Follicular Lymphoma
Michael Bassetti PhD
July 26th, 2007
Clinical Rotation Talk
Overview of Presentation
• Follicular Lymphoma
– Epidemiology
– Diagnosis
– Grade/Stage
– Treatments
– Future Directions
• radioimmunotherapy
Lymphomas
Large B-cell
14%
2%
6%
30%
Follicular
Marginal zone
PTCL
6%
Mantle cell
SLL/CLL
6%
Mediastinal
7%
8%
22%
Anaplastic L cell
Hodgkin’s
11858 cases of follicular lymphoma (2002 SEER database. O’Connor)
Follicular Lymphoma
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•
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•
•
•
•
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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
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
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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
Score
0-1
2
3-5
Prognosis
good
moderate
poor
% Patients
36
37
27
OS (10 yr)
71
51
36
Solal-Céligny et al.
Grade Determines Outcomes
Non-Hodgkin's Lymphoma
Low Grade
"indolent"
Intermediate Grade
"aggressive"
High Grade
"highly aggressive"
Follicular Lymphoma (grade I,II)
MALT, SLL, Marginal Zone
Follicular Lymphoma (grade III)
DLBCL,
Burkitt's
Stage I,II
22-33%
Stage III,IV
67-78%
Untreated Survival:
Years
Months
Weeks
Treatments
Indolent
Aggressive
Follicular Lymphoma (grade I,II)
Follicular Lymphoma (grade III)
Stage I,II
22-33%
Stage III,IV
67-78%
Stage I,II
Stage III,IV
IFRT (30-35 Gy)
Watch and Wait
R-CHOP
R-CHOP + IFRT
Watch and Wait
R-CHOP
= curable
= incurable
IFRT +/- Chemotherapy in Stage I,II
Follicular Lymphoma
First Author
(year)
Soubeyran, 1988
Kelsey, 1994
Institution
Fondation Bergonié,
France
BNLI
Number of
Patients
Freedom from
Treatment Relapse (10 y)
Overall
Survival (10 y)
103
148
RT ± CT
RT + CT
RT
49%
42%
33%
56%
42%
52%
208
RT
47%
64%
58
177
80
83
RT
RT
RT
RT + CT
43%
44%
41% (15 y)
72%
79%
64%
43% (15 y)
80%
Petersen, 2004
BNLI
Royal Marsden
Hospital, London
Stanford
MDAH
MDAH
Princess Margaret
Hospital
460
RT
51%
62%
Guadagnolo, 2006
JCRT, Boston
106
RT ± CT
46%
75%
Vaughan Hudson,
1994
Pendlebury, 1995
MacManus, 1996
Wilder, 2001
Seymour, 2003
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
Follicular Lymphoma (grade I,II)
Follicular Lymphoma (grade III)
Stage I,II
22-33%
Stage III,IV
67-78%
Stage I,II
Stage III,IV
IFRT (30-35 Gy)
Watch and Wait
R-CHOP
R-CHOP + IFRT
Watch and Wait
R-CHOP
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
401 patients
stage I,II intermediate Grade
CHOP x8
CHOP x3 + RT
40-50 Gy
(5 yr) PFS= 64%
(5 yr) OS 72%
(5 yr) PFS= 77%
(5 yr) OS 82%
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
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Every 3 months for first 2 years
Every 6 months for next 3 years
H&P, labs, CXR
+/- CT, PET scans
Recap
Follicular Lymphoma (grade I,II)
Follicular Lymphoma (grade III)
Stage I,II
22-33%
Stage III,IV
67-78%
Stage I,II
Stage III,IV
IFRT
Watch and Wait
R-CHOP
R-CHOP + IFRT
Watch and Wait
R-CHOP
Salvage Treatment
Follicular Lymphoma (grade I,II)
Initial Rx
Follicular Lymphoma (grade III)
Stage I,II
22-33%
Stage III,IV
67-78%
Stage I,II
Stage III,IV
IFRT
Watch and Wait
R-CHOP
R-CHOP + IFRT
Watch and Wait
R-CHOP
Salvage Rx
R-CHOP
radioimmunotherapy
IFRT 4 Gy in 2 Fx
RR
56%
85%
92%
CR
16%
33%
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 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
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
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
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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
Overall Survival
Survival Probability
Freedom from
Treatment Failure
Time (Years)
Time (Years)
Guadagnolo et al