Hodgkin and Indolent
Lymphomas: 2016
Sonali M. Smith, MD
Associate Professor, Section of Hematology/Oncology
Director, Lymphoma Program
The University of Chicago
Chicago, IL
Disclosures and COI
Activity
Consultant
Company
Genentech, Celgene,
Gilead, Pharmacyclics,
JUNO, AbbVie, TGTX,
Portola, 47, Amgen
HODGKIN LYMPHOMA
General approach to cHL
Favorable
Early/limited
stage
Bulky
IIB, III/IV
Unfavorable
ABVD2 plus ISRT
ABVD4 plus ISRT
Stanford V plus IFRT
ABVD6
ABVD3 if PET3 neg
ABVD6 plus RT
Stanford V
ABVD6
Stanford V
5-Point Scale for Interim-PET Interpretation
First International Workshop on Interim PET Scan in Lymphoma
Deauville, France
1. No uptake
2. Uptake ≤ mediastinum
3. Uptake > mediastinum but ≤ liver
Negative
scan
4. Moderately increased uptake compared to liver
Positive
scan
5. Markedly increased uptake compared to liver or
new areas of FDG uptake
SLIDES COURTESY OF DAVID STRAUSS
PET—
ABVD x 2 cycles
PET+
Escalated BEACOPP x 2 cycles
+ 3060 cGy IF RT
Follow-up
Post cycle 2 PET/CT*
ABVD x 2 cycles
Registration
CALGB 50604 Design
*PET/CT reviewed centrally (2 reviewers, 1 adjudicator) assessed according to 5-point scale (Deauville criteria)

Phase II trial in newly-diagnosed stages I/II non-bulky HL
conducted in Intergroup (CALGB/Alliance, SWOG,
ECOG)
Prophylactic G-CSF only after febrile neutropenia or neutropenia and
infection with ABVD. Prophylactic G-CSF with escalated BEACOPP.
CALGB 50604 Consort Diagram
Registered to CALGB 50604
N = 164
Excluded (N=13)
Cancelled
Not eligible
w/d prior to cycle 2
n=6
n=4
n=3
PET assessment
N = 151
PET-negative
N = 137
Excluded (N=6)
Insufficient follow-up data
Analyzed
N = 131
PET-positive
N = 14
n=6
Excluded (N=1)
Insufficient follow-up data
Analyzed
N = 13
Data collected through June 10, 2015
n=1
CALGB 50604 Progression Free Survival
0.6
0.4
Follow-up time
Median: 2.1 years
Range: < 1month – 4.3 years
1 Death (Suicide – PET +)
0.2
PET-negative
PET-positive
N= 131
N= 13
Events= 8
Events= 4
p-value= 0.0008
0.0
Probability progression free
0.8
Post cycle 2 ABVD PET- and PET+ Patients
0
1
2
3
4
Years from Study Entry
Est. 3-yr PFS
Hazard Ratio
PET -
92% (84%-96%)
6.04 (1.82-20.08)
PET +
66% (32%-86%)
What about advanced stage and
bulky disease?
Results and Patient Allocation
SLIDES COURTESY OF Kerry Savage
Results: FFTF by end-PET uptake
SLIDES COURTESY OF Kerry Savage
Biologic rationale for PD-1 inhibition
in cHL
PD-L1 expression in cHL
Shipp M, et al., Blood 2010
Chen BJ, et al. Clin Cancer Res. 2013;19:3462–3473.
Ansell SM, et al. N Engl J Med. 2015;372:311–319.
Copy Gain
Amplification
PD-L1/L2 copy gains and amplification visible by FISH
Nivolomab extended follow up data
Slide courtesy
of Steve Ansell
KEYNOTE-013 cHL Pt Cohort:
Pembrolizumab After BV Failure
Armand P, et al. ASH 2015. Abstract 584.
ClinicalTrials.gov. NCT01953692.
INDOLENT LYMPHOMAS
Heterogeneous outcomes in FL
1990-1999
•Relative 5-year
survival 74%
•Relative 10-year
survival 51%
25% of patients are
<40 years
2-3% transformation
risk per year
Swenson, et al., J Clin Oncol 23:5019-5026, 2005
Identifying risk groups within FL
•
•
•
•
•
Grade 1-3a vs. 3b
FLIPI
PET-response to chemoimmunotherapy
EFS24
?mutational spectrum
Front-line
setting
• Line of treatment/resistance to prior therapies
R2 vs R: response and PFS in recurrent FL
Leonard JCO 2015
Outcome
Len
Ritux
ORR
53%
76%
CR
20%
39%
Med TTP
1.1y
2.0y
2-year TTP
27%
52%
Lenalidomide-rituximab toxicity profile
• In both arms, approximately 20% of patients discontinued therapy
early as a result of adverse event
• Dose modifications occurred in 67% of len arm versus 80% in R2
arm
• Dose intensity was 80% in both arms
Leonard JCO 2015
Moving R2 to frontline setting in FL
Study
Treatment regimen
n
ORR
CR
ALLIANCE
50803
Len 20mg D1-21 q28d x 12
Ritux weekly x 4, then qomonth
66
93%
72%
MDACC
Len 20mg D1-21 q28 x12
Ritux D1 of each cycle x 12
50
98%
87%
Len 15mg po x 19 weeks
Ritux weeks 1-4, then weeks 12-15
77
81%
36%
Ritux weeks 1-4, then weeks 12-15
77
61%
25%
SAKK
35/10 study
Martin ICML 2013 abstract 063; Fowler Lancet 2014; Kimby ASH 2014
abstract 799
Towards non-chemotherapy based treatment
of FL: the “RELEVANCE” trial
Lenalidomiderituximab (R2)
N=1000
stage II-IV
treatment-naïve FL
gr 1, 2, or 3a
Maintenance R2
CR
PR
Maintenance R
R-Bendamustine
R-CHOP
R-CVP
NCT01476787 (www.clinicaltrials.gov)
PI3K as a target: BCR dependent and
independent signaling
idelalisib
Fruman and Rommel Ca Discov 2011
Idelalisib monotherapy in “double
refractory” iNHL
Idela 150mg BID
Gopal NEJM 2014
Idelalisib in refractory FL grade 1-3a:
subset analysis (n=72)
Patient characteristics:
Median age 62y
High-risk FLIPI 54%
Bulky disease 22%
Refractory to last therapy 86%
Median 4 prior treatments
Salles ASCO 2015 abstract 8529
Pathologic features of colitis
Idelalisib-associated Colitis: Histologic Findings in 14
Patients.
Weidner, Anna-Sophie; Panarelli, Nicole; Geyer, Julia;
Bhavsar, Erica; Furman, Richard; Leonard, John; Jessurun,
Jose; Yantiss, Rhonda
American Journal of Surgical Pathology. 39(12):16611667, December 2015.
DOI: 10.1097/PAS.0000000000000522
• Idelalisib-related mucosal injury show
intraepithelial lymphocytosis of the surface
and crypt epithelium (A) with attenuation
of the surface epithelium (B).
• Large, "exploding" apoptotic epithelial cells
(arrow) are present in 50% of cases.
• Neutrophilic infiltration of the lamina
propria, cryptitis, and/or crypt abscesses
are common findings.
Another option for rituximab-refractory FL:
novel moAb against CD20
Phase II Gauguin study
showed ~50% ORR in
rituximab sensitive and
rituximab refractory iNHL
Salles JCO 31:2920-2926
Bendamustine-obinutuzumab vs.
bendamustine in ritux-ref FL
Bendamustine 120mg/m2
x 6 months
(n=202)
Ritux-ref iNHL
N=396
GA101 1000mg
Bendamustine 90mg/m2
x 6 months
(n=202)
Primary endpoint PFS
Median follow up 20 months
Sehn LH et al. Proc ASCO 2015;Abstract LBA8502.
GA101
maintenance
GADOLIN: PFS by Independent Radiology
Facility Review
Sehn LH et al. Proc ASCO 2015;Abstract LBA8502.
Cell Death is Governed by Interactions Among the BCL-2
Family of Proteins
Pro-Apoptotic
(e.g. BAX, BAK)
"Activating" BH3-Only
Proteins (e.g. BIM)
"Inactivating" BH3-Only
Proteins (e.g. BAD)
Anti-Apoptotic
(e.g. BCL-2, BCL-XL, MCL-1)
Slide courtesy of James LaBelle, University of Chicago
BR plus Venetoclax in NHL
• Open-label phase I study
Response, n
(%)
DLBCL
(n = 16)
FL
(n = 27)
MZL
(n =
5)
6 (38)
21 (78)
4 (80)
 CR
4 (25)
8 (30)
1 (20)
 PR
2 (13)
13 (48)
3 (60)
2 (13)
1 (4)
0 (0)
2 (7)
0 (0)
ORR
SD
PD
6 (38)
De
Vos S, et al. ASH 2015. Abstract
255.
48% grade 3/4
neutropenia
Questions/Discussion