Grade 1-2 Follicular Lymphoma

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Follicular Lymphoma: Updates on Treatment Strategies

Daryl TanRaffles Cancer CenterVisiting Consultant Singapore General HospitalAdjunct Assistant Professor,Duke-NUS Graduate Medical School

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Grade 1-2 Follicular Lymphoma

Limited Stage Advanced Stage, Stage II bulky or ‘B’

Curative Intent Radiotherapy

Asymptomatic,Low tumor burden

Symptomatic,High tumor burden

Watch and Wait Chemotherapy/ Immunotherapy

CR or PR

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? Consolidation RIT or

Maintenance Rituximab

GELF Criteria

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Advanced Stage, Stage II bulky or ‘B’


Watch and Wait Clinical Questions : •Is there still a role for watch and wait in rituximab era?

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

Watch and Wait in FL

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

Overall Survival of 1,333 FL Patients at Stanford by Time to First Treatment

P<0.001

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Median FU: 32 months

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Time To Initiation of New Therapy

Ardeshna KM et al. ASH 2010 Abstract 6

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Watch and Wait Clinical Questions : •Is there still a role for watch and wait in rituximab era?•Role of maintenance rituximab?

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• progression within 6 months of Rtx

• failure to respond to Rtx• inability to complete protocol• initiation of alternative therapy.

wks

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RESORT: Time to First Cytotoxic Therapy

3-yr Freedom from First Cytotoxic Chemo MR: 95% RR: 86%

Median FU : 3.8 yrs

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Ave Doses of Rtx Received

4.515.8

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Chemotherapy/ Immunotherapy

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

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RCTs on R-Chemo vs ChemoMarcus et al Salles et al

Hiddeman et al Harold et al Which R-Chemo for induction ?

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Federico M, et al. ASCO 2012: Abstract 8006

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 Fondazione Italiana Linfomi (N=534)

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Time-to-Treatment Failure (R-CHOP vs R-CVP vs R-FM)


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Adverse Events (≥grade 3) (R-CHOP vs R-CVP vs R-FM)


Second Malignancies: 2% 3% 8%

Bendamustine-Rituximab (B-R) vs CHOP-R

Bendamustine-RituximabBendamustine-Rituximab

(N=139)(N=139)- Bendamustine 90 mg/m- Bendamustine 90 mg/m22 day 1+2 day 1+2

-Rituximab 375 mg/mRituximab 375 mg/m22 day 1 day 1

CHOP-Rituximab CHOP-Rituximab (N=140)(N=140)- Cyclophosphamide 750 mg/m- Cyclophosphamide 750 mg/m22 day 1 day 1- Doxorubicin 50 mg/m- Doxorubicin 50 mg/m22 day 1 day 1- Vincristine 1.4 mg/m- Vincristine 1.4 mg/m22 day 1 day 1 - Prednisone 100 mg days 1-5Prednisone 100 mg days 1-5

- Rituximab 375 mg/mRituximab 375 mg/m22 day 1 day 1

FollicularFollicularWaldenströmWaldenström’’ssMarginal zoneMarginal zoneSmall lymphocyticSmall lymphocyticMantle cell (elderly)Mantle cell (elderly)

RRRR

StiL NHL 1-2003StiL NHL 1-2003

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

Median follow-up 45 monthsMedian follow-up 45 months

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Number (%) of patientsNumber (%) of patients

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

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

(10(1099/L)/L) B-RB-R 80 (30)80 (30) 85 (32)85 (32) 13 (5)13 (5) 98 (37)98 (37)

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

(10(1099/L)/L) B-RB-R 61 (23)61 (23) 53 (20)53 (20) 24 (9)24 (9) 77 (29)77 (29)

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

(10(1099/L)/L) B-RB-R 38 (14)38 (14) 122 (46)122 (46) 74 (28)74 (28) 196 (74)196 (74)

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

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

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

(10(1099/L)/L) B-RB-R 19 (7)19 (7) 15 (6)15 (6) 2 (<1)2 (<1) 13 (5)13 (5)

Number (%) of patientsNumber (%) of patients

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

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

(10(1099/L)/L) B-RB-R 80 (30)80 (30) 85 (32)85 (32) 13 (5)13 (5) 98 (37)98 (37)

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

(10(1099/L)/L) B-RB-R 61 (23)61 (23) 53 (20)53 (20) 24 (9)24 (9) 77 (29)77 (29)

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

(10(1099/L)/L) B-RB-R 38 (14)38 (14) 122 (46)122 (46) 74 (28)74 (28) 196 (74)196 (74)

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

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

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

(10(1099/L)/L) B-RB-R 19 (7)19 (7) 15 (6)15 (6) 2 (<1)2 (<1) 13 (5)13 (5)

Worst CTCAE Grades for Hematology Tests ResultsWorst CTCAE Grades for Hematology Tests Results

Courtesy of Mathias Rummel

ToxicitiesToxicities (all CTC-grades)(all CTC-grades)

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

(no. of pts)(no. of pts) (no. of pts)(no. of pts) PP value value

AlopeciaAlopecia -- ++++++ < 0.0001< 0.0001

ParesthesiasParesthesias 1818 7373 < 0.0001< 0.0001

StomatitisStomatitis 1616 4747 < 0.0001< 0.0001

Skin (erythema)Skin (erythema) 4242 2323 = 0.0122= 0.0122

Allergic reaction (skin)Allergic reaction (skin) 4040 1515 = 0.0003= 0.0003

Infectious complicationsInfectious complications 9696 127127 = 0.0025= 0.0025

- Sepsis- Sepsis 11 88 = 0.0190= 0.0190


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B-RB-R CHOP-RCHOP-R

(n=261) (n=261) (n=253) (n=253) PP value value

ORRORR 92,7 %92,7 % 91,3 %91,3 %

CRCR 39,8 %39,8 % 30,0 %30,0 % = 0.021= 0.021

SDSD 2,7 %2,7 % 3,6 %3,6 %

PDPD 3,5 %3,5 % 2,8 %2,8 %

Results Response ratesResults Response rates

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

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PFS: follicular (n=279) PFS: follicular (n=279) 45 months follow-up45 months follow-up

Median (months)Median (months)

B-RB-R n. y. r. n. y. r.

CHOP-RCHOP-R 40.9 40.9




0.00.0

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

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

p = 0.0072p = 0.0072


p = 0.0072p = 0.0072

0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months


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








p = 0.0428p = 0.0428


p = 0.0428p = 0.0428

0.00.0

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



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

0.00.0

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


p = 0.0679p = 0.0679


p = 0.0679p = 0.0679


B-RB-R 53.4 53.4



B-RB-R 53.4 53.4




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0.00.0

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

1.01.0Median (months)Median (months)

B-RB-R 53.6 53.6



B-RB-R 53.6 53.6


Age: 61 yrs and older ( n = 315 ) Age: 61 yrs and older ( n = 315 )


p = 0.0022p = 0.0022


p = 0.0022p = 0.0022



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0.00.0

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

Age: 60 yrs and younger ( n = 199 ) Age: 60 yrs and younger ( n = 199 )


B-RB-R 71.6 71.6



B-RB-R 71.6 71.6



p = 0.0022p = 0.0022


p = 0.0022p = 0.0022



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0.00.0

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

Overall survival Overall survival

2 yrs2 yrs 3 yrs3 yrs 4 yrs4 yrs 5 yrs5 yrs 6 yrs6 yrs 7 yrs7 yrs

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

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

2 yrs2 yrs 3 yrs3 yrs 4 yrs4 yrs 5 yrs5 yrs 6 yrs6 yrs 7 yrs7 yrs

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

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

B-RB-RB-RB-R

CHOP-RCHOP-RCHOP-RCHOP-R



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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?

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?

The Kiss of Death in Follicular Lymphoma

Ramsay, et al. The Kiss of Death in FL. Blood 2011; 118: 5365-5366Laurent, et al. Distribution, function, and prognostic value of cytotoxicT lymphocytes in FL. Blood 2011;118(20):5371-5379

CTL: Cytotoxic T lymphocyte, FL: follicular lymphoma

Lenalidomide:Mechanisms of Action in Lymphoma

1. 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.

2. 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

Nathan Fowler, Sattva Neelapu, 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/MyelomaMD Anderson Cancer Center, Houston, Texas

Courtesy of Nathan Fowler

Study Design

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

Months1 2 3 4 5 6

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

If clinical benefit, can proceed to 12

cycles

•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

R= RESTAGING R

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

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

R RR

7 8 9 10 11 12

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

Response Rates

SLL (N=30)

Marginal (N=27)*

Follicular(N=46)*

All PatientsEval

(N=103)ITT

(N=110)

ORR, n (%) 24 (80) 24(89) 45(98) 93(90) 93(85)

CR/Cru 8(27) 18(67) 40(87) 66(64) 66(60)

PR 16(53) 6(22) 5(11) 27(26) 27(25)

SD, n (%) 4(13) 3(11) 1(2) 8(8) 8(7)

PD, n (%) 2(7) 0 0 2(2) 2(2)

*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

Marianna Shafarenko

It may be good to include the median follow-up time...

PFS (months)

Perc

en

t su

rviv

al

0 12 24 360

20

40

60

80

100

Progression Free Survival

N=10336 mo PFS*:78%

*Projected 3 year PFS

All Evaluable Patients


Grade ≥ 3 Hematologic Toxicity

5 patients developed grade 3 neutropenic fever

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)

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

• LYSA (PI: Morschhauser) + North America (PI: Fowler)






CR or PR Clinical Question :

•Role of maintenance rituximab?Consolidation RIT or

Maintenance Rituximab

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

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

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Time to next lymphoma treatment

Overall Survival Time to next Chemotherapy

Progression Free Survival

Median follow-up: 36 months

75%

58%


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Grade 3 / 4 Adverse Events

P=0.0026

Fulminant Hep B (n=1)

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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 B-R is less toxic and more effective than CHOP-R • Impressive data with frontline IMiD + RImpressive data with frontline IMiD + R• Maintance rituximab 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

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Thank You

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Rituximab era

Aggressive chemo/ Purine analogue

Anthracycline

Pre- anthracycline

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Comparison of Observed vs Expected survival in follicular lymphoma

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

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

EFS1 OS-post first relapse

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

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