Follicular Lymphoma

1. Follicular Lymphoma Michael Bassetti PhD July 26th, 2007 Clinical Rotation Talk

2. Overview of Presentation • Follicular Lymphoma • Epidemiology • Diagnosis • Grade/Stage • Treatments • Future Directions • radioimmunotherapy

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

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

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

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(-),

7. 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

8. Ann Arbor Staging Lymphomation.com

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

10. Why its called “Follicular” Normal reactive lymph node Follicular Lymphoma

11. Follicular Lymphomas Express Bcl-2 Follicular Lymphoma Normal Reactive Follicle Warnke et al

12. 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”

13. Peripheral Blood Centrocytes Warnke et al

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

15. FLIPI- Follicular Lymphoma International Prognostic Index Solal-Céligny et al.

16. Grade Determines Outcomes Untreated Survival: Years Months Weeks

17. Treatments Indolent Aggressive

18. IFRT +/- Chemotherapy in Stage I,II Follicular Lymphoma Tsang et al

19. Stanford Study

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

21. Treatments

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

23. No Advantage of Alternative Chemotherapy over CHOP Freedom from Treatment Failure Overall Survival

24. Standard Treatment Stage I,II Intermediate Grade, “aggressive” Lymphoma • Horning et al, JCO 2004 ; ECOG E1484 • Miller et al, NEJM 1998 ; SWOG 8735

25. Miller et al, NEJM 1998 ; SWOG 8735

26. Rituximab (anti-CD20 MAb) Feugier et al

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

28. Treatment

29. Follow up • Every 3 months for first 2 years • Every 6 months for next 3 years • H&P, labs, CXR • +/- CT, PET scans

30. Recap

31. Salvage Treatment Initial Rx Salvage Rx Haas et al; JCO 2003; 21(13)

32. Palliative RT for Relapsed Indolent Lymphoma Progression Free Survival Haas et al

33. Local Progression Free Survival Haas et al

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

35. Infusions and scan

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

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

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

39. The End

40. Freedom From Treatment Failure and Survival Curves Freedom from Treatment Failure Overall Survival Survival Probability Time (Years) Time (Years) Guadagnolo et al