Follicular Lymphoma Michael Bassetti Ph D July 26

Follicular Lymphoma Michael Bassetti Ph. D July 26 th, 2007 Clinical Rotation Talk

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

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

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 • 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 • t(14: 18)(q 32; q 21) 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 • P 53 mutations are associated with transformation to more DLBCL type • Immunophenotype - Ig(+), CD 10(+), CD 19(+), CD 20(+), CD 21(+), HLA-DR(+) • CD 3(-), CD 5(-),

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

Ann Arbor Staging Lymphomation. com

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” Normal reactive lymph node Follicular Lymphoma

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

Warnke et al Follicular Lymphoma Grading Grade I 0 -5 centroblasts/HPF Centrocytes “Small cleaved follicle cells” Grade II 6 -15 centroblasts/HPF Mixed Grade III >15 centroblasts/HPF Centroblasts “large blastic follicle cells”

Peripheral Blood Centrocytes Warnke et al

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 Solal-Céligny et al.

Grade Determines Outcomes Untreated Survival: Years Months Weeks

Treatments Indolent Aggressive

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

Stanford Study years Overall Survival Relapse free survival 10 64 44 15 44 40 20 35 37

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

Treatments

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 Freedom from Treatment Failure Overall Survival

Standard Treatment Stage I, II Intermediate Grade, “aggressive” Lymphoma • Horning et al, JCO 2004 ; ECOG E 1484 • Miller et al, NEJM 1998 ; SWOG 8735

Miller et al, NEJM 1998 ; SWOG 8735

Rituximab (anti-CD 20 MAb) DFS % PFS % 5 year OS % 5 year CHOP 55 30 45 Rituximab + CHOP 66 54 58 Feugier et al

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

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

Recap

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

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

Local Progression Free Survival Haas et al

Anti-CD 20 Immunotherapy • Two FDA approved anti-CD 20 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 64 h, tissue penetration ~ 5 mm

Infusions and scan

Initial Therapy in Advanced low grade NHL • 76 patients with Stage III, IV Follicular lymphoma • 75 c. Gy of total body irradiation • Median follow up 5. 1 years Bexxar RR CR Bcl-2 PCR neg 95% 75% 80% PFS 5 year OS 5 year 59% 89% Kaminski et al; NEJM 352 (5); 2005

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 • • • Autologous transplants Bcl-2 small molecule inhibitors Low dose 4 Gy palliative treatment Immunotherapy Radioimmunotherapy – Bexxar I 131 tositumomab – Zevalin Y 90 ibritumomab tiuxetan

The End

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