Kein Folientitel

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Follicular Lymphoma Updates on Treatment
StrategiesDaryl 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
GELF Criteria
Curative Intent Radiotherapy
Asymptomatic, Low tumor burden
Symptomatic, High tumor burden
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
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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?

4
Watch and Wait in FL
Horning S, SA Rosenberg. NEJM 19843111471-76
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Overall Survival of 1,333 FL Patients at Stanford
by Time to First Treatment
Plt0.001
Tan D, Horning S, et al. ASH 2007. Abstract 3428
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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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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?

10
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 4.5 15.8
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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
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RCTs on R-Chemo vs Chemo
Marcus et al
Salles et al
Which R-Chemo for induction ?
Hiddeman et al
Harold et al
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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 (N534)
Federico M, et al. ASCO 2012 Abstract 8006
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Time-to-Treatment Failure (R-CHOP vs R-CVP vs
R-FM)
Federico M, et al. ASCO 2012 Abstract 8006
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Adverse Events (grade 3) (R-CHOP vs R-CVP vs
R-FM)
Federico M, et al. ASCO 2012 Abstract 8006
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Bendamustine-Rituximab (B-R) vs CHOP-R
StiL NHL 1-2003

• Bendamustine-Rituximab
• (N139)
• - Bendamustine 90 mg/m2 day 12
• Rituximab 375 mg/m2 day 1

Follicular Waldenströms Marginal zone Small
lymphocytic Mantle cell (elderly)
R

• CHOP-Rituximab (N140)
• - 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
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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
(lt1) 12 (5) (g/L) B-R 44 (16) 6 (2) 2 (lt1) 8
(3) Platelets CHOP-R 20 (8) 11 (4) 5 (2) 16
(6) (109/L) B-R 19 (7) 15 (6) 2 (lt1) 13 (5)
Courtesy of Mathias Rummel
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Toxicities (all CTC-grades)
B-R (n261) CHOP-R (n253) (no. of pts) (no. of
pts) P value Alopecia - lt
0.0001 Paresthesias 18 73 lt 0.0001 Stomatitis 16 4
7 lt 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
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Results
Response rates

B-R CHOP-R (n261) (n253) 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)
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PFS follicular (n279) 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
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PFS follicular, FLIPI low (0-2) (n152
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
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PFS follicular, FLIPI high (3-5) (n127
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
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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
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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
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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
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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 gtRCHOPgt RCVP
• DO WE REALLY NEED CHEMO UPFRONT ?
• Role of maintenance rituximab?
• What is the optimal sequence of treatment?

Chemotherapy/ Immunotherapy
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?
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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
2011118(20)5371-5379
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LenalidomideMechanisms 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. 2009114(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 2008144650-4657

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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/Myeloma
• MD Anderson Cancer Center, Houston, Texas

Courtesy of Nathan Fowler
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Study Design

• Months
• 1 2 3 4
  5 6

7 8 9 10
11 12
Lenalidomide 20mg Days 1-21 Cycles 1-6
Rituximab 375mg/M2 Day 1 of Cycles 1-6
R
R
R RESTAGING
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)
• N30 Small lymphocytic lymphoma
• N30 Marginal zone lymphoma
• Groups analyzed independently for response and
  toxicity

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Response Rates
SLL (N30) Marginal (N27) Follicular (N46) All Patients All Patients
SLL (N30) Marginal (N27) Follicular (N46) Eval (N103) ITT (N110)
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
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Progression Free Survival
All Evaluable Patients
N103 36 mo PFS78
Projected 3 year PFS
Courtesy of Nathan Fowler
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Grade 3 Hematologic Toxicity
5 patients developed grade 3 neutropenic fever
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Grade 3 Non Hematologic Adverse Events (gt1 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

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RELEVANCE Study Design(Rituximab and
LEnalidomide versus Any ChEmotherapy)

• RChemo
• Investigators 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
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Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or B
Symptomatic, High tumor burden
Chemotherapy/ Immunotherapy
CR or PR

• Clinical Question
• Role of maintenance rituximab?

Consolidation RIT or Maintenance Rituximab
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R-Maintenance vs Observation After R-Chemo
Induction (PRIMA)
Salles G, et al. Lancet 2010 377 4251
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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 4251
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Grade 3 / 4 Adverse Events
P0.0026
Salles G, et al. Lancet 2010 377 4251
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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
• 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 pts 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)
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Impacts of Frontline and Salvage Tx on OS- The
Stanford Experience
OS-post first relapse
EFS1
Tan D, et al. J Clin Oncol 2008 (suppl abstr
8535)
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B-Cell Lymphomas Express Several Antigens that
can be Targeted
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Novel Strategies in B-cell Lymphoma Targeting
B-cell Receptor Signaling
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Follicular Lymphoma Response Tumor Burden,
Molecular Response
BY GELF CRITERIA N46 BY GELF CRITERIA N46 BY GELF CRITERIA N46 BY GELF CRITERIA N46 BY GELF CRITERIA N46 BY GELF CRITERIA N46 BY GELF CRITERIA N46 BY GELF CRITERIA N46
GELF () HIGH TUMOR BURDEN N22 (48) GELF () HIGH TUMOR BURDEN N22 (48) GELF () HIGH TUMOR BURDEN N22 (48) GELF () HIGH TUMOR BURDEN N22 (48) GELF (-) HIGH TUMOR BURDEN N24 (52) GELF (-) HIGH TUMOR BURDEN N24 (52) GELF (-) HIGH TUMOR BURDEN N24 (52) GELF (-) HIGH TUMOR BURDEN N24 (52)
SD PR CR/Cru ORR SD PR CR/Cru ORR
0 1 (5) 21(95) 100 1(4) 4(17) 19 (79) 96
BY BULK OF DISEASE N46 BY BULK OF DISEASE N46 BY BULK OF DISEASE N46 BY BULK OF DISEASE N46 BY BULK OF DISEASE N46 BY BULK OF DISEASE N46 BY BULK OF DISEASE N46 BY BULK OF DISEASE N46
BULKY N13 (28) BULKY N13 (28) BULKY N13 (28) BULKY N13 (28) NON-BULKY N33 (72) NON-BULKY N33 (72) NON-BULKY N33 (72) NON-BULKY N33 (72)
SD PR CR/CRu ORR SD PR CR/CRu ORR
0 1(8) 12(92) 100 1(3) 4 (12) 28 (85) 97
MOLECULAR RESPONSE N44 (eval) MOLECULAR RESPONSE N44 (eval) MOLECULAR RESPONSE N44 (eval)
PCR POSITIVE PCR NEGATIVE
PRETREATMENT 17(41) 26(59)
POST CYCLE 3 5(11) 39(89)
POST CYCLE 6 2(5) 42(95)

• Bone marrow and peripheral blood for major or
  minor breakpoint

1. Brice P, et al. JCO 1997 1511101117.