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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

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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


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

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

  • 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

  • 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

  • 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 Staging

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”

Normal reactive lymph node

Follicular Lymphoma

Follicular Lymphomas Express Bcl-2

Follicular Lymphoma

Normal Reactive Follicle

Warnke et al

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”

Peripheral Blood Centrocytes

Warnke et al

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

FLIPI- Follicular Lymphoma International Prognostic Index

Solal-Céligny et al.

Grade Determines Outcomes

Untreated Survival:







IFRT +/- Chemotherapy in Stage I,II Follicular Lymphoma

Tsang et al

Stanford Study

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

  • IFRT was the historical treatment

  • cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is used for systemic control

No Advantage of Alternative Chemotherapy over CHOP

Freedom from Treatment Failure

Overall Survival

Standard Treatment Stage I,II Intermediate Grade, “aggressive” Lymphoma

  • Horning et al, JCO 2004 ; ECOG E1484

  • Miller et al, NEJM 1998 ; SWOG 8735

Miller et al, NEJM 1998 ; SWOG 8735

Rituximab (anti-CD20 MAb)

Feugier et al


  • 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

  • Every 3 months for first 2 years

  • Every 6 months for next 3 years

  • H&P, labs, CXR

  • +/- CT, PET scans


Salvage Treatment

Initial Rx

Salvage Rx

Haas et al; JCO 2003; 21(13)

Palliative RT for Relapsed Indolent Lymphoma

Progression Free Survival

Haas et al

Local Progression Free Survival

Haas et al

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

Infusions and scan

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

  • Autologous transplants

  • Bcl-2 small molecule inhibitors

  • Low dose 4 Gy palliative treatment

  • Immunotherapy

  • Radioimmunotherapy

    • Bexxar I131 tositumomab

    • Zevalin Y90 ibritumomab tiuxetan

The End

Freedom From Treatment Failure and Survival Curves

Freedom from Treatment Failure

Overall Survival

Survival Probability

Time (Years)

Time (Years)

Guadagnolo et al

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