Contemporary Treatment Strategies and Optimal Sequencing Educational Objectives After completing this program participants should be able to Summarize the incidence and patient demographics of indolent Bcell NHL NonHodgkin Lymphoma including prognostic factors that aid in accurate diagnos ID: 540990
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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-1a
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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