update in hodgkins & dlbcl
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
Update in Hodgkins & DLBCL
Andy Chen, MD PhDCenter for Hematologic Malignancies
Knight Cancer InstituteOregon 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
Meyer, NEJM, 2011 & ASH 2011
OS: 87 vs 94 at 12 yrs
PFS: 92 vs 87 at 12 yrs
Early Hodgkins: NCIC ABVD vs XRT
Event XRT*(N = 203)
ABVD (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
* Most XRT Deaths in ‘poor risk’ group^ Other: Alzheimers, drowning, suicide, respiratory failure, unknown
Early Hodgkins: chemo or chemoXRT ?
Meyer, NEJM, 2011Engert, NEJM, 2010
Study 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 riskescBEACOPPx2 + ABVDx2 + 30 Gy
744 3 97 95
Eich, JCO, 2010Borchmann, 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 FFS82 vs 64%p<.001
10 yr86 vs 75%p<.001
HD2000 Esc x4 +Base x2
ABVD x6 197 41 5 yr FFS78 vs 65%p=.04
5 yr92 vs 84%p=.89
MGI Esc x4 +Base x4
ABVD x6-8 331 61 5 yr FFP85 vs 73%p=.004
5 yr89 vs 84%P=.39
Rummel, JCO, 2009 Federico, JCO, 2009 Gianni, NEJM, 2011
*All studies allowed consolidative XRT to bulky or residual sites
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
Balzarotti, ASH, 2011
29 No residual masses
105 negative PET post treatment74 first line + 31 first relapse
76 CT-scan residual > 2cm
50<4 cm
26> 4 cm
11 (22%)relapse
12 (46%)relapse
3 (10%)relapse
Single institution Italian series
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 c3-6No 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 EORTC 20012 results pending
Consider XRT to residual large nodes even if PET negative 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, 2003Pfreundschuh, Lanc Onc, 2006Tilly, Blood, 2003Reyes, NEJM, 2005
Pfreundschuh, Lanc Onc, 2008Nickelsen, ASH, 2009Milpied, ASH, 2010
Habermann, JCO, 2006Cunningham, ASCO, 2009Delarue, ASH, 2009
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
Schmitz, ASCO, 2011
SWOG 9704 Italian DLCL04German
MegaCHOEP
Criteria IPI 3-5 aaIPI 2-3 aaIPI 2-3
Chemo (R) CHOP x8 R-CHOP-14 x8 R-CHOEP-14 x8
BMT CBV, BEAM or TBI R-MAD + BEAM R-MegaCHOEP x4
N 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 %
Vitolo, ICML, 2011Stiff, 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-ICE: PFSR-DHAP: PFS
Thieblemont, JCO, 2011
GCB by Hans IHC algorithm CD10+ CD10-, BCL6+, MUM1/IRF4-
DLBCL: CORAL post-BMT maintenance
Gisselbrecht, ICML, 2011
EFS (months)
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60 72
p = 0.7435
Observation n = 120
Rituximab n = 122
DLBCL: Improving BMT - BexxarBEAM
Months0 12 24 48
100
0
20
40
60
80
90
10
30
50
70
0
100
20
40
60
80
90
10
30
50
70
6 18 30 36 42
Rituxan/BEAM (N=113)
Bexxar/BEAM (N=111)
Bexxar/BEAM @ 2 yrs: 48.6% (95% CI, 39.0%, 57.5%) p=0.65
Rituxan/BEAM @ 2 yrs: 49.0% (95% CI, 39.3%, 58.0%)
No difference in PFS, OS, TRMSignificant increase in mucositis
Vose, ASH, 2011
BMT CTN 0401
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