Update on Follicular Lymphoma: - PowerPoint Presentation

Slide1

Update on Follicular Lymphoma: Contemporary Treatment Strategies and Optimal SequencingSlide2

Educational Objectives

After completing this program, participants should be able to:

Summarize the incidence and patient demographics of indolent B-cell NHL (Non-Hodgkin Lymphoma), including prognostic factors that aid in accurate diagnosis and guide treatment decisions 

Assess options for first-line and subsequent lines of therapy for indolent  B-cell NHL and determine the role of radioimmunotherapy

Describe the demonstrated efficacy and safety of agents for primary,  relapsed, and refractory follicular lymphoma (FL)

Formulate treatment strategies for relapsed and refractory indolent B-cell NHL using currently available options in order to optimize outcomes for individual patients.

Identify the mechanisms of resistance of current antibody therapies and the existing treatment options

Recall potential barriers of use of

radioimmunotherapy

in the community practice settingSlide3

Topics Included in the LibraryOverview of NHL/FLCurrently approved treatments for FL and their applicationsCurrent patient management practices in FLWhere does RIT fit into current treatment paradigms?Novel applications of existing treatments and emerging treatment approaches for FLClinical cases and evidence-based treatment strategiesSlide4

OVERVIEW OF NHL and FLSlide5

Breast 231,840 29%

Lung & bronchus 105,590 13%Colon & rectum 63,610 8%Uterine corpus 54,870 7%Thyroid 47,230 6%

NHL 32,000 4%

Melanoma of skin 31,200 4%

Pancreas 24,120 3%

Leukemia 23,370 3%

ALL SITES 810,170 100%

Prostate 220,800 26%

Lung & bronchus 115,610 14%

Colon & rectum 69,090 8%

Urinary bladder 56,320 7%

Melanoma of skin 42,670 5%

NHL 39,850 5%Kidney & renal pelvis 38,270 5%Oral cavity & pharynx 32,670 4%Leukemia 30,900 4%ALL SITES 848,200 100%

Females

Males

Estimated New Cancer Cases in the US (2015)

Siegel, et al.

CA Cancer. J Clin

. 2015;65(1):5-29.Slide6

Lungs & bronchus 71,660 26%

Breast 40,290 15%Colon & rectum 23,600 9%Pancreas 19,850 7%

Ovary 14,180 5%

Leukemia 10,240 4%

Uterine corpus 10,170 4%

NHL 8,310 3%

Liver & intrahepatic 7,520 3%

bile duct

ALL SITES 277,280 100%

Lung & bronchus 86,380 28%

Prostate 27,540 9%

Colon & rectum 26,100 8%

Pancreas 20,710 7%

Liver & intrahepatic 17,030 5% bile duct Leukemia 14,210 5%Esophagus 12,600 4%Urinary bladder 11,510 3%

NHL 11,480 3%

ALL SITES 312,150 100%Females

Males

Estimated Cancer Deaths in the US (2015)

Siegel, et al.

CA Cancer. J Clin

. 2015;65(1):5-29.Slide7

MALT=mucosa-associated lymphoid tissue; NHL=non-Hodgkin’s lymphoma NK=natural killer

Lichtman MA. Williams Hematology. 7th ed. New York, NY: McGraw Hill. 2006;1408.

T and NK cell

(12%)

Other subtypes

(9%)

Burkitt

(2.5%)

Mantle cell

(6%)

Diffuse large B cell (DLBCL)

(30%)

Follicular

(25%)

Small lymphocytic

(7%)

MALT-type marginal-zone B cell (7.5%)Nodal-type marginal-zone B cell (<2%)Lymphoplasmacytic (<2%)NHL SubtypesSlide8

Armitage & Weissenburger, 1998; ACS, 2015.

Relative Incidence of NHL Subtypes

>71,000 New Cases in US in 2015

Marginal zone B-cell

6%

Lymphoplasmacytic

1

%

Lymphoblastic

2%

Anaplastic large T-/null-cell

(ALCL) 2

%

Primary mediastinal large

B-cell (PMLBCL) 2

%

Burkitt’s-like2%Peripheral T-cell (PTCL)6%Mantle cell (MCL)6%Composite13%Diffuse large B cell (DLBCL)32%FollicularLymphoma22%Small lymphocytic (SLL)6%Slide9

Follicular Lymphoma

Second most common lymphoma in the USAGraded as 1, 2, 3a, and 3b

Grading can be difficult

and may need hematopathologic review

Grade 3a lymphoma

may be

treated

as indolent lymphoma

Follicular 3B

should be

treated as diffuse large B-cell NHL

Advanced stage FL not curable with standard therapy

Modified from Skarin AT, Dorfman DM.

CA Cancer J Clin. 1997;47:351-72.Slide10

Grade 1

Follicular small cleaved cell

Grade 2

Follicular mixed small &

large cell

Grade 3

Follicular large cell

Images courtesy of J. Connors, MD

Grade 3a

Grade 3b

Aggressive lymphoma

Ott, et al.

Blood.

2002;15;99:3806-3812.

FL—GradingSlide11

<5/hpf

Grade 1

Grade 2

6-15/hpf

Grade 3a

Grade 3b

>15/hpf

Sheet

Zelenetz. ASCO, 2006.

FL—Grade Influences PrognosisSlide12

FL Grade 1-2—Workup According to NCCN GuidelinesESSENTIALPhysical exam: attention to node-bearing areas, including Waldeyer’s ring, and to size of liver and spleenPerformance statusB symptomsBlood analysis

CBC, differential, plateletsLDHBeta-2-microglobulin Comprehensive metabolic panelHepatitis B testingChest/abdominal/pelvic CT with contrast of diagnostic quality and/or PET-CT scan

Bone marrow biopsy + aspirate to document clinical stage I-II disease

Pregnancy testing in women of child-bearing age (if chemotherapy planned)

NCCN Guidelines Version 2.2015Slide13

FL Grade 1-2—Workup According to NCCN GuidelinesUSEFUL IN SELECTED CASESMUGA scan/echocardiogram if anthracycline or anthracenedione-based regimen is indicatedNeck CTUric acidDiscussion of fertility issues and sperm bankingSPEP and/or quantitative immunoglobulin levelsHepatitis C testing

NCCN Guidelines Version 2.2015Slide14

FL—Staging and Diagnostic WorkupHistory and complete physical examinationLaboratory evaluationBone marrow

Bilateral bone marrow biopsies or unilateral (at least 2-cm specimen) ± flow cytometryRadiologic studiesCT scans (abdomen, pelvis, and thorax)/PET in selected histologies

Skarin and Dorfman.

CA Cancer J Clin.

1997;47:351.Slide15

Diagnosis—PathologyExcisional biopsy preferredFNA unacceptableCore needle biopsy only if disease difficult to access If can not be defined, consider more definitive proceduresReview by hematopathologist

Bone marrow – bilateral or unilateralUseful under certain circumstances

Aspiration and biopsy

No cytogenetics unless MDS suspected

NCCN Guidelines Version 2.2015Slide16

Diagnosis—ImmunophenotypingAntigen Expression in B-Cell Lineage

Pre-B

Early B

Mature B

Plasmacytoid B

±CD5

CD19

CD20

CD22

CD52

Plasma

Intermediate B

?

?

?

Stem cell

Burkitt’s, FL, DLCL, HCLALL CLL, PLL

WM

MMSlide17

Diagnosis—ImmunophenotypingCharacteristic immunophenotypeSmall cellsCD5-, CD10+, BCL6+, BCL2+

Cytogenetics/FISHt(14;18)(q32;q21) occurs in >80% of cases of FLBcl-2

juxtaposition into the

IgH

heavy chain locus

Deregulated bcl-2 expression

85% of FL will be BCL2+ or t(14;18)+

NCCN Guidelines Version 2.2015Slide18

Diagnosis—Immunophenotypic Markers Distinguishing FL from other NHLs

Neoplasm

CD5

CD10

Bcl-2

IgD

Bcl-6

CD43

Cyclin D1

CD23

MCL

+

-

+

+

-++-/+CLL/SLL+-++ -+-/++Follicular lymphoma-++-/+ +*---/+MALT--+--+/--

-MZL – nodal--++/- -/++/---MZL – splenic--++----LPL/Waldenstrom’s macroglobulinemia--/++---/+--/+Hairy cell leukemia--/++--NT+

-/+

- indicates < 5%; -/+ indicates 5

–

25%; +/- indicates 25

–

50%; + indicates > 50%; NT indicates not tested.

CD5 to distinguish from MCL, CD10 to distinguish from MZLSlide19

Diagnosis—Imaging CT scan – chest/abdomen/pelvisPET/CT also acceptable

PET required to confirm stage I/II diseaseSlide20

Diagnosis—Blood

CBC with WBC differential[1]

Calculate absolute lymphocyte and monocyte count from differential

Peripheral blood absolute lymphocyte count/absolute monocyte count ratio at diagnosis (ALC/AMC-DX) ≥2.1 have better prognosis

[2]

Creatinine, AST, calcium, sodium, bilirubin, potassium, alkaline phosphatase

[1]

LDH, uric acid, beta-2

microglobulin

[1]

Hepatitis B and C serology

[1]

HIV testing (optional)

[1][1] NCCN Guidelines Version 2.2015 [2] Porrata, et al.

British J Haematol. 2012;157:321-330.Slide21

Diagnosis—Staging EvaluationHistory and complete physical examinationLaboratory evaluationStandard blood studiesComplete blood count, differential blood count, blood smear examination

LDH and β2-microglobulin Liver function testsRenal function testsSerum electrolyte, calcium and uric acid levels

Bone marrow

Bilateral bone marrow biopsies or unilateral (at least 2-cm specimen) ± flow cytometry

Radiologic studies

CT scans (abdomen, pelvis and thorax)/PET in selected histology'sSlide22

Staging—Ann Arbor Classification(Cotswolds Revision)

A: absence of B symptoms

B: presence of B symptoms (fevers, night sweats, weight loss)

E: extranodal disease or extension from known nodal site of disease

X: bulky disease : >1/3 widening of the mediastinum at T5-T6, or maximum

of nodal mass>10cm

Stage I

Involvement of a single lymph node region or a lymph node structure or a single extralymphatic site

Stage II

Involvement of two or more lymph node regions on the same side of the diaphragm or localized contiguous involvement of an extralymphatic site and lymph node organ

Stage III

Involvement of lymph node regions on both sides of the diaphragm

Stage IV

Diffuse or disseminated involvement of one or more extranodal organs or tissues, with our without associated lymph node involvement Slide23

Staging—The Lugano Classification

PET/CT at diagnosis and end of therapy

Deauville 5-point scale criteria

FL is considered a “FDG-avid lymphoma”

Still measure nodes if PET positive

No more than 6 lesions

Node >1.5 cm; EN lesion >1.0 cm

Record a node as “0” if its gone

Record as 0.5 x 0.5 if small and nonmeasureable

No more routine BM for HL and DLBCL

Allow unilateral for FL and other low grade

Cheson B et al.

J Clin Oncol

. 2014;32:3059-3068.Slide24

Staging—Deauville 5-point Scale CriteriaMeignan, et al. Leuk Lymphoma. 2009;50:1257-1260.

ScoreFinding

1

No PET uptake

2

PET uptake ≤ mediastinum

3

PET uptake > mediastinum but ≤ liver

4

PET uptake moderately higher than liver

5

PET uptake markedly higher than liver and/or new sites of disease

XImplies PET uptake in new sites unrelated to lymphoma

PET, positron emission tomography Collaboration with a radiologist is encouraged for interpretation of the PET-CT scansSlide25

Prognostic Factors

Prognostic FactorsReferences

FLIPI-1

Solal-Celigny P, et al.

Blood

. 2004;104:1258-1265.

FLIPI-2

Federico M, et al.

J Clin Oncol.

2009;27:4555-4562.

GELF

(Groupe D’Etude des Lymphomes Folliculares)

Brice P, et al.

J Clin Oncol. 1997;15:1110-1117.SWOG Prognostic IndexPress O, et al. Clin Cancer Res. 2013;19:6624-6632.EFS12 Maurer M, et al. Blood. 2014;124:1664.Casulo C, et al. J Clin Oncol. 2015;33:2516-2522.

Vitamin D

Kelly J et al. J Clin Oncol. 2015;33:1482-1490.BCL2 mutationsCorreia C, et al. Blood. 2015;125:658-667.Slide26

Adapted from Solal-Celigny P, et al.

Blood

. 2004;104:1258-1265.

Survival probability

Low risk

Intermediate risk

High risk

0

0.2

0.4

0.6

0.8

1.0

Years

0

1234567No Nodal regions  4L LDH increasedA Age ≥60S Stage III/IVH Hemoglobin <120 g/LFLIPI—Overall Survival According Clinical Prognosis FactorsRisk GroupNo. of Factors% of Pts5-y OS (%)10-y OS (%)Low0-13690.670.7Intermediate23777.8

50.9High3-52752.535.5p<10-4Slide27

FLIPI—Lymph Node Groups

Each of the right or left cervical, axillary, epitrochlear, inguinal, or popliteal nodal areas are considered separate areas.

Solal-Celigny, et al.

Blood

. 2004;104:1258

.

Cervical

Pre-Auricular

Upper Cervical

Median or Lower

Postcervical

Supraclavicular

Axillary

Axillary

EpitrochlearEpitrochlearMesentericSplenic HilarPortalCeliacMesentericInguinalInguinalFemoralPoplitealPoplitealCervicalPre-AuricularUpper CervicalMedian or LowerPostcervicalSupraclavicularMediastinalParatrachealMediastinalHilarAxillaryAxillaryEpitrochlearEpitrochlearPara-AorticPara-AorticCommon IliacExternal IliacInguinalInguinalFemoral

PoplitealPoplitealRight

LeftSlide28

FLIPI-2—Risk Assessment

Federico M, et al. J Clin Oncol. 2009;27:4555-4562.

FLIPI 2

Age >60 yrs

BM involvement

Anemia (Hgb <12 g/dL)

Nodes >6 cm

β

2

m > ULNSlide29

BM = bone marrow; Hgb = hemoglobin; ULN = upper limit of normal.

[1] Solal-Celigny, et al.

Blood

. 2004;104:1258. [2]

Federico M, et al.

J Clin Oncol.

2009;27:4555-4562.

.

FLIPI and FLIPI-2—Adverse Factors

FLIPI

[1]

FLIPI-2

[2]

Age >60 years

Age >60 yearsStage III-IVBM involvementAnemia (Hgb <12 g/dL)Anemia (Hgb <12 g/dL)>4 involved nodal areasNodes >6 cmLDH >ULNΒeta-2-microglobulin >ULNSlide30

GELF Criteria—Treatment Deferral vs Initiation

All of the Following:Maximum diameter of disease <7 cmFewer than 3 nodal sitesNo systemic symptomsSpleen <16 cm on computed tomography (CT)

No significant effusions

No risk of local compressive symptoms

No circulating lymphoma cells

Brice P, et al.

J Clin Oncol.

1997;15:1110-1117.

GELF, Groupe pour l’Etude de Lymphome Folliculaire Slide31

ECOG Protocol 4402— Definition of Low Tumor Burden in FL

No mass > 7 cm< 3 masses each greater than 3 cm in diameter

No systemic or B symptoms

No splenomegaly > 16 cm by CT scan

No risk of vital organ compression

No leukemic phase with > 5,000/

μ

L circulating lymphocytes

No cytopenias defined as:

Platelets < 100,000/

μ

L

Hemoglobin < 10 g/dLAbsolute neutrophil count < 1,500/μL

Kahl, et al. J Clin Oncol. 2014;32:3096-3102.Slide32

SWOG Follicular Prognostic Index

Utilized patients from S0016 CHOP plus RIT versus RCHOP

532 patients

FLIPI vs FLIPI 2 vs LDH plus

β

2M

All three prognostic models predicted both PFS and OS

Easiest model was LDH plus

β

2M

32

Press, et al

. Clin Cancer Res

. 2013;19:6624-6632.Slide33

Figures from Press, et al. Clin Cancer Res

. 2013;19:6624-6632.SWOG Follicular Prognostic IndexSlide34

SWOG Follicular Prognostic Index—

β

2M and LDH

Press, et al

. Clin Cancer Res

. 2013;19:6624-6632.Slide35

National LymphoCare Study

Early PROG …Bad OSHazard ratio of 12.3

At 5 years…Patients with early PROG

OS of 50% vs OS of 95%

(

Ref group)

Factors for early PROG

High LDH

Poor PS

B symptoms

Bone marrow involvement

Casulo, et al.

J Clin Oncol

. 2015;33:2516-2522. Slide36

m7-FLIPI—Clinicogenetic Risk Model Developed an improved prognostic algorithm that can be applied to patients receiving first-line immunochemotherapyIncludes the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), FLIPI, and ECOG performance statusA freely accessible online tool is now available to calculate the m7-FLIPI

Pastore, et al. Lancet Oncol. 2015;16:1111-1122. Slide37

m7-FLIPI—Clinicogenetic Risk Model

Failure-free Survival

Graphs from: Pastore, et al.

Lancet Oncol

. 2015;16:1111-1122.

High-risk m7-FLIPI

High-risk m7-FLIPI

High-risk FLIPI

High-risk FLIPI

Low-risk m7-FLIPI

Low-risk m7-FLIPI

Low/int-risk FLIPI

Low/int-risk FLIPI

GLSG2000 training cohort BCCA validation cohort Slide38

EFS12 for Follicular Lymphoma

38

Figures from Maurer, M et al.

Blood

2014;124:1664.

Group that needs attentionSlide39

Low Serum Vitamin D Levels Are Associated with Inferior Survival in FL

Figures from Kelly J, et al. J Clin Oncol. 2015;33:1482-1490.

SWOG Cohorts

Lymphoma Study

Association CohortsSlide40

Why is Vitamin D Important?

It is one of the few prognostics factors that isActionable

Inexpensive

Key questions

Is it merely a surrogate for more ill patients?

Will replacing really help?

40Slide41

BCL2 Gene is Critical to FL PathogenesisLocated on chromosome 18

Bcl-2 protein inhibits apoptosis (pro-survival)

Bcl-2 binds and neutralizes activated pro-apoptotic Bcl-2 family members such as Bax and Bak

Bax and Bak are on the outer mitochondrial membrane

Bcl-2 binds and neutralizes intracellular stress sensors such as Bim and Puma

Normal function of Bim and Puma is proapoptotic by activating Bak and Bax

41

Correia C, et al.

Blood.

2015;125:658-667.Slide42

BCL2—Predicting Death

42

Figure from: Correia C, et al.

Blood.

2015;125:658-667.Slide43

BCL2—Predicting Transformation

43

Figure from: Correia C, et al.

Blood.

2015;125:658-667.Slide44

Implications of BCL2 Gene Mutations

Predicting transformation and death

Albeit years later…

Likely more important for young people

Potential for choosing therapy with agents that directly target bcl-2 (ABT-199)

44

Correia C, et al.

Blood.

2015;125:658-667.Slide45

Histologic Transformation in FLRecognized in40%-60% of patients>90% at autopsy

Heralded by a change in clinical courseNew symptomsRapidly progressive (often localized)Elevated LDH

Gallium avidity

Generally poor prognosis

Extended survival possible when large-cell component can be “cured” (localized, minimal prior therapy)Slide46

631 patients with newly diagnosed grade 1 to 3a FL (median age, 60 years)Median follow-up of 60 months (range, 11 to 110 months)79 patients had died60 patients developed transformed lymphoma (biopsy proven in51)

Link, et al. J Clin Oncol. 2012;48:3990.Risk of Transformation in FL

Follicular transformation rates in the immunochemotherapy era are similar to risk of death without transformation

5-year Overall Transformation

Rate

Rituximab monotherapy

Observation

10.7%

14.4%

3.2%

Estimated Transformation rate

2%

per

yearOS following Transformation (median)50 months5-year OSTransformation ≥18 monthsTransformation <18 months48%76%22%P = .021

P

< .001Slide47

Figure from: Link, et al. J Clin Oncol. 2012;48:3990.Risk of Transformation in FL

Risk of transformation with death as a competing riskSlide48

Figure from: Link, et al.

J Clin Oncol

. 2012;48:3990.

Risk of Transformation—

Risk of Transformation by Initial FL Treatment

Observation (n = 208)

Alkylator (n = 137)

Rituximab monotherapy (n = 78)

Anthracycline (n = 127)Slide49

Figure from: Link, et al. J Clin Oncol. 2012;48:3990.Risk of Transformation in FL—OS After TransformationSlide50

Principles for Dealing with FL

Get adequate tissue to an expert pathologist to get the right diagnosisAge of the patient

Co-morbidities of the patient

Symptoms?

Organs at risk?

Pace of the disease?

Can I cure this patient?Slide51

Principles for Dealing with FL

Could this patient someday be a transplant candidate?Can I treat to

avoid

chemotherapy and preserve quality of life?

A patient who feels “normal” cannot feel better on chemotherapy

Being off treatment is good

What does the patient think?Slide52

Problems With Clinical Trials in FL

There is always something new that has happened by the time you publish your trialStudies published on PFS; OS is the key

That “new something” always causes people to doubt your conclusions. “What if they had done ____?”Slide53

CURRENT PATIENT MANAGEMENT PRACTICES IN FL: FIRST-LINE TREATMENTSlide54

How Does One Decide Which Treatment to Recommend?Classification Subtype (follicular vs diffuse large B-cell)Growth rate (grade)

Indolent vs aggressiveStage of diseaselocal, distant, widespread

Prognostic Factors

IPI; FLIPI

Other factorsSlide55

FL—Factors to Consider When Choosing TherapyPATIENT CharacteristicsAge

SymptomsShort & long term goalsComorbidity

Preserve future options

DISEASE

Characteristics

Stage

Grade

Transformation

Sites of involvementSlide56

First-line Treatment Regimens 2015

ImmunotherapySingle agent rituximab

±

maintenance

Radioimmunotherapy

Ibritumomab tiuxetan

Tositumomab

[currently

unavailable]

Chemotherapy

Bendamustine/rituximab (BR)

R-CHOP

R-CVP

Other regimensBVR as in ECOG2408Rituximab + lenalidomide (R2) or R2 maintenanceSlide57

INDUCTION

CONSOLIDATION

MAINTENANCE

Types of therapy:

Combination chemo- or

immunochemotherapy

Types of therapy:

Radiolabeled immunotherapy

Types of therapy:

Immunotherapy

Prevent relapse by maintaining best response

Reduce tumor load and induce initial response

Quality of Remission (CR Rate)

Remission Duration

Goals of therapy over a patient’s course of treatment

Maximize response by rapidly improving quality of response to induction

Options for the Management of FLSlide58

NCCN Practice Guidelines for FL—2015Additional Therapy

Initial Therapy

Stage I, II

Stage II bulky,

Stage III, IV

ISRT

ImmunoRx ± Chemo Rx ± RT

Observe (if tx not indicated)

Clinical trial

Bendamustine + Rituximab

Chemo Rx

Rituximab

Lenalidomide + Rituximab

Local

RT (palliation)Observe (if tx not indicated)

Without transformationClinical trialChemoRxRituximabLenalidomide  RituximabRITIdelalisibChemotherapy  RituximabLocal RT (palliation)Observe (if tx not indicated)Transformed to DLBCLClinical trial RITChemotherapy ± RituximabISRTChemotherapy ± Rituximab ± RTRITASCTBest supportive careNCCN Practice Guidelines in Oncology, v.2.2015.Progressive Disease or No ResponseFirst-line Consolidation or Extended Dosing (optional)Rituximab RIT (after induction with chemoRx or chemoimmunoRX)Slide59

FDA-Approved Agents for FL—First-line

Bendamustine

Rituximab

RIT

59Slide60

Targeted Therapies for FL—FDA Approved and Under DevelopmentTable from: Ujjani. Oncology (Williston Park). 29:760-768.Slide61

Table from: Ujjani. Oncology (Williston Park). 29:760-768.

Targeted Therapies for FL—

FDA Approved and Under DevelopmentSlide62

Symptomatic

Asymptomatic

New Untreated Follicular

Young

Older; Co-morbidities

R-CVP;

BR

Observe

or RIT or R-Maintenance

R-CHOP;

BR

Observation

Low bulk

Rituximab

RIT

Stage IEBRTSlide63

Friedberg JW.

J Clin Oncol

.2009;27:1202-1208.

Observation

(Watch and Wait)

18%

Radiotherapy 6%

Rituximab Monotherapy

14%

Chemotherapy +

Rituximab

52%

Chemotherapy 3%

Clinical trial

6%

Other 2%Current Practice: the LymphoCare Study—First-line Treatment2004-2007 N=2728 at 265 US Sites: 80% Nonacademic, 20% AcademicSlide64

Figure from: Cartron, G. et al. Blood 2004;104:2635-2642

Rituximab—Main Mechanisms of Action and Directions to Increase Clinical EfficacySlide65

Management of FL by Burden—Low Burden (No GELF; FLIPI 0)

Individualize management—No survival advantage for any therapy

Acceptable options are:

Observation (preferred)

Rituximab x 4 without maintenance

Based on NCCTG,

[1]

Ardeshna

et al,

[2]

and ECOG RESORT

[3]

Radioimmunotherapy

[4-6] [1] Witzig, et al. J Clin Oncol. 2005;23:1103-1108. [2] Ardeshna, et al. Lancet Oncol. 2014;15:424-435. [3] Kahl, et al. J Clin Oncol.2014;56:5853. [4] Kaminski,et al. N Engl J Med. 2005; 352:441-449. [5] Scholz, et al. J Clin Oncol. 2013;31:308-313. [6] Ibatici, et al.

Br J Haematol. 2014;164;710-716.Slide66

Study

Regimen

n

ORR

CR

TTF/PFS (months)

Colombat P, et al.

[1]

Rituximab monotherapy

(patients with low tumor burden)

49

74%

49%

24

Witzig TE, et al

.[2] Rituximab monotherapy3772%36%26Management of FL by Burden—Low Burden[1]. Colombat, et al. ASH. 2006:abstract 486. [2] Witzig, et al. J Clin Oncol. 2005;23:1103-1108.Slide67

0

10

20

30

40

50

60

70

80

90

100

CHOP-R

FND-R

Fludarabine-R

PR

CR

CHOP-R

CHOP-R

FN-R

CVP-R

Czuczman

Zinzani

1

McLaughlin

Czuczman

Hiddemann

Zinzani 2

Marcus

Rummel

Bendamustine-R

Fludarabine

Courtesy of Oliver W. Press, MD, PhD, and Stephanie A. Gregory, MD.

Chemotherapy/Rituximab Trials for Initial Therapy of FLSlide68

Management of Disease by Burden—High Burden

Patients who meet GELF criteriaFLIPI2:

3-5 risk factors

Off-Study– Rituximab/chemotherapy

R-bendamustine x 4 - 6

R-CVP x 6

R-CHOP x 6Slide69

Management of Disease by Burden—High Tumor Burden after R-Chemo

Three options

Observation every 6 months (Mayo standard)

Rituximab every 2 mos x 2 ys (PRIMA)

[1]

Single-dose RIT 0.3-0.4 mCi/kg (maximum 32

mCi)

[2]

Options 2,3 provide a PFS benefit over observation;

no overall survival benefit

[1] Salles, et al. Lancet. 2011;377:42-51. [2] Morschhauser,

J et al. Clin Oncol. 2008;26:5156-5164.Slide70

Management of Disease by Burden—High Tumor Burden after R-Chemo

Rituximab

m

aintenance

74.9%

Rituximab every 2 mos x 2 ys (PRIMA)

[1]

[1] Salles, et al.

Lancet

. 2011;377:42-51. [2] Morschhauser,

J

et al.

Clin Oncol. 2008;26:5156-5164.Single-dose RIT 0.3-0.4 mCi/kg (maximum 32 mCi)[2]

Observation

57.1%90Y-ibritumomab tiuxetan ControlPFS benefit over observation; no overall survival benefitSlide71

“Watch and Wait” vs Active Therapy

1737 pts with stage III/IV FL237 (14%) Observed (aka “watch and wait”)

1500 Active therapy (AT)

Factors favoring watch and wait:

Age >60; No sx; FL grade I/II; ECOG PS=0; no EN sites; and LDH normal

Median PFS

27 months (WW) vs 64 months (AT)

Next treatment decision

35 months

(WW) vs

not reached (AT)

No difference in OS

71 Sinha and Flowers, et al. ASH Annual Meeting Abstracts. 2011;118:775.Slide72

“Watch and Wait” vs Chemotherapy for Asymptomatic Patients with Advanced FL

Study

N

Chemotherapy Regimen

OS Chemotherapy

OS

Watch and Wait

Ardeshna et al

[1]

309

Chlorambucil

Median:

5.9 y

Median:

6.7 y

Brice et al[2]193Prednimustine5y: 70%5 y: 78%IFN-α5y: 84%Young et al[3]104ProMACE-MOPPMedian: NRMedian: NR[1] Ardeshna KM, et al. Lancet. 2003:362:516-522. [2] Brice P, et al. J Clin Oncol. 1997;15:1110-1117. [3] Young RC, et al. Semin Hematol. 1988;25:11-16.IFN=interferon; MOPP=mechlorethamine, vincristine, procarbazine, prednisone; NR=not reached; ProMACE=prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide.Slide73

“Watch and Wait” vs Rituximab (R) for Patients with Stage II-IV Asymptomatic, Nonbulky FL

InterventionObserve

R x 4 weeks

R x 4 weeks

Maintenance

---

---

R q 2 mos. x 2 years

Number

187

84

192

CR/PR (%)

2/343/3054/333-year PFS33%60%81%Time to next treatment33 monthsNot reachedNot reached

Patients had: stage II–IV, asymptomatic, non-bulky low-grade FL

Improved PFS in rituximab arms (P ≤.001)Time to initiation of new treatment in the rituximab arms33 months vs not reached at 4 years (P ≤.001)No difference in OS (P ≥.5)Quality of life no worseArdeshna KM, et al. ASH 2010. abstr 6 (oral, Plenary Session).Slide74

“Watch and Wait” vs Rituximab—PFS and OSFigure from: Ardeshna KM, et al. ASH 2010. abstr 6 (oral, Plenary Session).

Proportion of Patients PF

% of Patients Alive

PFS

OSSlide75

Figure from: Ardeshna KM, et al. ASH 2010. abstr 6 (oral, Plenary Session).“Watch and Wait” vs Rituximab—

Time to Initiation of New TherapySlide76

BendamustineAlkylating agentInduces durable DNA damage resulting in apoptosis and mitotic catastropheLacks cross resistance with other agents (including alkylators)

Rummel MJ, et al. J Clin Oncol. 2005;23:3383-3389. Friedberg JW, et al. Blood. 2005;106:abstr#229. Chovan JP, et al.

Drug Metab Dispos

. 2007;35:1744-53. Weide R.

Ther Clin Risk Manag

. 2008;4:727-732. Cheson BD, Rummel MJ.

J Clin Oncol

. 2009;27:1492-1501.

O

O

C

N

N

N

Cl

ClNitrogen mustardCarboxylic acidSlide77

ELIGIBILITYN=513Untreated pts with indolent and MCL

CD20+ FL (grade 1/2),

MCL, MZL, WM,

SLL, other LPL

Stage III/IV

No prior therapy

Age

≥18 years

R

A

N

D

O

MIZEn=260BR (× 6 cycles)

n=253R-CHOP

(× 6 cycles)Primary endpoint: Non-inferiority of BR vs R-CHOP in PFS (defined as a difference of less than 15% in PFS after 3 years)Secondary endpoint: ORR, OS, relapse-free survival, and safetyRummel MJ, et al. Blood. 2009;114:168-169;abstr #405. Rummel MJ, et al. Lancet. 2013;381:1203-1210.First-line Bendamustine/Rituximab (BR) vs R-CHOP in Indolent NHL Slide78

Figure from: Rummel MJ, et al. Lancet. 2013;381:1203-1210

First-line Bendamustine/Rituximab (BR) vs R-CHOP—PFS

Follicular Lymphoma

Mantle-cell Lymphoma

Marginal-zone Lymphoma

Waldenstrom's MacroglobulinaemiaSlide79

BR (n=261)

R-CHOP (n=253)

ORR

93%

91%

CR

40%

30% (

P

=.021)

Time to Next Treatment

(median)

NR

42.3 mos (P<.0001)

Deaths

4345Median OSNRNRMedian PFS69.5 mos31.2 mos (P<.0001)Infections96127 (P =.019)Rummel MJ, et al. Lancet. 2013;381:1203-1210.First-line Bendamustine/Rituximab (BR) vs R-CHOP—All SubtypesSlide80

Grade 3/4

Hematological Toxicities

Number of Patients

(%)

BR

R-CHOP

Leukocytopenia

98 (37%)*

181 (72%)*

Neutropenia

77 (29%)*

173 (69%)*

Lymphocytopenia

196 (74%)

106 (43%)

Anemia8 (3%)12 (5%)Thrombocytopenia13 (5%)16 (6%)G-CSF Administered4%20%Rummel MJ, et al. Lancet. 2013;381:1203-1210.First-line Bendamustine/Rituximab (BR) vs R-CHOP—All SubtypesP<.0001 between groupsSlide81

Non-hematological Toxcities

Number of Patients (%)

P

value

BR

n = 260

R-CHOP

n = 253

Alopecia

0

245 (100%)

<.0001

Paresthesia

18(7%)

73 (29%)

<.0001Stomatitis16 (6%)47 (19%)<.0001Sepsis1 (<1%)8 (3%).019Infectious Complications (All Grades)96 (37%)127 (50%).0025Skin (Erythema, All Grades)42 (16%)23 (9%)0.24Allergic Skin Reactions (All Grades)40 (15%)15 (6%).0006Patients in the BR group had fewer toxic effects than did those in the R-CHOP group, with serious adverse events occurring in 49 (19%) and 74 (29%) of patients (all subtypes)Rummel MJ, et al. Lancet. 2013;381:1203-1210.First-line Bendamustine/Rituximab (BR) vs R-CHOP—All SubtypesSlide82

CaveatsBR is as good as R-CHOP

No survival difference yet

In the pre-maintenance era

In the pre-FIT era

Rummel MJ, et al.

Lancet

. 2013;381:1203-1210.

First-line Bendamustine/Rituximab (BR) vs R-CHOP for Treatment

of Indolent NHL Slide83

The BRIGHT Study—First-line BR vs R-CHOP or R-CVP for Treatment of Indolent NHL or MCL

Randomized, noninferiority, global, phase III study

Treatment naïve patients with indolent NHL or MCL

BR vs R-CHOP or R-CVP

Six cycles (2 more at investigator discretion)

BR: n= 224

R-CHOP/R-CVP: n= 223

Flinn I, et al.

Blood

. 2014;123:2944-2952.Slide84

The BRIGHT Study—Response Rates

Conclusion: BR is not inferior to standard

Flinn I, et al.

Blood

. 2014;123:2944-2952.

BR

R-CHOP/R-CVP

P

value

Complete

Response

Rate

31%

25%P = .02Partial Response65%66%NA Stable Disease3%9%NA

Progressive Disease<1%<1%NA

Unknown0 <1NAOverall Response Rate97%91%P =.01Slide85

IRC = independent review committee

IRC Assessment of Response by Histology

Complete

Response

Complete

Response + Partial Response

BR

n/N (%)

R-CHOP/R-CVP

n/N (%)

BR

n/N (%)

R-CHOP/R-CVP

n/N (%)

Indolent

NHL49/178 (28)43/174 (25)173/178 (97)160/174 (92)Follicular Lymphoma45/148 (30)37/149 (25)147/148 (>99)140/149 (94)Marginal-zone Lymphoma5/25 (20)4/17 (24)23/25 (92)12/17 (71)Lymphoplasmacytic Lymphoma 0/51/6 (17)3/5 (60)6/6 (100)Mantle-cell Lymphoma17/34 (50)9/33 (27)32/34 (94)28/33 (85)The BRIGHT Study—Response Rates by HistologyConclusion: BR is not inferior to standardFlinn I, et al. Blood. 2014;123:2944-2952.Slide86

The BRIGHT Study—Grade ≥3 Adverse Events Flinn I, et al.

Blood. 2014;123:2944-2952.

Grade

≥3 AEs (occurring in ≥3% of patients), n (%)

Preselected

for R-CHOP

Preselected

for R-CVP

(n=116 )

BR

(n

=103)

R-CHOP

(n=98)BR (n=118 )HematologicWhite blood cell count33 (32)71 (72) a51 (43)44 (38)Absolute neutrophil count40 (39)85 (87) a58 (49)65 (56)Lymphocyte count63 (61)32 (33) a74 (63)32 (28)aHemoglobin03 (3)6 (5)6 (5)Platelet count10 (1)12 (12)6 (5)2 (2)Non-hematologicNausea3 (3)01 (<1)0Vomiting5 (5)02 (2)0Abdominal pain2 (2)3 (3)03 (3)Drug hypersensitivity3 (3)02 (2)0Fatigue4 (4)2 (2)4 (3)1 (<1)Pneumonia2 (2)05 (4)1 (<1)Infusion-related reaction6 (6)4 (4)7 (6)4 (3)

Infection12 (12)5 (5)8 (7)8 (7)Hyperglycemia02 (2)1 (<1)5 (4)Back pain01 (1)04 (3)Syncope1 (<1)003 (3)Dyspnea2 (2)2 (2)3 (3)1 (<1)aP<.0001Slide87

RELEVANCE Study (NCT01650701)—R

2 vs R-CHOP or R-CVP or R-Bendamustine

87

Primary endpoint:

CR/CRu rate at 120 weeks defined by IWG Response Criteria (Cheson 1999), PFS

Secondary end points:

TTTF,EFS,TTNLT, TTNCT, OS, ORR, safety, QoL

ELIGIBILITY

Previously untreated histologically confirmed FL grades 1, 2, and 3a

At least one mass lesion > 2 cm

Stage II, III or IV disease

≥ 18 years of age

ECOG PS ≤ 2

Adequate hematological function

R

2 (Rituximab +Lenalidomide)R- CHOP, or R - CVP, or R- BendamustineRandomizeAfter 8 weeks, responding patients continue rituximab every 8 weeks for 12 cycles Enrollment completed, but no results are availableSlide88

ECOG 2408Enrollment completed, but no results are available

ELIGIBILITY

High-risk FL

(FLIPI 1 score 3-5

or GELF high

tumor burden)

Stratification according to FLIPI1 and GELF

Randomize

BR

(Bendamustine, Rituximab) x 6 cycles

BVR

(Bortezomib, Rituximab, Bendamustine) x 6 cycles

BR

(Bendamustine, Rituximab) x 6 cycles

Registration

RituximabRituximabLenalidomide +RituximabINDUCTIONCONTINUATIONSlide89

CURRENT PATIENT MANAGEMENT PRACTICES IN FL: MAINTENANCESlide90

GELA PRIMA Phase III Study—Rituximab Maintenance in FL

CHOP x 6 +

Rituximab x 8

(74%)

CVP x 8 +

Rituximab x 8

(23%)

FCM x 6 +

Rituximab x 8

(4%)

ELIGIBILITY

Patients with previously untreated grade I–III FL

n = 1,200

CR/CRu, PR

RANDOMIZEDMaintenance Rituximab 375 mg/m2 q2mos x 2 yrsObservationSalles GA, et al. Lancet. 2011;377:42-51.1,217 patients in 223 centers, 25 countries43% FLIPI 3-5Median age 56 y90% stage III-IVSlide91

PRIMA—Rituximab Maintenance for FLEvent-free Survival

The risk of progression was significantly reduced for the rituximab maintenance group (HR 0.55, 95% CI: 0.44–0.68)

Figure from:

Salles GA, et al.

Lancet

. 2011;377:42-51.

Rituximab maintenance 74.9%

Observation 57.1%Slide92

Treatment

PFS*

%CR @

2 yrs

%OS @

2 yrs

Rituximab

75%

(130 Prog)

72

>95%

Observation

58%

(218 Prog)52

>95%

92* Median follow-up 3 yearsSalles GA, et al. Lancet. 2011;377:42-51.PRIMA—Rituximab Maintenance for FLSurvivalSlide93

Figure from: Salles GA, et al. Lancet

. 2011;377:42-51.

PRIMA—Rituximab Maintenance for FLSlide94

94

Salles GA, et al. Lancet

. 2011;377:42-51.

PRIMA—Maintenance for FL

Grade ≥ 3 Adverse Events (>2%)

Observation

n = 508

n

(%)

Rituximab

Maintenance n = 501

n (%)

All

Adverse Events84 (17%)121 (24%)Neoplasia17 (3%)20 (4%)Neutropenia5 (1%)18 (4%)Febrile Neutropenia2 (<1%)1 (<1%)

Infections5 (1%)22 (4%)

CNS disorders13 (3%)10 (2%)Cardiac disorders5 (1%)11 (2%)Slide95

Salles G, et al

. Blood. 2013;122:509.

Updated PRIMA—6-year

Follow-up with

Rituximab

Maintenance for FL

Observation

Rituximab Maintenance

6-year PFS

42.7%

59.2%

a

Median PFS48 monthsNRaRate of Transformation24 (of 114 relapses)16 (of 80 relapses)Overall Reponse Rate 2nd-line Therapy CR/CRu

PR

79% (180/227)61%19%76% (109/144)b51%22% 6-year Overall Survival88.7%87.4%aP<. 0001, bNS There was a significant reduction in the risk of starting a new anti-lymphoma treatment or starting a new chemotherapy with rituximab maintenance.Slide96

Figure from: Salles G,

et al. Blood. 2013;122:509.

Updated PRIMA—6-year

Follow-up with

Rituximab

Maintenance for FLSlide97

The following factors predicted for a longer PFSRituximab maintenance (HR,

0.57; P

<.0001)

Older age (HR,

0.79;

P

=.015)

Female sex (HR,

0.72;

P

=.0003)

Low or intermediate FLIPI (HR; 0.67; P<.0001)Abnormal PET scanNo difference in overall survival

97

Salles G, et al. Blood. 2013;122:509.Updated PRIMA—6-year Follow-up with Rituximab Maintenance for FLSlide98

RESORT Study Design—Rituximab Extended Schedule or Re-Treatment for Low-burden FL

Rituximab

Retreatment at

Progression

a

375 mg/m

2

qw



4

(n = 143)

R

A

N

D

OMIZERituximab375 mg/m2 qw  4(n = 408)CR or PR(n = 299)RituximabMaintenancea375 mg/m2 q 3 months(n = 146)aContinue until treatment failureNo response to retreatment or PD within 6 months of RInitiation of cytotoxic therapy or inability to complete treatmentKahl, et al. J Clin Oncol.2014;56:5853Slide99

RESORT Study Design—Rituximab Extended Schedule or Re-Treatment for Low-burden FLFigures from: Kahl, et al.

J Clin Oncol.2014;56:5853

Treatment Failure-free Survival

Cytotoxic Therapy-free SurvivalSlide100

RESORT Study Design—Rituximab Extended Schedule or Re-Treatment for Low-burden FLFigures from: Kahl, et al.

J Clin Oncol.2014;56:5853

Progression-free Survival

Progression-free Survival

Assigned to RR according to first rituximab treatmentSlide101

CURRENT PATIENT MANAGEMENT PRACTICES IN FL: RELAPSED or REFRACTORY DISEASESlide102

Relapsed vs Refractory FL

Relapsed

Initial response (CR or PR)

Progress >6 months following completion of standard induction therapy

Poor-risk relapse

PET/CT scan positive post-induction

<12 months following treatment

Refractory

<PR to standard induction

CR or PR that lasts <6 months

NCCN Practice Guidelines in Oncology, v.2.2015.Slide103

20% of Patients With FL Experience Disease Progression Within 24 Months of Chemoimmunotherapy

Casulo, et al. Proc ASH 2013;Abstract 510.

Press et al (2013). SWOG S0016.

J Clin Oncol.

60

R-CHOP

100

80

60

40

20

0

2

4

30

364248

54061218Time (months)Progression-Free Survival (%)1.0Event-Free RateSalles et al (2011). PRIMA Lancet.

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).

Lancet.

BR

R-CHOP

Time (months)

0

6

12

18

24

30

36

42

48

54

60Slide104

FDA-Approved Agents (US) for Relapsed/Refractory FL

BendamustineRituximab

Idelalisib

RITSlide105

NCCN Practice Guidelines for FL—2015Additional Therapy

Initial Therapy

Stage I, II

Stage II bulky,

Stage III, IV

ISRT

ImmunoRx ± Chemo Rx ± RT

Observe (if tx not indicated)

Clinical trial

Bendamustine + Rituximab

Chemo Rx

Rituximab

Lenalidomide + Rituximab

Local RT (palliation)

Observe (if tx not indicated)

Without transformationClinical trialChemoRxRituximabLenalidomide  RituximabRITIdelalisibChemotherapy  RituximabLocal RT (palliation)Observe (if tx not indicated)Transformed to DLBCLClinical trial RITChemotherapy ± RituximabISRTChemotherapy ± Rituximab ± RTRITASCTBest supportive careNCCN Practice Guidelines in Oncology, v.2.2015.Progressive Disease or No ResponseSecond-line Consolidation or Extended Dosing (optional)Rituximab High-dose therapy with autologous stem cell rescueAllogeneic stem cell transplant (selected patients)Slide106

Recurrent FL—Many OptionsConventional strategiesNovel strategies

Rituximab ± MaintenanceChemoimmunotherapy ± MaintenanceRadioimmunotherapyExternal beam radiation

Autologous transplant

Allogeneic transplant

PI3K inhibitors

Idelalisib

Bruton's tyrosine kinase (BTK) inhibitors

Ibrutinib

Immunomodulatory drugs (IMiDs)

Lenalidomide

Antibody-drug conjugate (ADC)

ObinutuzumabBCL-2 antagonists

ABT-199

NCCN Practice Guidelines in Oncology, v.2.2015.Slide107

Indolent RelapseLow bulk

No symptomsLong TTP

No transformation

Normal LDH

Aggressive Relapse

High bulk

Symptoms

TTP <12 months

Transformed

High LDH

Salvage chemotherapy

Radioimmunotherapy

Repeat chemotherapy

New chemotherapy

Rituximab ± maintenance

Auto SCTInadequate response or RelapseAllo SCTRelapsed FLSlide108

Relapsed FL—Questions Worth Asking

Evidence for transformation?

Yes…consider transplant; especially if early transformation

Last treatment? Did I already give doxorubicin?

Length of previous remission helps choose Rx

Pace of the disease

Compare CT scans or your exam

Age and co-morbidities of the patient

Symptoms? Bulk? Organ compromise?

Transplant candidate?

Young, short TTP on an anthracycline-based regimen - consider SCTSlide109

Friedberg JW, et al. J Clin Oncol. 2008;26:204-210.

Bendamustine for Rituximab-Refractory iNHL

Primary end point

: ORR

Secondary end points:

Safety, PFS, and duration of response

ELIGIBILITY:

N=76 patients

WHO performance status ≤ 2

Indolent (80%) or transformed (20%) NHL

Refractory/intolerant to prior rituximab

≤ 3 unique chemotherapy regimens

Bendamustine

Days 1 and 2 of each 21-day cycle(up to 12 cycles)Median of 2 prior regimens (range, 1-5)Median 5 cycles (range, 1-9)Slide110

Friedberg JW, et al. J Clin Oncol. 2008;26:204-210.

Bendamustine for Rituximab-Refractory iNHL

All patients

(n = 74)

FL

(n = 45)

SLL

(n = 11)

LPL

(n = 1)

MZL

(n =

2)

Transformed (n = 15)CR/CRu34%37%36%100%50%13%PR43%44%27%0%50%53%SD4%

4%0%0%0%7%

PD17%11%36%0%0%27%Slide111

Bendamustine for Rituximab-Refractory iNHL

82% ORR in FL

Duration of response:

9

mos

66% ORR in transformed

2 CR; 8 PR

Duration of response:

2.3 mos

Median PFS: 7.1 months (all patients)Figure from: Friedberg JW, et al.

J Clin Oncol. 2008;26:204-210. Slide112

Bendamustine Monotherapy for Rituximab-Refractory iNHLSingle-arm, multicenter trial in patients with rituximab-refractory indolent NHLMedian age, 60 years; 76% with advanced-stage disease; Follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas

Patients received a median of 2 previous regimens (range, 0-6 previous regimens), and 36%were refractory to their most recent chemotherapy regimenKahl BS, et al.

Cancer

2010; 116:106-14.

ELIGIBILITY

N= 100

18 years of age

WHO PS 2

At least one lesion measuring 2 cm

1 to 3 previous chemotherapies

Bendamustine:

days 1 and 2, q21 days x 6-8 cycles

Primary endpoints:

ORR, duration of response (DOR)Secondary endpoints: Safety, PFSSlide113

Response rates did not significantly differ by histologyMedian PFS: 9.3 months Median DOR: 9.2 months

Kahl BS, et al.

Cancer

2010; 116:106-14.

Bendamustine Monotherapy

for Rituximab-Refractory iNHL

All patients

(n = 100)

FL

(n = 62)

SLL

(n = 21)

LPL

(n = 1)Lymph Node Marginal Zone (n = 9)Extralymph Node Marginal Zone(n = 7)ORR75%74%71%100%78%

86CR34%15%

5%0%11%43CRu5%00%0%0PR43%55%67%100%67%43SD4%15%19%0%22%14PD17%10%5%0%0%0Slide114

Grade 3/4a reversible hematologic toxicities includedNeutropenia (61%), thrombocytopenia (25%), and anemia (10%)The most frequent nonhematologic adverse events (any grade) included Nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).

Kahl BS, et al. Cancer 2010; 116:106-14. Bendamustine Monotherapy

for Rituximab-Refractory iNHL

a

Determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]Slide115

WHERE DOES RIT FIT INTO CURRENT TREATMENT PARADIGMS?Slide116

Radiolabeled Monoclonal Antibodies for Radioimmunotherapy (RIT)Proliferating tumor cells are inherently sensitive to radiationContinuous rather than intermittent RTCrossfire effect—kill tumor cells a few mm from the bound antibody & antigen-negative tumor cellsSlide117

Crossfire Enhances Efficacy

Unlabeled “Cold” Antibody

Radiolabeled Antibody

Courtesy of Andrew D. Zelenetz, MD, PhD.Slide118

Radiolabeled Monoclonal Antibodies

Monoclonal antibody

Bond or Chelator

Radionuclide



RadiationSlide119

RIT Historical

Timeline1985

1990

1995

2000

2005

2010

Trials of RIT begin

Phase I/II trial of I-131 tositumomab begins at Michigan

Phase I/II trial of Y-90 ibritumomab begins

FDA approvals of both agents in 2002 & 2003

First reports of frontline RIT

Randomized trial of RIT consolidation reported

Frontline trial of

131

I tositumomab begins (1996)Chemo + RIT in frontline begins (2000)Durable remissions from all previous studies continueCourtesy of Mark S. Kaminski, MD.Slide120

Regulatory Status of Anti-CD20 RIT

RIT Agent

FDA Approval

Indication

Y-90 ibritumomab tiuxetan

[1]

2002

Relapsed/refractory, low-grade or follicular NHL

2009

Previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy

I-131 tositumomab

[2]

2003*

Patients with CD20 antigen-expressing relapsed/refractory, low-grade, follicular, or transformed NHL, including rituximab-refractory*Not available as of February 2014[1] ZEVALIN® (ibritumomab tiuxetan) [prescribing information]. Irvine, CA: Spectrum Pharmaceuticals, Inc.; revised 2013.[2] BEXXAR (tositumomab and iodineI 131 tositumomab) [prescribing information]. Wilmington, DE: GlaxoSmithKline; revised 2013.Slide121

I-131 Tositumomab & Y-90 Ibritumomab Tiuxetan

I-131 Tositumomab

Y-90 Ibritumomab

T

iuxetan

Mouse anti CD20

Mouse anti CD20

Direct iodination of tyrosine amino acids on the antibody, subject to dehalogenation

Indirect linkage via tiuxetan linker chelated to

90

Y and covalently linked to lysine and arginine amino acids

 &

1 mm

 emission5 mm  emission length8.0 day half life2.7 day half-lifeThyroid uptake of free 131I

──

50%-90% of 131I cleared in urine within 48 hour 5%-10% of 90Y-chelate cleared in urine, some through bowelScans needed to determine residence time and rate of clearance No scans neededSlide122

Clinical Criteria for RIT in Lymphoma

Relapsed low-grade, follicular, and/or transformed low grade B-cell lymphomaY-90 ibritumomab tiuxetan is also approved for

p

reviously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy

Normocellular marrow (30%-70%)

Bone marrow involvement

<

25%

ANC >1500/mm

3

Platelet count

:

150,000/mm

3 (lower dose if 100k-149k)No prior radioimmunotherapy (preferred)No prior stem cell transplant (preferred)Slide123

90Yttrium-Ibritumomab-Tiuxetan(90YIT)—

First-Line Treatment for FL

International Multicenter Phase II Clinical Trial

Scholz, et al.

J Clin Oncol

2013; 31(3): 308-313

ELIGIBILITY

N = 59

Untreated

Histologically confirmed CD20+ FL grade 1 to 3a requiring therapy

At least one of the following: “B” symptoms, tumor progression >50% in 6 months, organ compression by tumor, bulky disease, or grade 3a FL

Day 1: Rituximab

Day 8-9: Rituximab and 90YIT

CR, CRu, without evidence of MRD 6 months after

90

YIT: observed without further interventionPatients with CR but with persisting MRD: consolidation treatment with rituximabPrimary end point:Clinical and molecular response rateSecondary end points: Time to progression, safety, and tolerabilitySlide124

90Yttrium-Ibritumomab-Tiuxetan(90YIT)

— First-Line Treatment for FL

Scholz, et al.

J Clin Oncol

2013; 31(3): 308-313

Response

n (%)

CR

24 (41%)

CRu

9 (15%)

PR

18 (31%)

SD

2 (3%)

PD6 (10%)Deaths0Off Study0Response at 6 Months After Therapy With 90YITSlide125

90

Yttrium-Ibritumomab-Tiuxetan

(

90

YIT)

— First-Line Treatment for FL

Scholz, et al.

J Clin Oncol

2013; 31(3): 308-313

CR/CRu

PR

PFS According to Response

After a median follow-up of 30.6 months:

Median PFS for all patients was 25.9 months

Median OS has not been reached

Median time to next treatment has not been reachedSlide126

90Yttrium-Ibritumomab-Tiuxetan(90YIT)

— First-Line Treatment for FL

a

There were no Grade 3 or 4 nonhematologic AEs

Scholz, et al.

J Clin Oncol

.2013; 31(3): 308-313.

Hematologic

AEs

Grade 3

n (%)

Grade 4

n

(%)

Thrombocytopenia

24 (41%)4 (7%)Leukopenia19 (32%)1 (2%)Neutropenia9 (15%)10 (17%)Lymphopenia12 (20%)0 (0%)Anemia0 (0%)1 (2%)Nonhematologic AEsGrade 2n (%)Infections12 (20%)Gastrointestinal6 (10%)Cardiovascular 3 (5%)Vegetative3 (5%)Skin irritation 2 (3%)Mucositis1 (2%)Other10 (17%)Slide127

Ibatici, et al. Br J Haematol. 2014; 164;710-716.

90

Yttrium-Ibritumomab-Tiuxetan

(

90

YIT)

— First-Line Treatment for FL

Multicenter study aimed to evaluate the safety and the efficacy of “upfront” single-agent

90

YIT

in advanced-stage FL

50 patients with stage II “bulky”, III or IV FL

Primary endpoint

: CR, PRELIGIBILITYPreviously untreated adults (age >18 years) with stage II bulky (node >5 cm), III or IV, CD20+, grade 1 or 2, FL WHO performance status 0-2Day 1: Rituximab Day 8-9: Rituximab and 90YIT Slide128

Ibatici, et al. Br J Haematol. 2014; 164;710-716.

90

Yttrium-Ibritumomab-Tiuxetan

(

90

YIT)

— First-Line Treatment for FL

20/24 patients with pre-treatment bone marrow involvement achieved renormalization

16/47 patients (34%) who had achieved CR or PR had relapse or progression; no histological transformation

MRD-negativity had a significant favorable prognostic value on PFS

80% (BCL2/IGH-negative) vs

46% for (BCL2/IGH positive)

Response

n (%)ORR47 (94%)CR43 (86%)PR4PD1PFS (median)NRa3-year estimated PFS

63.4%a

OS (median)NRa3-year estimated OS90%aa At a median follow-up of 38·8 monthsSlide129

Figures from: Ibatici, et al. Br J Haematol. 2014; 164;710-716.

90

Yttrium-Ibritumomab-Tiuxetan

(

90

YIT)

— First-Line Treatment for FLSlide130

No grade 3/4 non-hematological toxicitiesGrade 3/4 neutropenia (30%) and thrombocytopenia (26%)No neutropenic fever or bleedingMyeloid growth factors were given to patients wit grade 4 neutropeniaGrade 3/4 myelosuppression improved to ≤1 by week 14No cases of secondary hematological malignancies

Ibatici, et al

. Br J Haematol

. 2014; 164;710-716.

90

Yttrium-Ibritumomab-Tiuxetan

(

90

YIT)

— First-Line Treatment for FLSlide131

FIRST-LINE CHEMOTHERAPY

CHOP/CHOP-like

CVP/COP

Rituximab combinations

Chlorambucil

Fludarabine combinations

NR

PD

CR/CRu or PR

Not Included

Enrollment in Study

Morschhauser et al.

J Clin Oncol.

2008;26.5156-5164.

CONTROL

(n=206)No Further Treatment First-Line Indolent Trial (FIT)—Adjuvant 90YIT After Chemotherapy for Advanced FLRANDOMIZATION90YIT (n=208) Day 1: Rituximab Indium-111 ibritumomab tiuxetanDay 7: Rituximab 90YIT 0.4 mCi/kgSlide132

First-Line Indolent Trial (FIT)—Overall CR Rates After Randomization

Morschhauser et al.

J Clin Oncol.

2008;26.5156-5164.

CR/CRu

Control, %

(n = 202)

90

Y-Ibritumomab, %

(n = 207)

After induction therapy

53

52

After randomization5387Slide133

Figure from: Morschhauser F, et al. J Clin Oncol . 2008;26:5156-5164.

First-Line Indolent Trial (FIT)— All Randomized PatientsSlide134

Figure from: Morschhauser F, et al. J Clin Oncol . 2008;26:5156-5164.

First-Line Indolent Trial (FIT)—Patients with Partial RemissionSlide135

Figure from: Morschhauser F, et al. J Clin Oncol . 2008;26:5156-5164.

First-Line Indolent Trial (FIT)—Patients with C

omplete RemissionSlide136

0

25

50

75

100

0

12

24

36

48

60

Cumulative Percentage90Y-ibritumomab: n = 207 Median TTNT: > 99 mo Control: n = 202 Median TTNT: 35 mo90Y-ibritumomab

Control

206

202

82

122

N

F

TTNT From Time of Randomization (months)

Morschhauser F, et al.

J Clin Oncol

. 2008;26:5156-5164.

First-Line Indolent Trial (FIT)—More than

5-year Advantage in TTNT with

90

YIT

TTNT=Time to next treatmentSlide137

90Yttrium-Ibritumomab-Tiuxetan(90YIT)— Randomized Phase III Study in Relapsed or Refractory Low Grade or Follicular NHL

Witzig, TE

et al.

J Clin Oncol

. May 2002;20:2453-2463.

ELIGIBILITY

Relapsed or refractory low-grade or follicular B-cell NHL

No prior rituximab therapy

Histologically confirmed NHL requiring therapy

WHO PS ≤2

<25% bone marrow involvement by NHL

No prior BMT

Acceptable hematologic function

90

YIT (n=64) Day 1: Rituximab Indium-111 ibritumomab tiuxetanDay 8: Rituximab 250mg/m2 90YIT 0.4 mCi/kgRituximab (n=66) Weeks 1-4: Rituximab 375 mg/m2N=130RANDOMIZATIONSlide138

[1] ZEVALIN

®

(ibritumomab tiuxetan) Package Insert, 2009. [2] Witzig, TE

et al.

J Clin Oncol

. May 2002;20:2453-2463.

90

YIT

—

Relapsed or Refractory Low-Grade or Follicular NHL

90

YIT (n=64)

Rituximab

(n=66)P value*Overall RR[1]83%55%<0.001CR/CRu rate[1]38%18%N/ADuration of Response (median) [2]14.2 months12.1 monthsP = .6Time to Progression[2]11.2 months10.1 monthsP = .173Durable Responses ≥ 6 months [2]64%47%P = .030Reversible myelosuppression was the primary toxicity noted with 90Y ibritumomab tiuxetan.Slide139

Efficacy of 90YIT in Patients with

Relapsed/Refractory CD20+ B-cell NHL

Reference

n

Patient Characteristics

Median Number of Prior Therapies

Response Rate

ORR CR

Disease Control

Median Duration of Response

Witzig TE, et al. J Clin Oncol 1999;17:3793-803

51

R/R low-grade or follicular NHL or intermediate-grade or mantle-cell NHL

2

67% 26%

Median TTP 12.9+ months11.7+ monthsWitzig TE, et al. J Clin Oncol 2002;20:2453-63143R/R low-grade, follicular, or transformed NHL280% CR 30%; CRu 4%Median TTP11.2 months14.2 monthsWiseman GA, et al. Blood 2002;99:4336-4230R/R low-grade, follicular, or transformed CD20+ NHL and mild thrombocytopenia283% CR: 37%; CRu: 6.7%Median TTP9.4 months (12.6 months in responders)11.7 monthsWitzig, et al. J Clin Oncol 2002;20:3262-954Rituximab-refractory follicular B-cell NHL474% 15%Median TTP6.8 months (8.7 months in responders)6.4 monthsGordon LI, et al. Blood 2004;103:4429-3151R/R low-grade or follicular B-cell NHL273% CR: 29%; CRu: 22%Median TTP9.3 months (12.6 months in responders)11.7 monthsWitzig TE, et al. Leukemia Lymphoma. 2011;52:1188-99.Slide140

I-131 Tositumomab and Y-90 Ibritumomab Tiuxetan Are Active in Patients with FL Who Are Refractory to RituximabY-90 ibritumomab tiuxetan[1]

54 patientsMedian age 54 y4 prior chemo med

44% >7cm bulk

32% BM involved

74% response rate

15% CR

6.4 mos median duration of response

7.2 mos CR duration

I-131 tositumomab

[2]

40 patients (35 fit criteria)

Median age 57 y

4 prior chemo median28% >7cm bulk32% BM involved68% response rate30% CR 14.7 mos median duration of response>2 yrs CR duration[1] Witzig TE, et al. J Clin Oncol. 2002;20:3262-3269. [2] Horning SJ, et al. J Clin Oncol 2005;23:712-719.Slide141

I-131 Tositumomab

—PFS Across Multiple Studies

Fisher RI, et al.

J Clin Oncol.

2005;23:7565-7573.Slide142

90YIT—PFS

Zevalin Package Insert. Spectrum Pharmaceuticals, Inc. 2011.

HR = 0.46 [95% CI: 0.35,0.60];

P

<0.0001Slide143

Earlier Is Better—Higher Responses with Y-90 Ibritumomab Tiuxetan if Fewer Prior Chemotherapy Regimens

1 prior

(n=63)

≥2

(n=148)

Complete Responders (%)

CR Patients

Number of prior chemotherapy regimens

P

<0.01

Emmanouilides C,

et al.

Leuk Lymphoma.

2006;47:629-36.

Number of prior regimensTime to progression112.6 mos≥27.9 mosP value<0.05Slide144

I-131 Tositumomab—Efficacy by Treatment Encounter

I-131 Tositumomab Use by Treatment Sequence

1

st

Line

(n=141)

2

nd

Line

(n=226)

3

rd

Line (n=228)

4

th

+ Line (n=540)Response rate, % 95735846Median duration of response, moNR351612Complete response (CR), % 78463223Median duration of CR, moNRNR3559PFS >1 year, % 82 594227All differences are statistically significant (P <.001). Gregory SA, et al. Proc Am Soc Clin Oncol. 2005;24:Abstr #6561.Slide145

After RIT—Chemotherapy, Radiation Therapy, and Rituximab Can Be Effective

153/521 (29%) patients received other treatment after 90YIT

Response data for 100/153 patients

First subsequent therapy after

90

YIT:

60/100 (60%) ORR

20/25 (80%) RR to focal radiation therapy

25/49 (53%) RR to chemotherapy

15/26 (58%) RR to rituximab

Schilder RJ [abstract #1064], Saleh F [abstract #30],

ASCO 2002.Slide146

After RIT—Subsequent Chemotherapy Regimens Are Well-Tolerated

58 patients (Mayo Clinic) who had disease progression after previous treatment with 90YIT

Median of 2 prior therapies before RIT

54 CHOP, 35 CVP, 24 rituximab, 20 chlorambucil, 11 fludarabine

1-7 subsequent chemo regimens

;

8 autologous stem cell transplants (7 PBSC)

Grade IV toxicity: 25% ↓ platelets, 33%↓ ANC

1/3 required CSF &/or hospitalized for febrile neutropenia and/or bleeding

S

imilar to contemporary cohort controls without RIT

Ansell SM, et al.

J Clin Oncol.

2002;20:3885-90.Slide147

After RIT—Low Incidence of Secondary Malignancies

90

Y IT registration trials

(n = 211)

Median follow-up, (range)

3.2 years

(1.2-75.5)

MDS/AML cases, n

7

Crude incidence of MDS/AML

3.3%

Annualized incidence of MDS/AML

0.70% per year

MDS/AML with chemotherapy (no high-dose therapy) Cumulative incidence

4% to 8% Annualized incidence

1% to 1.5%Bennett JM, et al. Blood. 2005;105:4576-82; Emmanoulides C, et al. Proc Am Soc Clin Oncol. 2004;23: Abstr #6696; Pedersen-Bjergaard, et al. Ann Intern Med. 1985;103:195-200; Greene MH, et al. Cancer Res. 1983;43:1891-8; Kantarjian HM, et al. Semin Oncol. 1987;14:435-43.Slide148

Questions

Answered questionsR-chemo is the standard for patients needing chemotherapy

BR as good or better than R-CHOP without OS benefit

Rituximab maintenance x 2 years as consolidation (per PRIMA) or RIT (per FIT) are FDA approved options but do not impact survival

Unanswered questions

Is R

2

maintenance better than R? – E2408

Can upfront RIT “cure” some patients? LS138DSlide149

NOVEL APPLICATIONS OF EXISTING TREATMENTS AND EMERGING TREATMENT APPROACHES FOR FLSlide150

Goals of Novel TherapiesHarness increasing understanding of biology and technology to improve lymphoma therapyDevelop “targeted” treatments selective for lymphoma cells and less toxic to healthy cellsRecruit the body’s immune system to fight lymphomaHelp improve the effects of existing treatments in combinationDecrease reliance on traditional chemotherapies

Induce longer remissions, and ultimately cure, with fewer side effectsSlide151

Emerging Agents and New Applications of Treatments for FLTherapeutic VaccinationAutologous tumor IdiotypeChemotherapy

BendamustineImmunomodulatory DrugsIMiDs: lenalidomide

B Cell Receptor Kinase Inhibitors

BTK:

PCI-32765 / Ibrutinib

PI3k

δ

:

CAL-101 / GS-1101

Monoclonal Antibody Derivatives

Bi-specific T-cell engagers (BiTEs):

blinatumomab CAR T Cells

CART19 T CellsSlide152

New Protocols

IdelalisibIbrutinib

Lenalidomide (BRR)

Anti-PD1

Venetoclax (ABT-199)Slide153

New Targeted AgentsAgent

TargetDaratumumab

CD38

Polatuzumab

vedotin

CD79b

Ibrutinib

Btk

ACP-196

Btk

GS-9973

Syk

Idelalisib

PI3-KGS9901PI3-KIPI-145PI3-KNivolumabPD-1PembrolizumabPD-1PidilizumabPD-1

ABT-199Bcl-2Selinexor

XP01 (Nuclear transport)Slide154

sIg

sIg

CD20

CD19

Ag

CD79A

CD79B

PI3K

δ

SYK

BTK

DNA

Therapeutic Vaccination

Chemotherapy

B Cell Receptor Kinase Inhibitors

CAR T Cells

BiTEs

Slide courtesy of Dr.

Schuster

B Cell or B-Cell Lymphoma Slide155

Targets of B-cell Receptor SignalingSlide156

NOVEL APPLICATIONS OF EXISTING TREATMENTS AND EMERGING TREATMENT APPROACHES FOR FL

mTOR InhibitorsSlide157

mTOR Inhibitors - the “Rapalogues”

R

Rapamycin

,

R

=

OH

Everolimus

,

R =

Temsirolimus, R =

O

OH

O

OOHOHPotent antiangiogenic and antiproliferativeSlide158

PI3K/Akt/mTOR Signaling PathwaySlide159

Response to Single Agent Everolimus

Witzig

,

et al.

Haematologia

. 2009;94 Supplement 2:436; abstract 1081Slide160

HDAC inhibitor + mTORC1 inhibitor

LBH589 – pan HDACiEverolimus – mTORC1 inhibitor

Combination synergistic

Gupta, et al.

Blood.

2009

30 patients have been treated.

SLL (n=1), FL (n=2), MCL(n=3), HL (n=12), DLBCL (n=7), T-cell (n=3), 2 discordant

DLT thrombocytopenia

LBH 20 tiw; Everolimus 10 mg qd for phase II

50% ORR

160

Younes A, et al ASH Annual Meeting Abstracts. 2011;118(21):3718Slide161

NOVEL APPLICATIONS OF EXISTING TREATMENTS AND EMERGING TREATMENT APPROACHES FOR FL

LenalidomideSlide162

Tumor Cells

Tumor Stroma

Dendritic

Cells

IL-6

TNF



IL-1a

IL-2

IFN



CD8+ T Cells

Blood Vessels

ICAM-1

VEGF

bFGF

NK Cells

PKC

NFAT

PI3K

IL-2

CD28

Chang.

Cancer Control

.

2005;12:91; Drach.

Expert Rev Cancer

2005;5:477.

Cereblon

Lenalidomide—Multiple Potential MechanismsSlide163

Figure from: Chanan-Khan AA, Cheson BD.

J Clin Oncol. 2008;25:1544-1552.

Effects of LenalidomideSlide164

Single-agent Lenalidomide25mg on Days 1-21 q 28 days

Relapsed indolent NHL[1]

All patients (N = 43) ORR 23%

FL

(grade 1 or 2; n = 22): ORR 27%

R

elapsed aggressive NHL

[2]

All patients (N = 49): ORR 35%

FL (grade 3; n = 5): ORR 60%

R

elapsed aggressive NHL

[3]

All patients (N = 217): ORR 35%FL (grade 3; n = 19): ORR 42%[1] Witzig, et al. J Clin Oncol. 2009;27:5404-5409. [2] Wiernik, et al. J Clin Oncol. 2008;26:4952-4957. [3] Witzig, et al. Ann Oncol. 2011;22:1622-1627. Slide165

Lenalidomide Monotherapy in R/R Indolent NHL

Witzig, et al.

J Clin Oncol

2009;27:5404-5409.Slide166

Lenalidomide Monotherapy in R/RAggressive NHLWitzig, et al. Ann Oncol.

2011;22:1622-1627.

PFS

Response Duration

FL

FLSlide167

Lenalidomide & Rituximab (R2)Not FDA approved in combination but both agents commercially available?SynergyLenalidomide restores T-cell synapse dysfunction[1]Lenalidomide enhances NK cell function (improves ADCC) [2,3]

Impressive data inR/R mantle-cell lymphoma (MCL), ORR 57% [4]R/R chronic lymphocytic leukemia (CLL), ORR 66% [5] Front-line FL, ORR 90% [6]

ADCC, antibody-dependent cellular cytotoxicity; NK, natural killer

[1] Ramsay AG, et al.

Blood

. 2009;114:4713-4720. [2] Reddy N, et al.

Br J Haematol

. 2008;140:36-45

. [

3] Wu L, et al.

Clin Cancer Res

. 2008;14:4650-4657.

[4]

Wang M, et al.

Lancet Oncol

. 2012;13:716-723. [5] Badoux XC, et al. J Clin Oncol. 2013;31:584-591. [6] Fowler N, et al. Blood. 2012;120: Abstract 901.Slide168

SAKK 35/10 Study—First-line Rituximab (R) vs Rituximide/Lenalidomade (R2) for Treatment of FLPhase II study of frontline R vs. R2

in FL grades 1, 2, and 3a and requiring systemic therapy Study goal: 20% increase for R2 over R with 90% power and type I error (α) of 0.10

Primary endpoint:

Complete response rate (CR/uCR) at week 23

Secondary end points:

ORR, DOR, PFS, OS, and safety

ELIGIBILITY

(N=154)

Previously untreated FL

Histologically confirmed FL grades 1, 2, and 3A

In need of systemic therapy

R

2

(n=77)

Rituximab +

LenalidomideRituximab (n=77)aTreatment discontinued Week 10 if <25% reduction in sum of product of tumor diameters..RandomizeKimby E et al. Proc ASH 2014;Abstract 799.Slide169

Week 23P=.002

SAKK 35/10—First-line R2 vs. R in FL Overall Response Rate

Week 10

P

<.0001

45%

75%

61%

81%

Kimby E et al.

Proc ASH

2014;Abstract 799.Slide170

SAKK 35/10—First-line R2 vs R in FLSafety

Treatment was discontinued by 21 patients (28%) in arm R (16 due to lack of response at Week 10 and in 1 due to toxicity), and by 19 patients (25%) in arm R2 (3 due to lack of response at Week 10 and in 13 due to toxicity)

One death due to progression: Review of initial biopsy showed FL Grade IIIb

Kimby E et al.

Proc ASH

2014;Abstract 799.

Select adverse events (Grade 3 or 4)

R

(n = 76)

R

2

(n = 77)

Fatigue

1.3%

2.6%

Allergic reaction0%2.6%Neutropenia1.3%19.5%Thrombocytopenia0%3.9%Rash maculopapular 0%5.2%Hypertension3.9%9.1%Slide171

CALGB 50803 (Alliance)—First-line R2 for Treatment of FL Multicenter phase II trial of lenalidomide plus rituximab (R2) in patients with previously untreated FL

Martin, et al.

J Clin Oncol .

2014;32:5s (suppl; abstr 8521).

Primary endpoint:

Evaluate complete response (CR) rate based on 2007 IWG criteria

ELIGIBILITY

N=65

Previously untreated FL

Grades 1, 2, and 3a FL

Stage 3-4 or bulky stage 2 (> 7 cm), FLIPI 0-2

In need of systemic therapy

R

2

(Rituximab + Lenalidomide

)Restaging was performed on weeks 10, 24, and 52, then q4 months for 2 years, and q6 months until progression for up to 10 yearsSlide172

CALGB 50803 (Alliance)—First-line Rituximide/Lenalidomade (R2) for Treatment of FL

Median follow-up: 2.3 yearsMedian time to first response: 10 weeksMedian time to complete response: 10 weeks

92% of PET negative CRs occurred by 24 weeks

8/65 evaluable patients have progressed so far

2 stopped after 1-2 cycles due to toxicity

2 had achieved a best response of CR

No patients have died

Martin, et al.

J Clin Oncol .

2014;32:5s (suppl; abstr 8521).Slide173

CALGB 50803 (Alliance)—First-line Rituximide/Lenalidomade (R2) for Treatment of 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%)PR14 (25%)4 (25%)9 (26%)-1 (50%)

SD

2 (4%)

0 (0%)

2 (6%)

-

-

Martin, et al.

J Clin Oncol .

2014;32:5s (suppl; abstr 8521).Slide174

CALGB 50803 (Alliance)—First-line Rituximide/Lenalidomade (R2) for Treatment of FL

Martin, et al.

J Clin Oncol .

2014;32:5s (suppl; abstr 8521).

With a median follow-up of 2.3 years, the 2-year PFS is 89%

0 0.5 1.0 1.5 2.0 2.5 3.0

Years from Study Entry

Probability

1.0

0.8

0.6

0.4

0.2

0Slide175

ELIGIBILITY

Relapsed FL grade 1, 2 or 3a

≥ 1 prior rituximab-based regimens

TTP≥ 6 months

since last rituximab

Rituximab (n=90)

Lenalidomide (n=45)

Rituximab

+

Lenalidomide (n=45)

Leonard, et al

.

J Clin Oncol (Meeting Abstracts).

2012 ;30(suppl 8000). Randomized phase II study, initially designed to evaluate 3 regimens: Rituximab alone, Lenalidomide alone or the combination of rituximab and lenalidomide (R2)The R alone arm was discontinued due to slow accrualRANDOMIZATIONCALGB 50401—Lenalidomide vs R2 in Patients with Recurrent FLSlide176

CALGB 50401—Lenalidomide vs R2 in Patients with Recurrent FL

Leonard, et al

.

ASCO 2012; Abstract 8000.

Response

Lenalidomide

(n=45)

R

2

(n=44)

OR

51%

73%

CR

13%36%Median EFS1.17 yrs1.96 yrs2 year EFS27%44%Median f/u 1.7 years (0.1 – 4.1)Slide177

Grade 3/4 Adverse Events, %

Lenalidomide (n=45)

R

2

(n=44)

Anemia

0

0

Neutropenia

16

19

Thrombocytopenia

0

10

Fatigue

914Rash48Infection40Thrombosis164Leonard, et al. ASCO 2012; Abstract 8000.CALGB 50401—Lenalidomide vs R2 in Patients with Recurrent FLSlide178

Lenalidomide/Rituximab (R2) for Treatment of Indolent Lymphoma

178

Fowler, et al.

Lancet Oncol

. 2014;15:1311-1318.

Primary endpoint:

ORR according to the International Working Group Criteria for NHL

ELIGIBILITY

Previously untreated N = 110 (

FL n = 50; MZ n = 30; SLL n = 30)

Stage III or IV FL, MZL (nodal or extranodal), SLL

Age ≥ 18 years

ECOG PS<2

Absolute neutrophil count ≥ 1·5 × 109/L, platelet count ≥ 100 × 109/L, and adequate organ function

R

2 (Rituximab + Lenalidomide)Response was determined by CT scans, and bone marrow biopsy when indicated to confirm CR PET-CT scans were conducted pre- and post-treatment in FL patientsMolecular response in FL was evaluated in bone marrow and/or peripheral blood samples by quantitative real-time PCR to detect t(14;18) IGH-BCL2 fusion DNA sequencesSlide179

179Adapted from Fowler, et al. Lancet Oncol

. 2014;15:1311-1318R2

for Treatment of Indolent Lymphoma

FL

(n = 46)

MZL

(n = 27)

SLL

(n = 30)

All Evaluable Patients

(n = 103)

Overall Response (n,%)

45 (98%)24 (89%)24 (80%)93 (90%)Complete Response (n,%)40 (87%)18 (67%)7 (23%)65 (63%)Partial Response (n,%)

5 (11%)6 (22%)17 (57%)28 (27%)

3-year PFS78.5%87.0%61.6%75.3%Median PFSNR53.8 months40.4 months53.8 months3-year Overall Survival94%100%96%96%Slide180

R2 for Treatment of Indolent Lymphoma—OS Adapted from Fowler, et al.

Lancet Oncol. 2014;15:1311-1318

0

6

12

18

24

30

36

42

48

54

60

0

20

406080100Overall Survival, %Follicular lymphomaMarginal zone lymphomaSmall lymphocytic lymphomaP = .6098503030Number at risk: FLMZLSLL48302948292948262845242740202130151420981382451110Slide181

R2 for Treatment of Indolent Lymphoma—OS 181

Figure adapted from Fowler, et al.

Lancet Oncol

. 2014;15:1311-1318Slide182

182Fowler, et al. Lancet Oncol

. 2014;15:1311-1318.R2 for Treatment of Indolent Lymphoma—Hematological AEs

Hematological adverse events occurring in >% of patients

Grade

1

Grade 2

Grade 3

Grade 4

All Grades

Anemia

61 (55%)

8 (7%)

0

069 (63%)Neutropenia14 (13%)32 (29%)27 (25%)11 (10%)84 (76%)Thrombocytopenia48 (44%)4 (4%)3 (3%)1 (<1%)56 (51%)Slide183

NOVEL APPLICATIONS OF EXISTING TREATMENTS AND EMERGING TREATMENT APPROACHES FOR FL

IbrutinibSlide184

Targeting Downstream Signaling Molecules in B Cells

Figure from Hallek. Blood. 2013;122:3723-3734.Slide185

Ibrutinib—A Selective Inhibitor of BTKForms a specific bond with cysteine-481 in BTKHighly potent BTK inhibition at IC50 = 0.5 nMOrally administered with once-daily dosing resulting in 24-hr target inhibition

No cytotoxic effect on T cells or NK cellsPromotes apoptosis and inhibits migration and adhesion in CLL cells Slide186

Phase II Consortium Trial—Ibrutinib Monotherapy in R/R FL

ELIGIBILITYGrade 1, 2, 3a R/R FL ≥1 prior chemotherapy

Measurable disease

ECOG PS 0-2

Ibrutinib 560 mg/day oral, 28-day cycles

Continuous dosing until progression/intolerable toxicity

Bartlett NL, et al.

Blood.

2014;124: Abstract 800.

Baseline evaluations

−Peripheral blood, lymph node biopsy

Restaging

−CT at cycle 3, Day 1, then every 3 cycles

−PET/CT at cycle 3, Day 1

End of treatment

−Lymph node biopsy at progressionPrimary endpoint: ORRSecondary endpoints: Safety and tolerability, OS, time to response, TTF, DOR, PFSSlide187

Phase II Consortium Trial—Ibrutinib Monotherapy in R/R FL

Bartlett NL, et al.

Blood.

2014;124: Abstract 800.

PFS

OS

100

80

60

40

20

0

0

3

6

9

12

15

18

Months

Median follow-up:

10.2 months

Alive and Progression Free (%)

1-year PFS: 50.1%

(95% CI: 35.3% to 71.1%)

100

80

60

40

20

0

0

3

6

9

12

15

21

Months

Surviving (%)

18Slide188

Phase II Consortium Trial—Ibrutinib Monotherapy in R/R FL

Bartlett NL, et al.

Blood.

2014;124: Abstract 800.

60

20

-20

-60

-100

Tumor Size

(% Change in SPD From Baseline)

Complete response

Partial response

Stable disease

Progressive disease

72% of patients had reduction

in tumor volumeIndividual Patients

Max Tumor Volume ReductionSlide189

Phase II Consortium Trial—Ibrutinib Monotherapy in R/R FL

Bartlett NL, et al.

Blood.

2014;124: Abstract 800.

Single-agent ibrutinib associated with antitumor responses in R/R FL

ORR: 28%

Potential for higher ORR in rituximab-responsive disease: 42% vs 6%

1-year PFS: 50%

Patients with SD appear to be deriving clinical benefit

Ibrutinib well tolerated in patients with FL

Toxicity profile as expected for labeled indications

No clear role for PET in assessment of early response in ibrutinib-treated pts with FL

Despite correlation of

maximum standardized uptake value (

SUVmax) with PFS and response at cycle 1, Day 8Slide190

SELENE Study—Ibrutinib + BR or R-CHOP for Patients with Previously Treated FL or MZLRandomized, double-blind, placebo-controlled, multicenter, phase III study of ibrutinib combined with either BR or R-CHOP for previously treated FL or MZLFowler, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr TPS8611).

6 cycles of BR or R-CHOP (based on prior treatment) + daily oral dose of 560 mg ibrutinib continued up to progression

6 cycles of BR or R-CHOP (based on prior treatment) + placebo continued up to progression

Primary endpoint

: PFS

Secondary endpoint:

OS, CR, ORR, patient-reported lymphoma symptoms, safety

Enrollment goal:

400 patients with FL or MZL relapsed/refractory to prior chemotherapySlide191

Rituximab ± Ibrutinib for Patients With Advanced FLClinicalTrials.gov Identifier: NCT02451111This study is currently recruiting participants.

Primary endpoint: CR at 24 months determined by PET/CT scanSecondary endpoints: CR at 30 months, MRD evaluation, OR, DOR, PFS, EFS, TTNT, AEs

ELIGIBILITY

Histologically confirmed FL CD20+

Grade 1, 2, 3a

Stage III+IV; stage II not suitable for radiotherapy

All FLIPI

Requires systemic therapy

WHO performance status 0-2

Rituximab + Placebo

Rituximab + IbrutinibSlide192

NOVEL APPLICATIONS OF EXISTING TREATMENTS AND EMERGING TREATMENT APPROACHES FOR FL

IdelalisibSlide193

Targeting Downstream Signaling Molecules in B Cells

Figure from Hallek. Blood. 2013;122:3723-3734.

IdelalisibSlide194

Phase I Study—Idelalisib for Relapsed iNHLPhase I study in 64 patients with relapsed indolent iNHLPrimary dose-ranging study through 48 weeks of idelalisib treatment, with an extension study for patients who were benefiting from continued idelalisib therapyEight dose regimens of idelalisib were evaluatedIdelalisib was taken once or twice daily continuously at doses ranging from 50 to 350 mg

After 48 weeks, patients still benefitting (n = 19; 30%) enrolled into an extension studyAdverse eventsMost common grade ≥ 3: diarrhea (8%), thrombocytopenia (11%), neutropenia (23%), and serum transaminase elevations (25%)

Flinn I et al.

Blood

. 2014;123:3406-3413. Slide195

195

Relapsed Indolent Lymphoma– Idelalisib

Flinn I ,et al.

Blood

. 2014;123:3406-3413. Slide196

Flinn I ,et al. Blood

. 2014;123:3406-3413.

Relapsed Indolent Lymphoma– IdelalisibSlide197

197

Relapsed Indolent Lymphoma– Idelalisib

Flinn I et al.

Blood

. 2014;123:3406-3413.

Disease regression: 46/54 (85%)

ORR: 30/64 (47%)Slide198

DELTA (Study 101-09)—Idelalisib Monotherapy for Patients with Relapsed iNHLGopal A, et al.

N Engl J Med. 2014;370:1008-1018.Single-group, open-label, phase 2 study, at 41 sites in the United States and Europe

ELIGIBILITY

B-cell iNHL w/o histologic transformation

≥1 lymph nodes measuring ≥2.0×≥1.0 cm

≥2 prior systemic therapies iNHL

Refractory to both rituximab and an alkylating agent

Karnofsky PS ≥ 60 or ECOG 0-2

Idelalisib

150 mg twice daily, until progression or unacceptable toxicity

Primary endpoint

:

ORR

Secondary Endpoints: TTR, DOR, PFS, OSSlide199

Characteristic

N = 125

Male/female, n

(%)

80/45

(64%/36%)

Age, median years, [range]

64 [33-87]

Disease type, n (%)

FL

SLL

LPL/WM

MZL

72 (58%)

28 (22%)

10 (8%) 15 (12%)Number of prior regimens4Median, [range][2-12]Gopal A, et al. N Engl J Med. 2014;370:1008-1018.DELTA (Study 101-09)—Idelalisib MonotherapyBaseline CharacteristicsSlide200

Characteristic

N = 125

ORR, n (%) [95% CI]

71 (57%) [48%, 66%]

Complete response

Partial response

Stable disease

Progressive disease

Not evaluated

7 (6%)

63 (50%)

42 (34%)

10 (8%)

2 (2%)

Median time to response, months, n = 71

1.9 monthsMedian Duration of response12.5 monthsMedian PFS11 monthsGopal A, et al. N Engl J Med. 2014;370:1008-1018.DELTA (Study 101-09)—Idelalisib MonotherapyResponse of All PatientsSlide201

Characteristic

FL, n = 39

ORR [95% CI]

54% [42%-66%]

Complete response

Partial response

8%

46%

Median time to response, months

1.9 months (range, 1.6-8.3)

Median Duration of response

Not Reached

ZYDELIG®(idelalisib) [prescribing information]. Foster City, CA:Gilead Sciences, Inc. Revised July 2014.

Gopal A, et al.

N Engl J Med

. 2014;370:1008-1018.DELTA (Study 101-09)—Idelalisib MonotherapyResponse of Patients with FLSlide202

DELTA (Study 101-09)—Idelalisib MonotherapyForest Plot of ORR

Dotted line: Null hypothesis <20% response rate

Overall (N = 125)

0.57 (0.48, 0.66)

Age <65 years (N = 69)

0.57 (0.44, 0.68)

≥65 years (N = 56)

0.57 (0.43, 0.70)

Male (N = 80)

0.55 (0.44,

0.66)

Female (N = 45)

0.60 (0.44, 0.74)

FL (n = 72)

0.54 (0.42, 0.66)SLL (N = 28)0.61 (0.41, 0.79)MZL (N = 15)0.47 (0.21, 0.73)LPL/WM (N = 10)0.80 (0.44, 0.98)Bulky disease: No (LD <7 cm) (N = 92) 0.57 (0.46, 0.67)Yes (LD ≥7 cm) (N = 33)

0.58 (0.29, 0.75)# Prior therapy: <4 (N = 52)0.50 (0.36, 0.64)≥4 (N = 73)0.62 (0.50, 0.73)Prior bendamustine: No (N = 44)0.57 (0.41, 0.72)Yes (N = 81)0.57 (0.45, 0.68)Refractory to bendamustine: No (N = 20)0.50 (0.27, 0.73)Yes (N = 61)0.59 (0.46, 0.71)Refractory to last therapy: No (N = 13)0.69 (0.39, 0.91)Yes (N = 112)0.55 (0.46, 0.65)ORR (95% CI)0.0 0.2 0.4 0.6 0.8 1.0ORR

Gopal A, et al.

Blood.

2013;122: Abstract 85.Slide203

DELTA (Study 101-09)—Idelalisib MonotherapyWaterfall Plot of Lymph Node Response

a

Criterion for lymphadenopathy response [Cheson 2007]

b

3 subjects no post baseline evaluation:

2 subjects NE 1 subject PD by Lymph Node biopsy

90% had improvement in lymphadenopathy

57% had ≥50% decrease from baseline

SPD of Measured Lymph Nodes,

Best % Change From Baseline

+50

+25

-50

a

-25

0-75-100

Gopal A, et al. Blood. 2013;122: Abstract 85.Slide204

Gopal A, et al. N Engl J Med. 2014;370:1008-1018.

DELTA (Study 101-09)—Idelalisib MonotherapyDuration of Response

100

75

50

25

0

Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to

independent review committee assessments

Median DOR = 12.5 months

0 3 6 9 12 15 18

(71) (54) (34) (17) (9) (0) (0)

% Continued Response

Time From Response, Months

(N, Patients at Risk)Slide205

Gopal A, et al. N Engl J Med. 2014;370:1008-1018.

DELTA (Study 101-09)—Idelalisib MonotherapyPFS and OS

Progression-free Survival

Overall SurvivalSlide206

Gopal A, et al. N Engl J Med. 2014;370:1008-1018.

DELTA (Study 101-09)—Idelalisib MonotherapyKey Adverse Events

AEs

Any grade

n, %

Grade ≥3

n, %

Diarrhea

54 (43%)

16 (13%)

Fatigue

37 (30%)

2 (2%)

Nausea

37 (30%)

2 (2%)Transaminases, n (%)Grade 1-2Grade 3Grade 4Any grade ALT or AST elevated44 (35%)13 (10%)3 (2%)60 (48%)Slide207

Severe hepatotoxicity, including one fatal case, has been reported in idelalisib-treated patients in clinical trialsElevations in ALT and AST (transaminase elevations) greater than 5 times the upper limit of normal have been observed in 109 of 760 patients (14%) included in the US New Drug Application Safety Update data setIdelalisib—Characteristics of Hepatic Adverse EventsSlide208

Transaminase ≥ Grade 3 elevationOccurs early – usually by week 8 and latest by week 16Identified with routine monitoringAsymptomatic and reversibleDid not commonly prevent idelalisib treatment Grade ≤

2 elevation dosed through and has resolvedGrade ≥3 elevation managed with dose interruption and reduction No Grade >3 bilirubin elevation74% of patients resumed treatment at a lower dose without recurrence

26% of patients had recurrence of ALT and AST elevations, despite lower idelalisib doses

Idelalisib—Characteristics of Hepatic Adverse EventsSlide209

Idelalisib—Diarrhea/Colitis Adverse Events

Severe Diarrhea/colitis During Idelalisib Treatment

Severe diarrhea/colitis

14% (106/760)

Fatality

<

.5% (1/1192)

Rechallanged

67% (71/106)

Rechallenged successfully regardless of dose

57.7%

(41/71)

Median time to onset All grades Grades 1-2 Grades >3

1.9 months (range, 0.0-29.8)1.5 months (range, 0.0-15.2)7.1 months (range, 0.5-29.8) Time to resolution92% resolved within 1 month (median)Slide210

Grade 1/2 DiarrheaFirst 8 weeks of treatment (median time to onset,1.5 months)Typically mild and self-limiting (loose stools)Grade 3/4 DiarrheaMedian time to onset of 7.1 months

Reported as watery, without cramps, not bloody or mucoid, culture negativePer protocol, idelalisib was interrupted in event of grade ≥ 3 Idelalisib—Diarrhea/Colitis

Adverse EventsSlide211

Idelalisib—Diarrhea/Colitis Adverse Events Management Across the Idelalisib Clinical Program

GS

-

101-09

(N=125)

GS-US-312-0116

(N=110)

Integrated Safety

Summary (ISS)

(N=650)

Grade ≥3 diarrhea and/or colitis

20 (16%)

6  (5%)

100 (15%)Budesonide use5/20 (20%)3/6 (50%)20/100 (20%)Re-challenge success rates8/12 (75%)3/5 (60%)32/64 (50%)

Median Time to Resolution per Treatment ApproachApproximately 1 month from the discontinuation of idelalisib regardless of treatment approach1 to 2 weeks from initiation of budesonide2 to 3 weeks from initiation of systemic steroidsResponded poorly to antidiarrheals or empiric antimicrobials Slide212

Idelalisib—Pneumonitis Observed Across the Clinical Trial Program Pneumonitis, including fatalities, occurred in 24 of 760 (3.2%) idelalisib-treated patients across clinical trials

Pneumonitis, including fatalitiesn/N (%)

Patients managed with corticosteroids

Resolved without corticosteroids

22/24 (92%)

2/24 (8%)

Serious

AEs

23/760 (3%)

Fatalities

3/760 (<.5%)

Treatment

Discontinuation18/24 (75%)Treatment interruption &

subsequent rechallenge13/24 (54%)Successful rechallenge (regardless of dose): 9/13 (16%)Patients with underlying Pneumocystis jirovecii pneumonia1/24 (4%)Slide213

NOVEL APPLICATIONS OF EXISTING TREATMENTS AND EMERGING TREATMENT APPROACHES FOR FL

Venetoclax (ABT-199)Slide214

Targeting Downstream Signaling Molecules in B Cells

Figure from Hallek. Blood. 2013;122:3723-3734.

Venetoclax (ABT-199)Slide215

Venetoclax (ABT-199)Small molecule, selective, potent, orally bioavailable BCL-2 inhibitorBinds BCL-2 with >1000-fold higher affinity than BCL-XL, BCL-W and MCL-1 Acts as a BH3-mimetic, displacing the BH3-only protein BIM from BCL-2 thereby inducing apoptosis in BCL-2 dependent lymphoid cells

ABT-199 has shown anti-tumor activity including complete remissions in patients with high-risk R/R CLL and SLLSlide216

Phase I Study of Venetoclax Monotherapy for Patients with R/R NHLPhase 1, open-label, dose-escalation, multicenter study to determine the safety, pharmacokinetics, and efficacy of venetoclax monotherapy2 cohorts (N = 106)Dose-escalation cohort: 3-week period with a stepwise, intrapatient dose ramp-up was used, starting at 200 mg and reaching a maximum dose level of 1,200 mg Safety-expansion cohort: stepwise escalation from 400 mg to 800 mg to 1200 mg

Gerecitano, et al. 57th ASH® Annual Meeting & Exposition. December 5-8, 2015. Abstract 254.Slide217

Phase I Study of Venetoclax Monotherapy for Patients with R/R NHL—DLBCL and FL

217

DLBCL (n = 41)

n

Age years, median

68 (range, 25-86)

DLBCL-Richter’s transformation

7

P

rimary mediastinal large B-cell lymphoma

2

Median number of prior therapies

3 (range,

1–8)

Disease refractory to rituximab5 (12%)Gerecitano, et al. 57th ASH® Annual Meeting & Exposition. December 5-8, 2015. Abstract 254.FL (n = 29)n Age years, median64 (range, 46-75)Median number of prior therapies3 (range, 1-10)Disease refractory to rituximab8 (28%)Analysis includes patients with DLBCL and FL from the dose-escalation and safety expansion cohortsSlide218

218

Phase I Study of Venetoclax Monotherapy for Patients with R/R NHL—DLBCL and FL

Gerecitano, et al. 57th ASH® Annual Meeting & Exposition. December 5-8, 2015. Abstract 254.

Best Response on Venetoclax

DLBCL

n=34

DLBCL-RT

n=7

FL

n=29

Median Duration of Treatment

5 months

(range, 0.4-9)

7 months

(range, 1-19)

Overall response rate (ORR)5 (15%)4 (57%)10 (34%) CR3 (9%)03 (14%) PR2 (6%)4 (57%)7 (24%) SD9 (26%)1 (14%)18 (62%) PD18 (53%)1 (14%)1 (3%)Discontinued Prior to Assessment01 (14%)0Median Duration of Response3.3 months (range, 2-4)10 months (range, 1-30)Median Duration of Stable Disease2.3 months (range: 1–15)4.2 months (range: 2–18)Slide219

Phase I Study of Venetoclax Monotherapy for Patients with R/R NHL—DLBCL and FL In total, 58 pts have discontinued (n=50 due to PD, n=3 due to AE, n=2 withdrew consent, n=2 proceeded to transplant and n=1 due to non-compliance)12 pts remain on treatment (2 DLBCL and 10 FL)

Dose Limiting Toxicities (DLTs) Two DLTs in Cohort 5 at 600 mg:

Grade 4 neutropenia

Grade 3 febrile neutropenia

219

All Grades

≥20% of Patients

n=70

Nausea

33%

Diarrhea

44%

Vomiting

23%

Fatigue

44%Grade 3/4n = 70Anemia14%Fatigue9%Thrombocytopenia7%Gerecitano, et al. 57th ASH® Annual Meeting & Exposition. December 5-8, 2015. Abstract 254.Slide220

Phase I study conclusionsDLBCL: initial response, but was not sustainedFL: ORR of 34%, with an extended duration of responseResults suggest the optimal role of venetoclax for the treatment of DLBCL and FL will be as a component in combination therapiesPhase II combination studies of venetoclax for FL are recruiting

Venetoclax plus bendamustine/rituximab vs bendamustine/rituximab or venetoclax/rituximab (NCT02187861)Venetoclax plus R/G-CHOP

220

Phase I Study of Venetoclax Monotherapy

for Patients with R/R NHL—DLBCL and FL

Gerecitano, et al. 57th ASH® Annual Meeting & Exposition. December 5-8, 2015. Abstract 254.Slide221

NOVEL APPLICATIONS OF EXISTING TREATMENTS AND EMERGING TREATMENT APPROACHES FOR FL

Chimeric Antigen ReceptorsSlide222

Immunotherapy has been transformed by immune checkpoint blockade

Figure from: Pardoll.

Nat Rev Cancer

. 2012;12:252-264.Slide223

CTLA-4 vs PD-1—Distinct Immune CheckpointsTopalian, et al. Curr Opin Immunol, 2012 24:207–212. Slide224

Chimeric Antigen Receptors (CAR)CARs and CAR-T cellsTarget surface moleculesNo HLA restrictionDo not require costimulatory molecule expression on tumor cells

Incorporation of activating or inhibitory domainsEnables redirection of engineered T cell subsets to a specified target antigen

Figure from: Turtle, et al.

Curr Opin Immunol

. 2012;24:633-639.

Recombinant antigen receptors:

Extracellular: scFv (antibody) for specificity

Intracellular: TCR complex signalingSlide225

Figure from: Turtle .

Int J Heme

. 2014;99:132-140.

Repeated antigen stimulation to enrich tumor-reactive T cells

Redirection

of antigen

specificity

Antigen Receptor Engineering to Rapidly Redirect Specificity of T Cells to TumorsSlide226

CTL019 T cells express a chimeric antigen receptor (CAR) that binds to CD19, activates T cells via the CD3-zeta domain, and provides a costimulatory signal via the CD137 (4-1BB) domainAutologous T-cells are engineered through lentiviral transduction to express a CD19-specific CARThe autologous T cells are collected through leukapheresis, modified, and then activated ex vivo using anti-CD3/CD28Schuster SJ, et al.

Hematol Oncol. 2015;33(suppl 1):175 [ICML abstract 139]. Image from: Turtle , et al. Curr Opin Immunol. 2012; 24: 633–639.

Phase I/II Study of CD19-specific CAR-T Cells for Advanced CD19

+

NHLSlide227

ELIGIBILITYHeavily pretreated patients (n= 22)a with CD19+ diffuse DLBCL (n = 13), MCL (n = 2), and FL (n = 7)19 patients evaluable

Schuster SJ, et al. Hematol Oncol. 2015;33(suppl 1):175 [ICML abstract 139].aPreinfusion chemotherapy regimens included EPOCH (n =2), cyclophosphamide (n =9), radiation + cyclophosphamide (n =2), bendamustine (n =6), and cyclophosphamide-fludarabine (n =1)

b

Patients had received a median of 5.5 prior therapies (range, 4-8), including 2 prior transplants’ 86% of patients had stage III-IV disease

Phase I/II Study of CD19-specific CAR-T Cells for Advanced CD19

+

NHL

Phase II study evaluated the safety and efficacy of CTL019 therapy in patients with R/R CD19+ NHL who lacked curative treatment options

Intravenous

infusion of

5 × 10

8

CTL019 cells

Collection of peripheral blood leukocytesLymphodepleting chemotherapy 1-4 daysSlide228

Schuster SJ, et al. Hematol Oncol. 2015;33(suppl 1):175 [ICML abstract 139].Phase I/II Study of CD19-specific CAR-T Cells for Advanced CD19

+ NHL

Characteristic

Enrolled patients, N

Patients

who

received CTL019 per protocol

specified cell dose, n

29 (19 DLBCL; 8 FL; 2 MCL)

20 (12 DLBCL;

7 FL

; 1 MCL)Median age56 years (range, 25-77)

Male: female ratio17:12Median number of prior therapies 4 (range, 1-8)Patients with prior ASCTn = 9 (31%)Disease stage n(%) IV III II IE 16 (55%)5 (17%)6 (21%)2 (7%Elevated LDH20 (69%)

Phase II study evaluated the safety and efficacy of CTL019 therapy in patients with R/R CD19+ NHL who lacked curative treatment options Slide229

Phase I/II Study of CD19-specific CAR-T Cells for Advanced CD19+ NHLAdverse events: Cytokine release syndrome in15 pts (grade 2 in 13 pts; grade 3 in 2 pts)

Neurologic toxicity occurred in 3 pts Transient delirium (grade 2 in 1 pt; grade 3 in 1 pt)1 pt had possibly related, grade 5 encephalopathy.

All Patients

n = 19

DLBCL

n = 13

FL

n = 7

ORR

68%

50%

100%

CR/CRu

42% (5/12 patients)57% (4/7 patients)PR8% (1/12 patients)43% (3/7 patients)PFSa 59%37%

100%

Schuster SJ, et al. Hematol Oncol . 2015;33(suppl 1):175 [ICML abstract 139].a After a median follow-up of 6 monthsSlide230

NOVEL APPLICATIONS OF EXISTING TREATMENTS AND EMERGING TREATMENT APPROACHES FOR FL

Anti-PD-1 InhibitorsSlide231

Immunotherapy has been transformed by immune checkpoint blockade

Figure from: Pardoll.

Nat Rev Cancer

. 2012;12:252-264.Slide232

CTLA-4 vs PD-1—Distinct Immune CheckpointsFigure from: Topalian, et al. Curr Opin Immunol, 2012 24:207–212. Slide233

Immune Checkpoint BlockadeFigure from: Drake, et al. Nature Reviews Clinical Oncology. 2014;11L24–37.Slide234

Anti-PD-1/L-1 Agents in Clinical DevelopmentMoreno & Ribas. Br J Cancer. 2015;112:1421–1427.

AgentsPrior NamesPotential Targets

Nivolumab

MDX1106, BMS936558

Melanoma,

NSCLC, renal cell carcinoma, R/R

HL, DLBCL,

R/R FL

, T-cell NHL, multiple myeloma

Pembrolizumab

Lambrolizumab,

MK-3475Melanoma, NSCLC, Renal cell carcinoma, Triple-negative breast cancer, R/R HL, R/ R FLPidilizumabCT-011R/R FL, DLBC, colorectal cancer, melanoma 

BMS936559 MDX1105NSCLC,

melanoma, colorectal cancer, renal cell carcinoma, ovarian cancerMPDL3280A RG7446Melanoma, NSCLC, renal cell carcinoma, triple-negative breast cancer, Bladder cancerMEDI4736Melanoma, NSCLCAvelumabMSB0010718CMetastatic or Locally Advanced Solid TumorsSlide235

Phase I Study of Nivolumab in Patients with R/R Lymphoid Malignancies

Lesokhin AM et al. Proc ASH 2014;Abstract 291.

Nivolumab

Dose escalation (n = 13)

a

1 mg/kg



3 mg/kg

Wk 1, 4 then q2wk

Dose expansion (n = 92)

b

3 mg/kg

ELIGIBILITY

(N = 105)R/R lymphoid cancersB-NHL (n=29)Primary mediastinal B-cell lymphoma (n=2)

T-NHL (n=23)MM (n=27)CML (n=1)

Primary endpoints: Safety and tolerabilitySecondary endpoints: Include best overall response, objective response, duration of response, progression-free survivalaB-cell lymphomas (BCL) (n = 8), CML (n = 1), multiple myeloma (n = 4)bBCL (n = 23), T-cell lymphoma (TCL) (n = 23), multiple myeloma (n = 23); patients with Hodgkin lymphoma (n = 23) are not included in this reportSlide236

Phase I Study of Nivolumab in Patients with R/R Lymphoid Malignancies

Lesokhin AM et al. Proc ASH 2014;Abstract 291.

Response

ORR

CR

PR

SD

BCL (n = 29)

FL (n = 10)

DLBCL (n = 11)

28%

40%

36%

7%

10%

9%21%30%27%48%60%27%TCL (n = 23) MF (n = 13) Peripheral TCL (n = 5)17%15%40%0%0%0%17%15%40%43%69%0%Multiple myeloma (n = 27)0%0%0%67%Primary mediastinal BCL (n = 2)0%0%0%100%Slide237

Phase I Study of Nivolumab in Patients with R/R Lymphoid Malignancies

Figure from Lesokhin AM et al. Proc ASH 2014;Abstract 291.

Median duration

of response

Ongoing/all responders

Median follow-up

FL (n = 10)

Not reached

4/4

Not reached

DLBCL (n = 11)

17 weeks

1/4

23 weeksSlide238

Phase I Study of Nivolumab in Patients with R/R Lymphoid Malignancies

Lesokhin AM et al. Proc ASH 2014;Abstract 291.

Select Adverse Events

N = 82

Any grade

Grade 3-5

Fatigue

13%

NR

Pneumonitis

11%

2%

Pruritus

9%

NR

Rash 9%2%Pyrexia 7%NRAnemia6%4%Diarrhea6%NRLeukopeniaNR2%Slide239

Phase II Trial of Pidilizumab Plus Rituximab for Patients Relapsed FLWestin, et al. Lancet Oncol. 2014;15(1):69-77..

ELIGIBILITY N =32Adult (≥18 years) patients with relapsed rituximab-sensitive FL

1 to 4 previous therapies

Pidilizumab

3 mg/kg q4 weeks x 4

8 optional infusions q4 weeks for patients with stable disease or better

Rituximab

17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m

2

weekly for 4 weeks

Primary endpoint

: ORRSlide240

The most common adverse events Grade 1: anemia (14 patients), fatigue (13 patients),Grade 2: respiratory infection (5 patients). Median follow-up was 15·4 months (IQR 10·1–21·0)

Phase II Trial of Pidilizumab Plus Rituximab for Patients Relapsed FLWestin, et al. Lancet Oncol

. 2014;15:69-77.

Response

n (%)

ORR (n = 29)

19 (66%)

CR

15 (52%)

PR

4 (14%)Slide241

Phase II Trial of Pidilizumab Plus Rituximab for Patients Relapsed FLFigure from Westin, et al. Lancet Oncol. 2014;15(1):69-77.Slide242

Phase II Trial of Pidilizumab Plus Rituximab for Patients Relapsed FLWestin, et al. Lancet Oncol. 2014;15(1):69-77.Slide243

CheckMate 140 Phase II Study—Nivolumab in Subjects with R/R FL ClinicalTrials.gov Identifier:NCT02038946This study is currently recruiting participants.

Primary endpoint: ORRSecondary endpoints: DOR, CRR, PR, PFS

Nivolumab

3 mg/kg every 2 weeks until disease progression or discontinuation due to toxicity

ELIGIBILITY

Grade 1, 2, or 3a R/R FL w/o pathologic evidence of transformation

≥ 2 prior treatment lines; each including CD20 antibody and/or an alkylating agent

ECOG PS 0-1Slide244

ConclusionsSeveral exciting new agents approved and in clinical trialsMore selective than chemotherapy but not without toxicityImmunotherapy promisingIs this the beginning of the end for chemotherapy?Slide245

DISCUSSION OF CLINICAL CASES AND EVIDENCE-BASED TREATMENT STRATEGIESSlide246

Summary of Cases Needed

Watch and waitPatient requiring treatment

Relapsed patient

Patient with transformed disease

Patient going to transplant

Images for each of the cases would be helpful

Slides neededSlide247

Case Study—Relapsed FL PATIENT HISTORY62-year-old female

Diagnosed with stage IV, grade 2 FL in 2010 Presented with lymphadenopathy

Elevated LDH

FLIPI score of 3

Normal hemoglobin & platelets levels

Elevated ALC

Bone marrow involvement

ECOG PS 1Slide248

PATIENT HISTORYTx with R-CVP x 6 followed by rituximab maintenance

when B symptoms presentedAchieved a PR

Relapse at 18 months with retroperitoneal adenopathy

BR given as 2

nd

line

PR but only lasted 8 months

B symptoms have recurred

BM involved

3 cm adenopathy

Platelets 65K

Case Study—Relapsed FL Slide249

Case Study—Relapsed FL PET positiveBiopsy with FL grade 2WBC 2.1ANC 1.8Hgb 9.0Platelets 60KWhat is next?Slide250

Case Study—Relapsed FL Started Idelalisib single-agentAchieved a PR with lymphocytosis at 2 monthsAt 9 months developed severe diarrhea (7-8 times daily)

Managed with steroids and had resolution of diarrheaSlide251

CONCLUSIONSSlide252

SummaryMany options of therapy exist for patients with follicular lymphomaThere is no standard of care for both front-line and relapsed diseaseRadioimmunotherapy is an effective therapy for indolent B-cell lymphomaOne course of therapy is as effective as multiple courses of chemotherapy

Patient selection is important to maximize benefit and minimize toxicityNew approaches include frontline treatment with RIT and RIT consolidation after chemotherapy for frontline treatment of follicular lymphoma Slide253

DISCUSSIONQUESTION & ANSWERSSlide254

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