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

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
Normal Reactive Follicle
Warnke et al

12. 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”

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 years Overall Survival Relapse free survival 10 64 4415 40 20 35 37

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)
DFS %
PFS %
5 year
OS %
CHOP 55 30 45
Rituximab + CHOP 66 54 58
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 RR CR
Bcl-2
PCR neg
PFS
5 year OS
Bexxar
95%
75%
80%
59%
89%
Kaminski et al; NEJM 352 (5); 2005

37. 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

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
Overall Survival
Survival Probability
Time (Years)
Time (Years)
Guadagnolo et al