Follicular Lymphoma: Applying Emerging Evidence in Practice

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



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



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


Comparison of Response Duration in Consecutive Recurrences of FL

0

5

10

15

20

25

30

35

Mon

ths



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


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)


FL Survival Is Improving for Most Patients


1990-1999 Relative 5-year

survival 74% Relative 10-year

survival 51%

Improvement in OutcomeAdjusted 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.

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


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)


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


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

Mon

ths



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?


Initial treatment

Maintenance


New and exciting

Delays next chemotherapy without risk to PFS2

Five Questions


Initial treatment

Maintenance


New and exciting


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 groupand 17 patients in the CHOP group have died(P=0.016).


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


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


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)


Initial treatment

Maintenance


New and exciting


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


Initial treatment

Maintenance


New and exciting




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


Initial treatment

Maintenance


New and exciting





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


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%


Probability of Progression Overall Survival

Lenalidomide vs Lenalidomide + Rituximab in Recurrent FL (cont.)


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.


T cell Tumor cell

MHCTCR

PD-L1PD-1- - -

T cellDendritic

cell

MHCTCR

CD28

B7 CTLA-4 - - -


migration to tumor)

B7 +++

+++

anti-PD-1


+++

PD-L2PD-1

anti-PD-1- - -

Lymph Node



T cell Tumor cell

MHCTCR

PD-L1PD-1- - -

T cellDendritic

cell

MHCTCR

CD28

B7 CTLA-4 - - -


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/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%


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


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


Initial treatment

Maintenance


New and exciting





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


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


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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References

Health & Medicine

Follicular Lymphoma: Applying Emerging Evidence in Practice