenlecleucel intravenous infusion
Administer 2 to 6 days after lymphodepleting chemotherapy is finished
Dosage Modifications
Cytokine release syndrome (CRS) management
Grade 1
Mild symptoms: Fatigue, low-level fever, anorexia
Grade 2
Symptoms require and respond to moderate intervention
Grade 3
Symptoms require and respond to aggressive intervention
Grade 4
Life-threatening symptoms
Dosing Considerations
only for autologous use



axicabtagene ciloleucel 

Target dose is 2 x 106 CAR-positive viable T cells/kg body weight, not more than 2 x 108 CAR-positive viable T cells
Dosage Modifications
Cytokine release syndrome (CRS) management
For Grade 1
Symptoms: Fever, myalgia, malaise, nausea, fatigue, headache
Symptomatic treatment only
For Grade 2
Administer tocilizumab 8 mg/kg intravenously infused over one hour
Not more than 3 doses in a day
For Grade 3
Administer tocilizumab 8 mg/kg intravenously infused over one hour
Administer methylprednisolone 1 mg/kg intravenously two times a day
For Grade 4
Administer methylprednisolone 1000 mg/day intravenously for three days
Dosing Considerations
Monitor signs and symptoms of cytokine release syndrome and neurologic toxicities for minimum for 7 days following infusion



copanlisib

Safety and efficacy not established



copanlisib

Refer adult dosing



https://pubmed.ncbi.nlm.nih.gov/26769125/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461914/

https://www.ncbi.nlm.nih.gov/books/NBK538206/