Jonathan W. Friedberg M.D., M.M.Sc.

University of Rochester Medical Center

Optimal frontline therapy for Follicular lymphoma:

Do we need to start with chemotherapy?

NO!

Follicular Lymphoma is Heterogeneous

Solal-Céligny et al. Blood. 104:1258

• Age (>60)Age (>60)• Ann Arbor stage (III-IV)Ann Arbor stage (III-IV)• Hemoglobin level (<120 g/L)Hemoglobin level (<120 g/L)• Serum lactate dehydrogenase (>ULN)Serum lactate dehydrogenase (>ULN)• Number of involved nodal sites (>4)Number of involved nodal sites (>4)

Follicular Lymphoma International Prognostic Index

FL-IPI clinical prognostic scoring system

Follicular LymphomaOverall Survival According to FL-IPI

Risk Group Factors (#) Patients (%) 5-Year OS (%) 10-Year OS (%)

Low 0–1 36 91 71

Intermediate 2 37 78 51

High ≥3 27 53 36

Time (Months)

Su

rviv

al P

rob

abil

ity

1.0

0.8

0.6

0.4

0.2

0 12 24 36 48 60 72 84 96 108 120

Low

Intermediate

High

P<10-4

0.0

Solal-Céligny et al. Blood. 104:1258

NEJM 351:2159

T cells

Macrophages

Macrophages

Dendritic cells

“Immune-response 1”

“Immune-response 2”

FavorableOS: > 10 years

UnfavorableOS: < 4 years

Biological heterogeneity of follicular lymphoma:Impact of nodal microenvironment

What is the aim of therapy in an incurable disease like follicular lymphoma?

• “Clinical benefit”

– Symptom relief (note most patients are not symptomatic)

– Quality of life

• Physical: decreased transfusions, decreased infections, etc.

• Psychological: “…better to be in remission…..”

– Change the natural history of disease

• Transformation, Overall survival

• Delay need for toxic therapy

Follicular LymphomaCommon Management Approach

After Staging Evaluation

Early stageAdvanced stage

Low Tumor Burden

Advanced stage

High Tumor Burden

Involved

Field RadiationObservation Therapy

TRANSFORMATION

Follicular LymphomaCommon Management Approach

After Staging Evaluation

Early stageAdvanced stage

Low Tumor Burden

Advanced stage

High Tumor Burden

Involved

Field RadiationObservation Therapy

TRANSFORMATION

“Watch and Wait” Strategy for Select Indolent NHL Patients

• Study of asymptomatic, advanced stage, low-grade NHL found no difference in OS between immediate chlorambucil vs delay of therapy until progression1

• Chlorambucil: 5.9 yr• Observation: 6.7 yr

• Current NCCN Guidelines recommend observation for select indolent NHL patients particularly if2:

• Advanced Age • Asymptomatic• Low Tumor Burden

1Ardeshna KM, et al. Lancet. 2003;362:516-522. 2NCCN guidelines. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.

Randomized Trial of Rituximab vs W&W in Patients With Stage II-IV Asymptomatic Non-Bulky FL

Ardeshna K, et al. Blood. 2010;116:5a. Abstract 6.

• Summary• Improved PFS in R arms (P < 0.001)• Improved time to initiation of new treatment in the R arms: 33

mo vs. not reached at 4 yr (P < 0.001)• No difference in OS (P > 0.5)• Quality of life no worse

Arm AArm A Arm BArm B Arm CArm C

Intervention Observe R x 4 wk R x 4 wk

Maintenance -- -- R q 2 mo x 2 yr

Number 186 84 192

CR/PR (%) 3/6 45/33 49/36

PFS 30% 60% 80%

TNT 33 mo NR NR

Ardeshna et al, ASH 2010 Plenary

Watchful waiting (WW) vs active treatment (AT): Lymphocare

2,727 patients with newly diagnosed FL enrolled

1,822 Stage III/IV

AT group n = 1,462

WW groupn = 270

R-monotherapy n = 232

R-chemotherapy n = 1,019

Other† n = 211

31 patients excluded*59 patients excluded*

Sinha et al, ASH 2011

Baseline characteristics (WW vs AT)

Characteristic, % WW

(n = 270)AT

(n = 1,462) p-value

Age, median years (range)61

(34–91)60

(22–97)0.9003

Male 45 49 0.2601FL grade: 1–2 79 68

0.0002

310 20

Mixed or unknown 11 12FLIPI risk: Good 18 14

< 0.0001 Intermediate 48 35 Poor 34 51

ECOG PS: 0 85 61< 0.0001

≥ 115 39

Patients receiving AT had higher percentages of stage IV, LDH > ULN, Hgb < 12 g/dL, and more than one extranodal site

Race, number of nodal sites and bone marrow involvement were not significantly different between groups (Pearson chi-square test, p > 0.05)

No differences in overall survivalat 5 years of follow-up

WW(n = 270)

R-mono(n = 232)

R-chemo(n = 1,019)

Other(n = 211)

Median follow-up time, months

60 57 59 62

Median OS Not reached

Deaths, % 18 25 20 18

SAKK 35/98 trial design: Standard vs. SAKK 35/98 trial design: Standard vs. Prolonged Rituximab in indolent NHLProlonged Rituximab in indolent NHL

375 mg/m375 mg/m² every 2 months x ² every 2 months x 44

n = 151n = 151

PDPDoffofftrialtrial

n = 202n = 202

ProlongedProlonged375 mg/m²375 mg/m²weekly x 4weekly x 4

StandardStandard

RSD,PR,CRSD,PR,CR

Characteristics of the patientsCharacteristics of the patients

IncludedIncluded RandomisedRandomised

(n = 202)(n = 202) (n = 151 )(n = 151 )

Median ageMedian age 5757 5757

PS 0-IPS 0-I 94 %94 % 97 %97 %

Stage III-IVStage III-IV 85 %85 % 85 %85 %

Involved BMInvolved BM 52 %52 % 50 %50 %

Bulky (Bulky (>> 5 cm) 5 cm) 53 %53 % 48 %48 %

Elevated LDHElevated LDH 37 %37 % 30 %30 %

Previous chemotherapyPrevious chemotherapy 68 %68 % 66%66%

Prolonged vs. standard rituximab EFS:Blood 103:4416 2004

Effect of schedule on event free survival:Effect of schedule on event free survival:Update 2009Update 2009

P = 0.0007 Median FU: 9.4 years

25% still in remissionat 8 years

EFS in chemo-naïve responders:EFS in chemo-naïve responders:Update 2009Update 2009

P<0.0001P<0.0001

45% of chemo-naiveresponders in remission

at 8 years

Overall Survival:Overall Survival:Update 2009Update 2009

P = 0.09

Conclusions: Ghielmini et alConclusions: Ghielmini et al

•Prolonged rituximab therapy is safe

•With 8 total doses of rituximab, the chance of being still in remission is ~25% at 5 and 8 years.

•Trend toward improved overall survival

•Excellent outcome for selected patients treated with rituximab alone.

•Would patients do better with chemotherapy?•Is it worth the risks?

E4402 (RESORT) Schema

Rituximabre-treatment atprogression*

375 mg/m2 qw 4

RANDOMIZE

Rituximab375 mg/m2 qw

4CR or PR

RituximabMaintenance*

375 mg/m2 q 3 months

*Continue until treatment failureNo response to retreatment or PD within 6 months of R

Initiation of cytotoxic therapy or Inability to complete rx

Kahl et al, ASH 2011

E4402 Major Eligibility

Indolent NHL Follicular grade 1 or 2 Small Lymphocytic MALT Marginal Zone nodal Marginal Zone splenic

No prior lymphoma therapy

Stage III or IV disease Measurable disease

Low tumor burden as defined by GELF No tumor mass > 7cm Fewer than 3 nodal masses

> 3 cm No system symptoms or B

symptoms No splenomegaly greater

than 16 cm by CT scan No risk of organ

compression No leukemic phase No cytopenias

Primary Endpoint: Time to Treatment Failure

Time to First Cytotoxic Therapy

90% of patients did not require cytotoxic therapy for first 5 years of

diagnosis

Conclusions: RESORT

• In this study of previously untreated low tumor burden FL:– Rituximab retreatment was as effective as

maintenance rituximab for time to treatment failure

– No benefit in QOL or anxiety at 12 months with MR

– Virtually all of these selected patients did extremely well without chemotherapy

Indolent CD20+ lymphoma

Central pathology

review

RANDOMIZATION

Rituximab x 4

Rituximab x 4

+ IFN x 5 weeks

EVALUATION

Rituximab x 4

+ IFN x 5 weeks)

SD, PD off protocol therapy

CR, CRu PR MR

Rituximab 375mg/m2 i.v. day 1

IFN-2a

3.0 MIU/day s.c. daily (Week 1)

4.5 MIU/day s.c. daily (Weeks 2–5)

Rituximab x 4

Randomized phase III trial ML16865

CHEMOTHERAPY

Kimby et al, ASH 2012

Overall survival: ITT follicular lymphoma patients

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0E

ven

t-fr

ee p

rob

abili

ty

6 18 30 36 42 480 12 24 54 60 66 72 78 84

134

122

130

120

126

115

123

111

109

97

96

86

135

122

132

120

129

116

82

79

74

64

60

53

41

39

30

29

23

17

Patients at risk:

Rituximab only

Rituximab + IFN

Time (months)

% pts with event Median 95% CI p value

Rituximab 13% NE NE

Rituximab + IFN 10% NE NE 0.4289

p-value obtained from stratified log-rank test (stratification: previous treatment for lymphoma)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0E

ven

t-fr

ee p

rob

abili

ty

6 18 30 36 42 480 12 24 54 60 66 72 78 84

108

104

80

81

56

62

50

56

43

45

37

40

135

122

92

92

66

69

26

34

23

26

21

21

15

15

12

12

10

6

Patients at risk:

Rituximab only

Rituximab + IFN

Time to treatment failure: ITT follicular lymphoma patients (n=257)

Time (months)

% pts with event Median 95% CI p value

Rituximab 67% 23.2 18.1–31.3

Rituximab + IFN 66% 31.7 21.9–43.3 0.3627

p-value obtained from stratified log-rank test (stratification: previous treatment for lymphoma)

Many patients with follicular lymphoma do not require chemotherapy

• Watch and wait– No overall survival benefit with early treatment– No change in transformation with early treatment

• Rituximab:– Highly active therapy in a variety of schedules– Long responses and outstanding survival

Phase 2 study of lenalidomide and rituximab for follicular lymphoma

Pre-Treatment Post-Treatment

Positive Negative Positive Negative

N 44 1 3 42*

% 98% 2% 7% 93%

1. Juweid, M. et al. JCO. 2007. 25(5): 571-578.

Lenalidomide 20 mgRituximab 375 mg

3 year PFS: 81%

PET Imaging Results

Progression-free survival

Fowler et al, ASH 2012

RELEVANCE Study Design(Rituximab and LEnalidomide versus Any ChEmotherapy)

1st line FL

N=1000R

R2

R + Chemo

R2 Maintenance

Rituximab Maint.

• R+Chemo:•Investigator’s choice of R-CHOP, R-CVP, BR

• Lenalidomide 20mg for 6 cycles, then 10mg if CR

Thank you!Questions?