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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)
2
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
29
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-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
34
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
37
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
38
Furman RR et al Cancer. 2010;116(23):5432-9.
Phase III Trials
RCHOP vs. Bor-RCHOP in UK
39
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)
41
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
42
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
43
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”
44