Follicular Lymphoma: Applying Emerging Evidence in Practice

Follicular Lymphoma
Applying Emerging Evidence in Practice
Louis F. Diehl, MD
Professor 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
MZL
6%
LPL
1%
LL
2%
ALCL
2%
PMLBCL
2%
Burkitt’s-like
2%
PTCL
6%
MCL
6%
SLL
Composite
13%
DLBCL
32%
FL
22%
>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 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

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.
Mortality
5%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.

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
0
10
20
30
40
50
60
70
80
90
Months
Presentation 1st Relapse 2nd Relapse 3rd Relapse

Comparison of Response Duration in
Consecutive Recurrences of FL
0
5
10
15
20
25
30
35
Months

FL Responds to Repeated Chemotherapy With
Shorter Durations of Response
Gallagher et al, 1986.
1st
2nd
3rd4th
1 2 3 4
0
20
40
60
80
100
Patients in
remission
(%)
Years
Chemotherapy
treatment (no.)
1
2
3
4
Duration
(months)
16.0
11.2
9.6
3.2
Responding patients (n=110) in remission through 4 treatments
with the same chemotherapy regimen
0

Duration of Response (Years)
ProportioninResponse
0.00.20.40.60.81.0
Duration of Response (Years)
ProportioninResponse
0.00.20.40.60.81.0
0 2 4 6 8
2nd Therapy
3rd Therapy
4th Therapy
5th Therapy
6th Therapy
>=7th Therapy
Leonard et al, 2004.
Duration of Response Following Chemotherapy

FL Survival Is Improving for Most Patients
1990-1999
 Relative 5-year
survival 74%
 Relative 10-year
survival 51%

Improvement in Outcome
Adjusted Death Hazard Ratios by Diagnosis Year

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.
Favorable
T-cell activation
Relative risk of
death 0.15
Unfavorable
monocyte activation
Relative 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

Survivalprobability
Low risk
Intermediate risk
High risk
0
0.2
0.4
0.6
0.8
1.0
Years
0 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 Categories
Low 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
FND
Zevalin
CVP
CHOP
Rituximab
Combinations
Bone Marrow Transplant
Bexxar
Watch and Wait
Bendamustine
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
Does Rituximab vs Watchful Waiting Result in a Significant Delay in
the Initiation of Chemotherapy or Radiotherapy?

Asymptomatic FL:
Wait and Watch vs Rituximab
Overall Survival Time to Histological Transformation

Asymptomatic FL:
Wait and Watch vs Rituximab (cont.)
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
Months
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 After
Watch and Wait
Time to New Treatment
WW vs R-mono
Time to New Treatment
WW vs R-chemo

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?

Initial treatment
Maintenance
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

Duration of Response

Overall Survival
After 3 years, 6 patients in the R-CHOP group
and 17 patients in the CHOP group have died
(P=0.016).

Herold et al, 2007.
Marcus et al, 2008.
R-CHOP = rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; R-CVP =
rituximab/cyclophosphamide/vincristine/prednisone
MCP = mitoxantrone/ chlorambucil/prednisone.
Impact of Rituximab on OS in Frontline FL

Comparative Trials of R-Chemo
in Frontline FL
Study N Regimen 1
0
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.

Untreated
stages II–IV
follicular
lymphoma
R-CVP x 8
R-CHOP x 6
R-fludarabine +
mitoxantrone x 6
Federico et al, 2013.
FOLLO5: Study Design

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
TreatmentFailure(%)
Time (months)
Progression-Free
Survival(%) Time (months)
A B
R-CVP
R-CHOP
R-FM
R-CVP
R-CHOP
R-FM
No. at risk
R-CVP
R-CHOP
R-FM
168
165
171
136
147
150
119
137
139
95
120
120
74
83
95
51
66
68
36
47
50
23
32
32
13
19
20
5
12
12
1
5
4
No. at risk
R-CVP
R-CHOP
R-FM
168
165
171
154
157
163
136
147
151
108
128
130
85
89
101
60
70
73
41
51
55
27
36
36
14
22
23
6
14
14
1
6
5

FOLL05: Grade 3/4 Toxicities by Arm
0.6
3.1 4.2
28.0
49.7
63.7
0.0
3.1
7.7
2.5 3.1 4.8
0
20
40
60
Anemia Neutropenia Thrombocytopenia Infections
R-CVP R-CHOP R-FM
Anemia P=0.089
Neutropenia P<0.001
Thrombocytopenia P<0.001
Infections P=0.527
2.4 4.7

Overall Survival in FL: LymphoCare Data

BR vs R-CHOP
Newly diagnosed
stage II–IV
indolent or mantle cell
lymphoma
R
A
N
D
O
M
I
Z
E
D
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 Toxicity
BR vs R-CHOP
0
10
20
30
40
50
60
70
80
R-CHOP
BR
Rummel et al, 2013.

BR vs R-CHOP Non-Heme Toxicities
Rummel et al, 2013.

All Grades Non-Hematologic Toxicity:
BR vs R-CHOP
0
20
40
60
80
100
120
R-CHOP
BR
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)

Initial treatment
Maintenance
New and exciting
Rituximab – survival
Bendamustine – 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/SD
off study
Rituximab maintenance
375 mg/m2
every 8 weeks
for 2 years
Observation
CR/CRu
PR
Random 1:1
Immunochemotherapy
8 x rituximab
+
8 x CVP or
6 x CHOP or
6 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.
Salles et al, 2011.
Overall Survival by Maintenance

RESORT Study Design
Rituximab
retreatment at
progressiona
375 mg/m2 qw  4
R
A
N
D
O
M
I
Z
E
Rituximab
375 mg/m2
qw  4
CR or PR
Rituximab
maintenancea
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.

Initial treatment
Maintenance
New and exciting
Rituximab – PFS advantage
Survival – 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
0
24 30 36 42 48 540 6 12 18
Time (months)
Progression-FreeSurvival(%)
1.0
Event-FreeRate
Salles et al, 2011.
Rituximab maintenance
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30 36 42 48 54 60
Time (months)
Probability
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
Progressor
Reference
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 10
0.0
0.2
0.4
0.6
0.8
Patients at risk:
101 78 69 58 49 45 33 14 6 0
Time (years)
SurvivalProbability
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 uptake
2. Uptake ≤ mediastinum
3. Uptake > mediastinum but ≤ liver
4. Uptake > liver at any site
5. 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.
Both PET Cut-Offs Predictive of PFS

87%
97%
HR 6.7, 95% CI 2.4-18.5, P=0.0002
Median OS: 79 months vs. NR
Postinduction PET Status (Cut-Off ≥4)
and Overall Survival

Follicular lymphoma
initial treatment
Prognostic factors
CT
PET
Progression
Early
progressors
Late
progressors
Schouten et al, 2003.
Early vs Late Progression

BR vs FR
Relapsed Indolent Lymphoma
R/R indolent or mantle
cell lymphoma
Not refractory to
rituximab, bendamustine
or purine analogue
drugs
R
A
N
D
O
M
I
Z
E
D
Bendamustine + Rituximab
(Bendamustine 90 mg/m2
D 1,2 every 28 days and
Fludarabine + Rituximab
(Fludarabine 25 mg/m2,
D1,2,3 every 28 days and
Rummel et al, 2016.

BR vs FR
Progression-Free Survival
Follicular Lymphoma
Overall Survival
All Indolent Lymphoma
Rummel et al, 2016.

BR vs FR:
Hematologic Toxicity
Rummel et al, 2016.

BR vs FR:
Nonhematologic Toxicity
Rummel et al, 2016.

Relapsed follicular
lymphoma
Responsive to
chemotherapy
R
A
N
D
O
M
I
Z
E
D
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

Initial treatment
Maintenance
New and exciting
Early vs late progressors
Transplant option
Five Questions

Follicular lymphoma
Grade 1,2,3a
Previous rituximab
treatment
TTP >6 months
R
A
N
D
O
M
I
Z
E
D
Lenalidomide
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
Lenalidomide vs Lenalidomide +
Rituximab in Recurrent FL

Lenalidomide vs. Lenalidomide +
Rituximab in Recurrent FL (cont.)
# OR CR
Median
TTP
(years)
PFS at
2 Years
Lenalidomide 45 53% 20% 1.1 27%
Lenalidomide + rituximab 46 76% 39% 2.0 52%

Probability of Progression Overall Survival
Lenalidomide vs Lenalidomide +
Rituximab in Recurrent FL (cont.)

Follicular lymphoma
Grade 1,2,3a
Untreated
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, 10
12 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
Overall
N=55
FLIPI 0-1
n=16
FLIPI 2
n=35
FLIPI 3
n=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
0
20
40
60
80
100
120
ORR CR PR SD
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
Probability
0.0 0.5 1.0 1.5 2.0 2.5 3.0
0.00.20.40.60.8 CALGB 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.
R
A
N
D
O
M
I
Z
E

0
5
10
15
20
25
30
35
40
45
50
CR/Cru PR SD PD/relapse
Rituximab
Rituximab +
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 NHL
Required treatment
CD20+
With previous
response to
rituximab-containing
regimen
R
A
N
D
O
M
I
Z
E
D
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.

Indolent B-Cell NHL : PFS
Sehn et al, 2015.

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 lymphoma
Relapsed or refractory
Grade 1,2,3a
Progressed during or after
1 or more chemotherapy
regimens
Ibrutinib 560 mg daily
Until progression or
unacceptable toxicity
Ibrutinib in Relapsed/Refractory FL
Bartlett et al, 2014.

Disease N CR PR
Reduction
in tumor
volume
PFS
(median)
Follicular
lymphoma
40 2 9 72% 9 months
Bartlett et al, 2014. 108
Grade 3/4 Toxicity
Any 30%
Anemia 2 (5%)
Neutropenia 3 (8%)
Infection 2 (5%)
Ibrutinib Monotherapy in
Relapsed/Refractory FL (N=40)

N=125
Continuous 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%
FL
n=72 56% (43–67)
ORR, % (95% CI)
14%
n=10
42%
n=30
32%
n=23
8%
n=11
SLL
n=28
MZL
n=15
LPL/WM
n=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
Complete
Response
Stable
Disease
Progressive
Disease
Not
evaluable
Partial
Response
Minor
Response
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.

54
13
7
27
2
6
0
10
20
30
40
50
60
Percent
Grade ≥3 Toxicity
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
MHC
TCR
PD-L1PD-1
- - -
T cell
Dendritic
cell
MHC
TCR
CD28
B7 CTLA-4
- - -
Activation
(cytokines, lysis, proliferation,
migration to tumor)
B7
+++
+++
Tumor Microenvironment
+++
PD-L2PD-1
- - -
Lymph Node
-
Courtesy of Jedd Wolchok, MD.

T cell
Tumor cell
MHC
TCR
PD-L1PD-1
- - -
T cell
Dendritic
cell
MHC
TCR
CD28
B7 CTLA-4
- - -
Activation
migration to tumor)
B7
+++
+++
anti-PD-1
+++
PD-L2PD-1
anti-PD-1
- - -
Lymph Node

T cell
Tumor cell
MHC
TCR
PD-L1PD-1
- - -
T cell
Dendritic
cell
MHC
TCR
CD28
B7 CTLA-4
- - -
Activation
migration to tumor)
B7
+++
+++
anti-PD-1
+++
PD-L2PD-1
anti-PD-1
- - -
Lymph Node
Nivolumab
Fully humanized
IgG4 monoclonal
PD-1 receptor
blocking antibody

Relapsed/refractory
lymphoid malignancies:
• NHL
• MM
• T-cell NHL
• Hodgkin lymphoma
Nivolumab
Dose 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 mediastinal
B-cell lymphoma
2 0 0 2(100)% 0
Mycosis fungoides 13 0 2(15%) 9(69%) 0
Peripheral T-cell
lymphoma
5 0 0 1(20%) 0
Other T-cell lymphoma 5 0 0 1(20%) 0
Multiple myeloma 27 0 0 18(67%) 15%
CML 1 0 0 1(100%) 100%

Phase I Trial of Nivolumab:
Adverse Events
Serious Adverse Event Percentage
Pneumonitis 7
Acute respiratory distress syndrome 3
Dermatitis 3
Diplopia 3
Enteritis 3
Eosinophilia 3
Mucosal inflammation 3
Pyrexia 3
Vomiting 3

Agent Target
Daratumumab CD38
Polatuzumab vedotin CD79b
Ibrutinib Btk
ACP-196 Btk
GS-9973 Syk
Idelalisib PI3-K
GS9901 PI3-K
IPI-145 PI3-K
Nivolumab PD-1
Pembrolizumab PD-1
Pidilizumab PD-1
ABT-199 Bcl-2
Selinexor XP01 (Nuclear transport)
New Targeted Agents

Initial treatment
Maintenance
New and exciting
Early vs late progressors
Transplant option
Lenalidomide, obinutuzumab,
ibrutinib, idelalisib, nivolumab
Five Questions

Historical Today
Cure
Improved survival
Improved quality of life
Early treatment
Does not prolong survival
May 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 wait
2. Rituximab monotherapy
3. R-CHOP
4. R-bendamustine

Question 1: Responses
20%
13%
0%
67%
0%
10%
20%
30%
40%
50%
60%
70%
80%

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-CHOP
2. R-ICE with autologous stem cell transplant
3. Idelalisib
4. Radioimmunotherapy with Y-90 ibritumomab
tiuxetan
5. Observe

0%
35%
52%
4%
0%
10%
20%
30%
40%
50%
60%

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 therapy
2. R-CHOP
3. Rituximab/lenalidomide
4. High-dose therapy with autologous stem cell
transplant

42%
8%
42%
8%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%

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