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. 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


Lymphomas

Lymphomas

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

Lymphomation.com


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

Centrocytes

Centroblasts

Mixed

“Small cleaved follicle cells”

“large blastic follicle cells”


Peripheral blood centrocytes

Peripheral Blood Centrocytes

Warnke et al


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


Flipi follicular lymphoma international prognostic index

FLIPI- Follicular Lymphoma International Prognostic Index

Solal-Céligny et al.


Grade determines outcomes

Grade Determines Outcomes

Untreated Survival:

Years

Months

Weeks


Treatments

Treatments

Indolent

Aggressive


Ifrt chemotherapy in stage i ii follicular lymphoma

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

Tsang et al


Stanford study

Stanford Study


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


Treatments1

Treatments


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


Follicular lymphoma

Miller et al, NEJM 1998 ; SWOG 8735


Rituximab anti cd20 mab

Rituximab (anti-CD20 MAb)

Feugier et al


Subsequent

Subsequent

  • R-CHOP becomes standard of care with multiple trials showing increased PFS and OS.

  • RT comes with it based of CHOP+ RT trials


Treatment

Treatment


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


Recap

Recap


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


Follicular lymphoma

Local 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


Infusions and scan

Infusions and scan


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


Conclusions

Conclusions

  • 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


The end

The End


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


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