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