indolent non-hodgkin’s lymphoma sharman slides
TRANSCRIPT
Jeff P. Sharman, MDMedical DirectorHematology Research US Oncology Eugene, Oregon
Indolent Non-Hodgkin’s Lymphoma
This program is supported by an educational grant from Gilead.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
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Faculty
Program Director:Ian W. Flinn, MD, PhDProgram DirectorDirector, Blood Cancer Research ProgramSarah Cannon Research InstituteNashville, Tennessee
Susan M. O’Brien, MDProfessor of MedicineDepartment of LeukemiaUniversity of Texas M. D. Anderson Cancer CenterHouston, Texas
Jeff P. Sharman, MDMedical DirectorHematology ResearchUS Oncology ResearchEugene, Oregon
Stephan Stilgenbauer, MDAssociate ProfessorDepartment of Internal Medicine II Ulm UniversityUlm, Germany
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Faculty Disclosures
Ian W. Flinn, MD, PhD, has disclosed that he has received funds for research support from Celgene, Gilead Sciences, Genentech, Infinity, Janssen Biotech, Millennium, Portola, Seattle Genetics, and Pharmacyclics.
Susan M. O’Brien, MD, has disclosed that she has received consulting fees from Amgen, Celgene, Emergent, Genentech, Gilead Sciences, GlaxoSmithKline, Infinity, Pharmacyclics, and Spectrum; has received funds for research support from Acerta, Emergent, Genentech, Gilead Sciences, Infinity, MorphoSys, Pharmacyclics, Spectrum, and TG Therapeutics; and has served on the advisory board for CLL Global Research Foundation.
Jeffrey P. Sharman, MD, has disclosed that he has received consulting fees from Gilead Sciences and Pharmacyclics and funds for research support from Celgene, Genentech, Gilead Sciences, and Pharmacyclics.
Stephan Stilgenbauer, MD, has disclosed that he has received consulting fees and funds for research support from AbbVie, Amgen, Celgene, Gilead Sciences, GlaxoSmithKline, Janssen Biotech, and Roche.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Initial Treatment by Population for Follicular Lymphoma
Initial Treatment: All Pts (N = 2728)
Clinical trial6.1%
Other1.6% Observation
17.7%Chemotherapy
3.2%
Chemotherapy + rituximab
51.9%
Radiotherapy 5.6%
Rituximabmonotherapy
13.9%
Friedberg JW, et al. J Clin Oncol. 2009;27:1202-1208.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Original GELF Criteria
Any nodal or extranodal tumor mass > 7 cm diameter
≥ 3 nodal sites involved, each with > 3 cm diameter
Presence of any systemic of B symptoms
Splenic enlargement with inferior margin below umbilical line
Compression syndrome (ureteral, orbital, gastrointestinal)
Pleural or peritoneal serous effusion (regardless of cell content)
Leukemia (> 5.0 x 109/L circulating malignant cells)
Cytopenia (< 1.0 x 109/L granulocytes and/or < 100 x 109/L platelets)
Solal-Celigny P, et al. J Clin Oncol. 1998;16:2332-2338.
Low Tumor Burden
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Phase III Study: Rituximab vs Watchful Waiting in Asymptomatic FL
Watchful waiting with regular clinic visits(n = 187)
Rituximab 375 mg/m2
wkly for 4 wks(n = 84)
Mo 3
Pts with asymptomatic stage II, III, IV nonbulky FL
(N = 463)
Rituximab 375 mg/m2
wkly for 4 wks(n = 192)
Rituximab 375 mg/m2
every 2 mos
Mo 7CT scan*
Regular clinic visits
Mo 13CT scan if
clinical CR* Mo 25
CT scan*
*If CT shows CR, bone marrow assessed for histology and minimal residual disease.
Continued follow-up
Ardeshna KM, et al. Lancet Oncol. 2014;15:424-435.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Rituximab vs Watchful Waiting in Asymptomatic FL: Remissions, Responses
Radiographically Assessed Spontaneous Remissions and Responses, n/N (%)
7 Mos 13 Mos 25 Mos
Watch and Wait
Overall remission 9/155 (6) 14/145 (10) 15/128 (12)
CR (spontaneous) 3/155 (2) 7/145 (5) 8/128 (6)
PR (spontaneous) 6/155 (4) 7/145 (5) 7/128 (5)
No change 116/155 (75) 94/145 (65) 60/128 (47)
Disease progression 30/155 (19) 37/145 (26) 53/128 (41)
Rituximab Induction
Overall response 62/81 (77) 57/80 (71) 43/75 (57)
CR 29/81 (36) 31/80 (39) 25/75 (33)
CRu 9/81 (11) 8/80 (10) 8/75 (11)
PR 24/81 (30) 18/80 (23) 10/75 (13)
No change 14/81 (17) 12/80 (15) 6/75 (8)
Disease progression 5/81 (6) 11/80 (14) 26/75 (35)
Maintenance Rituximab
Overall response 162/184 (88) 160/180 (89) 144/173 (83)
CR 93/184 (51) 109/180 (61) 119/173 (69)
CRu 16/184 (9) 15/180 (8) 11/173 (6)
PR 53/184 (29) 36/180 (20) 14/173 (8)
No change 16/184 (9) 8/180 (4) 8/173 (5)
Disease progression 6/184 (3) 12/180 (7) 21/173 (12)
Ardeshna KM, et al. Lancet Oncol. 2014;15:424-435.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Rituximab Maintenance vs Watchful Waiting in Asymptomatic FL: Outcomes
Ardeshna KM, et al. Lancet Oncol. 2014;15:424-435.
100
75
50
25
00 1 2 3 4 5 6 7
HR: 0.21 (95% CI: 0.14-0.31;log-rank P < .0001)
Pts at Risk, nWatch and wait
Maintenancerituximab
187192
139184
111176
66146
3359
610
11
00
Time to Start of New Treatment
No
Ne
w T
rea
tme
nt
(%)
100
75
50
25
00 1 2 3 4 5 6 7
Pts at Risk, n Watch and wait
Maintenancerituximab
187192
181189
175186
130163
6872
1816
43
00
OS
Yrs From Randomization
100
75
50
25
00 1 2 3 4 5 6 7
187192
121183
92165
54138
2856
69
11
00
PFS
PF
S (
%)
HR: 0.23 (95% CI: 0.16-0.32;log-rank P < .0001)
HR: 0.62 (95% CI: 0.31-1.26;log-rank P = .19)
100
75
50
25
00 1 2 3 4 5 6 7
187192
177187
168182
121158
6469
1515
43
00
Time to Histological Transformation
No
His
tolo
gic
al
Tra
ns
form
ati
on
(%
)HR: 0.73 (95% CI: 0.34-1.54;log-rank P = .40)
OS
(%
)
Yrs From Randomization
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Rituximab Induction vs Watchful Waiting in Asymptomatic FL: Quality of Life
Quality of Life at Baseline and Mo 7
Watch and Wait(n = 187)
Maintenance Rituximab (n = 192)
P Value Between Groups
Illness Coping Style
Baseline 159 (70) 171 (72) --
Mo 7 134 (66) 170 (75) .0002
Difference 119 (-5.0) 153 (2.9) .0012
P value baseline vs Mo 7 .0063 .072 --
Illness Impact Bank
Baseline 163 (62) 174 (61) --
Mo 7 137 (67) 175 (71) .095
Difference 125 (4.2) 160 (9.1) .024
P value baseline vs Mo 7 .0089 < .0001 --
Mental Adjustment to Cancer Scale
Baseline 163 (73) 173 (72) --
Mo 7 137 (70) 176 (81) .0004
Difference 125 (-3.2) 160 (8.4) .0004
P value baseline vs Mo 7 .19 .0001 --
Ardeshna KM, et al. Lancet Oncol. 2014;15:424-435.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Maintenance vs Re-Treatment With Rituximab in Low Tumor Burden FL Randomized phase III trial
of maintenance rituximab vs retreatment with rituximab as needed in pts with previously untreated low tumor burden FL (N = 289)
Primary endpoint: time to treatment failure
Secondary endpoints: time to first cytotoxic therapy, health-related quality of life
Kahl BS, et al. J Clin Oncol. 2014;32:3096-3102.
0 1 2 3 4 5 6 7Yrs Since Random Assignment
Tre
atm
en
t-F
ail
ure
F
ree
Su
rviv
al
(%)
100
80
60
40
20
0
Median FU: 4.5 yrs2-sided log-rank P = .54
Re-treatmentMaintenance
At Risk143146
Failure8078
3 Yrs, %6573
5 Yrs, %5053
0 1 2 3 4 5 6 7Yrs Since Random Assignment
Cy
tox
ic T
he
rap
y-
Fre
e S
urv
iva
l (%
)
80
60
40
20
0
Median FU: 4.2 yrs 2-sided log-rank P = .03
Re-treatmentMaintenance
At Risk143146
Cytotoxic288
3 Yrs, %8495
5 Yrs, %8092
100
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Maintenance vs Re-Treatment With Rituximab in Low Tumor Burden FL: PFS
Kahl BS, et al. J Clin Oncol. 2014;32:3096-3102.
100
80
60
40
20
0
Pro
gre
ssio
n F
ree
(%)
0 1 2 3 4 5 6 7
Yrs Since First Documented Response
Median FU: 3.8 yrs
Re-treatmentMaintenance
At Risk140141
Progression7332
1 Yr, %7690
3 Yrs, %5078
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Trial SAKK 35/98: Single-Agent Rituximab at 2 Different Schedules in FL
OS by Treatment Arm
Martinelli G, et al. J Clin Oncol. 2010;29:4480-4484.
EFS by Treatment Arm in Previously Untreated Pts
Responding to Induction Treatment
Yrs
100 1 2 3 4 6 7 8 95
1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ility
ProlongedStandard
P = .045
Yrs
100 1 2 3 4 6 7 8 95
1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ility
ProlongedStandard
P = .0813
High Tumor Burden
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Chemo Regimens in Lymphoma
Friedberg JW, et al. J Clin Oncol. 2009;27:1202-1208.
R-CHOP
R-CVPR-Flu
Other55%
23%
16%
6%
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Phase III StiL Trial Frontline BR vs R-CHOP in MCL or CD20+ iNHL: Outcomes
PFS FL
Rummel MJ, et al. Lancet. 2013;381:1203-1210.
PFS OS1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60 72 84 96
Mos
B-RR-CHOP
Median, Mos69.531.2
HR: 0.58 (95% CI: 0.44-0.74;P = .0000148 stratified log-rank)
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60 72 84 96
Mos
B-R
R-CHOP
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60 72 84 96
Mos
B-RR-CHOP
Median, MosNYR40.9
HR: 0.61 (95% CI: 0.42-0.87; P = .0072)
Pro
bab
ilit
y
Pro
bab
ilit
y
Pro
bab
ilit
y
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
StiL: Hematologic Adverse Events
Grade 3/4 Events, n (%) R-CHOP Bendamustine + Rituximab
Leukocytopenia 181 (72)* 98 (37)*
Neutropenia 173 (69)* 77 (29)*
Lymphocytopenia 106 (43) 196 (74)
Anemia 12 (5) 8 (3)
Thrombocytopenia 16 (6) 13 (5)
Rummel MJ, et al. Lancet. 2013;381:1203-1210.
*P < .0001 between groups.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
StiL: Nonhematologic Toxic Events
All Grade Events, n (%) Bendamustine + Rituximab (n = 261)
R-CHOP (n = 253)
P Value
Alopecia 0 245 (100)* < .0001
Paresthesia 18 (7) 73 (29) < .0001
Stomatitis 16 (6) 47 (19) < .0001
Skin (erythema) 42 (16) 23 (9) .024
Skin (allergic reaction) 40 (15) 15 (6) .0006
Infectious episodes 96 (37) 127 (50) .0025
Sepsis 1 (< 1) 8 (3) .019
Rummel MJ, et al. Lancet. 2013;381:1203-1210.
*Includes pts who received ≥ 3 cycles.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Top 5 Regimens for FL From 6/2012 to 6/2014
*1396 pts with FL met the inclusion/exclusion criteria and started LOT1 regimens between 6/2012-6/2014.
Market Connect: McKesson Specialty Health. 2014.
Bendamustine + rituximab (n = 489, 35.0%)
Rituximab (n = 431, 30.9%)
R-CHOP (n = 266, 19.1%)
R-CVP (n = 153, 11.0%)
Other (n = 57, 4.1%)
Follicular Lymphoma LOT1 Top 5 Regimens
35%
31%
19%
11%4%
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Response, % StiL[1] BRIGHT[2]
BR(n = 261)*
R-CHOP(n = 253)*
BR(n = 224)
R-CHOP/R-CVP
(n = 223)
ORR 93 91 97 91
CR 40 30 31 25
First-line Bendamustine + Rituximab vs R-CHOP/R-CVP
1. Rummel MJ, et al. Lancet. 2013;381:1203-1210. 2. Flinn IW, et al. Blood. 2014;123:2944-2952.
*Number assessed.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
BRIGHT Study: Response Rate by Subtype CR rates with bendamustine + rituximab vs R-CHOP or
R-CVP similar among pts with indolent NHL
CR rate ratio significantly better for bendamustine + rituximab in pts with MCL (P = .018)
Flinn IW, et al. Blood. 2014;123:2944-2952.
Pt Population, n/N (%) CR
BR R-CHOP/R-CVP
Indolent NHL 49/178 (28) 43/174 (25)
Follicular 5/148 (30) 37/149 (25)
Marginal zone 5/25 (20) 4/17 (24)
Lymphoplasmacytic 0/5 1/6 (17)
MCL 17/34 (50) 9/33 (27)*
*R-CHOP, n = 22
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Trotman J, et al. Lancet Haematology. 2014;1:e17-e27.
Prognostic Value of PET-CT After 1st Line Therapy in FL
PFS According to PET Scan Score (Cutoff ≥4)
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96
PF
S (
%)
Negative (< 4 points)Positive (≥ 4 points)
PFS at 3 Yrs
100
80
60
40
20
0
Pts
(%
)
74
32
PET-CT negativePET-CT positive
P < .0001
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Regimen, % ORR/CR 3-Yr PFS
Bendamustine + rituximab[1] 95/35 65
R-CHOP[1] 91/30 50
Lenalidomide + rituximab[2] 90/65 79
Lenalidomide + Rituximab in Untreated iNHL
1. Rummel MJ, et al. Lancet. 2013;381:1203-1210. 2. Fowler NH, et al. Lancet Oncol. 2014;[Epub ahead of print].
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Lenalidomide + Rituximab for Follicular NHL
Response, % Lenalidomide Monotherapy
Lenalidomide + Rituximab
Relapsed/refractory follicular lymphoma[1]
ORR 49 75
CR 13 36
First-line follicular lymphoma[2,3]
OR NA 90-98
CR NA 63-87
1. Leonard J, et al. ASCO 2012. Abstract 8000. 2. Martin P, et a l. Proc ICML 2013. Abstract 063. 3. Fowler NH, et al. Lancet Oncol. 2014;[Epub ahead of print].
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Phase III Study of First-line Lenalidomide + Rituximab for Indolent NHL Randomized, open-label phase III study
Treatment-naive pts with CD20-positive iNHL
with at least 1 lesion > 2 cm not previously irradiated;
stage II-IV; ECOG ≤ 2(planned N = 1000)
Lenalidomide + Rituximab(n = 390)
R-CHOP or R-CVP or BR(n = 397)
Primary endpoints: CR/CRu, PFS
Lenalidomide: 20 mg on Days 2-22 q4w x 6; if CR then 10 mg on Days 2-22 q4w x 12; if PR after 6 cycles, continue 20 mg for 3-6 cycles, then 10 mg on Days 2-22 q4w cycles for up to 18 cycles.Rituximab: 375 mg/m2 on Days 1, 8, 15 and 22 of cycle 1, Day 1 of cycles 2-6; 8 wks later responding pts continue q8w x 12.
Clincaltrials.gov. NCT01650701. Fowler NH, et al. Lancet Oncol. 2014;[Epub ahead of print].
Relapsed Disease
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Top 5 Regimens for FL From 6/2012 to 6/2014
Market Connect: McKesson Specialty Health. 2014.
*440 pts with FL met the inclusion/exclusion criteria and started LOT2 regimens between 6/2012-6/2014.
Bendamustine + rituximab (n = 190, 43.2%)
Rituximab (n = 129, 29.3%)
Other (n = 75, 17.1%)
RCHOP (n = 25, 5.7%)
Bendamustine (n = 21, 4.8%)
43%
29%
17%
6%5%
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
ORR, % CR, % PFS, Mos
Rituximab (n = 33)[1] 64 39 14
Radioimmunotherapy (n = 142)[2] 67 50 18
Bendamustine + rituximab (n = 37)[3] 86 35 23
Efficacy Following Rituximab Therapy
1. Tobiani K, et al. Cancer Sci. 2011;102:1698-1705. 2. Leahy MF, et al. Blood. 2011;117:45-52. 3. Robinson KS, et al. J Clin Oncol. 2008;26:4473-4479.
Novel Agents
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
B-Cell Receptor Signaling Pathway
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Phase II Study 101-09: Idelalisib Monotherapy in Refractory iNHL
Gopal A, et al. N Engl J Med. 2014;370:1008-1018.
2 pts had no baseline evaluation
1 pt had disease progression on the basis of lymph node biopsy, no baseline evaluation
FL (n = 72)SLL (n = 28)MZL (n = 15)LPL/WM (n = 10)
75
50
25
0
-25
-50
-75
-100Individual Pts
(N = 125)
SP
D o
f M
easu
red
Lym
oh
No
des
(B
est
% C
han
ge
Fro
m B
asel
ine)
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Phase II Study of Idelalisib Monotherapy in Refractory iNHL: PFS and DOR
PFS Duration of Response
Gopal A, et al. N Engl J Med. 2014;370:1008-1018.
100
75
50
25
0
Per
cen
t W
ith
PF
S
Median: 11 mos(N = 125)
Mos From Start of Idelalisib
180 3 6 9 12 15
Pts at Risk, n 125 100 59 39 20 13 0
100
75
50
25
0P
erce
nt
Wit
h C
on
tin
ued
R
esp
on
se
Median: 12.5 mos(N = 71)
Mos From Response
180 3 6 9 12 15
Pts at Risk, n 71 54 34 17 9 0 0
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Phase II Study of Idelalisib Monotherapy in Refractory iNHL: Pt DispositionDuration of Idelalisib Therapy, Mos
Median 6.6
Range 0.6-23.9
Treatment Disposition, n (%)
Ongoing 40 (32)
Discontinued 85 (68)
Progressive disease 41 (33)
Adverse event 25 (20)
Death 8 (6)
Investigator request 7 (6)
Withdrew consent 4 (3)
Gopal A, et al. N Engl J Med. 2014;370:1008-1018.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Idelalisib Indications and Usage
Relapsed CLL in combination with rituximab, in pts for whom rituximab monotherapy would be appropriate
Relapsed FL,* in pts with ≥ 2 previous systemic therapies
Relapsed SLL,* in pts with ≥ 2 previous systemic therapies
Idelalisib [package insert].
*Accelerated approval was given based on ORR, with limited evidence regarding pt survival and disease symptoms. Continued approval is contingent upon confirmatory trials and verification of clinical benefit.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Idelalisib Label Black Box Warning
Fatal and/or serious hepatotoxicity occurred in 14% of pts in clinical trials
– Hepatic function should be monitored before and during treatment
– Dose adjustments/discontinuation should be considered when necessary
Fatal and/or serious and severe diarrhea or colitis occurred in 14% of pts in clinical trials
– Pts should be monitored for these symptoms and dose adjustments or discontinuation should be considered when necessary
Fatal and serious pneumonitis and intestinal perforation can occur during treatment
– Dose adjustments or discontinuation should be considered when necessary
Idelalisib [package insert].
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Ibrutinib Efficacy in FL Pts
Median DORMedian PFS
10.3 mos13.4 mos
12.3 mos19.6 mos
NENE
55% 56%
25%
Fowler NH, et al. ASH 2014. Abstract 156
0
20
40
60
80
100
1.25 mg/kg/day(n = 4)
≥ 2.5 mg/kg/day (n = 11)
≥ 5.0 mg/kg/day (n = 9)
CR PR
25% 27.3% 33.3%
27.3% 22.2%
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Ibrutinib Efficacy in iNHL: Patients’ Time on Study Treatment by Best Response
Advani RH, et al. J Clin Oncol. 2013;31:88-94.
CLL/SLLMCLDLBCLFLOther indolent NHL
Max % Change in Tumor Burden (n = 48)
200
150
100
50
0
-50
-100Ch
an
ge
Fro
m B
as
eli
ne
SP
D (
%)
0 5 10 15 20 25 30
CL
L/S
LL
MC
LF
LD
LB
CL
Oth
er
Ind
ole
nt
NH
L
Mos on Study
DLTDisease progressionOff study, pt/ investigator decisionIntercurrent illness/ adverse eventOn study
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Ibrutinib in Relapsed/Refractory FL
Response, n (%) Pts (N = 16)
ORR 6 (38)
CR 3 (19)
PR 3 (19)
Median DOR, mos 12.3
Median time to first response, mos (range) 4.7 (2-12)
Median time to first PR, mos (range) 4.6 (2-11)
Median time to first CR, mos (range) 11.5 (5-12)
Median PFS, mos 13.4
OS No deaths
Advani RH, et al. J Clin Oncol. 2013;31:88-94. Fowler NH, et al. ASH 2014. Abstract 156.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Ibrutinib Indications and Usage
For pts with MCL who have received at least 1 previous therapy*
In CLL pts who have received at least 1 previous therapy
In CLL pts with 17p deletion
Ibrutinib [package insert].
*Accelerated approval received for this specific indication was established on ORR. Improvements in survival or disease-related symptoms have not been proven. Continued approval for this indication is contingent upon clinical benefit being confirmed in ongoing clinical trials.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Ibrutinib Warning and Precautions
Hemorrhage: monitor for bleeding
Infections: monitor for fever and infections
Cytopenias: monitor CBC monthly
Atrial fibrillation
Second primary malignancies: includes skin cancers and other carcinomas
Embryo-fetal toxicity: can cause fetal harm
Ibrutinib [package insert].
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Lenalidomide + Rituximab vs Lenalidomide for Relapsed FL Randomized phase II study (N = 89)
Eligibility: relapsed FL with previous rituximab, TTP ≥ 6 mos from last dose
Efficacy Lenalidomide(n = 45)
Lenalidomide + Rituximab(n = 44)
ORR, % (95% CI) 51 (36-66) 73 (52-85)
CR, % 13 36
PR, % 38 36
Median EFS, yrs 1.2 2.0
2-yr EFS, % 27 44
Leonard J, et al. ASCO 2012. Abstract 8000.
Rituximab
Lenalidomide + Rituximab(n = 44)
Lenalidomide(n = 45)
Modified study design to exclude rituximab-only armGrade 1-3a relapsed
FL after ≥ 1 rituximab-based
regimen
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Polatuzumab Vedotin and Pinatuzumab Vedotin Activity in Rel/Ref NHL
Morschhauser F, et al. ASCO 2014. Abstract 8519.
Antibody With Potential Conjugation Sites for VC-MMAE (*)
VC-MMAE (linker-drug)
MMAEMC VC PABC
Protease cleavage
ADC binds to receptor
ADC-receptor complex is internalizedADC in circulation
Apoptosis (cell death)Cytotoxic agent is released in lysosomes Microtubule
disruption
** ******
*-Cys
SONO O
O
O
NH
HN
NH
OO
NO
NH
ON
OON
OO
NH OH
HN
H2NO
SAR-3419 CD-19 – DM4SGN-CD19a CD19 – MMAF
Pinatuzumab CD22 – MMAEPolatuzumab CD79 – MMAE
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
CD79b and CD22 Activity in Relapsed/ Refractory NHL: Study Design
Relapsed/refractory FL = 41
Relapsed/refractory DLBCL = 81
Rituximab + CD22 ADC
Rituximab + CD79b ADC
Rituximab 375 mg/m2 + ADC 2.4 mg/kg administered in every-21-day cycles up to 1 yr
Morschhauser F, et al. ASCO 2014. Abstract 8519.
Biopsy at progression
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Phase II Polatuzumab vs Pinatuzumab: Tumor Response and Survival in FL Pts
Morschhauser F, et al. ASCO 2014. Abstract 8519.
1.0
0.8
0.6
0.4
0.2
00 2 4 6 8 10 12 14
Mos
Su
rviv
al P
rob
abil
ity
CD22 + RCD79b + R
Median PFS for FL not reported due to
insufficient duration of follow-up
Pinatuzumab (Anti-CD22 ADC) + R Polatuzumab (Anti-CD22 ADC) + R
Rituximab-containing regimen Non-rituximab–containing regimen Not refractory
100
50
0
-50
-100
100
50
0
-50
-100Max
% C
han
ge
Tu
mo
r D
ecre
ase
Fro
m B
ase
lin
e
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Polatuzumab (CD79b) + R vs Pinatuzumab (CD22) + R: TEAEs
Morschhauser F, et al. ASCO 2014. Abstract 8519.
FatigueDiarrhea
Peripheral neuropathyNausea
NeutropeniaConstipation
Peripheral sensory neuropathyDecreased appetite
AstheniaPyrexia
VomitingCough
InsomniaDyspnea
Abdominal painArthralgia
AnemiaAlopecia
Pain in extremetyHeadacheBack painDizziness
Peripheral edemaMyalgia
Decresed weightDyspepsia
30 20 10 0 0 10 20 30Frequency (%) Frequency (%)
CD22 + R CD79b + RA
E P
refe
rre
d T
erm
1
2
3
4
Grade
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Summary
Agent ORR, % CR, % PFS, Mos Comment
Idelalisib[1] 57 6 11 Good study
Ibrutinib[2] 38 19 14 Phase 1, small study
Lenalidomide + rituximab[3]
73 36 24 Suboptimal rituximab
CD79-ADC[4] 70 40 N.R. Neuropathy
1. Gopal A, et al. N Engl J Med. 2014;370:1008-1018. 2. Advani RH, et al. J Clin Oncol. 2013;31:88-94. 3. Leonard J, et al. ASCO 2012. Abstract 8000. 4. Morschhauser F, et al. ASCO 2014. Abstract 8519.
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Phase III RELEVANCE Study: Len/R vs R-Chemo in Untreated FL
Treatment arms
– R + chemo: Investigator’s choice of R-CHOP, R-CVP, BR for 6-8 cycles
– R2: R + lenalidomide 20 mg for 6 cycles, and then 10 mg if CR
Morschhauser F, et al. ICML 2013. Abstract 136. ClinicalTrials.gov. NCT01650701.
First-line FL(N = 1000
Planned enrollment)
R2 Arm R2 Maintenance
R + Chemo Rituximab maintenance
clinicaloptions.com/oncologyIndolent Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia
Conclusions
In frontline management of indolent lymphoma, management currently stratified based on disease bulk
Several recent data sets shed light on use of rituximab monotherapy in low tumor burden indolent lymphoma
In high tumor burden indolent lymphoma, BR has displaced R-CHOP and other frontline treatment options
Lenalidomide and rituximab may be next paradigm change in frontline indolent NHL
Standards in relapsed disease far from standardized
Multiple new agents with novel mechanisms of action promise to bring more change in this space soon
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clinicaloptions.com/oncology