bachy and salles. seminars in hematology, vol 52, no 2, april 2015

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