1. Management of Hodgkin Lymphoma:
An ASCO/ICML Update
F B Hagemeister, MD
Professor of Medicine
Department of Lymphoma and Myeloma
M D Anderson Cancer Center
Bangkok 28 August 2015
2. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
3. BV Consolidation After Auto SCT for
Primary Refractory HL
• 2 yr PFS and 3 Yr OS rates for this group are 40% and
50%, respectively, post autoAST.
• AETHERA: BV vs placebo for Rel/Ref HL after ASCT
Initial
Therapy
Relapse
Assess
RFs
Primary
Refractory
< 12 Mo
remission
Relapse > 12
Mo with EN DZ
Salvage
Therapy
PD
Off
Study
ASCT
BV
Placebo
Moskowitz et al. ICML-13, 2015, #120.
CR
PR
SD
Treatment Schema
Crossover to
BV at PD
4. BV after ASCT for Primary Refractory HL
Subgroup Feature No. Pts (%) HR Range
EN DZ Yes 53 (27) 0.37 0.18-0.78
No 143 (73) 0.61 0.37-0.98
B Symptoms Yes 56 (28) 0.36 0.19-0.72
No 140 (72) 0.63 0.38-1.04
# Prior TXs > 2 97 (49) 0.39 0.22-0.71
2 99 (51) 0.79 0.44-1.4
# of RFs > 1 196 (100) 0.55 0.37-0.83
> 2 175 (90) 0.47 0.31-0.72
> 3 110 (57) 0.4 0.24-0.66
Moskowitz et al. ICML-13, 2015, #120.
• Study of 196 Patients with Primary Refractory HL.
• PFS results favor BV in all groups.
• The lower the HR, the more significant the difference
5. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
6. Phase II BV Plus AVD for
34 Non-Bulky Stage I-II HL
• Treatment Schema
Abramson et al. ASCO 2014, Abst 8505.
BV x 2
1.2mg/k
g q 2 wk
PET CR,
PR, SD
Enroll
PD off
study
A-AVD
X 2
PET CR
PET PR
or SD
PD off
study
A-AVD X 2
A-AVD X 4
• Patients: Favorable in 68%, unfavorable in 32%.
• CR rates: After BV, 18 pt (53%). After 2 A-AVD, 33 pt (97%).
At end of therapy, CR=88%, and 6/8 Pos PETs were
false positive (? due to BV).
• Gr 3-4 AEs: FN in 29%, PN in 24%
• At med f/u of 14 mo, PFS=90% and OS= 97%.
• Randomized study needed to prove benefit of BV
7. Phase I/II Brentuximab Plus Bendamustine
for Relapsed/Refractory HL
• CR rates for Rel/Ref HL with standard agents range 19-60%
– Brentuximab vedotin alone: CR 34%
– Bendamustine alone: CR 33%
• Treatment Plan: 1.8 mg/m2 BV day 1, Benda 90 mg/m2 days 1,2.
– Cycles repeated q 3 wks
– Benda de-escalated if DLT (delay of > 2 wk) in > 3/10 pts.
• Tolerability: No DLT reached
• Infusion Reactions before adding Steroids and Antihistamines
LaCasce et al. ASH 2014 # 293; Kuruvilla et al. ICML-13, 2015, # 80.
Tming # Pts SAEs Gr 3 Stop Tx
Prior to giving S and A 36 6 8 6
After adding S and A 20 0 2 1
8. Phase I/II Brentuximab Plus Bendamustine
for Relapsed/Refractory HL
• For a total of 54 patients, 48 are evaluable
• Features:
• Comparisons of Therapy
• 20 pts went to SCT with good collections,1 relapsed
Disease Status Dur Prior Resp Patients (%)
Primary Refractory Not applicable 27 (50)
Relapsed < 1 Yr 10 (19)
Relapsed > 1 Yr 17 (31)
Studies ORR (%) CR (%) MED PFS
BV Alone 75 34 12 mo for CRs
BV + Benda 96 83 NR for ORRs
LaCasce et al. ASH 2014 # 293; Kuruvilla et al. ICML-13, 2015, # 80.
9. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
10. FDG-PET positive
16 Patients, prog=11
2-year PFS 0%
1.0
.08
.06
.04
.02
0.0
PercentProgression-Free
PET neg
61 Pts, 3 prog
2 yr PFS 96%
3210
PET after 2 cycles
P < .001
Years
1.0
.08
.06
.04
.02
0.0PercentProgression-Free
CR, PR
2 Pts, 0 prog
2 yr PFS 100%
3210
CT after 2 cycles
< PR
62 Pts, 11 prog
2 yr PFS 82%
P < .554
Years
PET vs CT for Stage I-IV HL: PFS by
Radiographs after 2 CT Cycles
Hutchings et al. Blood 107:52-59, 2006
PET ps
14 Pts, 11 prog
2 yr PFS 0%
11. Reasons for the “False Positive” PET
Intrinsic – hardware
– Improved detection
Criteria for positive
– Visual or SUV
– Reader variation
Benign variants
– Sarcoidosis
– Thyroiditis
Inflammation
– Infection
– Trauma
Iatrogenic causes
– Injections
– Post RT
– Post Surgery
Type/Location of lymphoma
– Marginal Zone/SLL/T-Cell
– Bowel, Marrow Disease
– Hyperplasia?
Other tumors
– Benign
• Warthin’s
• Thyroid adenomas
• Bowel adenomas
– Malignant (Any)
Therapy
– Use of Rituximab
– G-CSF
Timing of scan
– How many days after last
chemotherapy
12. Routine Imaging Strategies (RIS) for
Classical HL in First Remission
• Three centers: Retrospective comparison of Clinical (CS)
and RIS
• RIS by NCCN: Imaging Q 6 mo for 2-3 years
Chemotherapy: ABVD - 79%, Stanford V - 15%
Pingali et al, ASCO 2013 # 8505.
Group Mean #
scans
%
Deaths
%
Relapses
Scans per
Relapse
CS, n=77 1.14 4.6 6.6 17.6
RIS, n=164 4.25 5.3 4.6 122.3
• RIS conferred no OS advantage (p=0.47)
• CR rates with relapse therapies were also similar for
CS and RIS Suggests that routine imaging after
therapy is completely unnecessary.
13. IFRT vs None for After 3 ABVD for PET Neg
Stage I-IIA HL: The UK NCRI RAPID Trial
602 cases with newly diagnosed, stage IA/IIA HL
without bulky med mass after 3 cycles of ABVD
Therapy Choice according to the PET Result, n=571
PET Negative (75%) PET Positive
IF RT
(n=209)
No Further
Therapy (n=211)
4th ABVD cycle +
IF RT (n=145)
Radford et al. NEJM 372: 1598-1607, 2015.
14. IFRT vs None for PET Negative HL
After 3 ABVD: The RAPID Trial
Result IF RT
(n=209)
No RT
(n=211)
4xABVD + IF
RT (n=145)
Progressive DZ 8 20 12
3 YR PFS 94.5% 90.8% 86%
3 YR OS 97.1% 99.5% 94%
Radford et al. NEJM 372: 1598-1607, 2015
From randomization From registration
Median FU:
48.6 months
There is a 4% improvement by giving RT to those with
negative PET, considered “acceptable” for no RT.
16. PET Scan Results From the RAPID Trial:
Prognostic Value of the Positive PET
Radford et al. ICML-13, 2015, #82
• Positive PET after 3 ABVD defined as Deauville
score of 3-5
• 145 received a 4th
ABVD and IFRT
• 88% and 85% had risk criteria to define EORTC
and GHSG favorable HL (66% and 68%,
respectively).
• P values by MVA: PET 3-5: 0.001, EORTC: 0.48,
GHSG: 0.62
• By Hazard Ratios: PET 5 vs 4- 6.7, vs 3- 9.3, vs 2-
3.2, vs 1- 5.1.
17. 2 ABVD
2 ABVD
2 BEACOPPesc + RT 30
H10H10
FavFav P
E
T
2 ABVD
1 ABVD + RT 30PET
+
-
+
2 ABVD
4 ABVD
2 BEACOPPesc + RT 30
H10H10
UnfavUnfav P
E
T
2 ABVD
2 ABVD + RT 30PET
+
-
+
RR
RR
EORTC/GELA/IIL HD10 Study of ABVD for
Early-Staged HL
Using PET
Raemakers et al. JCO 32: 1-
8, 2014
18. Intergroup H10 Trial of PET Driven Therapy
for Stage I/II HL: An Interim Analysis
Favorable: Supradiaphragmatic disease, CS1-2 with 1-3 nodal
areas, MTR < .35, Age <50, ESR < 50 with B SX or < 30 with B SX
Unfavorable: Any of the above features
Raemakers et al. JCO 32: 1-8, 2014
Feature Therapy No. Pt Relapse 1 Yr PFS % P
Favorable 3 ABVD/RT 188 1 100
4 ABVD 193 9 94.9 0.017
Unfavorable 4 ABVD/RT 251 7 97.3
6 ABVD 268 16 94.7 0.026
Despite these good results, because of the inferior results
with only chemotherapy, the chemotherapy-only arms
were closed to patient entry.
19. The HD10 Trial: BEACOPP for PET
Positive HL After Two ABVD
• EORTC-defined Stage I-II HL
• PET positive considered Deauville Score 3-5
N=1950 Randomized
Unfavorable
N=1196
Favorable
N=754
ABVD
N=54,14%
BEACOPP
N=43,11%
ABVD
N=138,23%
BEACOPP
N=126, 21%
PET Positive
Raemakers et al. ICML 2015
5 Yr Result ABVD + RT (%) BEACOPP + RT (%) P value
PFS 77 91 0.002
OS 89 96 0.062
20. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
21. ABVD vs BEACOPP vs CEC for Advanced
HL: The Fondazione Italiana HD 2000 Trial
ABVD x 6 (N=103)
BEACOPPesc x 4,
BEACOPPstd x 2
(N=100)
CEC x 6
(alternating
COPP/EBV/CAD)
(N=102)
R
Merli et al. ASH 2014 # 499
RT
in
130
305 Pts
cHL
Stages
IIB, III, IV
22. 10 Yr Results ABVD BEACOPP CEC P
PFS (%) 69 74 74 0.64
OS 84 84 86 0.88
# MDS/AML 0 1 1 -
# NHL 0 1 1 -
# Solid
Tumors
1 4 2 -
2nd
Ca Risk 0.9 6.7 4.4 ** P = 0.027 for BEACOPP vs ABVD
• Early data had better PFS with BEACOPP than ABVD
• With longer follow-up, PFS advantage of BEACOPP is
diminished by deaths due to second cancers
ABVD vs BEACOPP vs CEC for Advanced
HL: The HD 2000 Trial
Merli et al. ASH 2014 # 499
23. GITIL HD0607 Study of BEACOPP + R After 2
ABVD for PET Positive Stage II-IV 497 HL
PET
IIB-IVB, IIA
with >3 nodal
sites, ESR >
50, or bulky dz
PET positive, n=41, 15% PET negative, n=222, 84%
Gallamini et al, ASCO 2010 # 8006
Gallamini et al, ASH 2012 #.550
CR n=212/222CR n=30/41 REF n=6REF n=8
Primary
endpoint:
3 Yr FFS
ABVD x2
ABVD x4 ± RT
PR n=1
4 escBEACOPP vs
4 escBEACOPP
+ R
PR n=2
If PET Neg after
4 ABVD, RT randomized
24. BEACOPP + R for PET Pos Stage II-IV HL
After 2 ABVD: The GITIL/FIL HD0607 Study
Gallamini et al, ASCO 2010 # 8006
Gallamini et al, ASH 2012 # 550
PET Neg
PET Pos
All Patients
(Comparison Data)
Failure Free Survival Results
Updated 1 YR PFS
Results:
97.3, 94.7, 80.5%
25. BEACOPP + R for PET Positive PET After
Two ABVD: ICMLTreatment Outcomes
Response PET2 Neg % PET2 Pos % Total
CR 520 96 89 75 605
PR 4 0.7 3 2.6 7
SD 4 0.7 1 0.9 5
PD 6 1.1 13 11 19
Relapse 4 0.7 7 6 11
Gallamini et al. ICML-13, 2015
2 Yr FFS
PET Neg
ABVD + RT (%) ABVD No RT (%) P value
88 94 0.063
2 Yr FFS
PET Pos
R-BEACOPP (%) BEACOPP (%)
62 72 0.27
2 Yr OS by PET Pos, 91% Neg, 99% <0.001
26. Phase II ASCT for PET Positive HL
After Two ABVD: A FIL HD0801 Trial
1. 512 patients with Untreated Stage IIB-IV HL
2. Therapy: 2 ABVD then a PET
• Negative PET (Deauville 1-2) receives 4 ABVD
1) If Pos at end, off study
2) If Neg at end, randomize RT
• Positive PET (Deauville 3-5) receives 4 IGEV
1) If Pos at end, and no donor, receives M/BEAM
and ASCT
2) If Pos at end, with donor, receives M and AlloSCT
3) If Neg at end, receives BEAM and SCT
Zinzani et al. ICML-13, 2015.
Result All (%) Pos (%) Neg (%) P value
2 Yr PFS from PET2 79 76 81 NS
2 Yr OS from Start 96 - - -
27. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
28. PD-1 is Inactivated by PD-L1 and PD-L2
on Tumor Cells
• PD-1 is a protein on T-Cells that dampens the normal
immune response
•Tumor cells can evade normal T-cell attack
• Inactivate T-cell function by activation of PD-1 via PD-L1 and
PD-L2
• T-Cells are “exhausted”
• Cannot attack tumor cells
• Inactivation is reversible
29. PD-L1 is Upregulated in Tumor cells
• Chromosome 9p24.1 amplification upregulates
PD-L1, as can EBV infection
• Multiple tumor types utilize the PD-L1 and PD-L2
interaction with PD-1 to escape immune
surveillance
– Breast, NSCLC, Kidney, Colon, Melanoma,
Hematologic Malignancies overexpress PD Ligands
– Pembrolizumab FDA-approved for Metastatic
Melanoma
– Nivolumab recently approved for Metastatic
Melanoma
– Ongoing studies in many other tumors
30. Phase I Nivolumab in Rel/Ref HL: Preliminary
Safety, Efficacy and Biomarker Results
• 23 Hodgkin lymphoma patients from larger study in
hematologic malignancies
– Dosing: 1-3 mg/kg with no MTD reached in Phase I
– Expansion cohort 3 mg/kg chosen, week 1, 4 and q 2
wk for maximum 2 years
• Drug-related adverse events (> 10%, all reversible)
Armand et al. ASH 2014 # 289; Timmerman et al. ICML-13, 2015, # 10.
Event Any Gr, # (%) Gr 3, # (%)
Any 18 (78) 5 (22)
Rash 5 (22) 0
Platelets 4 (17) 0
Fatigue, fever, diarrhea,
nausea, pruritis
3 each (13) 0
31. Armand et al. ASH 2014 # 289; Timmerman et al. ICML-13, 2015, #10.
Phase I Nivolumab in Rel/Ref HL: Preliminary
Safety, Efficacy and Biomarker Results
Response Pts,
N =24
(%)
SCT Fail,
BV Fail
N=15, %
SCT Naïve,
BV Fail
N=3, %
BV
Naïve
N=5,%
Overall 20 (87) 87 100 80
Best Resp CR 4 (17) 7 0 60
PR 16 (70) 80 100 20
SD 3 (13) 13 0 20
6 MO PFS % 86 85 n/c 80
1st
evaluation at 8 weeks of therapy
Median follow-up – 40 weeks
32. Phase Ib Pembrolizumab (MK-3475) for HL after
Brentuximab Failure: KEYNOTE-013
• 31 with Rel/Ref HL: Path NS or MC
– All relapsed from or failed BV therapy
– 3 or more prior therapies in 28 (97%)
– Prior ASCT = 20 (69%)
• Pembrolizumab given 10mg/kg every 2 weeks
– Evaluation based on response at 12 weeks (6 doses)
• Tolerability: 16 (55%) of pts experienced one or more
treatment-related Aes, but no Gr 4-5 events.
• Results at med follow-up at 38 weeks
– 29 Cases evaluable
– ORR 66%, CR 21%, PR 45%, SD 21%
Moskowitz, ASH 2014 # 290
34. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
35. Gem/Bu/Mel SCT for Refractory or High-Risk
HL: Comparison with Other Regimens
Nieto et al. Biol Blood Marrow Transplant 19: 410-417, 2013.
EFS Results
P=0.01
OS Results P=0.04
36. Management of Hodgkin Lymphoma:
An ASCO/ICML Update
F B Hagemeister, MD
Professor of Medicine
Department of Lymphoma and Myeloma
M D Anderson Cancer Center
Bangkok 28 August 2015
