Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida

Diffuse Large Cell Lymphoma Cell of Origin – Ready for Prime Time?

Thomas Witzig, MDHematology Malignancy Program

Mayo Clinic Cancer Center

Disclosure

Research funding from Celgene, Novartis, Millenium for clinical trials

Research funding from Millenium for preclinical work

Advisory boards for Spectrum, Celgene, and Bayer (no personal compensation)

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Time for Action?

Origins Research in DLBCL

Lancet Oncol. 2014 Jun;15(7):674-5

Cell of Origin Techniques

Gene expression profiling Microarrays on RNA expression Frozen tissue Thousands of genes Year 2000 onward

Immunohistochemistry 2004; Many algorithms; Hans still most

widely used 2014 - Lymph2Cx

Blood. 2014 Feb 20;123(8):1214-7

15 Years Ago

Nature. 2000 Feb 3;403(6769):503-11.

“And like most overnight successes, it was about twenty years in the making” S. Walton originator of WalMart

Nature. 2000 Feb 3;403(6769):503-11.

Nature. 2000 Feb 3;403(6769):503-11.

Prognostic in the Pre-RCHOP Era

Hans Method – 10 Years Ago

Hans et al Blood. 2004;103(1):275-82.

OS by TMA

Hans et al Blood. 2004;103(1):275-82.

Meyer PN et al J Clin Oncol 2011;29(2):200-7.

• 262 cases of DLBCL; 192 had GEP

Meyer P N et al. JCO 2011;29:200-2072011 by American Society of Clinical Oncology

Event-free survival of patients with diffuse large B-cell lymphoma according to immunophenotype by each algorithm.

Meyer P N et al. JCO 2011;29:200-2072011 by American Society of Clinical Oncology

Tally

Hans

Overall survival of patients with diffuse large B-cell lymphoma according to immunophenotype by each algorithm.

Meyer P N et al. JCO 2011;29:200-207

©2011 by American Society of Clinical Oncology

Tally

Hans

Blood. 2014 Feb 20;123(8):1214-7

Blood. 2014 Feb 20;123(8):1214-7

Lymph2Cx

Blood. 2014 Feb 20;123(8):1214-7

Lymph2Cx

Matched FFPE and frozen Traditional GEP; IHC; and Lymph2Cx Training cohort – 51 cases

20 GCB; 19 ABC; 12 unclassified Validation cohort – 68 cases

28 GCB; 30 ABC; 10 unclassified 10 micron scrolls; Qiagen AllPrep FFPET kit

Extract RNA from FFPE tissue slice Digital GEP on 200 ng RNA using Nanostring

technology Sample split and run independently in 2 labs

Blood. 2014 Feb 20;123(8):1214-7

Lymph2Cx

Tested 93 genes found by Lenz et al to differentiate GCB from ABC (Lenz NEJM 2008)

20 were all that were needed 15 of the 93 and 5 “housekeeping genes”

NanoString technology on 20 genes was used in these two datasets

Blood. 2014 Feb 20;123(8):1214-7

Lymph2Cx

Gold Standard GEP

PFS OS

Prognosis or Helping Choose Therapy?Which drug to add?????

Cell of Origin

65 Years of Lymphoma Rx

1949 1963 1997 ‘02

Rituximab

RIT

RCHOP2-CDA

19991975

CHOPABVD

NitrogenMustard

VincristineDoxorubicin

1993

CHOPWins!

VP-16

1978

Autologous SCTCis-platinum

03

Bort

1953

Methotrexate

1983 ‘07

LenalidomideEverolimusVorinostat

‘05

Bendamustine

‘09

PralatrexRomadep

Era of Targeted TherapyEra of Chemotherapy

2011

BrentuxIbrutinib

Lenalidomide

2013

Idelalisib

2014

CP1171726-10

R-CHOP is 15% Better than CHOPR-CHOP is 15% Better than CHOP

Pro

babi

lity

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

HR=0.64p=0.003HR=0.64p=0.003

R-CHOPR-CHOP

CHOPCHOP

Pro

babi

lity

Pro

babi

lity

Years from Induction RandomizationYears from Induction Randomization

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

HR=0.72p=0.05HR=0.72p=0.05

R-CHOPR-CHOP

CHOPCHOP

Failure-Free Failure-Free SurvivalSurvival

Overall Overall SurvivalSurvival

Coiffier et al N Engl J Med. 2002; Habermann et al J Clin Oncol 2006

R(X)CHOP Era – what is X?

Epratuzumab - ERCHOP Lenalidomide – R2CHOP Bortezomib – Bor-RCHOP Everolimus – ER-CHOP; maintenance

E inCRADN2301 (enrolled)

Everolimus – EverRCHOP – N1085 Ibrutinib – IR-CHOP

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Ann Oncol. 2014. Epub 2014/03/15

MC078E – Phase II Results

Phase I/II trial of R2CHOP for untreated DLBCL Any age RCHOP + lenalidomide 25 mg days 1-10 q21 x 6

cycles ASA daily Pegfilgrastim day 2 No maintenance

Cell of origin by Hans algorithm

Nowakowski G et al J Clin Oncol. 2014. Epub 2014/08/20

MC078E

64 patients enrolled; 60 evaluable 87 controls at same time with RCHOP ORR 98% (59/60) CR 80% (48/60) Event-free survival at 24 months - 59% Overall survival at 24 months - 78% No difference in GCB vs non-GCB in R2CHOP arm

Nowakowski G et al J Clin Oncol. 2014. Epub 2014/08/20

MC078E

RCHOP control EFS/OS at two years for GCB: 46% and 78% EFS/OS at two years for non-GCB: 28% and 64%

R2CHOP EFS/OS at two years for GCB: 60% and 83% EFS/OS at two years for non-GCB: 59% and 75%

Nowakowski G et al J Clin Oncol. 2014. Epub 2014/08/20

Nowakowski G et al J Clin Oncol. 2014. Epub 2014/08/20

R2CHOP R2CHOP

RCHOP RCHOP

Nowakowski G et al J Clin Oncol. 2014. Epub 2014/08/20

R2CHOPRCHOP R2CHOPRCHOP

RCHOP

R2CHOP

Italian R2CHOP

DLBCL and FL 3b R2CHOP in 13 centers in Italy GCB vs non-GCB by IHC (Hans) Standard RCHOP x 6 Lenalidomide 15 mg days 1-14 q 21 49 patients 92% (45/49) ORR with 86% functional CR

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Lancet Oncol. 2014;15(7):730-7.

Outcome of R2CHOP (Italian)

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Vitolo et al Lancet Oncol. 2014;15(7):730-7.

GCB vs. non-GCB31

Lancet Oncol. 2014;15(7):730-7.

©2011 MFMER | slide-32

©2011 MFMER | slide-33

ECOG 1412

• Randomized phase II of RCHOP vs. R2CHOP

• First patient in September 19, 2013

• GCB and ABC

• Endpoint is response in ABC as defined by GEP• Nanostring on paraffin-embedded tissue

• 110 patients accrued as of October 2014

DLBCL-002

FDA registrational, International Phase III RCHOP x 6 vs. R2CHOP x 6 Lenalidomide 15 mg days 1-14 vs. placebo

Untreated DLBCL Stage II-IV Ages 18-80 years Requires excisional biopsy ABC by Nanostring GEP on FFPE tissue

Promised 5 day turnaround; steroids allowed 600 patients Opening Dec 2014

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Furman RR et al Cancer. 2010;116(23):5432-9.

L. Staudt

Bortezomib R-CHOP

20 patients – 16 DLBCL/4 MCL Median age 66 years (range, 29-84) Standard RCHOP-21 Bortezomib - Days 1 and 4 of each cycle

0.7 mg/m2 - 4 patients 1.0 mg/m2 - 9 patients 1.3 mg/m2 - 7 patients

No DLT with any dose; grade 3 neuropathy in 1

95% CR

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Furman RR et al Cancer. 2010;116(23):5432-9.

Bortezomib R-CHOP

At a median follow-up of 56 months Overall survival at 4 years was 75% Progression-free survival was 58%

Randomized phase II of RCHOP vs. RBCHOP in progress in US

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Furman RR et al Cancer. 2010;116(23):5432-9.

Phase III Trials

RCHOP vs. Bor-RCHOP in UK

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Start May 2011 and predicted to end in 2015

Ibrutinib with RCHOP40

Younes A et al Lancet Oncol. 2014 Aug;15(9):1019-26.

IR-CHOP

Phase 1/2 DLBCL, MCL, FL June 2012 – May 2013 No ASA, warfarin, heparin allowed RCHOP x 6 + ibrutinib daily No maintenance No prophylactic G-CSF (allowed but not

mandated)

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Younes A et al Lancet Oncol. 2014;15(9):1019-26

IR-CHOP

33 patients No MTD for ibrutinib; thus 560 mg/d

continuously with standard RCHOP-21 18% febrile neutropenia 18 pts with DLBCL in the phase 2

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Younes A et al Lancet Oncol. 2014;15(9):1019-26

IR-CHOP

100% ORR in the DLBCL (18/18) 15 CR and 3 PR 4/4 nonGCB – CR 5/7 GCB – CR

PK not affected for either ibrutinib or vincristine

A randomized phase III is ongoing –placebo controlled (NCT01855750) for non-GCB type

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Younes A et al Lancet Oncol. 2014;15(9):1019-26

Summary about COO in DLBCL Increases understanding of the biology Helps predict prognosis but not particularly

well May guide therapy

New treatments with lenalidomide and ibrutinib are focusing on ABC-type

New techniques of GEP will enhance the clinical utility and “bring it to your hospital”

Prediction – you will use COO to “choose X”

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