Update in Hodgkins & DLBCL
Andy Chen, MD PhD
Center for Hematologic Malignancies
Knight Cancer Institute
Oregon Health & Science University
January 2012
Disclosures

Clinical trials: Seattle Genetics, Otsuka, Genentech

Advisory role*: Seattle Genetics, Novartis

Honoraria*: Seattle Genetics

This presentation will discuss off-label use and
investigational therapies
*All personal compensation donated to charity
Early stage Hodgkins: NCIC XRT vs ABVD




N 405
Stage IA or IIA non-bulky
 Poor risk: age ≥ 40, ESR ≥ 50, ≥ 4 sites, MC or LD histology
Randomization
 Chemo: ABVD x4-6 (only 4 if CR by CT after c2)
 XRT: STNI (+ initial ABVD x2 if poor risk)
STNI = mantle + spleen + upper abdomen

Primary endpoint: OS
Secondary endpoints: PFS, EFS

Closed early due to EORTC H8F: chemoXRT > XRT for 10 yr OS

Meyer, NEJM, 2011 & ASH, 2011
Early Hodgkins: NCIC XRT vs ABVD
OS: 87 vs 94 at 12 yrs
PFS: 92 vs 87 at 12 yrs
Meyer, NEJM, 2011 & ASH 2011
Early Hodgkins: NCIC ABVD vs XRT
XRT*
ABVD
(N = 203)
(N =196)
Death from Hodgkins
4
6
Any second cancer
23
10
Deaths from second cancer
10
4
Any cardiac
26
16
Death from cardiac
2
2
Death from infection
3
0
Other deaths
5^
0
Total deaths
24
12
Event
* Most XRT Deaths in ‘poor risk’ group
^ Other: Alzheimers, drowning, suicide, respiratory failure, unknown
Early Hodgkins: chemo or chemoXRT ?
N
(arm)
Median
f/u (yrs)
PFS
OS
NCIC ABVD x4-6
196
11
87
94
GHSG HD10 good risk
- ABVD x2 + 20 Gy
299
7
88
95
GHSG HD11 poor risk
- ABVD x4 + 30 Gy
356
7
85
94
GHSG HD14 poor risk
escBEACOPPx2 + ABVDx2 +
30 Gy
744
3
97
95
Study
Meyer, NEJM, 2011
Engert, NEJM, 2010
Eich, JCO, 2010
Borchmann, ASH, 2010
Advanced Hodgkins: MGI ABVD vs BEACOPP


N 331
Advanced Hodgkin (IIB, III, IV) or IPS ≥ 3

Randomization (stratified by stage or IPS)
 BEACOPP: 4 escalated + 4 basic
 ABVD x6-8 (only 6 if CR by CT after c4)

Planned salvage autoBMT if relapsed/refractory

Primary endpoint: freedom from 1st progression
Secondary endpoints: OS, freedom from 2nd progression, EFS

Gianni, NEJM, 2011
Advanced Hodgkins: MGI ABVD vs BEACOPP
Gianni, NEJM, 2011
Advanced Hodgkins: MGI ABVD vs BEACOPP
Gianni, NEJM, 2011
Advanced Hodgkin: ABVD vs escBEACOPP
Study
BEACOPP
Comparator
N
Median
f/u (mo)
Disease
Control
Overall
Survival
HD9
Esc x8
ABVD/COPP
alternatingx8
727
111
10 yr FFS
82 vs 64%
p<.001
10 yr
86 vs 75%
p<.001
HD2000
Esc x4 +
Base x2
ABVD x6
197
41
5 yr FFS
78 vs 65%
p=.04
5 yr
92 vs 84%
p=.89
MGI
Esc x4 +
Base x4
ABVD x6-8
331
61
5 yr FFP
85 vs 73%
p=.004
5 yr
89 vs 84%
P=.39
*All studies allowed consolidative XRT to bulky or residual sites
Rummel, JCO, 2009
Federico, JCO, 2009
Gianni, NEJM, 2011
Hodgkins: Consolidative XRT
Who needs consolidative XRT after chemo?

Prospective GHSG HD15 (BEACOPP): PET NPV 94%
Prospective studies after ABVD

Most early stage trials pre-PET & limited to low risk patients

Meta-analysis of early stage RCT: chemoXRT > chemo

British Columbia: retrospective series – omit if PET negative

EORTC H10: ABVD ± interim PET2 guided XRT

Chemo only arm closed early for increased failure ??
Hodgkins: Residual CT size in PET negative
105 negative PET post treatment
74 first line + 31 first relapse
76 CT-scan residual > 2cm
50
<4 cm
11 (22%)
relapse
26
> 4 cm
12 (46%)
relapse
29 No residual masses
3 (10%)
relapse
Single institution Italian series
Balzarotti, ASH, 2011
Hodgkins: Residual CT size in PET negative
Balzarotti, ASH, 2011
Hodgkins: Brentuximab vedotin + ABVD

Phase 1 dose escalation

Age 18-60, Stage IIa bulky or IIb-IV

Treatment Design
»
28 day cycles (x6) with SGN35 on d1 & 15 with chemo
»
Chemo: ABVD → AVD
Younes, ASH, 2011
Hodgkins: Brentuximab vedotin + ABVD

All evaluable (N 10) pts reached CR

97% PET2 negative (N 37)

No DLTs in cycle 1 in any cohort

MTD not reached
Younes, ASH, 2011
Hodgkins: Brentuximab vedotin + ABVD
ABVD cohorts: 40% pulmonary toxicity (10 of 25 pts)
» 20% severe (grade 3/4)
» Occurred during c3-6
No pulmonary toxicity in AVD cohorts
7% pts in ABVD cohorts discontinued due to neuropathy
» 52% incidence of any neuropathy
» All grade 1/2

Recommended dose for ph 3: 1.2 mg/kg + AVD
»
Note: AVD inferior to ABVD in GHSG HD13
Younes, ASH, 2011
Hodgkins: Key Points

ABVD alone: option in non-bulky early stage

Consider for young women
 Toxicity of more chemo vs modern XRT ?

escBEACOPP : OS benefit still uncertain


Consider XRT to residual large nodes even if PET negative


EORTC 20012 results pending
Multiple studies ongoing
Brentuximab vedotin (SGN35) + bleomycin → high toxicity

Not ready for frontline use
DLBCL: Frontline therapy
R-CHOP is standard

Intensive regimens not superior to CHOP
»
»
Exception French ACVBP ?
R-EPOCH vs R-CHOP ongoing

No benefit from maintenance R

Dose dense q14 days not superior to q21

8 cycles not better than 6 (at least for q14)

No proven benefit to intrathecal prophylaxis
Fisher, NEJM, 2003
Pfreundschuh, Lanc Onc, 2006
Tilly, Blood, 2003
Reyes, NEJM, 2005
Habermann, JCO, 2006
Cunningham, ASCO, 2009
Delarue, ASH, 2009
Pfreundschuh, Lanc Onc, 2008
Nickelsen, ASH, 2009
Milpied, ASH, 2010
DLBCL: Improving R-CHOP
Modifications to immuno-therapy
 Dosing of Rituximab
 Next generation anti-CD20
 Additional target (CD22)
Modifications to chemo
 Bortezomib
»

especially in Activated B cell (ABC) type?
‘Targeted’ agents
Protein kinase C (PKC) inhibitor (enzastaurin)
» Lenalidomide
»
DLBCL: Consolidative autoBMT
SWOG 9704
Italian DLCL04
German
MegaCHOEP
Criteria
IPI 3-5
aaIPI 2-3
aaIPI 2-3
Chemo
(R) CHOP x8
R-CHOP-14 x8
R-CHOEP-14 x8
CBV, BEAM or TBI
R-MAD + BEAM
R-MegaCHOEP x4
370
392
262
PFS
2 yr: 69 vs 56 %
2 yr: 71 vs 59 %
3 yr: 70 vs 74 %
OS
2 yr: 74 vs 71 %
2 yr: 83 vs 83 %
3 yr: 77 vs 85 %
BMT
N
Stiff, ASCO, 2011
Vitolo, ICML, 2011
Schmitz, ASCO, 2011
DLBCL: Consolidative autoBMT - Notes
SWOG 9704: most benefit in high IPI (2 yr OS 82 vs 64%)
- 55% pts got CHOP (no Rituximab)
- No benefit from Rituximab on PFS or OS
Italian DLCL04: no difference R-CHOP vs augmented R-CHOP
MegaCHOEP: non-standard chemo/BMT regimen
- only 4 cycles & significantly increased toxicity
French GELA & British BNLI studies ongoing
DLBCL: Improving Salvage - CORAL


N 398
Median f/u 2 yrs
Gisselbrecht, JCO, 2010
DLBCL: Improving Salvage - CORAL
Restrict to early relapse
All pts by Tx Arm
Gisselbrecht, JCO, 2010
DLBCL: Improving Salvage - CORAL
R-DHAP: PFS
R-ICE: PFS
GCB by Hans IHC algorithm
 CD10+
 CD10-, BCL6+, MUM1/IRF4-
Thieblemont, JCO, 2011
DLBCL: CORAL post-BMT maintenance
Observation n = 120
1.0
Rituximab n = 122
0.8
0.6
0.4
0.2
p = 0.7435
0.0
0
12
24
36
48
60
72
EFS (months)
Gisselbrecht, ICML, 2011
DLBCL: Improving BMT - BexxarBEAM
BMT CTN 0401
100
100
No difference in PFS, OS, TRM
Significant increase in mucositis
90
80
90
80
70
70
Rituxan/BEAM (N=113)
60
60
50
50
Bexxar/BEAM (N=111)
40
40
30
30
20
20
Bexxar/BEAM @ 2 yrs: 48.6% (95% CI, 39.0%, 57.5%)
10
p=0.65
10
Rituxan/BEAM @ 2 yrs: 49.0% (95% CI, 39.3%, 58.0%)
0
0
0
6
12
18
24
30
36
42
48
Months
Vose, ASH, 2011
DLBCL: Key Points

R-CHOP-21 still the standard

Consolidative (frontline) autoBMT remains controversial

Early relapse after R-CHOP has very poor prognosis

Consider R-DHAP to salvage Germinal Center subtype

No benefit from Rituximab maintenance after autoBMT

No benefit from radio-immunotherapy in BMT
Aggressive lymphoma: Missing in Action

Effective therapy for ‘double hit’ (unclassifiable, Myc+)

Optimal treatment for Peripheral T cell lymphoma

Novel drugs for relapsed/refractory DLBCL
In Rituximab era:
More pts cured upfront,
But - fewer pts salvaged at relapse,
= NO net improvement in cure rates