Diffuse Large Cell Lymphoma Cell
of Origin – Ready for Prime Time?
Thomas Witzig, MD
Hematology Malignancy Program
Mayo Clinic Cancer Center
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Disclosure
2
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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)
Origins Research in DLBCL
Time for Action?
Lancet Oncol. 2014 Jun;15(7):674-5
Cell of Origin Techniques
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Gene expression profiling
 Microarrays
on RNA expression
 Frozen tissue
 Thousands of genes
 Year 2000 onward
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Immunohistochemistry
 2004;
Many algorithms; Hans still most widely
used
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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.
Prognostic in the Pre-RCHOP Era
Nature. 2000 Feb 3;403(6769):503-11.
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.
• 262 cases of DLBCL; 192 had GEP
Meyer PN et al J Clin Oncol 2011;29(2):200-7.
2011 by American Society of Clinical Oncology
Meyer P N et al. JCO 2011;29:200-207
Event-free survival of patients with diffuse large B-cell lymphoma according to
immunophenotype by each algorithm.
Hans
Tally
Meyer P N et al. JCO 2011;29:200-207
2011 by American Society of Clinical Oncology
Overall survival of patients with diffuse large B-cell lymphoma according to
immunophenotype by each algorithm.
Hans
Tally
Meyer P N et al. JCO 2011;29:200-207
©2011 by American Society of Clinical Oncology
Blood. 2014 Feb 20;123(8):1214-7
Lymph2Cx
Blood. 2014 Feb 20;123(8):1214-7
Lymph2Cx
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Matched FFPE and frozen
Traditional GEP; IHC; and Lymph2Cx
Training cohort – 51 cases
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Validation cohort – 68 cases
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28 GCB; 30 ABC; 10 unclassified
10 micron scrolls; Qiagen AllPrep FFPET kit
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20 GCB; 19 ABC; 12 unclassified
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
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Tested 93 genes found by Lenz et al to differentiate
GCB from ABC (Lenz NEJM 2008)
20 were all that were needed
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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
PFS
OS
Lymph2Cx
Gold Standard
GEP
Blood. 2014 Feb 20;123(8):1214-7
Cell of Origin
Prognosis or Helping Choose Therapy?
Which drug to add?????
Bendamustine
65 Years of Lymphoma Rx
Lenalidomide
Everolimus
Vorinostat
Rituximab
RIT
Autologous SCT
Cis-platinum
Methotrexate
Pralatrex
Romadep
CHOP
ABVD
CHOP
Wins!
Vincristine
Doxorubicin
Nitrogen
Mustard
1949
RCHOP
2-CDA
Bort
VP-16
1953 1963
1975
1978 1983 1993 1997
Era of Chemotherapy
Brentux
2011
Ibrutinib
Lenalidomide
2013
1999 ‘02 03 ‘05‘07 ‘09
Era of Targeted Therapy
Idelalisib
2014
R-CHOP is 15% Better than CHOP
1.0
Probability
0.8
R-CHOP
0.6
0.4
HR=0.64
p=0.003
0.2
0.0
0.0
0.5
1.0
1.5
CHOP
2.0
2.5
3.0
3.5
4.0
4.5
Failure-Free
Survival
5.0
1.0
R-CHOP
Probability
0.8
0.6
CHOP
0.4
Overall
Survival
HR=0.72
p=0.05
0.2
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Years from Induction Randomization
Coiffier et al N Engl J Med. 2002; Habermann et al J Clin Oncol 2006
CP1171726-10
R(X)CHOP Era – what is X?
22
Epratuzumab - ERCHOP
 Lenalidomide – R2CHOP
 Bortezomib – Bor-RCHOP
 Everolimus – ER-CHOP; maintenance E in
CRADN2301 (enrolled)
 Everolimus – EverRCHOP – N1085
 Ibrutinib – IR-CHOP

Ann Oncol. 2014. Epub 2014/03/15
MC078E – Phase II Results
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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
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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
R2CHOP
R2CHOP
RCHOP
RCHOP
Nowakowski G et al J Clin Oncol. 2014. Epub 2014/08/20
RCHOP
RCHOP
R2CHOP
RCHOP
R2CHOP
Nowakowski G et al J Clin Oncol. 2014. Epub 2014/08/20
Italian R2CHOP
29
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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
Lancet Oncol. 2014;15(7):730-7.
Outcome of R2CHOP (Italian)
30
Vitolo et al Lancet Oncol. 2014;15(7):730-7.
GCB vs. non-GCB
31
Lancet Oncol. 2014;15(7):730-7.
©2011 MFMER | slide-32
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
©2011 MFMER | slide-33
DLBCL-002
34
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FDA registrational, International Phase III
 RCHOP
x 6 vs. R2CHOP x 6
 Lenalidomide 15 mg days 1-14 vs. placebo
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Untreated DLBCL Stage II-IV
Ages 18-80 years
Requires excisional biopsy
ABC by Nanostring GEP on FFPE tissue
 Promised
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5 day turnaround; steroids allowed
600 patients
Opening Dec 2014
Furman RR et al Cancer. 2010;116(23):5432-9.
L. Staudt
Bortezomib R-CHOP
37
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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
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No DLT with any dose; grade 3 neuropathy in 1
95% CR
Furman RR et al Cancer. 2010;116(23):5432-9.
Bortezomib R-CHOP
38
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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
Furman RR et al Cancer. 2010;116(23):5432-9.
Phase III Trials
39
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RCHOP vs. Bor-RCHOP in UK
Start May 2011 and predicted to end in 2015
Ibrutinib with RCHOP
40
Younes A et al Lancet Oncol. 2014 Aug;15(9):1019-26.
IR-CHOP
41
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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)
Younes A et al Lancet Oncol. 2014;15(9):1019-26
IR-CHOP
42
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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
Younes A et al Lancet Oncol. 2014;15(9):1019-26
IR-CHOP
43

100% ORR in the DLBCL (18/18)
 15
CR and 3 PR
 4/4 nonGCB – CR
 5/7 GCB – CR
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PK not affected for either ibrutinib or vincristine
A randomized phase III is ongoing –placebo
controlled (NCT01855750) for non-GCB type
Younes A et al Lancet Oncol. 2014;15(9):1019-26
Summary about COO in DLBCL
44
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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
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New techniques of GEP will enhance the clinical
utility and “bring it to your hospital”
Prediction – you will use COO to “choose X”