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Follicular LymphomaApplying Emerging Evidence in Practice
Louis F. Diehl, MDProfessor of Medicine
Duke University School of Medicine
Disclosures
Dr. Diehl will discuss unlabeled use of ibrutinib and idelalisib
Dr. Diehl has no commercial relationships to disclose
Nursing Learning Objectives Describe clinical challenges associated with the
contemporary management of follicular lymphoma Evaluate patient- and tumor-related factors that inform
evidence-based treatment planning Recognize the clinical application of novel therapies in
the treatment of newly diagnosed and relapsed/refractory follicular lymphoma
Assess side-effect profile of novel therapies for follicular lymphoma
NHL = non-Hodgkin lymphoma; FL = follicular lymphoma; DLBCL = diffuse large B-cell lymphoma.Armitage & Weissenburger, 1998; ACS, 2015.
Relative Incidence of NHL Subtypes
MZL6%
LPL1%
LL2%
ALCL2%
PMLBCL2%
Burkitt’s-like2%
PTCL6%
MCL6%
SLL
Composite13%
DLBCL32%
FL22%
>71,000 new cases in US in 2015
6%
Follicular Lymphoma Overview
2nd most common non-Hodgkin lymphoma in the US– 15,000 new cases/year
Prototype of low-grade lymphomas– Indolent course with median survival 12 years– Waxing and waning course– Incurable
Increases with age– Median age 6th decade of life
Risk of transformation over time
25% of patients are <40 years
Armitage & Weissenburger, 1998; ACS, 2015.
Photo courtesy of Randy D. Gascoyne, MD.
Follicular Lymphoma
Principles
1. We do not cure this disease2. Early treatment does not provide benefit (watch and
wait)3. With each successive treatment, both the depth and
duration of response decrease (Law of Diminishing Returns)
4. Preservation of options
Cure Principle
Swenson et al, 2005.
1990-1999 Relative 5-year
survival 74% Relative 10-year
survival 51%
75% mortality in 15 years
5% mortality per year
Low-Grade NHL (Follicular) Prognosis:Follicular Lymphoma International Prognostic Index
Solal-Celigny et al, 2004.
Mortality5%year
Principles
1. We do not cure this disease
2. Early treatment does not provide benefit (watch and wait)3. With each successive treatment, both the depth and
duration of response decrease (Law of Diminishing Returns)
4. Preservation of options
Low-Grade Lymphoma: Overall Survival With Watch and Wait
Portlock & Rosenberg, 1979.
Low-Grade NHL:Watch and Wait vs Aggressive Treatment
Patients– Untreated– Stages IIIA, III3B, IVA,
IVB– Not need immediate
treatment
Lymphomas– Follicular small cleaved
(FSCL)– Follicular mixed (FML)– Diffuse intermediate
differentiated lymphoma (DIDL)
– Diffuse small cleaved-cell lymphoma (DSCL)
Treatment– ProMACE-MOPP + XRT– Watch and wait ± XRT
ProMACE = cyclophosphamide/etoposide/methotrexate/folinic acid; MOPP = mustargen/vincristine/procarbazine/prednisone; XRT = X-ray therapy. Young et al, 1988.
Low-Grade NHL:Watch and Wait vs Aggressive Treatment (cont.)
Watch and Wait ProMACE-MOPP + XRT
Patients 41 43
Alive off therapy 5/16 (31%) 25/43 (58%)
Alive without disease 5/41 (12%) 2/43 (51%)
Alive, continuously free of disease 0/41 (0%) 22/43 (51%)
Alive 34/41 (83%) 36/43 (84%)
Young et al, 1988.
Principles1. We do not cure this disease2. Early treatment does not provide benefit (watch and wait)3. With each successive treatment, both the depth and
duration of response decrease (Law of Diminishing Returns)
4. Preservation of options
Comparison of Response Rates, Response Durations, and Survival After Treatment of Consecutive Recurrences of FL
No Treated
Response Rate (%)
Median Response Duration (months)
Median Survival Duration (years)
Median Survival From
Response (years)
Presentation 204 88 31 9.2 9.6 First Recurrence 110 78 13 4.6 4.9 Second Recurrence 63 76 13 3.5 3.5 Third Recurrence 37 68 6 2 1.2
Johnson et al, 1995.
Comparison of Response Rate in Consecutive Recurrences of FL
0102030405060708090
Mon
ths
Presentation 1st Relapse 2nd Relapse 3rd Relapse
Johnson et al, 1995.
Comparison of Response Duration in Consecutive Recurrences of FL
0
5
10
15
20
25
30
35
Mon
ths
Presentation 1st Relapse 2nd Relapse 3rd Relapse
Johnson et al, 1995.
FL Responds to Repeated Chemotherapy With Shorter Durations of Response
Gallagher et al, 1986.
1st
2nd
3rd4th
1 2 3 40
20
40
60
80
100
Patients in remission
(%)
Years
Chemotherapytreatment (no.)
1234
Duration (months)
16.011.2 9.6 3.2
Responding patients (n=110) in remission through 4 treatments with the same chemotherapy regimen
0
Duration of Response (Years)
Pro
porti
on in
Res
pons
e0.
00.
20.
40.
60.
81.
0
Duration of Response (Years)
Pro
porti
on in
Res
pons
e0.
00.
20.
40.
60.
81.
0
0 2 4 6 8
2nd Therapy3rd Therapy4th Therapy5th Therapy6th Therapy>=7th Therapy
Leonard et al, 2004.
Duration of Response Following Chemotherapy
Principles
1. We do not cure this disease
2. Early treatment does not provide benefit (watch and wait)
3. With each successive treatment, both the depth and duration of response decrease (Law of Diminishing Returns)
4. Preservation of options
FL Survival Is Improving for Most Patients
Swenson et al, 2005.
1990-1999 Relative 5-year
survival 74% Relative 10-year
survival 51%
Improvement in OutcomeAdjusted Death Hazard Ratios by Diagnosis Year
Swenson et al, 2005.
Goals of Treatment Live longer Feel well Response Progression-free survival
Treatment Biology
Limiting Toxicity
Kikorian et al, 1980.
Spontaneous Regression of Non-Hodgkin Lymphoma
44 patients followed without treatment until needed, 7 spontaneous regressions.
Dave et al, 2004.
FavorableT-cell activationRelative risk of death 0.15
Unfavorablemonocyte activationRelative risk of death 9.35
Multivariate Model of Survival in FL Using Survival Signatures
Immune Response-1 Survival Predictor Signature Is Derived From Non-Malignant Cells in FL
Dave et al, 2004.
Immune Response-2 Survival Predictor Signature Is Derived From Non-Malignant Cells in FL
Dave et al, 2004.
Immune Response-1 and 2 Survival Predictor Signature Is Derived From Non-Malignant Cells in FL
Favorable Unfavorable
Principles
1. We do not cure this disease
2. Early treatment does not provide benefit (watch and wait)
3. With each successive treatment, both the depth and duration of response decrease (Law of Diminishing Returns)
4. Preservation of options
Surv
ival
pro
babi
lity
Low risk
Intermediate risk
High risk
0
0.2
0.4
0.6
0.8
1.0
Years0 1 2 3 4 5 6 7
Nodal regions 4
Elevated LDH
Age ≥60
Stage III/IV
Hemoglobin <120 g/L
Overall Survival According to FLIPI: Clinical Prognostic Factors
Risk Group No. of Factors % of Patients 5-Yr OS (%) 10-Yr OS (%)
Low 0-1 36 90.6 70.7
Intermediate 2 37 77.8 50.9
High 3-5 27 52.5 35.5
P<10-4
FLIPI = Follicular Lymphoma International Prognostic Index; LDH = lactate dehydrogenase; OS = overall survival.Solal-Céligny et al, 2004.
Buske et al, 2006.
Previous
Modified
Previous CategoriesLow risk 0-1 factors
Intermediate risk 2 factors
High risk 3-5 factors
Modified Categories(All Stage III/IV)
Factor 1,2
Factor 3
Factor 4,5
Modified FLIPI in Rituximab Era: Time to Treatment Failure
40,320 Combinations
Fludarabine Flu-Cy
Chlorambucil
FNDZevalin
CVP
CHOP
Rituximab Combinations
Bone Marrow Transplant
Bexxar
Watch and WaitBendamustine
CHOP = rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; CVP = cyclophosphamide/vincristine/prednisone.
Watch and wait still valid
Initial treatment
Maintenance
Subsequent treatment
New and exciting
Five Questions
WW = watch and wait; Clb = chlorambucil.Ardeshna et al, 2003.
WW vs Clb in Advanced Stage Asymptomatic Untreated FL
Overall Survival
Cause-Specific Survival
Asymptomatic Advanced Stage FL:
Advanced-stage asymptomatic
FL
Observation
Rituximab x 4
Rituximab x 4 plus maintenance rituximab q8 wks
x 2 yrs
Ardeshna et al, 2014.
Does Rituximab vs Watchful Waiting Result in a Significant Delay in the Initiation of Chemotherapy or Radiotherapy?
Asymptomatic FL: Wait and Watch vs Rituximab
Ardeshna et al, 2014.
Overall Survival Time to Histological Transformation
Asymptomatic FL:Wait and Watch vs Rituximab (cont.)
Ardeshna et al, 2014.
Time to Start of New Treatment Progression-Free Survival
Comparison of Response Duration in Consecutive Recurrence of FL
0
5
10
15
20
25
30
35
Mon
ths
Presentation 1st Relapse 2nd Relapse 3rd Relapse
Johnson et al, 1995.
Rituximab one time only use problem
If you use the rituximab up front, it will not be beneficial at relapse.
National LymphoCare Study National LymphoCare Study Follicular lymphoma Diagnosed 2004-2007 United States Received
– Watch and wait– Rituximab monotherapy– Rituximab + chemotherapy
Program Median TTT
Median PFS2
Watch and wait 2.3 years 8 years
Rituximab 4.4 years 7 years
R + chemotherapy NR NR
TTT = time ; PFS2 = progression-free survival 2.Nastoupil et al, 2016.
Time to New Treatment AfterWatch and Wait
Time to New TreatmentWW vs R-mono
Time to New TreatmentWW vs R-chemo
Nastoupil et al, 2016.
Watch and Wait Still Valid?
PFS Improved
TTNT Improved
OS Same
Transformation Same
TTNT = time to next treatment.
PFS Improved
TTNT Improved
PFS2 Same
OS Same
Transformation Same
Do the Data on PFS2 Change the Balance?
Watch and wait still valid
Initial treatment
Maintenance
Subsequent treatment
New and exciting
Delays next chemotherapy without risk to PFS2
Five Questions
Watch and wait still valid
Initial treatment
Maintenance
Subsequent treatment
New and exciting
Delays next chemotherapy without risk to PFS2
Five Questions
Follicular and Mantle Cell Lymphoma:CHOP vs R-CHOP
Hiddemann et al, 2005.
Time to Treatment Failure
Hiddemann et al, 2005.
Duration of Response
Hiddemann et al, 2005.
Overall Survival
After 3 years, 6 patients in the R-CHOP groupand 17 patients in the CHOP group have died(P=0.016).
Hiddemann et al, 2005.
Hiddemann et al, 2005.Herold et al, 2007.
Marcus et al, 2008.
R-CHOP = rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; R-CVP = rituximab/cyclophosphamide/vincristine/prednisoneMCP = mitoxantrone/ chlorambucil/prednisone.
Impact of Rituximab on OS in Frontline FL
Comparative Trials of R-Chemo in Frontline FL
Study N Regimen 10 endpt
FOLL05 IIL 534 R-CVP vs R-CHOP vs. R-FCM TTF
StIL 546 R-CHOP vs BR PFS
BRIGHT trial
400+ R-CVP or R-CHOP vs BR CR
PRIMAa 1202 R-CVP or R-CHOP or R-FM n/a
NLCSa 926 Varied PFS, OS
aNot randomized for chemotherapy. R-FCM = rituximab/fludarabine/cyclophosphamide/mitoxantrone; BR = bendamustiine/rituximab;TTF = time to treatment failure; CR = complete response.Federico et al, 2013; Rummel et al, 2013; Flinn et al, 2014; Salles et al, 2013; Casulo et al, 2013.
Untreatedstages II–IV
follicular lymphoma
R-CVP x 8
R-CHOP x 6
R-fludarabine +mitoxantrone x 6
Federico et al, 2013.
FOLLO5: Study Design
Federico et al, 2013.
FOLLO5: TTF and PFS
100
80
60
40
20
0 6 12 18 24 30 36 42 48 54 60
100
80
60
40
20
0 6 12 18 24 30 36 42 48 54 60
Trea
tmen
t Fai
lure
(%)
Time (months)
Prog
ress
ion-
Free
Surv
ival
(%)
Time (months)
A B
R-CVPR-CHOPR-FM
R-CVPR-CHOPR-FM
No. at riskR-CVPR-CHOPR-FM
168165171
136147150
119137139
95120120
748395
516668
364750
233232
131920
51212
154
No. at riskR-CVPR-CHOPR-FM
168165171
154157163
136147151
108128130
8589
101
607073
415155
273636
142223
61414
165
Federico et al, 2013.
FOLL05: Grade 3/4 Toxicities by Arm
0.6 3.1 4.2
28.0
49.7
63.7
0.03.1
7.72.5 3.1 4.8
0
20
40
60
Per
cent
age
Anemia Neutropenia Thrombocytopenia Infections
R-CVP R-CHOP R-FM
Anemia P=0.089Neutropenia P<0.001Thrombocytopenia P<0.001Infections P=0.527
2.4 4.7
Nastoupil et al, 2015.
Overall Survival in FL: LymphoCare Data
BR vs R-CHOP
Newly diagnosedstage II–IVindolent or mantle cell lymphoma
RANDOMIZED
Bendamustine + Rituximab(Bendamustine 90 mg/m2
D 1,2 every 28 days and rituximab 375 mg/m2 D 1)
R + CHOP(Standard)
Rummel et al, 2013.
Rummel et al, 2013.
BR vs R-CHOP in Untreated FL: PFS
Rummel et al, 2013.
BR vs R-CHOP: Heme Toxicity
Grade 3/4 Hematologic ToxicityBR vs R-CHOP
Leuc
ocyto
penia
Neutro
penia
Lymph
ocyto
penia
Anemia
Thrombo
cytop
enia
0
10
20
30
40
50
60
70
80
R-CHOPBR
Rummel et al, 2013.
BR vs R-CHOP Non-Heme Toxicities
Rummel et al, 2013.
All Grades Non-Hematologic Toxicity:BR vs R-CHOP
Alopec
ia
Paresth
esia
Stomati
tis
Skin (e
rythe
ma)
Skin (a
llergi
c)
Infec
tious
episo
des
Sepsis
0
20
40
60
80
100
120
R-CHOPBR
Rummel et al, 2013.
*Up to eight cycles at investigator discretion.Flinn et al, 2014.
BRIGHT Study Design
aR-CHOP, n=22.IRC = independent review committee; iNHL = indolent NHL; PR = partial response; MZL = marginal zone lymphoma; LPL = lymphoplasmacytic lymphoma; MCL = mantle cell lymphoma.Flinn et al, 2014.
BRIGHT: Response Rates
IRC Assessment of Response by Histology, n/N (%)
CR CR + PR
BR R-CHOP/R-CVP BR R-CHOP/R-CVP
iNHL 49/178 (28) 43/174 (25) 173/178 (97) 160/174 (92)
FL 45/148 (30) 37/149 (25) 147/148 (>99) 140/149 (94)
MZL 5/25 (20) 4/17 (24) 23/25 (92) 12/17 (71)
LPL 0/5 1/6 (17) 3/5 (60) 6/6 (100)
MCL 17/34 (50) 9/33 (27)a 32/34 (94) 28/33 (85)a
aP<0.0001. AEs = adverse events.Flinn et al, 2014.
BRIGHT: Grade ≥3 Adverse Events Grade ≥3 AEs (occurring in ≥3% of patients), n (%)
Preselected for R-CHOP Preselected for R-CVP
BR (n=103) R-CHOP (n=98) BR (n=118 ) R-CVP (n=116)
Hematologic
White blood cell count 33 (32) 71 (72) a 51 (43) 44 (38)
Absolute neutrophil count 40 (39) 85 (87) a 58 (49) 65 (56)
Lymphocyte count 63 (61) 32 (33) a 74 (63) 32 (28)a
Hemoglobin 0 3 (3) 6 (5) 6 (5)
Platelet count 10 (10) 12 (12) 6 (5) 2 (2)
Non-hematologic
Nausea 3 (3) 0 1 (<1) 0
Vomiting 5 (5) 0 2 (2) 0
Abdominal pain 2 (2) 3 (3) 0 3 (3)
Drug hypersensitivity 3 (3) 0 2 (2) 0
Fatigue 4 (4) 2 (2) 4 (3) 1 (<1)
Pneumonia 2 (2) 0 5 (4) 1 (<1)
Infusion-related reaction 6 (6) 4 (4) 7 (6) 4 (3)
Infection 12 (12) 5 (5) 8 (7) 8 (7)
Hyperglycemia 0 2 (2) 1 (<1) 5 (4)
Back pain 0 1 (1) 0 4 (3)
Syncope 1 (<1) 0 0 3 (3)
Dyspnea 2 (2) 2 (2) 3 (3) 1 (<1)
Watch and wait still valid
Initial treatment
Maintenance
Subsequent treatment
New and exciting
Delays next chemotherapy without risk to PFS2
Rituximab – survivalBendamustine – equal efficacy,
less toxicity (watch lymphopenia)
Five Questions
PRIMA Study Design
CRu = Complete response unconfirmed; PD = progressive disease; SD = stable disease.Salles et al, 2013.
PD/SDoff study
Rituximab maintenance375 mg/m2
every 8 weeks for 2 years
Observation
CR/CRuPR
Random 1:1
Immunochemotherapy8 x rituximab
+8 x CVP or
6 x CHOP or6 x FCM
High tumor burden
untreated follicular lymphoma
INDUCTION MAINTENANCE
5 YEARS FOLLOW-UP
Registration
Salles et al, 2013.
PRIMA 6-Year Follow-Up:2-Year R Maintenance Shows Benefit
Martinelli et al, 2010.Hochster et al, 2009.
Ardeshna et al, 2010.Salles et al, 2011.
Overall Survival by Maintenance
RESORT Study Design
Rituximabretreatment atprogressiona
375 mg/m2 qw 4
RANDOMIZE
Rituximab375 mg/m2 qw
4CR or PR
Rituximabmaintenancea
375 mg/m2 q 3 months
aContinue 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, 2014.
Kahl et al, 2014.
RESORT: TTF
Watch and wait still valid
Initial treatment
Maintenance
Subsequent treatment
New and exciting
Delays next chemotherapy without risk to PFS2
Rituximab – survivalBendamustine – equal efficacy,
less toxicity (watch lymphopenia)
Rituximab – PFS advantageSurvival – mixed/weak data
Five Questions
Five Questions
Watch and wait still valid Initial treatment Maintenance Subsequent New and exciting
Casulo et al, 2013.
Press et al, 2013.
60
R-CHOP
100
80
60
40
20
024 30 36 42 48 540 6 12 18Time (months)
Pro
gres
sion
-Fre
e S
urvi
val (
%)
1.0E
vent
-Fre
e R
ate
Salles et al, 2011.
Rituximab maintenance0.8
0.6
0.4
0.2
0.00 6 12 18 24 30 36 42 48 54 60
Time (months)
Pro
babi
lity
1.0
0.8
0.6
0.4
0.2
0.0
Rummel el al, 2013.
B-R
R-CHOP
Time (months)0 6 12 18 24 30 36 42 48 54 60
This suggests a high-risk group of patients who will relapse
early despite different treatment approaches including
maintenance.
20% of Patients With FL Experience Progression Within 24 Months of Chemoimmunotherapy
aX2.Hgb = hemoglobin; ECOG PS = Eastern Cooperative Oncology Group performance status.Casulo et al, 2013.
Characteristic Early
ProgressorReference
Group Significancea
Grade 3 histology 34% 40% P=0.50
High-risk FLIPI 57% 40% P=0.01
Elevated LDH 43% 28% P=0.01
Low Hgb 35% 22% P=0.01
≥2 nodal sites 40% 25% P=0.01
Poor ECOG PS 16% 4% P<0.01
Distribution of Characteristics by Group
CI = confidence interval.Casulo et al, 2013.
122 patients were classified as early progressors (n=110 POD and n=12 non-POD deaths within 2 years)
2-year OS (95% CI) was 71% (61.5-78.0) 5-year OS (95% CI) was 50% (40.3-58.8)
1.0
0 1 2 3 4 5 6 7 8 9 100.0
0.2
0.4
0.6
0.8
Patients at risk:101 78 69 58 49 45 33 14 6 0
Time (years)
Sur
viva
l Pro
babi
lity
122
Early Progressor
420 420 407 387 363 344 252 144 33 0420Reference Early
Reference Group
OS of Patients With FL Who Relapsed Within 2 Years of R-CHOP (“Early POD”)
CT = computed tomography.Trotman et al, 2014.
SD/PD vs PR, HR 4.2 CRu, HR 5.6 CR, HR 7.8, P<0.0001
PR vs CR/CRu, HR 1.7 (1.1-2.5),
P=0.02
CRu/PR vs CR, HR 1.6 (1.1-2.4),
P=0.02
PFS According to CT Response
5-Point Scale (Deauville Criteria)
The 5-Point Scale scores the most intense uptake in a site of initial disease, if present, as follows:1. No uptake2. Uptake ≤ mediastinum3. Uptake > mediastinum but ≤ liver4. Uptake > liver at any site5. Uptake > liver and new sites of disease Score X: new areas of uptake unlikely to be related
to lymphoma
Barrington et al, 2010.
Score ≥3 Score ≥4
HR 3.9 (95% CI 2.5-5.9, P<0.0001)Median PFS: 16.9 (10.8-31.4) vs. 74.0 months (54.7-NR)
63%
23%
PET = positron emission tomography.Trotman et al, 2014.
Both PET Cut-Offs Predictive of PFS
87%
97%
HR 6.7, 95% CI 2.4-18.5, P=0.0002Median OS: 79 months vs. NR
Trotman et al, 2014.
Postinduction PET Status (Cut-Off ≥4) and Overall Survival
Follicular lymphomainitial treatment
Prognostic factorsCTPETProgression
Early progressors
Late progressors
Schouten et al, 2003.
Early vs Late Progression
BR vs FRRelapsed Indolent Lymphoma
R/R indolent or mantle cell lymphomaNot refractory to rituximab, bendamustine or purine analogue drugs
RANDOMIZED
Bendamustine + Rituximab(Bendamustine 90 mg/m2
D 1,2 every 28 days and rituximab 375 mg/m2 D 1)
Fludarabine + Rituximab(Fludarabine 25 mg/m2,
D1,2,3 every 28 days and rituximab 375 mg/m2 D 1)
Rummel et al, 2016.
BR vs FR
Progression-Free SurvivalFollicular Lymphoma
Overall SurvivalAll Indolent Lymphoma
Rummel et al, 2016.
BR vs FR:Hematologic Toxicity
Rummel et al, 2016.
BR vs FR:Nonhematologic Toxicity
Rummel et al, 2016.
Follicular lymphomainitial treatment
Prognostic factorsCTPETProgression
Early progressors
Late progressors
Schouten et al, 2003.
Early vs Late Progression
Relapsed follicular lymphoma
Responsive to chemotherapy
RANDOMIZED
Chemotherapy
Autologous transplant unpurged
Autologous transplant purged
Chemotherapy vs Autologous Unpurged Transplant vs Autologous Purged Transplant
Schouten, 2003.
Progression-Free Survival Overall Survival
Schouten, 2003.
Autologous Stem Cell Transplant
van Besien et al, 1998.
Low-Grade Lymphoma: Allogeneic Transplant
van Besien et al, 1998.
Low-Grade Lymphoma: Allogeneic Transplant (cont.)
Autologous vs Allogeneic vs Syngeneic:Disease-Free Survival
Bierman et al, 2003.
Allogeneic
Syngeneic
Autologous
Watch and wait still valid
Initial treatment
Maintenance
Subsequent treatment
New and exciting
Delays next chemotherapy without risk to PFS2
Rituximab – survivalBendamustine – equal efficacy,
less toxicity (watch lymphopenia)
Rituximab – PFS advantageSurvival – mixed/weak data
Early vs late progressorsTransplant option
Five Questions
Follicular lymphomaGrade 1,2,3aPrevious rituximab treatment TTP >6 months
RANDOMIZED
Rituximab 375 mg/m2 D1,8,15,22
Lenalidomide 15 mg/d D 1-21 every 28 days and 20 mg/d cycle 2 and 25 mg/d
cycles 3+Rituximab 375 mg/m2 D 8,15,22,29
Leonard et al, 2015.
Lenalidomide vs Lenalidomide + Rituximab in Recurrent FL
Lenalidomide vs. Lenalidomide + Rituximab in Recurrent FL (cont.)
# OR CRMedian
TTP(years)
PFS at 2 Years
Lenalidomide 45 53% 20% 1.1 27%
Lenalidomide + rituximab 46 76% 39% 2.0 52%
Leonard et al, 2015.
Probability of Progression Overall Survival
Lenalidomide vs Lenalidomide + Rituximab in Recurrent FL (cont.)
Leonard et al, 2015.
Follicular lymphomaGrade 1,2,3aUntreated FLIPI 0-2
Lenalidomide 20 mg D 1-21 x 12 cycles every 28 days
Rituximab 375 mg/m2 D 8,15,22,29 cycle 1 and D 1 of cycles 4, 6, 8, 1012 total cycles
Martin et al, 2014.
Lenalidomide + Rituximab in Untreated FL
ORR = overall response rate; R2 = rituximab/lenalidomide.Martin et al, 2014.
CALGB 50803: R2 in Previously Untreated FL
OverallN=55
FLIPI 0-1n=16
FLIPI 2n=35
FLIPI 3n=2
FLIPI Unknown
n=2
ORR 53 (96%) 16 (100%) 33 (94%) 2 (100%) 2 (100%)
CR 39 (71%) 12 (75%) 24 (69%) 2 (100%) 1 (50%)
PR 14 (25%) 4 (25%) 9 (26%) - 1 (50%)
SD 2 (4%) 0 (0%) 2 (6%) - -
Four additional patients in PET CR but not confirmed by bone marrow biopsy.There was no significant association between CR rate and FLIPI score, presence of bulky disease, or grade.
Rituximab + Lenalidomide in Untreated FL: Response by FLIPI
ORR CR PR SD0
20
40
60
80
100
120
ALL N=55 FLIPI 0-1 N=16 FLIPI 2 N=35 FLIPI 3 N=2 FLIPI UNKN N=2
Martin et al, 2014.
Martin et al, 2014.
CALGB 50803: PFS
Years from Study Entry
Pro
ba
bili
ty
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0.0
0.2
0.4
0.6
0.8CALGB 50803
Progression-Free Survival
SAKK 35/10 Study Design
Response per NCI Cheson 1999 criteria
Previously untreated FL (N=154)• Histologically
confirmed FL grades 1,2,3A
R2 (n=77): Rituximab (see below) + lenalidomide
15 mg/d orally for 19 weeks total(2 weeks prior, 15 weeks during,
and 2 weeks after rituximab)
Rituximab (n=77)375 mg/m2, Day 1 of Weeks 1, 2, 3,
4, 12, 13, 14, and 15
aTreatment discontinued Week 10 if <25% reduction in sum of the product of tumor diameters.DOR = duration of response; NCI = National Cancer Institute.Kimby et al, 2014.
RANDOMIZE
CR/Cru PR SD PD/relapse0
5
10
15
20
25
30
35
40
45
50
RituximabRituximab + Lenalidomide
Frontline R2 vs R in FL: Response
Kimby et al, 2014.
Frontline R2 vs R in FL: Safety
Adverse Events (>1 patient), n (%)
Rituximab (n=76) R2 (n=77)
Grade 3 Grade 4 Grade 3 Grade 4
Neutropenia − 1 (1) 11 (14) 4 (5)
Thrombocytopenia − − 2 (3) 1 (1)
Suicide attempt − 1 (1) − −
Hypertension 3 (4) − 7 (9) −
Fatigue 1 (1) − 2 (3) −
Maculopapular rash − − 4 (5) −
Allergic reaction − − 2 (3) −
UTI − − 2 (3) −
Depression − − − 1 (1)
Psychosis − − − 1 (1)
Treatment was discontinued by 21 patients (28%) in arm R, in 16 due to lack of response at Week 10 and in 1 due to toxicity, and by 19 patients (25%) in arm R2, in 3 due to lack of response at Week 10 and in 13 due to toxicity.
UTI = urinary tract infection.Kimby et al, 2014.
Indolent NHLRequired treatmentCD20+With previous response to rituximab-containing regimen
RANDOMIZED
Rituximab 375 mg/m2 D 1,8,15,22
Then every 2 months until progression for 2 years
Obinutuzumab 1,000 mg D 1,8,15,22
Then every 2 months until progression for 2 years
GAUSS: Study Design
Sehn et al, 2015.
Treatment N ORR CR PD Deaths Disease deaths
Obinutuzumab 74 47% 5.4% 6 18 10
Rituximab 75 27% 4.0% 3 11 5
Obinutuzumab vs Rituximab in Relapsed CD20+ Indolent B-Cell NHL (cont.)
Sehn et al, 2015.
Obinutuzumab vs Rituximab in Relapsed CD20+ Indolent B-Cell NHL : PFS
Sehn et al, 2015.
Obinutuzumab vs Rituximab in Relapsed CD20+ Indolent B-Cell NHL: Adverse Events
Adverse Event Obinutuzumab Rituximab
Infusion-related reaction 74% 51%
Fatigue 26% 20%
Cough 24% 9%
Grade 3/4 infusion reaction 11% 5%
Grade 3/4 infection 0 5%
Grade 3/4 neutropenia 0 1%
Sehn et al, 2015.
Young & Staudt, 2013.
Cell Proliferation, Migration, Growth, Survival
B-Cell Receptor
Follicular lymphomaRelapsed or refractory
Grade 1,2,3aProgressed during or after 1 or more chemotherapy
regimens
Ibrutinib 560 mg dailyUntil progression or
unacceptable toxicity
Ibrutinib in Relapsed/Refractory FL
Bartlett et al, 2014.
Disease N CR PRReduction in tumor volume
PFS(median)
Follicular lymphoma 40 2 9 72% 9 months
Bartlett et al, 2014. 108
Grade 3/4 ToxicityAny 30%
Anemia 2 (5%)
Neutropenia 3 (8%)
Infection 2 (5%)
Ibrutinib Monotherapy in Relapsed/Refractory FL (N=40)
Young & Staudt, 2013.
Cell Proliferation, Migration, Growth, Survival
B-Cell Receptor
N=125Continuous therapy
Idelalisib 150 mg BID
Week 0 48
Long-term Follow-upStudy 101-09
Therapy maintained until progression
• 125 patients• Indolent lymphoma• No response to
rituximab and alkylating agent or relapsed within 6 months
Idelalisib(PI3K Inhibitor)
Idelalisib in Relapsed Indolent Lymphoma
Gopal et al, 2014.
0% 20% 40% 60% 80% 100%
FLn=72 56% (43–67)
ORR, % (95% CI)
14%n=10
42%n=30
32%n=23
8%n=11
SLLn=28
MZLn=15
LPL/WMn=10
61% (41–79)
47% (21–73)
80% (44–98)
57%n=16
40%n=6
70%n=7
10%n=1
36%n=10
47%n=7
10%n=1
10%n=1
4%n=1
1%n=1
4%n=1
7%n=1
7%n=1
CompleteResponse
StableDisease
ProgressiveDisease
Notevaluable
PartialResponse
M
Overall Response Rate By Disease Subgroups: 2014
Idelalisib in Relapsed Indolent Lymphoma
Gopal et al, 2014.
Idelalisib in Relapsed Indolent Lymphoma: Waterfall Plot
Gopal et al, 2014.
All Patients Subtype of Indolent Lymphoma
Idelalisib in Relapsed Indolent Lymphoma: PFS
Gopal et al, 2014.
Any Diarrhea Pneumonia Neutropenia Anemia Thrombocy-topenia
0
10
20
30
40
50
60
54
13
7
27
26
Grade ≥3 Toxicity
Per
cent
Idelalisib in Relapsed Indolent Lymphoma:Grade ≥3 Toxicity
Gopal et al, 2014.
Fight infection Inhibit autoimmune
Immune Checkpoint Inhibitors
Mellman et al, 2011.
PD-1 Checkpoint Blockade
T cell Tumor cell
MHCTCR
PD-L1PD-1- - -
T cellDendritic
cell
MHCTCR
CD28
B7 CTLA-4 - - -
Activation(cytokines, lysis, proliferation,
migration to tumor)
B7 +++
+++
Tumor Microenvironment
+++
PD-L2PD-1- - -
Lymph Node
-
Courtesy of Jedd Wolchok, MD.
PD-1 Checkpoint Blockade
T cell Tumor cell
MHCTCR
PD-L1PD-1- - -
T cellDendritic
cell
MHCTCR
CD28
B7 CTLA-4 - - -
Activation(cytokines, lysis, proliferation,
migration to tumor)
B7 +++
+++
anti-PD-1
Tumor Microenvironment
+++
PD-L2PD-1
anti-PD-1- - -
Lymph Node
Courtesy of Jedd Wolchok, MD.
PD-1 Checkpoint Blockade
T cell Tumor cell
MHCTCR
PD-L1PD-1- - -
T cellDendritic
cell
MHCTCR
CD28
B7 CTLA-4 - - -
Activation(cytokines, lysis, proliferation,
migration to tumor)
B7 +++
+++
anti-PD-1
Tumor Microenvironment
+++
PD-L2PD-1
anti-PD-1- - -
Lymph Node
Nivolumab
Fully humanized
IgG4 monoclonal
PD-1 receptor
blocking antibody
Courtesy of Jedd Wolchok, MD.
Relapsed/refractorylymphoid malignancies:
• NHL• MM• T-cell NHL• Hodgkin lymphoma
NivolumabDose escalation 1 mg/kg and
3 mg/kg for 2 years
Phase I Study of Nivolumab in Patients With Refractory Lymphoid Malignancies
Lesokhin et al, 2014
Phase I Trial of Nivolumab in Lymphoproliferative Disease
Disease N CR PR SD PFS (24 wks)DLBCL 11 1(9%) 3(27%) 3(27%) 24%Follicular lymphoma 10 1(10%) 3(30%) 6(60%) 68%Other B-cell NHL 8 0 0 5(63%) 38%Primary mediastinalB-cell lymphoma 2 0 0 2(100)% 0
Mycosis fungoides 13 0 2(15%) 9(69%) 0Peripheral T-cell lymphoma 5 0 0 1(20%) 0
Other T-cell lymphoma 5 0 0 1(20%) 0Multiple myeloma 27 0 0 18(67%) 15%CML 1 0 0 1(100%) 100%
Lesokhin et al, 2014
Phase I Trial of Nivolumab: Adverse Events
Serious Adverse Event PercentagePneumonitis 7
Acute respiratory distress syndrome 3
Dermatitis 3
Diplopia 3
Enteritis 3
Eosinophilia 3
Mucosal inflammation 3
Pyrexia 3
Vomiting 3
Lesokhin et al, 2014
Agent TargetDaratumumab CD38Polatuzumab vedotin CD79bIbrutinib BtkACP-196 BtkGS-9973 SykIdelalisib PI3-KGS9901 PI3-KIPI-145 PI3-KNivolumab PD-1Pembrolizumab PD-1Pidilizumab PD-1ABT-199 Bcl-2Selinexor XP01 (Nuclear transport)
New Targeted Agents
Watch and wait still valid
Initial treatment
Maintenance
Subsequent treatment
New and exciting
Delays next chemotherapy without risk to PFS2
Rituximab – survivalBendamustine – equal efficacy,
less toxicity (watch lymphopenia)
Rituximab – PFS advantageSurvival – mixed/weak data
Early vs late progressorsTransplant option
Lenalidomide, obinutuzumab, ibrutinib, idelalisib, nivolumab
Five Questions
Historical Today
Cure Improved survivalImproved quality of life
Early treatment Does not prolong survivalMay delay toxic therapy
Law of diminishing returns Waterfall plots
Preservation of options Critical New treatments
Principles
Case Discussion 1: Initial Treatment of FL
70-year-old woman with a history of a herniated disc was having a routine follow-up CT scan, which revealed: – Left-sided hydronephrosis caused by a nodal mass 11.1 x 10.5 cm– Inguinal, paraaortic, and portacaval adenopathy – Spleen enlarged at 15 cm
Laboratory studies showed a mild anemia and creatinine of 2.4 mg/dL Fine needle aspiration of her enlarged right inguinal node was nondiagnostic.
Subsequent excisional lymph node revealed grade 1/2 FL When questioned carefully, patient reported 5 pounds of unintentional weight
loss, a sense of abdominal fullness, but no fevers or night sweats Bone marrow biopsy revealed 10% involvement by FL Now patient’s performance status is 2. CBC reveals a hematocrit of 32%,
absolute neutrophil count of 750/mm3, and platelets of 80,000/mm3. Bone marrow biopsy reveals 30% infiltration by FL
Question 1: Which initial treatment approach would you recommend for this patient?
1. Watch and wait2. Rituximab monotherapy3. R-CHOP4. R-bendamustine
Question 1: Responses
Watch and Wait Rituximab R-CHOP R-bendamustine0%
10%20%30%40%50%60%70%80%90%
100%
0% 0% 0% 0%
Case Discussion 2: Relapsed FL Previously healthy 68-year-old man presented with complaints of
fatigue, drenching night sweats, a 10-pound weight loss, and a mass in his neck
CT scan revealed diffuse lymphadenopathy and PET scan confirmed FDG-avidity with standard uptake values in the range of 6-12. One of the brightest nodes was biopsied and the pathology was interpreted as grade 2 FL
Received six cycles of R-CHOP to a complete remission that lasted for 4 years. Subsequently experienced increasing adenopathy and splenomegaly, with a return of symptoms. Bendamustine/rituximab was administered for six cycles
Achieved a good partial response but experienced prolonged neutropenia and thrombocytopenia. At approximately 12 months, at age 73, his disease recurs
Question 2: Which treatment approach would you recommend for this patient?1. Repeat R-CHOP2. R-ICE with autologous stem cell transplant3. Idelalisib4. Radioimmunotherapy with Y-90 ibritumomab
tiuxetan
Question 2: Responses
0%20%40%60%80%
100%
0% 0% 0% 0%
Case Discussion 3: Refractory FL A 56-year-old woman noticed new lumps around her neck, making it difficult to button
her blouse. She visited her primary care physician who, despite any other symptoms, administered a series of antibiotics, with no resolution
Fine needle aspiration was nondiagnostic. Excisional biopsy revealed a diagnosis of grade 3a FL
Patient was referred to an oncologist who completed staging:– Normal CBC and liver chemistries, with elevated LDH– PET/CT scan revealed diffuse adenopathy, with several nodal masses of 4-5 cm in the
axillae, abdomen, and retroperitoneum– Bone marrow biopsy showed 40% peritrabecular infiltration with small cleaved cells,
consistent with FL Patient received bendamustine/rituximab for six cycles, which was well tolerated Posttreatment PET/CT scan showed a moderate amount of persistent disease, with
only a 35% reduction in tumor volume. She declined stem cell transplant As the patient was asymptomatic, the decision was made to watch and wait to
determine the pace of her disease. However, in 11 months, substantial progression was noted
Question 3: Which treatment approach would you recommend for this patient?
1. Clinical trial of a novel targeted therapy2. R-CHOP3. Rituximab/lenalidomide4. High-dose therapy with autologous stem cell
transplant
Question 4: Responses
Novel therapy R-CHOP Rituximab/lenalidomide
High-dose therapy with
ASCT
0%10%20%30%40%50%60%70%80%90%
100%
0% 0% 0% 0%
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