DLBCL

Matthew CheungSunnybrook Health Sciences CentreNovember 2011

Outline

• Review of DLBCL– A focus on key trials/advances– Highlights of disease/treatment

mechanisms• Advanced stage• Limited stage• Relapsed

Key Points

• Current classification system - WHO

Follicular (22%)Follicular (22%)

Diffuse large B cell (31%)Diffuse large B cell (31%)

Small lymphocytic (6%)Small lymphocytic (6%)

Mantle cell (6%)Mantle cell (6%)

Peripheral T cell (6%)Peripheral T cell (6%)

Marginal zone B cell, Marginal zone B cell, MALT (5%)MALT (5%)

Other subtypes with a Other subtypes with a frequency < 2% (9%)frequency < 2% (9%)

Marginal zone B cell, nodal (1%)Marginal zone B cell, nodal (1%)Lymphoplasmacytic (1%)Lymphoplasmacytic (1%)

Composite lymphomas (13%)Composite lymphomas (13%)

Ann Arbor Staging

Lymphomation.com

Comparison of CHOP with Three Intensive Chemotherapy Regimens for Advanced NHL

Fisher, NEJM 1993

Overall Survival

CD20:An Ideal B-cell Target

• 297 amino acid membrane-associated phosphoprotein (33–37 kD)

– Not shed– No known membrane/secreted

molecular analogues (target interference)

– Calcium channel function (?)

• B-cell lineage antigen, not on:– Stem cells, early pre-B cells,

or plasma cells

• Anti-CD20 binding:– Does not down-modulate expression

of CD20– Does not cause internalization of

CD20

Johnson P, Glennie M. Semin Oncol. 2003;30:3-8. Golay J et al. Blood. 2000;95:3900–3908.

Mechanisms of Antibody-Mediated Cell Killing

Antibody-dependentcellular cytotoxicity

(ADCC)

Apoptosis viainduction of intracellular

signaling pathwaysComplement-dependent

cytotoxicity (CDC)

Target cell

Target cell

Target cell

NK cell

Basic Science - Mechanism

Coiffier, NEJM 2002

• Clinical trials– Infusional side effects (~10% grade III/IV)

• 2009 - product monograph– Hepatitis B reactivation (1 in 10,000)– Bowel perforation (1 in 20,000)– PML (cases)

International Prognostic Index

One point each for:• Age >60 years• Performance status 2+• LDH >ULN• Stage III or IV• More than one extranodal site

Low risk: 0-1 factor, Int: 2-3, high: 4-5

IPI

Risk Group

# Factors

% Patients

4-year

PFS (%)

4-year

OS (%)

Very Good

0 10 94 94

Good 1,2 45 80 79

Poor 3,4,5 45 53 55

Sehn et al, ASH 2006

Outcome According to Revised IPI (R-IPI)

Progression-Free Survival According to Revised IPI (R-

IPI)

Percent Survival

Very Good

Good

Poor

P<0.0001

DLBCL (ABC type)

GCB subtype correlated with better survival

NEJM, 2002

IHC can be used to differentiate GC vs. non-GC

Nyman H et al, Modern Pathology 2009; 22 : 1094-1101

Hansalgorithm

Murisalgorithm

Nymanalgorithm

Nyman H et al, Modern Pathology 2009; 22 : 1094-1101

Nyman

Muris

Hans

Rituximab + CHOP is recommended in all the following except?

• Transformed NHL (FL --> DLBCL)

• Primary Mediastinal B-cell Lymphoma

• DLBCL

• HIV-related DLBCL

• Pediatric DLBCL

Kaplan et al. (AMC Study), Blood 2005

AMC RCT of CHOP-R vs. CHOP (AMC RCT of CHOP-R vs. CHOP (++ HAART) HAART)

CHOP + R CHOP p-value

Regimen CHOP+R + rituximab q month x3

CHOP

n 96 47

CR 57% 49% NS

Death due to lymphoma

10% 19.5% NS

Rituximab and Infection

Kaplan et al. (AMC Study), ASH 2003

CHOP + R CHOP p-value

Infectious deaths

14% 2% 0.027

n=14 patients dying of infection

-7 culture-positive sepsis-4 culture-negative sepsis-2 pneumonia-1 fungal

60% deaths in patients with CD4 <5040% deaths during the maintenance phase of R

Alternatives to R-CHOP-21

• R-CHOP-14 (GELA study)

• R-EPOCH– Dose-adjusted/continuous infusion– Phase III pending

LNH03-6B GELA Trial

IPI ≥1, age 60-80N = 202

R-CHOP14N = 103

R-CHOP21N = 99

Complete treatment received : N = 73Premature withdrawal : N = 30

Complete treatment received : N = 74No treatment received : N = 1Premature withdrawal : N = 24

Dose-intensity

Is R-CHOP14 given every 14 days ?

R-CHOP14 R-CHOP21Median interval between two

cycles

15 days(9 – 70)

21 days(19 – 63)

Median dose-intensity

R-CHOP14 R-CHOP21

Cyclo 84 % 96%

Dox 83 % 95 %

18/103 patients in R-CHOP14 group

received R-CHOP ≥ 18 days

R-CHOP14 R-CHOP21G-CSF use

90 % 68 %

R-CHOP14 = 125 % of R-CHOP21

• Hematologic toxicities greater for R-CHOP14

• Patients on R-CHOP14 had higher rates of febrile neutropenia, hospitalization, and death due to toxicity

LNH03-6B GELA Trial: Toxicities

Delarue R, et al. ASH 2009. Abstract 406.

R-CHOP14R-CHOP21

11152221

36

50

2226

69

8373

83

Pat

ien

ts (

%)

100908070605040302010

0Grade 3/4

LeukocytesGrade 3/4

NeutrophilesGrade 3/4

HemoglobinRBC

TransfusionGrade 3/4Platelets

PlateletTransfusion

LNH03-6B GELA Trial: Results

Delarue R, et al. ASH 2009. Abstract 406.

Outcome R-CHOP21(n = 99)

R-CHOP14(n = 103)

P Value

2-yr EFS, % 61 48 .11

Median EFS, mos Not reached 22 --

2-yr PFS, % 63 49 .12

Median PFS, mos Not reached 23 --

2-yr OS, % 70 67 .37

CR + CRu 75 67 NS ORR 84 81 NS

Event-free survival

Median EFS : - 22 months (R-CHOP14) vs NR (R-CHOP21)

2-year EFS :- 48% (R-CHOP14) vs 61% (R-CHOP21)

Overall survival

-2-year OS:- 67% (R-CHOP14) vs 70% (R-CHOP21)

Role of upfront high-dose therapy and ASCT?

• Prior to rituximab era:– Phase II studies suggested 60-80% of high-risk aggressive

lymphomas could achieve long-term PFS.– Eleven phase III studies have now addressed this question –

mixed results– Meta-analyses – heterogeneity and conflicting results preclude

definite answer re: benefit of HDT/ASCT• Low-risk patients do not benefit compared to conventional therapy

• Benefit in the era of rituximab unknown– ASBMT – upfront transplant indicated for high-intermediate and high-

risk IPI groups

– NCCN – appropriate for trials

Randomized phase III U.S./Canadian intergroup trial (SWOGS9704) comparing CHOP-R for eight cycles to CHOP-R

for six cycles followed by autotransplant for patients with high-intermediate (H-Int) or high IPI grade diffuse aggressive

non-Hodgkin lymphoma (NHL)

• Study design:

Stiff PJ Abstract 8001 ASCO 2011

Outcome

%

ASCT arm Conventional arm

Hazard ratio P-value

2-year PFS 69 56 1.72 .005

2-year OS 74 71 1.24 .16

Stiff PJ Abstract 8001 ASCO 2011

Other Alternatives:• Cardiac toxicity

– Substitution of etoposide (R-CEOP) –ASH 2009

– 50mg/m2 day 1 and 100mg/m2 po days 2-3– Pts with LV dysfunction or intolerance of doxorubicin

– BCCA Retrospective/Population review (n=81)

Elderly• R-mini-CHOP (ASH 2010)

• doxorubucin 25mg/m2• N=151 patients • ORR 74% (CR 40% and CRu 23%)• 2-year PFS 47.4%• 2-year OS 59%• FN 7%

• Pre-treatment (vincristine/prednisone)• Liposomal doxorubicin• DA-(E)POCH

Revised Response Criteria for Malignant Lymphomas from the Members of the International Harmonization Project of the Competence Network Malignant

Lymphoma

Cheson BD, Pfistner B, Juweid ME, Spect L, Rosen ST, Gascoyne R, Stroobants S, Diehl V.

Rationale

• IWG response criteria (1999)• extranodal sites not included • dependent on older technologies/methods

– CXR/CT/MRI unable to distinguish tumour vs. necrosis

– SPECT-gallium outdated

• unclear (?CRu)

Response Assessment of Aggressive NHL

Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005

IWC + PET

IWC CR CRu PR SD PD Total

CR 17 0 0 0 0 17

CRu 5 0 2 0 0 7

PR 10 0 9 0 0 19

SD 2 0 1 6 0 9

PD 1 0 0 0 1 2

Total 35 0 12 6 1 54

Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005

IWC + PET

IWC CR CRu PR SD PD Total

CR 17 0 0 0 0 17

CRu 5 0 2 0 0 7

PR 10 0 9 0 0 19

SD 2 0 1 6 0 9

PD 1 0 0 0 1 2

Total 35 0 12 6 1 54

Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005

IWC + PET

IWC

CR CRu PR SD PD Total

CR 17 0 0 0 0 17

CRu 5 0 2 0 0 7

PR 10 0 9 0 0 19

SD 2 0 1 6 0 9

PD 1 0 0 0 1 2

Total 35 0 12 6 1 54

Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005

Progression-free survival by the International Workshop Criteria (IWC) and IWC plus positron emission tomography (PET) based on the Kaplan-

Meier method

IHP Recommendations• FDG PET or PET/CT should be integrated into new

IWG criteria• Pre-treatment - recommended, not required• Response assessment

– required for DLBCL/HL

• CR - new definition• No clinical evidence of disease or symptoms• Residual mass/node of any size allowable if PET negative if

typical FDG-avid lymphoma or PET positive prior to treatment• Regression to <1.5 cm in GTD if >1.5 cm pretreatment if

variable FDG-avid lymphoma or PET negative prior to treatment• Bone marrow negative

• CRu - now obsolete

Conclusion - Advanced DLBCL• R-CHOP x 6 cycles is the standard of care

– In elderly population:• expect to cure ~60%• expect long-term survival ~70%

– 6 cycles equivalent to 8 cycles (and less neurotoxicity)– R-CHOP-21 likely as good as R-CHOP-14 (and better tolerated)– Role of upfront ASCT – still unclear– Rituximab not recommended for HIV+ DLBCL– No role for maintenance rituximab in DLBCL

• Prognosis– Improved in the rituximab era– Also determined by gene expression profile

• Response criteria– PET is now included at the end of therapy to confirm CR vs. PR (and eliminate

CRu designation)

Eligible Patients

Stage I – II aggressive NHL

CHOP x 3 +

IF-RT 40 - 55 Gy

CHOP x 8

SWOG prospective RCT of 401 patients

Patients with bulky ( > 10 cm ) stage II were not included

Miller et al

Update : Ann Hematol 2001; 80

Results:

With a median FU of 8 years:

PFS and OS overlap at 7 and 9 years respectively

Published only as an abstract

• Updated SWOG study– suggests that XRT cannot replace

inadequate/abbreviated chemotherapy

• Is there a group of patients that do well with abbreviated chemotherapy + RT?

Fisher, Miller et al

Am Soc Hematol Educ Program 2004: 221-236

Patients with unfavourable risk factors do poorly with only 3 cycles of CHOP

In contrast, in patients with no stage adjusted risk factors, 3 CHOP + RT yielded a 5Y OS of 94%

Updated analysis of SWOG 8736 accounting for IPI risk factors

IS THERE ANY ROLE FOR RT?

Horning JCO 2004

8 CHOP 8 CHOP + RT

6Y DFS 56% 73% p = 0.05

6Y TTP 67% 80% p = 0.06

6Y OS 71% 82% p = 0.24

For patients in CR after CHOP, low-dose RT

prolonged DFS and improved local control, but yielded no

survival benefit

Exam Answer:

• CHOP-R x 3 cycles and IFRT– However….if >1 IPI risk factor - evolving

evidence suggests high risk of late (?distant) relapses - would recommend 6 cycles

– IFRT appears to improve long-term local control

Failure of Primary Therapy

• Patients who relapse after a good response have poor prognosis

• Patients who progress on therapy do even worse

• Only curative potential is aggressive chemotherapy followed by stem cell transplantation– <65 years– Functionally well

Parma Study

RANDOMISED

ARM 1:

R maintenanc

e

ARM 2: Observation

C1 C2 C3

C1 C2 C3

S0 S3 S6

S0 S3 S6

Evaluation

ARM B: R-DHAP

ARM A: R-ICE

S9

S9

BEAM

+ autogra

ft

Evaluation

+M1 +M3 +M5 +M9+M7 +M11 +M12

+M3 +M7 +M12

RANDOMISED

CORAL trial:R-ICE vs R-DHAP

Coral Study:Patient Characteristics

• Chemotherapy: CHOP-like 85%ACVB-like 13%

rituximab 62%─Local radiation 23%

• Age-adjusted IPI 0,1 50%

(PS, stage, LDH) 2,3 50%

• Prior CR/CRu 65%

progression on Rx 11%

CORAL: main resultsResponse

ICE DHAPCR 36% 40%Overall 63% 64%

C Gisselbrecht, et al, J Clin Oncol 2010

Secondary analysis: importance of prior rituximab, time to progression

Progression < 12 mos

Progression > 12 mos

C Gisselbrecht, et al, J Clin Oncol 2010

• At a median follow-up of 45 months, mobilization-adjusted ORR comparable after induction therapy

– 51.5% for R-ICE vs 56.5% for R-DHAP – Fewer adverse events observed with R-ICE

• EFS and OS rates comparable between R-ICE (29% and 48%, respectively) and R-DHAP (33% and 51%)

• Nearly all patients achieved PR or better after induction therapy

Outcome 4- years % R-maintenance No further treatment P-value

EFS 55 53 .7435

PFS 55 57 .8314

OS 64 67 .7547

Gisselbrecht C. Abstract 8004 ASCO 2011

Limitations to second line therapy

All relapses

Eligible for intensive salvage

Response to second line therapy

Able to proceed to ASCT

Long-term survivors

100100

5050

2525

2020

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