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Follicular Lymphoma. Michael Bassetti PhD July 26th, 2007 Clinical Rotation Talk. Overview of Presentation. Follicular Lymphoma Epidemiology Diagnosis Grade/Stage Treatments Future Directions radioimmunotherapy. Lymphomas.

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follicular lymphoma

Follicular Lymphoma

Michael Bassetti PhD

July 26th, 2007

Clinical Rotation Talk

overview of presentation
Overview of Presentation
  • Follicular Lymphoma
    • Epidemiology
    • Diagnosis
    • Grade/Stage
    • Treatments
    • Future Directions
      • radioimmunotherapy

11858 cases of follicular lymphoma (2002 SEER database. O’Connor)

follicular lymphoma1
Follicular Lymphoma
  • Cancer arising from lymphocytes
  • Mature B cell origin
  • Rising in incidence (4% per year)
  • Median age of onset is 60
  • Accounts for 70% of low grade lymphomas
  • Slight female:male predominance
  • Less common in Asian and African Americans
  • Extremely sensitive to radiation, and to chemotherapy.
  • Association with hepatitis C. Response to IFN/ribavirin
typical presentation
Typical Presentation
  • Lymphadenopathy
  • Typically cervical, axillary, inguinal, but can be in anywhere including extranodal
  • nontender, firm, rubbery
  • Waxing and waning
  • 10% B symptoms
    • Fever, night sweats, weight loss
  • 50% splenomegaly
genetic changes
Genetic Changes
  • t(14:18)(q32;q21) Bcl-2 translocation in 85% of cases.
    • Bcl-2/Ig heavy chain
  • Bcl-2 is a potent suppressor of apoptosis
  • Bcl-6 is also occasionally expressed
  • P53 mutations are associated with transformation to more DLBCL type
  • Immunophenotype - Ig(+), CD10(+), CD19(+), CD20(+), CD21(+), HLA-DR(+)
  • CD3(-), CD5(-),
ann arbor staging
Ann Arbor Staging
  • Stage IInvolvement of a single lymph-node region (I) or a single extralymphatic organ or site (IE)
  • Stage IIInvolvement of two or more lymph-node regions on the same side of the diaphragm (II) or localized involvement of an extra-lymphatic organ or site (IIE)
  • Stage IIIInvolvement of lymph-node regions on both sides of the diaphragm (III) or localized involvement of an extra-lymphatic organ or site (IIIE), spleen (IIIS), or both (IIISE)
  • Stage IVDiffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph-node involvement; the organ(s) involved should be identified by a symbol: (P) pulmonary, (O) osseous, or (H) hepatic.

In addition,

(A) indicates an asymptomatic patient;

(B) indicates the presence of fever, night sweats, or weight loss > 10% of body weight.

* The designation "E" generally refers to extranodal contiguous extension

ann arbor staging1
Ann Arbor Staging

diagnostic workup
Diagnostic workup
  • Pathology by excisional biopsy or core, avoid FNA if possible
  • CBC with differential and blood smear
  • Serum electrolytes and creatinine
  • Chest x-ray, CT chest, abdomen and pelvis
  • PET/CT
  • Liver function tests
  • Serum LDH, uric acid
  • Serum protein electrophoresis
  • Bone marrow biopsy
why its called follicular
Why its called “Follicular”

Normal reactive lymph node

Follicular Lymphoma

follicular lymphomas express bcl 2
Follicular Lymphomas Express Bcl-2

Follicular Lymphoma

Normal Reactive Follicle

Warnke et al

follicular lymphoma grading

Warnke et al

Follicular Lymphoma Grading

Grade I

Grade II

Grade III

0-5 centroblasts/HPF

6-15 centroblasts/HPF

>15 centroblasts/HPF




“Small cleaved follicle cells”

“large blastic follicle cells”

international prognostic index
International Prognostic Index
  • Age greater than 60 years
  • Stage III or IV disease
  • Elevated serum LDH
  • ECOG performance status of 2, 3, or 4
  • More than 1 extranodal site
grade determines outcomes
Grade Determines Outcomes

Untreated Survival:







rt for stage i ii follicular lymphoma
RT for Stage I, II Follicular Lymphoma
  • IFRT produces local control for >95% of patients
  • No benefit to adding chemotherapy
  • Without therapy 38% require treatment by a median of 7 years.
  • Relapses after 10 years <10%
  • Relapses occur outside irradiated field
  • ~40-50% potential cure rate
treatment stage i ii intermediate grade aggressive lymphoma
Treatment Stage I,II Intermediate Grade, “aggressive” Lymphoma
  • IFRT was the historical treatment
  • cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is used for systemic control
no advantage of alternative chemotherapy over chop
No Advantage of Alternative Chemotherapy over CHOP

Freedom from Treatment Failure

Overall Survival

standard treatment stage i ii intermediate grade aggressive lymphoma
Standard Treatment Stage I,II Intermediate Grade, “aggressive” Lymphoma
  • Horning et al, JCO 2004 ; ECOG E1484
  • Miller et al, NEJM 1998 ; SWOG 8735
  • R-CHOP becomes standard of care with multiple trials showing increased PFS and OS.
  • RT comes with it based of CHOP+ RT trials
follow up
Follow up
  • Every 3 months for first 2 years
  • Every 6 months for next 3 years
  • H&P, labs, CXR
  • +/- CT, PET scans
salvage treatment
Salvage Treatment

Initial Rx

Salvage Rx

Haas et al; JCO 2003; 21(13)

palliative rt for relapsed indolent lymphoma
Palliative RT for Relapsed Indolent Lymphoma

Progression Free Survival

Haas et al

anti cd20 immunotherapy
Anti-CD20 Immunotherapy
  • Two FDA approved anti-CD20 radiolabelled antibodies

Bexxar, tositumomab, iodine 131

Beta and Gamma emitter, half life of 8 days, tissue penetration ~ 1 mm

effective half life is much less.

Zevalin, Ibritumomab, yttrium 90

Beta emitter, half life of 64h, tissue penetration ~ 5 mm

initial therapy in advanced low grade nhl
Initial Therapy in Advanced low grade NHL
  • 76 patients with Stage III, IV Follicular lymphoma
  • 75cGy of total body irradiation
  • Median follow up 5.1 years

Kaminski et al; NEJM 352 (5); 2005

  • Low Grade Follicular Lymphoma
    • Early stage radiation therapy ~50% curative
    • Late stage non-curative. Chemotherapy, radioimmunotherapy,or trials.
  • Intermediate Grade
    • Radiation and Chemotherapy together with immunotherapy
  • Salvage Treatment
    • Low dose radiation can give sustained palliation, and be used repeatedly
future direction of treatments
Future direction of Treatments
  • Autologous transplants
  • Bcl-2 small molecule inhibitors
  • Low dose 4 Gy palliative treatment
  • Immunotherapy
  • Radioimmunotherapy
    • Bexxar I131 tositumomab
    • Zevalin Y90 ibritumomab tiuxetan
freedom from treatment failure and survival curves
Freedom From Treatment Failure and Survival Curves

Freedom from Treatment Failure

Overall Survival

Survival Probability

Time (Years)

Time (Years)

Guadagnolo et al