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Follicular Lymphoma: Updates on Treatment Strategies Daryl Tan Raffles Cancer Center Visiting Consultant Singapore General Hospital Adjunct Assistant Professor, Duke-NUS Graduate Medical School. Grade 1-2 Follicular Lymphoma. Limited Stage. Advanced Stage, Stage II bulky or ‘ B ’.

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slide1

Follicular Lymphoma: Updates on Treatment StrategiesDaryl TanRaffles Cancer CenterVisiting Consultant Singapore General HospitalAdjunct Assistant Professor,Duke-NUS Graduate Medical School

slide2

Grade 1-2 Follicular Lymphoma

Limited Stage

Advanced Stage, Stage II bulky or ‘B’

GELF Criteria

Symptomatic,

High tumor burden

Asymptomatic,

Low tumor burden

Curative Intent Radiotherapy

Chemotherapy/ Immunotherapy

Watch and Wait

Clinical Questions :

  • Is there still a role for watch and wait in rituximab era?
  • What is the optimal frontline therapy?

Which R-Chemo?

  • Role of maintenance rituximab?

CR or PR

Consolidation RIT or Maintenance Rituximab

slide3

Grade 1-2 Follicular Lymphoma

Advanced Stage, Stage II bulky or ‘B’

Asymptomatic,

Low tumor burden

Watch and Wait

Clinical Questions :

  • Is there still a role for watch and wait in rituximab era?
slide4

Watch and Wait in FL

Horning S, SA Rosenberg. NEJM 1984;311:1471-76

slide5

Overall Survival of 1,333 FL Patients at Stanford

by Time to First Treatment

P<0.001

Tan D, Horning S, et al. ASH 2007. Abstract 3428

slide8

Time To Initiation of New Therapy

Ardeshna KM et al. ASH 2010 Abstract 6

slide9

Grade 1-2 Follicular Lymphoma

Advanced Stage, Stage II bulky or ‘B’

Asymptomatic,

Low tumor burden

Watch and Wait

Clinical Questions :

  • Is there still a role for watch and wait in rituximab era?
  • Role of maintenance rituximab?
slide10

wks

  • progression within 6 months of Rtx
  • failure to respond to Rtx
  • inability to complete protocol
  • initiation of alternative therapy.
slide11

RESORT: Time to First Cytotoxic Therapy

3-yr Freedom from First Cytotoxic Chemo

MR: 95%

RR: 86%

Median FU : 3.8 yrs

slide13

Grade 1-2 Follicular Lymphoma

Advanced Stage, Stage II bulky or ‘B’

Symptomatic,

High tumor burden

Clinical Questions :

  • Is there still a role for watch and wait in rituximab era?
  • What is the optimal frontline therapy?
  • Role of maintenance rituximab?

Chemotherapy/ Immunotherapy

slide14

RCTs on R-Chemo vs Chemo

Marcus et al

Salles et al

Which R-Chemo for induction ?

Hiddeman et al

Harold et al

slide15

Phase III Study of R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: final results of the FOLL05 trial from the FondazioneItalianaLinfomi (N=534)

Federico M, et al. ASCO 2012: Abstract 8006

slide16

Time-to-Treatment Failure

(R-CHOPvsR-CVPvsR-FM)

Federico M, et al. ASCO 2012: Abstract 8006

slide17

Adverse Events (≥grade 3)

(R-CHOP vs R-CVP vs R-FM)

Second Malignancies: 2% 3% 8%

Federico M, et al. ASCO 2012: Abstract 8006

bendamustine rituximab b r vs chop r
Bendamustine-Rituximab (B-R) vs CHOP-R

StiL NHL 1-2003

  • Bendamustine-Rituximab
  • (N=139)
  • - Bendamustine 90 mg/m2 day 1+2
  • Rituximab 375 mg/m2 day 1

Follicular

Waldenström’s

Marginal zone

Small lymphocytic

Mantle cell (elderly)

R

  • CHOP-Rituximab (N=140)
  • - Cyclophosphamide 750 mg/m2 day 1
  • - Doxorubicin 50 mg/m2 day 1
  • - Vincristine 1.4 mg/m2 day 1
  • Prednisone 100 mg days 1-5
  • Rituximab 375 mg/m2 day 1

Median follow-up 45 months

Lancet 2012, accepted for publication; J Clin Oncol 30, 2012 (suppl; abstr 3)

Courtesy of Mathias Rummel

slide19

Worst CTCAE Grades for Hematology Tests Results

Number (%) of patients

Treatment group Grade 2 Grade 3 Grade 4 Grade 3-4

Leukocytes CHOP-R 39 (15) 110 (44) 71 (28) 181 (72)

(109/L) B-R 80 (30) 85 (32) 13 (5) 98 (37)

Neutrophils CHOP-R 19 (8) 70 (28) 103 (41) 173 (69)

(109/L) B-R 61 (23) 53 (20) 24 (9) 77 (29)

Lymphocytes CHOP-R 72 (29) 87 (35) 19 (8) 106 (43)

(109/L) B-R 38 (14) 122 (46) 74 (28) 196 (74)

Hemoglobin CHOP-R 84 (33) 10 (4) 2 (<1) 12 (5)

(g/L) B-R 44 (16) 6 (2) 2 (<1) 8 (3)

Platelets CHOP-R 20 (8) 11 (4) 5 (2) 16 (6)

(109/L) B-R 19 (7) 15 (6) 2 (<1) 13 (5)

Courtesy of Mathias Rummel

toxicities all ctc grades
Toxicities(all CTC-grades)

B-R (n=261) CHOP-R (n=253)

(no. of pts) (no. of pts)P value

Alopecia - +++ < 0.0001

Paresthesias 18 73 < 0.0001

Stomatitis 16 47 < 0.0001

Skin (erythema) 42 23 = 0.0122

Allergic reaction (skin) 40 15 = 0.0003

Infectious complications 96 127 = 0.0025

- Sepsis 1 8 = 0.0190

Courtesy of Mathias Rummel

slide21

Results Response rates

B-R CHOP-R(n=261) (n=253) P value

ORR 92,7 % 91,3 %

CR 39,8 % 30,0 % = 0.021

SD 2,7 % 3,6 %

PD 3,5 % 2,8 %

Lancet 2012 in press; J Clin Oncol 30, 2012 (suppl; abstr 3)

slide22

Median (months)

B-R n. y. r.

CHOP-R 40.9

PFS: follicular (n=279) 45 months follow-up

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

Hazard ratio, 0.61 (95% CI 0.42 - 0.87)

p = 0.0072

0.1

0.0

0 12 24 36 48 60 72 84 96 months

Courtesy of Mathias Rummel

slide23

Median (months)

B-R n. y. r.

CHOP-R 46.6

PFS: follicular, FLIPI low (0-2) (n=152; 54.5%)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

Hazard ratio, 0.56 (95% CI 0.31 - 0.98)

p = 0.0428

0.1

0.0

0 12 24 36 48 60 72 84 96 months

Courtesy of Mathias Rummel

slide24

Median (months)

B-R 53.4

CHOP-R 34.9

PFS: follicular, FLIPI high (3-5) (n=127; 45.5%)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

Hazard ratio, 0.63 (95% CI 0.38 - 1.04)

p = 0.0679

0.1

0.0

0 12 24 36 48 60 72 84 96 months

Courtesy of Mathias Rummel

slide25

Median (months)

B-R 53.6

CHOP-R 31.5

Age: 61 yrs and older ( n = 315 )

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

Hazard ratio, 0.62 (95% CI 0.45 - 0.84)

p = 0.0022

0.1

0.0

0 12 24 36 48 60 72 84 96 months

Courtesy of Mathias Rummel

slide26

Median (months)

B-R 71.6

CHOP-R 30.9

Age: 60 yrs and younger ( n = 199 )

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

Hazard ratio, 0.52 (95% CI 0.33 - 0.79)

p = 0.0022

0.1

0.0

0 12 24 36 48 60 72 84 96 months

Courtesy of Mathias Rummel

slide27

Overall survival

1.0

0.9

0.8

B-R

0.7

0.6

CHOP-R

0.5

0.4

2 yrs 3 yrs 4 yrs 5 yrs 6 yrs 7 yrs

89.7% 85.6% 82.3% 80.1% 80.1% 75.9%

89.5% 86.7% 84.2% 77.8% 75.5% 59.5%

0.3

0.2

0.1

0.0

0 12 24 36 48 60 72 84 96 months

Courtesy of Mathias Rummel

slide28

Grade 1-2 Follicular Lymphoma

Advanced Stage, Stage II bulky or ‘B’

Symptomatic,

High tumor burden

Clinical Questions :

  • Is there still a role for watch and wait in rituximab era?
  • What is the optimal frontline therapy?
    • Which R-Chemo ? BR >RCHOP> RCVP
    • DO WE REALLY NEED CHEMO UPFRONT ?
  • Role of maintenance rituximab?
  • What is the optimal sequence of treatment?

Chemotherapy/ Immunotherapy

the kiss of death in follicular lymphoma
The Kiss of Death in Follicular Lymphoma

CTL: Cytotoxic T lymphocyte, FL: follicular lymphoma

Ramsay, et al. The Kiss of Death in FL. Blood 2011; 118: 5365-5366

Laurent, et al. Distribution, function, and prognostic value of cytotoxicT lymphocytes in FL. Blood 2011;118(20):5371-5379

lenalidomide mechanisms of action in lymphoma
Lenalidomide:Mechanisms of Action in Lymphoma

Ramsay AG, et al. Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood. 2009;114(21):4713-4720.

Lei W, et al. Lenalidomide Enhances Natural Killer Cell and Monocyte-Mediated Antibody-Dependent Cellular Cytotoxicity of Rituximab-Treated CD20+ Tumor Cells. Clin Cancer Res 2008;14:4650-4657

lenalidomide and rituximab for untreated indolent lymphoma final results of a phase ii study

Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study

Nathan Fowler, SattvaNeelapu, Frederick Hagemeister, Peter McLaughlin, Larry W Kwak, Jorge Romaguera, Michele Fanale, Luis Fayad, Robert Orlowski, Michael Wang, Francesco Turturro, Yasuhiro Oki, Linda Lacerte, Felipe Samaniego

Department of Lymphoma/Myeloma

MD Anderson Cancer Center, Houston, Texas

Courtesy of Nathan Fowler

study design
Study Design

7 8 9 10 11 12

Lenalidomide 20mg Days 1-21 Cycles 1-6*

Months

1 2 3 4 5 6

Lenalidomide 20mg Days 1-21 Cycles 7-12*

Rituximab 375mg/M2 Day 1 of Cycles 1-6

Rituximab 375mg/M2 Day 1 of Cycles 7-12

R

R

R= RESTAGING

R

R

If clinical benefit, can proceed to 12 cycles

*SLL patients: Dose escalation of lenalidomide starting with cycle 1: (10mg, 15mg, 20mg)

  • Phase II, single institution
  • Planned Enrollment
    • N= 50 Follicular lymphoma (grade I/II)
    • N=30 Small lymphocytic lymphoma
    • N=30 Marginal zone lymphoma
  • Groups analyzed independently for response and toxicity
response rates
Response Rates
  • *7 pts not evaluable for response:
    • 5 due to adverse event in cycle 1
    • 1 due to non-compliance
    • 1 due to withdrawal of consent

Courtesy of Nathan Fowler

slide36

Progression Free Survival

All Evaluable Patients

N=103

36 mo PFS*:78%

*Projected 3 year PFS

Courtesy of Nathan Fowler

slide37

Grade ≥ 3 Hematologic Toxicity

5 patients developed grade 3 neutropenic fever

slide38

Grade ≥ 3 Non Hematologic Adverse Events (>1 pt.)

  • Five secondary malignancies reported
    • 75 yo: recurrent bladder cancer
    • 53 yo: localized melanoma
    • 53 yo: stage 0 DCIS of breast
  • 81 yo: multiple myeloma
  • 75 yo: recurrent localized prostate cancer
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
  • LYSA (PI: Morschhauser) + North America (PI: Fowler)

Courtesy of Nathan Fowler

slide40

Grade 1-2 Follicular Lymphoma

Advanced Stage, Stage II bulky or ‘B’

Symptomatic,

High tumor burden

Chemotherapy/ Immunotherapy

Clinical Question :

  • Role of maintenance rituximab?

CR or PR

Consolidation RIT or Maintenance Rituximab

slide41

R-Maintenance vs Observation After R-Chemo Induction (PRIMA)

Salles G, et al. Lancet 2010; 377: 42–51

slide43

Median follow-up: 36 months

Time to next lymphoma treatment

Progression Free Survival

75%

58%

Overall Survival

Time to next Chemotherapy

Salles G, et al. Lancet 2010; 377: 42–51

slide45

Grade 3 / 4 Adverse Events

P=0.0026

Fulminant Hep B (n=1)

Salles G, et al. Lancet 2010; 377: 42–51

conclusions btg 2013
Conclusions-BTG 2013
  • Certainly still a role for watchful waiting
  • R-FM a/w increased toxicity
  • B-R is less toxic and more effective than CHOP-R
  • Impressive data with frontline IMiD + R
  • Maintance rituximab
    • Observed improvements in PFS and Time to Next Tx

not been shown to translate into OS benefit

    • MR should be weighed against increased risk of toxicity, other potential complications, resources and pt’s preference
slide51

Rituximab era

Aggressive chemo/ Purine analogue

Anthracycline

Pre- anthracycline

slide52

Comparison of Observed vsExpected survival in follicular lymphoma

Tan D, et al. J ClinOncol 2008 (suppl; abstr 8535)

slide53

Impacts of Frontline and Salvage Tx on OS- The Stanford Experience

OS-post first relapse

EFS1

Tan D, et al. J ClinOncol 2008 (suppl; abstr 8535)

slide55

Novel Strategies in B-cell Lymphoma:

Targeting B-cell Receptor Signaling

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