follicular lymphoma laurie h. sehn, mdcm, mph bc cancer agency vancouver, canada

Follicular Lymphoma

Laurie H. Sehn, MDCM, MPHBC Cancer Agency

Vancouver, Canada

Pathogenesis of Follicular LymphomaPathogenesis of Follicular Lymphoma

t(14;18)

t(14;18) B cell

GC reaction

SHM machinery

Additional genetic alterations

6q- -1p36.3 +der18 +7, +8Additional genomic alterations

Immune Response 2

Immune Response 1

B cell

Adverse Course Favorable Course

Ag

Host Genetics

Host Genetics

Bcl-2

N-glycosylation

RFH

FL

Dave, NEJM, 2004;351:2159

Reported Molecular Markers in FL Favorable Unfavorable

Bcl-6 expression

CD-10 expression

MUM1 negative

PU.1

Cyclin B1

Immune response IR-1

Chromosomal gains (+7, +12q13-14, +18q)

Chromosomal losses(del6q, -9p21, -17p13)

Bcl-2 expression

BCL-6 translocation

MDM2 expression

Bcl-XL

Macrophage content

Microvessel density

81-gene predictor (variable)

Immune response IR-2

Follicular Lymphoma Grades

X

Grade 1 Grade 2

Grade 3a

Grade 3b

MIB1

MIB1

WHO Lymphoid Neoplasm ClassificationRevisions 2008

Maintains Grading Grade 1/2 (low grade) 0-15 centroblasts/hpf – Grade 1 0-5 centroblasts/hpf – Grade 2 6-15 centroblasts/hpf

Grade 3– Grade 3A > 15 centroblasts/hpf – Grade 3B solid sheets of centroblasts

Any diffuse areas with >15 centroblasts/hpf is now called DLBCL with follicular lymphoma

Follicular Lymphoma International Prognostic Index (FLIPI)

Factor Adverse

Nodal Sites ≥5

LDH >Normal

Age ≥60

Stage III-IV

Hemoglobin <12 g/dL

PrognosisNumber of Factors

Patients (%)

5-year OS(%)

10-year OS(%)

Good 0-1 36 91 71

Intermediate 2 37 78 51

Poor ≥3 27 53 36

Solal-Celigny et al, Blood 2004

Comparison of IPI and FLIPI Indices

IPI

FLIPI

Perea, Annals Oncol 2005

HR

HRHR

HR

IR

IR

IR

IR

LR

LR

LR

LR

TTF According to FLIPI Following R-CHOP

Buske, Blood 2006

Indolent LymphomaAge Adjusted Mortality vs Normal

Indolent LymphomaAge Adjusted Mortality vs Normal

Agegroup

U.S. populationexpected %1-yr

mortality

LGL 60% 1-yr

mortality

60-64 1.62 29.5

65-69 2.60 26.0

70-75 5.33 45.1

75 6.87 65.9

Overall 2.52 32.1

Weisdorf, J Clin Oncol 1992;10:942

Indolent lymphoma

> 75

Treatment Options for Follicular Lymphoma

Interferon

Autologous

Allogeneic(full or non-

myeloablative)

Alkylator-based treatment

CVPChlorambucil

CHOP

Specific Nonspecific

Purine analogsFludarabine

Fludarabine-basedcombination

Chemotherapy-based

Antibody-basedRituximab alone

Chemo-immunotherapy

RadioimmunotherapyTositumomab

Ibritumomab tiuxetan

Biologic-based Transplantation

Optimal Therapy in FL Should be Individualized

Curative therapy has not been identified

Treatment decisions must be individualized and should consider:– Goal of therapy– Efficacy of therapy– Toxicity– Patient’s medical condition– Patient preferences– Lifelong management– Appropriate sequencing

Watch and Wait

No survival advantage to starting therapy early– Young, RC et al. Semin Hematol 1988– Brice, P et al. J Clin Oncol 1997– Ardeshna, KM et al. Lancet 2003

Avoids unnecessary toxicity and maintains QOL

Allows new information and therapies to emerge

Not yet tested in era of immuno-chemotherapy

Randomized Trials of Rituximab and Chemotherapy in Untreated Follicular NHL

Trial Treatment CR%ORR

%Results

MarcusBlood 2005, JCO 2008

CVP vs

R-CVP

10

41

57

81Improved TTP

and OS

Hiddemann Blood 2006

CHOP vs

R-CHOP

17

20

90

96Improved TTF

and OS

HeroldASH 2005, ASH 2006

MCP vs

R-MCP

25

50

75

92Improved EFS

and OS

Salles, Foussard

J Clin Oncol 2008

CHVP/IFN vs

R-CHVP/IFN

63

79

73

84Improved EFS

Time to Treatment FailureR-CVP versus CVP

Time to Treatment FailureR-CVP versus CVP

Study month

Ev

en

t-fr

ee

pro

ba

bil

ity

06 12 18 24 30 36 42 48 540 60

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

R–CVP: median 27 months

CVP: median 7 months

66 72

159CVP

R–CVP

Patients at risk:

162

86

123

51

113

34

98

30

93

21

76

17

69

14

63

10

53

6

37

3

14

1 0

3 0

p<0.0001

Median FU: 53 months

Marcus et al, ASH 2006

Marcus, R et al. J Clin Oncol 2008

Overall survival R CVP versus CVP

Do we need to use an Anthracycline?

No survival advantage to using an anthracycline– Dana, et al. J Clin Oncol 1993 – Peterson, et al. J Clin Oncol 2003

Greater Toxicity

Variable results reported with R-CHOP– Czuczman, et al. J Clin Oncol 2004– Hiddemann, et al. Blood 2005

Consider lifelong management (transformation risk)

Risk of Transformation by Initial Treatment

Al-Tourah et al. J Clin Oncol, 2008

Follicular Lymphoma GradingGrade 1 FL Grade 3a FL

Grade 2 FL

The spectrum of FL is a continuum from grade 1 grade 3a

Increasing Proliferation

Overall Survival of Grade 3A FL According to Treatment

1614121086420

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Time (years)

1614121086420

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Time (years)

Overall Survival Disease Specific Survival

Anthracycline (n=32)

Anthracycline (n=32)

No Anthracycline (n=67)

No Anthracycline (n=67)

Shustik et al, Lugano 2008

MJRMJR

PFS : Bendamustine-R vs R-CHOPPFS : Bendamustine-R vs R-CHOP

B-RB-R

CHOP-RCHOP-R

p = 0,11p = 0,11

00 1212 2424 36360.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

Pro

babi

lity

Pro

babi

lity

48 months48 months

Median observation period 18 monthsMedian observation period 18 months

Rummel et al, ASH 2007

Randomized Maintenance Rituximab Trials in Indolent NHL

Trial Patients Induction Results

HochsterJ Clin Oncol 2009

Untreated CVP Improved EFS

Ghielmini Blood 2004

Untreated/

RelapsedRituximab Improved EFS

HainsworthJ Clin Oncol 2005

Relapsed Rituximab Improved PFS

Forstpointner Blood 2006

Relapsed FCM v R-FCMImproved

Response Duration

van OersBlood 2006, ASH 2009

Relapsed CHOP v R-CHOPImproved PFS

and ?OS

RANDOMISE

CHOP q21dmaximum 6 cycles

R-CHOP q21dmaximum 6 cycles

RANDOMISE

Observation

Rituximab maintenance

therapy*

* 375 mg/m2 every 3 months for 2 years or until relapse

CRPR

n = 234

n = 231

n = 167

n = 167

van Oers M, et al. Blood 2006

Rituximab in Induction and Maintenance Treatment of Relapsed Follicular NHL- EORTC Trial

Rituximab maintenance prolongs PFS by more than 3 years

Rituximab maintenance median: 51.5 months

Observation median: 14.9 months

p < 0.001

Years0 1 2 3 4 5

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts (

%)

PFS > 3 years

PFS after R-CHOP/CHOP induction in EORTC 20981 trial


Rituximab maintenance improves PFS irrespective of induction regimen

PFS after CHOP induction PFS after R-CHOP induction

ObservationMedian: 23.0 months

MaintenanceMedian: 51.8 months

p = 0.004

Maintenancemedian: 42.2 months

Observationmedian: 11.6 months

p < 0.001

Years0 1 2 3 4 5

0

20

40

60

80

100

Years0 1 2 3 4 5

0

20

40

60

80

100


Rituximab maintenance significantly improves overall survival

Years0 1 2 3 4 6

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

(%

)

p = 0.011HR: 0.52

5

Rituximab maintenance: 3 years 85.1%

Observation: 3 years 77.1%

OS after CHOP/R-CHOP induction in EORTC 20981 trial


Vidal et al, J Natl Cancer Inst 2009

Meta-Analysis: Overall Survival with Rituximab Maintenance versus Observation

Vidal et al, J Natl Cancer Inst 2009

Meta-Analysis: Infection-Related Adverse Events with Rituximab Maintenance

FIT Study Design

ZEVALIN (n = 208)

Rituximab 250 mg/m2 IV day -7 and day 0 +Zevalin 14.8 MBq/kg (max 1184 MBq/kg)

day 0

Advanced Stage FLFirst-line CVP, CHOP-

like, fludarabine combinations,

chlorambucil, or rituximab combination

INDUCTION

CONSOLIDATION

No further treatment (n = 206)

NRPD

CR/CRu or PR

No inclusion

RANDOMIZATION

CONTROLCONTROL

Start of study

Morschhauser et al, J Clin Oncol 2008

Progression-Free Survival 90Y-ibritumomab tiuxetan versus Observation

90Y-ibritumomab tiuxetan (n=208) Median 36.5 mos

P<0.0001

Control (n=206) Median 13.3mos

Overall Survival 90Y-ibritumomab tiuxetan versus Observation

Morschhauser et al, J Clin Oncol 2008

Ladetto et al, Blood 2008

Overall Survival Event-Free Survival

Outcome in Untreated FL Following CHOP-R versus Rituximab and ABMT

Rezvani, et al. J Clin Oncol 2008

Outcome Following Reduced-Intensity

Allogeneic Transplantation - Seattle

n=16n=16

n=46n=46

Impact of Transformation on Survival of pts with Follicular Lymphoma

Al-Tourah et al, J Clin Oncol, 2008

Risk of Transformation = 3% per year

10 y Risk = 30%10 y Risk = 30%

Transformation Risk in FLBritish Columbia (N= 600)


Transformation is a heterogenous process

mutation of P53

P16 alterations

rearrangements involving c-myc

secondary non-random cytogenetic

changes

5’UTR Bcl-6 mutations

mutations in

Bcl-2

Transformation

Impact of Initial Management On Risk of Transformation


14121086420

1.0

.8

.6

.4

.2

0.0

Post-Transformation Survival by Treatment: CHOP-R vs CHOP- Like

CHOP-R (N= 23)

5yr OS 61%

CHOP-Like (N= 85)

5yr OS 33%

P= 0.01

Pro

port

ion

Sur

vivi

ng

Post-Transformation Survival (y)

Al-Tourah, ASH 2007, Abst # 790

Follicular Lymphoma in BC by Era

80-88 (367) 89-97 (710) 98-06 (941)

Overall survival (y)

2520151050

Cum

Sur

viva

l

1.0

.8

.6

.4

.2

0.01980-88 n = 367

1998-2006 n = 941

1989-97 n = 710

33 % decrease

in 10 y mortality

Outcome for Follicular Lymphoma in BC by Era

Conclusion

• Combined chemoimmunotherapy improves survival in patients who need treatment

• Maintenance rituximab significantly prolongs remission

• Transformation remains a treatment challenge and greatly impacts survival

• Challenge Use biologic insight of key factors at play in individual patients to guide treatment

follicular lymphoma laurie h. sehn, mdcm, mph bc cancer agency vancouver, canada

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