bachy and salles. seminars in hematology, vol 52, no 2, april 2015
TRANSCRIPT
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Burhan Ferhanoglu M.D.
Koç University Medical School Istanbul/TurkeyAegean Hematology Oncology Symposium 17-20 Sep 2015
Is R-CHOP the standart
treatment for high-risk DLBCL
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Objectives• Introduction and risk assesment of DLBCL• Outcome of high risk DLBCL with R-CHOP• Outcome with other combined chemotherapy
regimens• High dose chemotherapy with stem cell support• PET guided treatment strategy• Moleculer subtypes driven therapies
• GEP based therapy• DHL and DEL
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DLBCL, NOS and other Large B-cell Disorders:WHO 2008
• DLBCL is a heterogenous group of disorders with varied natural history, genetic abnormalities, and response to therapy
• Diffuse large B-cell lymphoma (DLBCL), NOS 30%• Primary mediastinal large B-cell lymphoma 3%• Variants: ~5%
• T-cell/histiocyte rich large B-cell lymphoma • Primary cutaneous DLBCL, leg type • EBV positive DLBCL of the elderly • DLBCL associated with chronic inflammation • Lymphomatoid granulomatosis (EBV) • Intravascular large B-cell lymphoma • ALK positive large B-cell lymphoma • Primary CNS large B cell lymphoma
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Clinical predictors of outcome
Bachy and Salles. Seminars in Hematology, Vol 52, No 2, April 2015
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Outcome of high risk DLBCL with R-CHOP
55%
Sehn et al. Blood 2007 Coiffie et al. Blood 2010
Age +16Newly diagnosed DLBCLTreated with R-CHOP
Age 60-80Newly diagnosed DLBCLTreated with CHOP vs R-CHOP
34 %
21%
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Outcome of high risk DLBCL with R-CHOP
64%
29%
Ozturk et al. Leukemia&Lymphoma 2015
67 %
44%
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Outcome with other combined chemotherapy regimens
• Is R-ACVBP more effective than R-CHOP?• Yes for only aaIPI:1 and age 18-59
92%
84%
Recher et al. Lancet 2011 Molina et al. JCO 2014
Frequent febrile neutropenia, secondary malignancy
OS
GC
B
OS
n
on
-G
CB
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Is R-CHOEP more effective than R-CHOP?• There is no randomised study.• According to Danish population-based study
A.O. Gang et al. Annals of Oncology 2012 A.O. Gang et al. Leuk&Lymp 2015
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Is Da-EPOCH-R more effective than R-CHOP?
• There is no randomised study.
68 DLBCLAge 18-75IPI>2, aaIPI>1
Purroy et al. BJH 2014
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High dose chemotherapy with stem cell support
Study group n
CT protocol İnclusion crit outcome
Italian Lymphoma FoundVitolo UAnn Oncol. 2011;22. abst 072
399
R-CHOP+BEAMR-CHOP(8)
aaIPI: HI,H 2 year PFS(70 vs 59)P=0.0128OS.NS
SWOG.US/Canadian int Stiff PJ.NEJM 2013
397
R-CHOP+HDTR-CHOP(8)
aaIPI:HI,H 2yr PFS69 vs 56%P=0.02
Schmitz N.GHNHLLancet Oncol 2012
230
R-CHOEPX8R-mCHOEP(4)+OKIT
aaIPI:HI,H 3yrOS84.6vs 77%p:=Sign aaIPI:2
GOELAM 075Le GouilleS.JCO.2011;29,abstr 8003
340
R-CHOP14X82XR-CHOP+Mtx+ ARA-C+HDT
aaIPI1-2+bulkyaaIPI 3-4
OS%83NS
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USA/Canada Phase III SWOG S9704 studyPhase III study, Intermediate-High and High risk IPI, DLBCLFirst line: 5 CHOP or 5 R-CHOPResponse ≥PR 1 R-CHOP + SCT vs 3 R-CHOP
IPI 2 years PFS % (SCT vs Standard)
2 years OS %(SCT vs Standart)
H-I 66 vs 63 70 vs 75
High 75 vs 41 82 vs 64
p 0.02 NS
Phase III Randomized Trials in Post-Riruximab Era
Stiff et al. NEJM 2013
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Outsid
e of c
linica
l tria
ls firs
t lin
e chem
othera
py with
stem
cell
support
is n
ot recc
omended
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PET guided treatment
•PET guided Treatment of Aggressive Lymphomas (PETAL) Study
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PETAL studyOBJECTIVES•To determine the effect of iPET guided therapy on the outcome of aggressive lymphomas•Between 2007-2012, age range 18-80•926 aggressive lymphoma patients recruited from 57 oncological centers and iPETs analyzed in 23 nuclear imaging centers
• 757 CD20+ lymphomas (DLBCL, mediastinal B cell, grade 3 Follicular lymphoma)• 13 CD20- lymphomas• 83 peripheralT cell lymphomas
METHODS•Treatment decided according to the iPET result following the second cycle of R-CHOP
• iPET evaluated 3 weeks after 2nd R-CHOP (to avoid inflammatory reactions)• No G-CSF after 2nd R-CHOP (to avoid altered glucose biodistribution)
•Objective evaluation regarding Standardized Uptake Value (SUV)•Favorable response defined as >66% decrease in maximum SUV
Duehrsen et al. ASH 2014 Abstract #391
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PETAL – Study Design
Initial treatment:2 R-CHOP
Favorable iPET (n=746)
Unfavorable iPET (n= 107)
4 R-CHOP
4 R-CHOP + 2 R
6 R-CHOP
6 cycle of more complex and intensive treatment (Burkitt Protocol)
PART
A
PART
B
RANDOMIZATION
•853 patients of 926 were evaluable in the intend to treat population at a median follow-up of 33 months
•No beneficial effect on • Treatment Failure, • CR rate and, • Overall Survival
in the unfavorable group switched from R-CHOP to Burkitt protocol
•Burkitt protocol associated with more severe
• Grade ¾ Leukopenia (p=0.043)
• Thrombocytopenia (p=0.007)
• Mucositis (p=0.002)
Duehrsen et al. ASH 2014 Abstract #391
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Moleculer subtype driven therapies
High
Level of geneexpression
Low
Gen
es
Rosenwald A et al. N Engl J Med. 2002;346:1937-1947.
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Slide 11
Presented By David Scott at 2015 ASCO Annual Meeting
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Cell-of-origin – a scaffold
Presented By David Scott at 2015 ASCO Annual Meeting
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Slide 44
Presented By David Scott at 2015 ASCO Annual Meeting
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Agents targeting specific
subtypes of DLBCL
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How can we improve R-CHOP?
• Bortezomib + R-CHOP• Ibrutinib + R-CHOP• Lenalidomide + R-CHOP (R2-CHOP)• ABT-199 + R-CHOP
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• Phase 2 trial • 164 patients with non-GCP DLBCL • R-CHOP vs VR-CAP• No difference in OS, PFS and SAE
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Ibrutinib R-CHOP
• 100% ORR in the DLBCL (18/18)
• 15 CR and 3 PR
• Non-GCB CR:4/4
• GCG CR:5/7
• PK not affected for either ibrutinib or vincristine
Younes et al. Lancet oncology 2014
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Lenalidomide R-CHOP
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R2CHOP:Safety
• Well tolerated including elderly patients• Neutropenia & thrombocytopenia common but
neutropenic or bleeding complications rare• Infrequent grade 3/4 nonhematologic toxicities• Infrequent thrombosis
Vitolo et al. Lancet Ocol 2014Nowakowski et al. JCO 2015