Optimal frontline therapy for Follicular lymphoma:
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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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Jonathan w friedberg m d m m sc

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


Jonathan w friedberg m d m m sc

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


Follicular lymphoma common management approach

Follicular LymphomaCommon Management Approach

TRANSFORMATION


Follicular lymphoma common management approach1

Follicular LymphomaCommon Management Approach

TRANSFORMATION


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)


    No differences in overall survival at 5 years of follow up

    No differences in overall survivalat 5 years of follow-up


    Jonathan w friedberg m d m m sc

    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


    Jonathan w friedberg m d m m sc

    Characteristics of the patients

    IncludedRandomised

    (n = 202)(n = 151 )

    Median age5757

    PS 0-I94 %97 %

    Stage III-IV85 %85 %

    Involved BM52 %50 %

    Bulky (> 5 cm)53 %48 %

    Elevated LDH37 %30 %

    Previous chemotherapy68 %66%


    Prolonged vs standard rituximab efs blood 103 4416 2004

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


    Jonathan w friedberg m d m m sc

    Effect of schedule on event free survival:

    Update 2009

    P = 0.0007 Median FU: 9.4 years

    25% still in remission

    at 8 years


    Jonathan w friedberg m d m m sc

    EFS in chemo-naïve responders:

    Update 2009

    P<0.0001

    P<0.0001

    45% of chemo-naive

    responders in remission

    at 8 years


    Jonathan w friedberg m d m m sc

    Overall Survival:

    Update 2009

    P = 0.09


    Jonathan w friedberg m d m m sc

    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


    Primary endpoint time to treatment failure

    Primary Endpoint: Time to Treatment Failure


    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


    Jonathan w friedberg m d m m sc

    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


    Jonathan w friedberg m d m m sc

    Thank you!

    Questions?


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