Transcript Follicular Lymphoma Michael Bassetti PhD July 26th, 2007 Clinical Rotation Talk Overview of Presentation • Follicular Lymphoma – Epidemiology – Diagnosis – Grade/Stage – Treatments – Future Directions • radioimmunotherapy.

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
PTC L
6%
Mantle cell
SLL/C LL
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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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
Sc ore
0 -1
2
3 -5
P rognos is
good
moderate
poor
% P atients
36
37
27
O S (1 0 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 W ait
R-CHOP
R-CHOP + IFRT
Watch and W ait
R-CHOP
= curable
= incurable
IFRT +/- Chemotherapy in Stage I,II
Follicular Lymphoma
First A ut hor
(year)
Number of
Instit ut ion
Pat ient s
Fondation Bergonié,
S oubeyran, 1 9 8 8 Franc e
103
Kels ey, 1 9 9 4
BN L I
148
V aughan H uds on,
1994
BN L I
Royal M ars den
P endlebury, 1 9 9 5 H os pital, L ondon
M ac M anus , 1 9 9 6 S tanford
Wilder, 2 0 0 1
M DA H
S eymour, 2 0 0 3
M DA H
P rinc es s M argaret
P eters en, 2 0 0 4
H os pital
G uadagnolo, 2 0 0 6J C R T , Bos ton
Freedom f rom
Treat ment Relapse (10 y)
Overall
Survival (10 y)
RT ± C T
RT + C T
RT
49%
42%
33%
56%
42%
52%
208
RT
47%
64%
58
177
80
83
RT
RT
RT
RT + C T
43%
44%
4 1 % (1 5 y)
72%
79%
64%
4 3 % (1 5 y)
80%
460
RT
51%
62%
106
RT ± C T
46%
75%
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 W ait
R-CHOP
R-CHOP + IFRT
Watch and W ait
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 W ait
R-CHOP
R-CHOP + IFRT
Watch and W ait
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 W ait
R-CHOP
R-CHOP + IFRT
Watch and W ait
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