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
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
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
Clinical predictors of outcome
Bachy and Salles. Seminars in Hematology, Vol 52, No 2, April 2015
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%
Outcome of high risk DLBCL with R-CHOP
64%
29%
Ozturk et al. Leukemia&Lymphoma 2015
67 %
44%
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
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
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
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
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
Outsid
e of c
linica
l tria
ls firs
t lin
e chem
othera
py with
stem
cell
support
is n
ot recc
omended
PET guided treatment
•PET guided Treatment of Aggressive Lymphomas (PETAL) Study
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
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
Moleculer subtype driven therapies
High
Level of geneexpression
Low
Gen
es
Rosenwald A et al. N Engl J Med. 2002;346:1937-1947.
Slide 11
Presented By David Scott at 2015 ASCO Annual Meeting
Cell-of-origin – a scaffold
Presented By David Scott at 2015 ASCO Annual Meeting
Slide 44
Presented By David Scott at 2015 ASCO Annual Meeting
Agents targeting specific
subtypes of DLBCL
How can we improve R-CHOP?
• Bortezomib + R-CHOP• Ibrutinib + R-CHOP• Lenalidomide + R-CHOP (R2-CHOP)• ABT-199 + R-CHOP
• Phase 2 trial • 164 patients with non-GCP DLBCL • R-CHOP vs VR-CAP• No difference in OS, PFS and SAE
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
Lenalidomide R-CHOP
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