A CME-certified Oncology Exchange Program
Jointly provided by Potomac Center for Medical Education and Rockpointe
Supported by an educational grant from Seattle Genetics, Inc.
Faculty
Anas Younes, M.D.
Chief, Lymphoma Service
Memorial Sloan Kettering Cancer Center
New York
Jeremy S. Abramson, M.D.
Director, Center for Lymphoma
Massachusetts General Hospital Cancer Center
Off-label Discussion Disclosure
This educational activity may contain discussion of published
and/or investigational uses of agents that are not indicated
by the Food and Drug Administration. PCME does not
recommend the use of any agent outside of the labeled
indications. Please refer to the official prescribing information
for each product for discussion of approved indications,
contraindications and warnings. The opinions expressed are
those of the presenters and are not to be construed as those
of the publisher or grantors.
Learning Objectives
• Assess emerging frontline approaches for patients with
Hodgkin lymphoma
• Evaluate the efficacy and safety data for novel agents in
patients with relapsed/refractory Hodgkin lymphoma
• Discuss strategies to mitigate adverse effects to improve
long-term survival in Hodgkin lymphoma
Hodgkin Lymphoma
Introduction and
Initial Therapy
Case Study 1
• M.C. is a 23 yo woman who presents with painless
swelling of a right supraclavicular lymph node. She
was otherwise asymptomatic with a normal physical
examination
• A course of antibiotics was prescribed, without
response
• An FNA was performed and interpreted as consistent
wit a reactive lymphoid population
• An excisional lymph node biopsy was ultimately
performed
CD15
CD30
CD3
EBER
Staging and Pre-treatment Evaluation
• PET/CT showed non-bulky stage
IIA disease
• CBC, CMP unremarkable
• ESR 12 ml/hour
• HIV negative
• No bone marrow is performed
• Echocardiogram and PFTs show
no organ dysfunction
• What is the optimal therapy for
this patient?
Case 1: How will you treat this patient?
1. ABVD x 6 cycles followed by 30 Gy radiation
2. ABVD x 4 cycles followed by 30 Gy radiation
3. ABVD x 2 cycles followed by 20 Gy radiation
4. ABVD x 4-6 cycles without radiation
5. Escalated BEACOPP +/- radiation
Case 1: What if this patient was 73 years old
instead of 23?
1. ABVD x 4 cycles followed by 30 Gy radiation
2. ABVD x 2 cycles followed by 20 Gy radiation
3. ABVD x 4-6 cycles without radiation
4. AVD x 4-6 cycles (omit bleomycin) +/- radiation
5. ChlVPP +/- radiation
Epidemiology
• ~9200 cases/year in US
• ~1200 deaths
• Median age 35
– Bimodal distribution
• Slight male predominance
• Incidence is stable
Siegel, et al. CA Cancer J Clin. 2014; 64(1): 9-29.
Clinical Presentation
• 70% present with painless
lymph node enlargement
• Limited in 55%, Advanced
in 45%
• 30% will have “B”
symptoms
• Pruritus
• Rare pain with alcohol
ingestion
• Sites of involvement
– Nodal regions
•
•
•
•
•
•
•
•
Cervical/Supraclavicular (L>R) 60-70%
Mediastinal 60%
Axillary 25-35%
Hilar nodes 15-35%
Para-aortic 30-40%
Iliac 15-20%
Inguinal 8-15%
Mesenteric 1-4%
– Other lymphoid organs
Spleen 30-35%
• Waldeyer’s ring 1-2%
•
– Extranodal sites (10-15%)
Liver 2-6%
• Bone marrow 2-8%
• Other organs (lung, bone) 10%
•
Pathologic Classification
• Classical HL
–
–
–
–
• Nodular lymphocyte predominant HL
Nodular sclerosis
Mixed cellularity
Lymphocyte rich
Lymphocyte depleted
CD20
NS
LR
MC
LD
Initial Evaluation and Workup
• History
• Preparation for chemotherapy
• Physical exam
– Echocardiogram
• Staging studies
– Pulmonary Function Tests, with DLCO
– PET/CT scan
– Bone marrow (Can usually be omitted
based on PET findings)
• Labs
– CBC with differential
– Erythrocyte Sedimentation Rate
– Albumin, LFTs, Ca++, HIV
– Fertility considerations
Nodular Lymphocyte-predominant HL
• 5% of Hodgkin lymphomas
• Pathologically distinct from CHL
• Clinically distinct from cHL
– Indolent natural history
– Male predominance (75%)
– Median age in 30s
– Increased risk among first degree
family members
– Limited stage in 75%, usually
peripheral
– Extranodal disease, B symptoms
very uncommon
– ~12% rate of high-grade
transformation at 10y
• Treatment
– Radiation alone preferred for
limited stage: 10 year FFP ~ 80%
– Advanced stage extrapolated from
cHL +/- rituximab
•
ABVD +/- rituximab
•
R-CHOP
– Some suggest alkylators may be
more effective (controversial)
– Rituximab alone is an effective
option, particularly at relapse
– Late recurrences may occur
Nodular LP vs Classical HL:
GHSG Trials HD4-HD12
Freedom from Treatment Failure
Overall Survival
NLPHL
NLPHL
CHL
Nogova, et al. JCO 2008
CHL
Initial Treatment of Classical
Hodgkin Lymphoma (cHL)
Chemotherapy for cHL
• MOPP developed at National Cancer Institute in 1964
– 54% freedom from progression at 10 years
– Potentially sterilizing
– Potentially leukemogenic
• ABVD developed at Milan Cancer Institute in 1973
– Not sterilizing
– Not associated with MDS or leukemia
DeVita NEJM ‘03
MOPP versus ABVD for Advanced HL
Failure-free Survival
5 year FFS
MOPP-ABVD
ABVD
MOPP
Canellos, et al. NEJM. 1992
65%
61%
50%
Overall Survival
5 year OS
MOPP-ABVD
ABVD
MOPP
75%
73%
66%
Treatment Intensification:
Escalated BEACOPP versus ABVD
Viviani, et al. NEJM. 2011
Risk Factors in Advanced Stage CHL
• Age ≥45
• Male Gender
• Stage IV
• Hemoglobin <10.5 g/dL
• Leukocytosis >15k/mm3
• Lymphopenia <600/mm3 or
8%
• Hypoalbuminemia <4.6
Moccia, et al. JCO 2012; 30(27): 3383-3388.
5y FFP (%)
5y OS (%)
IPS
N
Original
BCCA
Original
BCCA
0
57
84
88
89
98
1
195
77
84
90
97
2
195
67
80
81
91
3
155
60
74
78
88
4
88
51
67
61
85
≥5
50
42
62
56
67
Advanced Stage disease
• ABVD x 6 cycles
• Outstanding questions
– Selection of high-risk patients for treatment intensification
– Role of PET-adapted therapy
– Incorporation of novel agents
Treatment of Limited
Stage cHL
Risk Stratification:
Adverse factors in Limited Stage Disease
EORTC
GHSG
• Large mediastinal mass
• Large mediastinal mass
• Age >50
• Extranodal disease
• >4 involved sites
• >3 nodal regions
• ESR> 30 with B sx OR >50
without B sx
• Elevated ESR
Combined Modality Therapy is Superior to
Radiation Alone in Early Favorable Disease
Ferme et al. N Engl J Med 2007; 357: 1916-27.
Combined Modality Therapy allows Reducing
Chemotherapy Cycles and Radiation Field
Ferme et al. N Engl J Med 2007; 357: 1916-27.
Beware the Late Effects of Therapy
Breast Cancer Incidence
Ng et al. J Clin Oncol 2002, 20(8): 2101-2108; De Bruin et al. J Clin Oncol 2009 , 27(26): 4239-4246.
Beware the Late Effects of Therapy
Angina Pectoris
Myocardial Infarction
Aleman, et al. Blood 2007, 109(5): 1878-1886.
All Cardiac Events
German Hodgkin Study Group : HD10 trial
CS I - II without risk factors*
ABVD
ABVD
ABVD
ABVD
ABVD
ABVD
ABVD
ABVD
ABVD
ABVD
ABVD
ABVD
30 Gy IF
20 Gy IF
30 Gy IF
20 Gy IF
• No risk factors: Large mediastinal mass, extranodal disease, >3
nodal regions, elevated ESR
Less is more: The GHSG HD10 trial
Engert et al. N Engl J Med 2010; 363(7): 640-652.
Chemotherapy alone for Limited-stage cHL
Stage I/II HL (N = 399)
Favorable (N = 123)
35Gy STNI
ABVDx4-6
Unfavorable (N = 276)
ABVDx2+STNI
ABVDx4-6
• Study excluded patients with bulk
– (M:T ratio >.33 or disease >10cm)
• Unfavorable = ESR ≥ 50 mm/hr, age ≥ 40, > 3 sites, MC/LD
Primary endpoint: 12 year overall survival
Chemotherapy Alone Versus
Radiation-containing Therapy at 12 Years
OS at 12-years
FFDP at 12-years
• ABVD 94%
• XRT/CMT 87% (HR 0.4; p=0.04)
• ABVD 87%
• XRT/CMT 92% (HR 3.03; p=0.01)
Meyer, et al. N Engl J Med 2012; 366(5): 399-408.
Are These Data Relevant in 2014?
NO
• Subtotal nodal radiotherapy is not the modern standard of care and leads
to increased radiation exposure compared to current involved field/nodal
techniques
• XRT likely didn’t cause late infections, Alzheimer’s disease or drowning
YES
• Though we radiate lower volumes today, modern radiation in HL often
includes the breasts, lungs, skin/soft tissues, and coronary ostia.
• ABVD alone produced 12-year overall survival of 94%, which is excellent
• This OS and FFDP is virtually identical to the GHSG HD11 trial results at
5 years using modern CMT with IFRT in the same population
Can Interim PET Scans be Used to Direct use of
Radiation Therapy?
H10
F
2 ABVD
1 ABVD + INRT 30 Gy (+ 6 Gy)
PET
Arm
events HR
CI
P
Standard
1/188
1.00
Experimental 9/193
9.36
2.4535.73
.017
Arm
events
HR
CI
Standard
7/251
9.36
Experimental
16/268
2.42
R
2 ABVD
H10
U
2 ABVD
P
E
T
+
2 ABVD
2 BEACOPPesc + INRT 30 Gy
(+ 6 Gy)
2 ABVD + INRT 30 Gy (+ 6 Gy)
PET
P
R
2 ABVD
P
E
T
-
4 ABVD
+
2 BEACOPPesc + INRT 30 Gy
(+ 6 Gy)
Raemaekers, et al. J Clin Oncol, 2014, 32: 1-8.
1.35-4.36 .026
Who Should Receive Radiation?
Not one size fits all
• Current data support combined modality therapy for bulky
limited stage disease
• For non-bulky patients, choice of therapy should be
informed by patient age, tumor location and patient
preference
• Further data anticipated regarding the role of PET-adapted
therapy
Treatment of Limited Stage disease
• Favorable
– ABVD x 2 cycles plus 20Gy IFRT
– ABVD x 4-6 cycles without XRT (for selected patients)
• Unfavorable, non-bulky
– ABVD x 4 cycles + 30 Gy IFRT
– ABVD x 6 cycles without XRT (for selected patients)
• Unfavorable, bulky
– ABVD x 6 cycles plus 30-36 Gy IFRT
– ABVD x 4 cycles without XRT if interim PET negative (for selected patients)
• Major ongoing questions
– PET-adapted therapy
– Incorporation of novel agents
The Challenge of Treating Older Adults with
Hodgkin Lymphoma
Advanced Stage HL in Older Adults
(E2496: ABVD/Stanford V)
Overall survival
Failure-free survival
90%
48%
Probability
Probability
74%
P=0.002
58%
P<0.0001
Year
<60 yr
≥ 60 yr
Year
• 24% of older patients developed bleomycin lung toxicity
• Treatment-related mortality: 9.3% vs. 0.3%, p<0.001)
Evens et al. BJH, 2013, 161(1): 76-86.
Limited Stage HL in Older Adults
(GHSG HD10-HD11: ABVD x4 + IFRT)
Overall Survival
Progression-free Survival
Time to HL death
Time to HL treatment failure
Boll et al. J Clin Oncol , 2013, 31(12): 1522-1529.
Chicago Elderly HL Prognostic Model
Adverse Risk factors:
1) ADL loss
2) >70 years
Event-free survival
100
0 Prognostic factor(s)
1 Prognostic factor(s)
2 Prognostic factor(s)
75
Percent survival
Percent survival
100
Overall survival
50
25
0 Prognostic factor(s)
1 Prognostic factor(s)
2 Prognostic factor(s)
75
50
25
0
0
0
30
60
90
120
Time in Months
150
180
0
30
60
90
Time in Months
Bleomycin lung toxicity 32% (Mortality: 25%)
Evens, et al. Blood 2013, 122(21).
120
150
180
Recommendations for Managing Older
Adults with HL
• Outcomes inferior to younger patients
• Increased toxicity and treatment-related mortality
• Take great caution regarding bleomycin lung toxicity and
neutropenic infections
• Low threshold to omit bleomycin (AVD)
• Short course therapy if possible
• Consider myeloid growth factor support
• Non-ABVD/AVD options include ChlVPP, CHOP
• Clinical trials preferred
• Ongoing studies examining incorporation of brentuximab vedotin into
frontline therapy
Targeted Therapy and New
Treatment Approaches
Case Study 2
32 yo woman was diagnosed with stage IV cHL a year
ago. She was treated with ABVD and achieved a
complete response.
Today, she presents with fatigue and enlarged right
cervical lymph node measuring 2 x 2 cm.
Imaging studies showed PET avid lesions above and
below the diaphragm, with the largest nodal mass
measuring 3 x 2 cm.
Bone marrow biopsy was negative. Echocardiogram
showed LVEF of 60%.
Case 2: You Would Recommend:
1. Brentuximab vedotin x 16 doses followed by ASCT
2. ICE x 2-3 cycles followed by ASCT
3. BEACOPP X 6 cycles
4. DHAP x 2-3 cycles followed by ASCT
5. GND x 2-3 cycles followed by ASCT
Case 2 (continued)
• The patient received 3 cycles of ICE and achieved a CR.
This was followed by stem cell collection, BEAM, and stem
cell re-infusion (ASCT).
• One year later, she had enlarged nodes above and below
the diaphragm, and a biopsy of a left inguinal node
confirmed the presence of relapsed HL.
Case 2: You Would Recommend:
1. Brentuximab vedotin x 16 doses followed by allogeneic
stem cell transplant
2. Brentuximab vedotin up to 16 doses, unless disease
progression or prohibitive toxicity
3. Brentuximab vedotin x 4 then PET/CT. If CR continue for
at least 8 doses and a maximum of 16 doses, followed by
observation
4. Clinical trial
ABVD
Relapse/Refractory
ICE
DHAP
Response
No Response
GVD
IGEV
Response
Cure
Brentuximab Vedotin
No Response
ASCT
No Response/Relapse
Brentuximab Vedotin
Results of Salvage Pre-transplant
Regimens in cHL
IGEV
mini-BEAM
ASHAP
MINE
PR
Dexa-BEAM
ICE
DHAP
GVD
GDP
ESHAP
0
20
40
60
% response rate
80
100
ICE + ASCT
Moskowitz C H et al. Blood 2001;97:616-623
Event-free Survival for Transplant-naive
Patients
GVD plus ASCT
GVD after failing a
prior transplant
GVD = gemcitabine, vinorelbine, and pegylated liposomal doxorubicin
Bartlett N et al. Ann Oncol 2007; 18: 1071-1079.
MSKCC 11-142: Relapsed/refractory HL
First TX following upfront therapy
Weekly BV x 2 cycles
PET
+
-
Augmented ICE x2
cycles
PET
+
Further treatment
according to treating
physician
Moskowitz, A et al ASH2013, Poster # 2099.
-
HDT/ASCT
Summary
• 80% CR rate achieved with PET adapted sequential
therapy with BV and augmented ICE
• 30% patients avoided ICE salvage therapy
• Of 40 evaluable patients
– 36 have completed ASCT
– 3 will undergo ASCT shortly
– 1 remains on treatment for persistent disease
Moskowitz, A et al ASH2013, Poster # 2099.
Overall Survival by Time to Relapse
After Transplant
TTR
>12 m
6-12 m
4-6 m
0-3 m
N Median OS (y)
172
4.6
165
2.4
204
1.5
215
0.7
Date of Prep 09/10/13 EUCAN/ADC/2013-10029l
Horning S et al, Ann Oncol 2008:19 (suppl 4):Abstract 118;
Arai S et al. Leukaemia and Lymphoma. 2013.
Targeted Therapy in Hodgkin Lymphoma
Lee & Younes, Hematology 2013: 394-399.
1992 (Cell): Durkop and Stein:
Molecular cloning of CD30 = TNF receptor family member
Younes A & Kadin M et al: J Clin Oncol, 21, 2003: 3526-3534.
Summary Results of Phase I/II
Clinical Trials Targeting CD30
Drug
Disease Antibody type
Phase
Number of
evaluable
patients
PR
CR
%PR + CR
MDX-060
HL, ALCL
Humanized
I
HL = 63
ALCL = 9
2
2
2
0
6%
22%
SGN-30
HL, ALCL
Chimeric
I
24
0
0
0
SGN-30
HL, ALCL
Chimeric
II
HL = 38
ALCL = 41
0
5
0
2
0
17%
Xmab2513
HL
Humanized
I
13
1
0
7%
131I-Ki4
HL
Murine
I
22
5
1
27%
Younes, A: Curr Opin Oncol. 2011, 23(6): 587-593.
Brentuximab Vedotin (SGN-35) Structure
Katz J, JanikJ, and Younes A . Clin Cancer Res 2011; 17: 6428-6436
Phase-I Brentuximab Vedotin in Relapsed HL
Treatment Response
Investigator Assessment
IRF Assessment
86% of patients achieved tumor reductions
83% of patients achieved tumor reductions
Younes et al. N Engl J Med 2010; 363(19): 1812-1821.
Phase I Brentuximab Vedotin in Relapsed HL
• 21-year-old female
• HL diagnosed 2003
–
–
–
–
ABVD + XRT to mediastinum
ICE
BEAMASCT
HDAC-inhibitor
• SGN-35 2.7 mg/kg x 8 cycles
– Best clinical response: CR
– CT 93% reduction, PET– PET negative
Younes A, et al. N Engl J Med 2010; 363(19): 1812-1821.
Brentuximab Vedotin: Pivotal Phase II trial
Maximum Tumor Reduction per IRF
Tumour size (% change from baseline)
100
Complete remission by PET
50
0
94% (96 of 102) of patients achieved tumor reduction
–50
–100
Individual patients (n=98*)
Younes et al. J Clin Oncol, 2012, 30(18): 2183-2189.
Brentuximab Vedotin: Pivotal Phase II trial
PFS Results By Best Response
• Phase II pivotal study of brentuximab vedotin in 102 patients
with relapsed/refractory HL post ASCT: PFS by best response
Three-year Follow-up Data and Characterization of LongTerm Remissions from an Ongoing Phase 2 Study of
Brentuximab Vedotin in Patients with Relapsed or
Refractory Hodgkin Lymphoma
Gopal A, et al ASH 2013
OS from ASCT by BV
Karuturi, M et al ASH 2012
Brentuximab Vedotin
Initial treatment vs retreatment
HL
sALCL
N=102
Bartlet et al , ASCO 2012
N=15
N= 58
N=8
Proposed Algorithm for Treating
Patients post ASCT
ASCT
<CR/Rel
apse
CR
Brentuximab Vedotin
Observe (Role of
adjuvant BV?)
CR
Continue BV to
8-16 doses
Relapse from CR
Retreat with BV then allo-SCT
<CR
Consider allo
SCT
Continue BV until
disease progression
Rationale for Using HDAC Inhibitors in HL
Betlevi and Younes, Hematology Am Soc Hematol Educ Program. 2013
Mocetinostat in Relapsed
Hodgkin Lymphoma
31 year old female
Extensive Prior Therapy
Regimen
Best Response
ABVD
PR
XRT
Not Eval
DHAP
PR
Auto Transplant
Not Eval
IGEV
Progression
DHAP
Progression
Fludarabine/
Melphalan Progression
Allo Transplant
Progression
Donor lymphocyte Progression
MOPP
Not Eval
ESHAP
Progression
IEV
Progression
Younes et al Lancet Oncology 2012
Baseline
PET
CT (– 52% = PR)
2 months
Mocetinostat in Relapsed HL:
Clinical Responses
85 mg
110 mg
58% of subjects experienced tumor
reduction
Younes A, et al, Lancet Oncology, 2012, 12(13), 1222-1228.
Panobinostat in Patients with
Relapsed/Refractory HL
40 mg (fixed dose) orally, 3 times/week
0
1
2
3
4
5
6
Week
Restage:
If no PD Give Panobinostat
until PD or tox
Younes A, et al. Blood. 2009;114: Abstract 923.
International Panobinostat Phase II Study in
Relapsed HL
71% of patients with tumor reduction
Best % Change in SPD From Baseline
(index lesions only)
100
Active
Discontinued
75
PD
50
25
4 patients - SD (0%)
0
-25
6 patients - off AE prior to Eval 1
1 patient - withdrew consent prior to Eval 1
-50
PR
-75
5 patients with SPD < 50% had new
lesions at Eval 1
-100
Younes A,Soreda A,, et al. JCO 2012
Phase I Panobinostat (LBH589) + ICE
ICE
Transplant
LBH
PET/CT
Dose Level
LBH589 (Panobinostat)
Dose mg
N
-1
10
0
0
20
6
1
30
14
Results:
Evaluable patients : N=21
ORR : 86%, CR: 71% and all proceeded to ASCT
Oki Y, et al ASH 2013.
PI3K Pathway Inhibitors
GPCR
RTK TNFR
BCR
CD19
Survival
Proliferation
Growth
Metabolism
Apoptosis
Motility
BAD
GSK3
FOXO
p53
PI 3-kinase
Idelalisib
IPI-145
BKM-120
XL-147
GDC-0941
GSK1059615
AKT
MK-2206
XL-418
VQD002
mTORC1
Everolimus
Temsirolimus
Ridaforolimus
AZD8055
S6K1
Younes a, ASH 2013
4EBP1
BEZ-235
BGT226
XL765
Activity of PI3K/mTOR Inhibitors in
Lymphoma
Pathway Drug
PI3K/AKT/
mTOR
Target
% Response Rate in Different Histologies
DLBCL
FL
MCL
SLL/CLL
T-Cell
HL
Everolimus
mTOR
30%
50%
32%
18%
63%
42%
Temsirolimus
mTOR
36%
56%
38%
10%
-
-
Idelalisib
PI3K-δ
-
57%
67%
72%
-
12%
IPI-145
PI3K-γδ
0%
67%*
67%
54%
33%
33%
BAY80-6946
PI3K-αδ
13%
40%
71%
43%
50%
-
Updated from Younes A & Berry D. Nature Rev Clin Oncol 2012
Targeting PD1-PDL1
McDermott et al, Cancer Medicine 2013; 2(5): 662–673.
PD1/PD-L1 Blocking Agents in Clinical Trials
Source
Target molecule
PD-1
Merck
MK-3475
(humanized IgG4)
CureTech/Teva
CT-011
(humanized IgG1)
AmpliImmune/GSK
BMS
Genentech/ROCHE
PD-L1/PDL2
AMP-224
(PD-L2/IgG1 fusion protein
MDX-1106/BMS-936558
(Fully human IgG4)
MDX-1105/BMS-936559
(Fully human IgG4)
MPDL3280A
(Engineered IgG1)
Immune regulatory effects of panobinostat in patients
with Hodgkin lymphoma through modulation of T-cell
PD1 expression
Oki Y, …Younes A: Blood Cancer Journal (2014) 4, e236.
Single Agent Activity of New Agents in
Post SCT Relapsed cHL
Comparison to multiagent chemotherapy GVD
% Response rate
100
80
60
40
20
0
Betlevi and Younes, Hematology Am Soc Hematol Educ Program. 2013
CR
PR
Brentuximab-Vedotin Combination Strategies
HDACi
PD1/PDL1
MoAb
Brentuximab
Vedotin
Chemo
therapy
PI3Ki/
mTORi