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Slide 1 - Follicular Lymphoma Michael Bassetti PhD July 26th, 2007 Clinical Rotation Talk
Slide 2 - Overview of Presentation Follicular Lymphoma Epidemiology Diagnosis Grade/Stage Treatments Future Directions radioimmunotherapy
Slide 3 - Lymphomas 11858 cases of follicular lymphoma (2002 SEER database. O’Connor)
Slide 4 - 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
Slide 5 - 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
Slide 6 - 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(-),
Slide 7 - 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
Slide 8 - Ann Arbor Staging
Slide 9 - 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
Slide 10 - Normal reactive lymph node Follicular Lymphoma Why its called “Follicular”
Slide 11 - Follicular Lymphomas Express Bcl-2 Follicular Lymphoma Normal Reactive Follicle Warnke et al
Slide 12 - Warnke et al Grade III Grade I Grade II Centrocytes Mixed Centroblasts Follicular Lymphoma Grading >15 centroblasts/HPF 6-15 centroblasts/HPF 0-5 centroblasts/HPF “Small cleaved follicle cells” “large blastic follicle cells”
Slide 13 - Peripheral Blood Centrocytes Warnke et al
Slide 14 - 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
Slide 15 - Solal-Céligny et al. FLIPI- Follicular Lymphoma International Prognostic Index
Slide 16 - Grade Determines Outcomes Years Months Weeks Untreated Survival:
Slide 17 - Treatments Indolent Aggressive
Slide 18 - IFRT +/- Chemotherapy in Stage I,II Follicular Lymphoma Tsang et al
Slide 19 - Stanford Study
Slide 20 - 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
Slide 21 - Treatments
Slide 22 - Treatment Stage I,II Intermediate Grade, “aggressive” Lymphoma IFRT was the historical treatment cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is used for systemic control
Slide 23 - No Advantage of Alternative Chemotherapy over CHOP Freedom from Treatment Failure Overall Survival
Slide 24 - Standard Treatment Stage I,II Intermediate Grade, “aggressive” Lymphoma Horning et al, JCO 2004 ; ECOG E1484 Miller et al, NEJM 1998 ; SWOG 8735
Slide 25 - Miller et al, NEJM 1998 ; SWOG 8735
Slide 26 - Rituximab (anti-CD20 MAb) Feugier et al
Slide 27 - Subsequent R-CHOP becomes standard of care with multiple trials showing increased PFS and OS. RT comes with it based of CHOP+ RT trials
Slide 28 - Treatment
Slide 29 - Follow up Every 3 months for first 2 years Every 6 months for next 3 years H&P, labs, CXR +/- CT, PET scans
Slide 30 - Recap
Slide 31 - Salvage Treatment Initial Rx Salvage Rx Haas et al; JCO 2003; 21(13)
Slide 32 - Palliative RT for Relapsed Indolent Lymphoma Progression Free Survival Haas et al
Slide 33 - Local Progression Free Survival Haas et al
Slide 34 - 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
Slide 35 - Infusions and scan
Slide 36 - 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
Slide 37 - 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
Slide 38 - 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
Slide 39 - The End
Slide 40 - Freedom From Treatment Failure and Survival Curves Freedom from Treatment Failure Overall Survival Time (Years) Time (Years) Survival Probability Guadagnolo et al