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Michael Bassetti PhD July 26th, 2007 Clinical Rotation Talk
Follicular Lymphoma Michael Bassetti PhD July 26th, 2007 Clinical Rotation Talk
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Overview of Presentation
Follicular Lymphoma Epidemiology Diagnosis Grade/Stage Treatments Future Directions radioimmunotherapy
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Lymphomas 11858 cases of follicular lymphoma (2002 SEER database. O’Connor)
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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
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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
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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(-),
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Ann Arbor Staging Stage I Involvement of a single lymph-node region (I) or a single extralymphatic organ or site (IE) Stage II Involvement 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 III Involvement 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 IV Diffuse 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
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Ann Arbor Staging Lymphomation.com
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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
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Why its called “Follicular”
Normal reactive lymph node Follicular Lymphoma
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Follicular Lymphomas Express Bcl-2
Normal Reactive Follicle Warnke et al
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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 Mixed Centroblasts “Small cleaved follicle cells” “large blastic follicle cells”
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Peripheral Blood Centrocytes
Warnke et al
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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
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FLIPI- Follicular Lymphoma International Prognostic Index
Solal-Céligny et al.
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Grade Determines Outcomes
Untreated Survival: Years Months Weeks
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Treatments Indolent Aggressive
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IFRT +/- Chemotherapy in Stage I,II Follicular Lymphoma
Tsang et al
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Stanford Study years Overall Survival Relapse free survival 10 64 44
15 40 20 35 37
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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
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Treatments
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Treatment Stage I,II Intermediate Grade, “aggressive” Lymphoma
IFRT was the historical treatment cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is used for systemic control
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No Advantage of Alternative Chemotherapy over CHOP
Freedom from Treatment Failure Overall Survival
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Standard Treatment Stage I,II Intermediate Grade, “aggressive” Lymphoma
Horning et al, JCO 2004 ; ECOG E1484 Miller et al, NEJM 1998 ; SWOG 8735
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Miller et al, NEJM 1998 ; SWOG 8735
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Rituximab (anti-CD20 MAb)
DFS % PFS % 5 year OS % CHOP 55 30 45 Rituximab + CHOP 66 54 58 Feugier et al
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Subsequent R-CHOP becomes standard of care with multiple trials showing increased PFS and OS. RT comes with it based of CHOP+ RT trials
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Treatment
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Follow up Every 3 months for first 2 years
Every 6 months for next 3 years H&P, labs, CXR +/- CT, PET scans
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Recap
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Salvage Treatment Initial Rx Salvage Rx Haas et al; JCO 2003; 21(13)
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Palliative RT for Relapsed Indolent Lymphoma
Progression Free Survival Haas et al
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Local Progression Free Survival
Haas et al
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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
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Infusions and scan
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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 RR CR Bcl-2 PCR neg PFS 5 year OS Bexxar 95% 75% 80% 59% 89% Kaminski et al; NEJM 352 (5); 2005
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Conclusions Low Grade Follicular Lymphoma Intermediate Grade
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
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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
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The End
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Freedom From Treatment Failure and Survival Curves
Overall Survival Survival Probability Time (Years) Time (Years) Guadagnolo et al
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