Follicular Lymphoma
Michael Bassetti PhD
July 26th, 2007
Clinical Rotation Talk
Overview of Presentation
• Follicular Lymphoma– Epidemiology– Diagnosis– Grade/Stage– Treatments– Future Directions
• radioimmunotherapy
30%
22%8%7%
6%
6%
6%2%
14% Large B-cell
Follicular
Marginal zone
PTCL
Mantle cell
SLL/CLL
Mediastinal
Anaplastic L cell
Hodgkin’s
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)(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(-),
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
Normal reactive lymph node
Follicular Lymphoma
Why its called “Follicular”
Follicular Lymphomas Express Bcl-2
Follicular Lymphoma Normal Reactive Follicle
Warnke et al
Warnke et al
Grade IIIGrade I Grade II
Centrocytes Mixed Centroblasts
Follicular Lymphoma Grading
>15 centroblasts/HPF6-15 centroblasts/HPF0-5 centroblasts/HPF
“Small cleaved follicle cells” “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
Solal-Céligny et al.
Score Prognosis % Patients OS (10 yr)0-1 good 36 712 moderate 37 513-5 poor 27 36
FLIPI- Follicular Lymphoma International Prognostic Index
Grade Determines Outcomes
Stage I,II22-33%
Stage III,IV67-78%
Follicular Lymphoma (grade I,II)MALT, SLL, Marginal Zone
Low Grade"indolent"
Follicular Lymphoma (grade III)DLBCL,
Intermediate Grade"aggressive"
Burkitt's
High Grade"highly aggressive"
Non-Hodgkin's Lymphoma
Years Months Weeks
Untreated Survival:
Treatments
IFRT (30-35 Gy)
Stage I,II22-33%
Watch and WaitR-CHOP
Stage III,IV67-78%
Follicular Lymphoma (grade I,II)
R-CHOP + IFRT
Stage I,II
Watch and WaitR-CHOP
Stage III,IV
Follicular Lymphoma (grade III)
= curable
= incurable
Indolent Aggressive
IFRT +/- Chemotherapy in Stage I,II Follicular Lymphoma
First Author (year) Institution
Number of Patients Treatment
Freedom from Relapse (10 y)
Overall Survival (10 y)
Soubeyran, 1988Fondation Bergonié, France 103 RT ± CT 49% 56%
Kelsey, 1994 BNLI 148 RT + CT 42% 42%RT 33% 52%
Vaughan Hudson, 1994 BNLI 208 RT 47% 64%
Pendlebury, 1995Royal Marsden Hospital, London 58 RT 43% 79%
MacManus, 1996 Stanford 177 RT 44% 64%Wilder, 2001 MDAH 80 RT 41% (15 y) 43% (15 y)Seymour, 2003 MDAH 83 RT + CT 72% 80%
Petersen, 2004Princess Margaret Hospital 460 RT 51% 62%
Guadagnolo, 2006 JCRT, Boston 106 RT ± CT 46% 75%
Tsang et al
Stanford Study
yearsOverall
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
IFRT (30-35 Gy)
Stage I,II22-33%
Watch and WaitR-CHOP
Stage III,IV67-78%
Follicular Lymphoma (grade I,II)
R-CHOP + IFRT
Stage I,II
Watch and WaitR-CHOP
Stage III,IV
Follicular Lymphoma (grade III)
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 E1484• Miller et al, NEJM 1998 ; SWOG 8735
(5 yr) PFS= 64%(5 yr) OS 72%
CHOP x8
(5 yr) PFS= 77%(5 yr) OS 82%
CHOP x3 + RT40-50 Gy
401 patientsstage I,II intermediate Grade
Miller et al, NEJM 1998 ; SWOG 8735
Rituximab (anti-CD20 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
IFRT
Stage I,II22-33%
Watch and WaitR-CHOP
Stage III,IV67-78%
Follicular Lymphoma (grade I,II)
R-CHOP + IFRT
Stage I,II
Watch and WaitR-CHOP
Stage III,IV
Follicular Lymphoma (grade III)
Salvage Treatment
IFRT
Stage I,II22-33%
Watch and WaitR-CHOP
Stage III,IV67-78%
Follicular Lymphoma (grade I,II)
R-CHOP + IFRT
Stage I,II
Watch and WaitR-CHOP
Stage III,IV
Follicular Lymphoma (grade III)
Initial Rx
Salvage Rx
R-CHOPradioimmunotherapy
IFRT 4 Gy in 2 Fx
RR CR56% 16% 85% 33% 92% 61%
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-CD20 Immunotherapy• Two FDA approved anti-CD20 radiolabelled antibodies
Bexxar, tositumomab, iodine 131Beta and Gamma emitter, half life of 8 days, tissue penetration ~ 1 mmeffective half life is much less.
Zevalin, Ibritumomab, yttrium 90 Beta emitter, half life of 64h, tissue penetration ~ 5 mm
Infusions and scan
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 CRBcl-2
PCR neg
PFS
5 year
OS
5 year
Bexxar 95% 75% 80% 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 I131 tositumomab– Zevalin Y90 ibritumomab tiuxetan
The End
Freedom From Treatment Failure and Survival Curves
Freedom from Treatment Failure
Overall Survival
Time (Years)Time (Years)
Su
rviv
al P
rob
abil
ity
Guadagnolo et al