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Optimal frontline therapy for Follicular lymphoma: Do we need to start with chemotherapy?. NO!. Jonathan W. Friedberg M.D., M.M.Sc. University of Rochester Medical Center. Follicular Lymphoma is Heterogeneous. Follicular Lymphoma International Prognostic Index

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slide1

Optimal frontline therapy for Follicular lymphoma:

Do we need to start with chemotherapy?

NO!

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

University of Rochester Medical Center

follicular lymphoma is heterogeneous
Follicular Lymphoma is Heterogeneous

Follicular Lymphoma International Prognostic Index

FL-IPI clinical prognostic scoringsystem

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

Solal-Céligny et al. Blood. 104:1258

follicular lymphoma overall survival according to fl ipi

1.0

0.8

Low

0.6

Intermediate

Survival Probability

0.4

High

0.2

P<10-4

0.0

36

120

12

48

84

108

24

60

0

72

96

Time (Months)

Follicular LymphomaOverall Survival According to FL-IPI

Solal-Céligny et al. Blood. 104:1258

slide5

Biological heterogeneity of follicular lymphoma:

Impact of nodal microenvironment

“Immune-response 1”

T cells

Macrophages

Favorable

OS: > 10 years

“Immune-response 2”

Macrophages

Dendritic cells

Unfavorable

OS: < 4 years

NEJM 351:2159

what is the aim of therapy in an incurable disease like follicular lymphoma
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
watch and wait strategy for select indolent nhl patients
“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
Randomized Trial of Rituximab vs W&W in Patients With Stage II-IV Asymptomatic Non-Bulky FL
  • Summary
    • Improved PFS in R arms (P < 0.001)
    • Improved time to initiation of new treatment in the R arms: 33 movs. not reached at 4 yr (P < 0.001)
    • No difference in OS (P > 0.5)
    • Quality of life no worse

Ardeshna et al, ASH 2010 Plenary

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

watchful waiting ww vs active treatment at lymphocare
Watchful waiting (WW) vs active treatment (AT): Lymphocare

2,727 patients with newly diagnosed FL enrolled

1,822 Stage III/IV

59 patients excluded*

31 patients excluded*

AT group n = 1,462

WW group

n = 270

Other†n = 211

R-monotherapy n = 232

R-chemotherapy n = 1,019

Sinha et al, ASH 2011

baseline characteristics ww vs at
Baseline characteristics (WW vs AT)

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)

slide14

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

Standard

n = 202

n = 151

R

375 mg/m²

weekly x 4

Prolonged

SD,PR,CR

375 mg/m² every 2 months x 4

PD

off

trial

slide15

Characteristics of the patients

Included Randomised

(n = 202) (n = 151 )

Median age 57 57

PS 0-I 94 % 97 %

Stage III-IV 85 % 85 %

Involved BM 52 % 50 %

Bulky (> 5 cm) 53 % 48 %

Elevated LDH 37 % 30 %

Previous chemotherapy 68 % 66%

slide17

Effect of schedule on event free survival:

Update 2009

P = 0.0007 Median FU: 9.4 years

25% still in remission

at 8 years

slide18

EFS in chemo-naïve responders:

Update 2009

P<0.0001

P<0.0001

45% of chemo-naive

responders in remission

at 8 years

slide19

Overall Survival:

Update 2009

P = 0.09

slide20

Conclusions: 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
E4402 (RESORT) Schema

R

A

N

D

O

M

I

Z

E

Rituximab

Maintenance*

375 mg/m2q 3 months

Rituximab

375 mg/m2 qw  4

CR or PR

Rituximabre-treatment atprogression*

375 mg/m2 qw  4

*Continue until treatment failure

No 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
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
time to first cytotoxic therapy
Time to First Cytotoxic Therapy

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

conclusions resort
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
randomized phase iii trial ml16865
Randomized phase III trial ML16865

RANDOMIZATION

EVALUATION

Rituximab x 4

Rituximab x 4

Indolent CD20+ lymphoma

Central pathology review

CR, CRu PR MR

Rituximab x 4

+ IFN x 5 weeks

Rituximab x 4

+ IFN x 5 weeks)

SD, PD off protocol therapy

  • Rituximab 375mg/m2i.v. day 1
  • IFN-2a
  • 3.0 MIU/day s.c. daily (Week 1)
  • 4.5 MIU/day s.c. daily (Weeks 2–5)

CHEMOTHERAPY

Kimby et al, ASH 2012

slide27

Overall survival: ITT follicular lymphoma patients

1.0

0.9

0.8

0.7

0.6

0.5

0.4

Event-free probability

0.3

0.2

0.1

0.0

0

54

60

36

84

78

66

72

42

48

30

24

6

18

12

130

120

132

120

23

17

30

29

129

116

134

122

135

122

82

79

74

64

126

115

123

111

60

53

41

39

109

97

96

86

Patients at risk:

Rituximab only

Rituximab + IFN

Time (months)

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

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

1.0

0.9

0.8

0.7

0.6

0.5

0.4

Event-free probability

0.3

0.2

0.1

0.0

24

66

72

6

18

12

0

54

60

30

36

84

78

42

48

66

69

21

21

15

15

43

45

37

40

80

81

108

104

92

92

135

122

26

34

23

26

56

62

50

56

12

12

10

6

Time (months)

Patients at risk:

Rituximab only

Rituximab + IFN

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

many patients with follicular lymphoma do not require chemotherapy
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
Phase 2 study of lenalidomide and rituximab for follicular lymphoma

Lenalidomide 20 mg

Rituximab 375 mg

3 year PFS: 81%

Progression-free survival

PET Imaging Results

Fowler et al, ASH 2012

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

relevance study design rituximab and lenalidomide versus any chemotherapy
RELEVANCE Study Design(Rituximab and LEnalidomide versus Any ChEmotherapy)

R2

R2 Maintenance

1st line

FL

N=1000

R

R+ Chemo

RituximabMaint.

  • R+Chemo:
    • Investigator’s choice of R-CHOP, R-CVP, BR
  • Lenalidomide 20mg for 6 cycles, then 10mg if CR
slide32

Thank you!

Questions?

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