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

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