DLBCL
Matthew Cheung
Sunnybrook Health Sciences Centre
November 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
Composite lymphomas (13%)
Small lymphocytic (6%)
Follicular (22%)
Mantle cell (6%)
Peripheral T cell (6%)
Marginal zone B cell,
MALT (5%)
Diffuse large B cell (31%)
Other subtypes with a
frequency < 2% (9%)
Marginal zone B cell, nodal (1%)
Lymphoplasmacytic (1%)
Ann Arbor Staging
Lymphomation.com
Comparison of CHOP with Three Intensive
Chemotherapy Regimens for Advanced NHL
Overall Survival
Fisher, NEJM 1993
CD20:
An Ideal B-cell Target
•
297 amino acid membrane-associated
phosphoprotein (33–37 kD)
–
–
–
•
B-cell lineage antigen, not on:
–
•
Not shed
No known membrane/secreted
molecular analogues (target
interference)
Calcium channel function (?)
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.
Basic Science - Mechanism
Mechanisms of Antibody-Mediated Cell Killing
NK cell
Target cell
Target cell
Antibody-dependent
cellular cytotoxicity
(ADCC)
Target cell
Apoptosis via
induction of intracellular
signaling pathways
Complement-dependent
cytotoxicity
(CDC)
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
Outcome According to Revised IPI
(R-IPI)
Risk
Group
Very
Good
Good
Poor
#
%
4-year 4-year
Factors Patients PFS (%) OS (%)
0
10
94
94
1,2
45
80
79
3,4,5
45
53
55
Sehn et al, ASH 2006
Progression-Free Survival
According to Revised IPI (R-IPI)
Very Good
1.0
Percent Survival
.9
.8
Good
.7
.6
Poor
.5
.4
.3
.2
P<0.0001
.1
0.0
0
1
2
3
4
5
DLBCL (ABC type)
GCB subtype correlated with
better survival
NEJM, 2002
IHC can be used to differentiate
GC vs. non-GC
Hans
algorithm
Muris
algorithm
Nyman
algorithm
Nyman H et al, Modern Pathology 2009; 22 : 1094-1101
Nyman
Muris
Hans
Nyman H et al, Modern Pathology 2009; 22 : 1094-1101
Rituximab + CHOP is recommended in
all the following except?
•
•
•
•
•
Transformed NHL (FL --> DLBCL)
Primary Mediastinal B-cell Lymphoma
DLBCL
HIV-related DLBCL
Pediatric DLBCL
AMC
RCT of CHOP-R vs. CHOP (+ 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
Kaplan et al. (AMC Study), Blood 2005
Rituximab and Infection
Infectious
deaths
CHOP + R
CHOP
p-value
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 <50
40% deaths during the maintenance phase of R
Kaplan et al. (AMC Study), ASH 2003
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 60-80
N = 202
R-CHOP14
N = 103
R-CHOP21
N = 99
Complete treatment received : N = 73
Premature withdrawal : N = 30
Complete treatment received : N = 74
No treatment received : N = 1
Premature withdrawal : N = 24
Dose-intensity
Is R-CHOP14 given
every 14 days ?
R-CHOP14
Median
interval
between
two cycles
15 days
(9 – 70)
Median dose-intensity
R-CHOP21
21 days
(19 – 63)
18/103 patients in R-CHOP14 group
received R-CHOP ≥ 18 days
R-CHOP14 R-CHOP21
Cyclo
84 %
96%
Dox
83 %
95 %
R-CHOP14 = 125 % of R-CHOP21
R-CHOP14 R-CHOP21
G-CSF use
90 %
68 %
LNH03-6B GELA Trial:
Toxicities
Patients (%)
• Hematologic toxicities greater for R-CHOP14
100
90
80
70
60
50
40
30
20
10
0
R-CHOP14
R-CHOP21
83
83
73
69
50
36
26 22
21 22
Grade 3/4
Grade 3/4
Grade 3/4
RBC
Grade 3/4
Leukocytes Neutrophiles Hemoglobin Transfusion Platelets
15 11
Platelet
Transfusion
• Patients on R-CHOP14 had higher rates of febrile neutropenia,
hospitalization, and death due to toxicity
Delarue R, et al. ASH 2009. Abstract 406.
LNH03-6B GELA Trial:
Results
Outcome
2-yr EFS, %
Median EFS, mos
2-yr PFS, %
Median PFS, mos
2-yr OS, %
 CR + CRu
 ORR
Delarue R, et al. ASH 2009. Abstract 406.
R-CHOP21
(n = 99)
61
Not reached
63
Not reached
70
R-CHOP14
(n = 103)
48
22
49
23
67
P Value
75
84
67
81
NS
NS
.11
-.12
-.37
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
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
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
IWC
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 KaplanMeier method
Juweid, M. E. et al. J Clin Oncol; 23:4652-4661 2005
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 8
CHOP x 3 +
IF-RT 40 - 55 Gy

SWOG prospective RCT of 401 patients

Patients with bulky ( > 10 cm ) stage II were not included
Miller et al
Update : Ann Hematol 2001; 80
Published only as an abstract
Results:
With a median FU of 8 years:
PFS and OS overlap at 7 and 9 years respectively
• 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
Updated analysis of SWOG 8736
accounting for IPI risk factors
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%
IS THERE ANY ROLE FOR RT?
For patients in CR after
CHOP, low-dose RT
prolonged DFS and improved
local control, but yielded no
survival benefit
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
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
CORAL trial:
R-ICE vs R-DHAP
ARM 1: R
maintenance
ARM A: R-ICE
C1
R
A
N
D
O
M
I
S
E
D
C2
C3
S9
S0
S3
S6
Evaluation
S0
S3
S6
S9
C1
C2
ARM B: R-DHAP
BEAM
+
autograft
R
A
N
D
O
M
I
S
E
D
+M1
+M3 +M5
+M7 +M9 +M11 +M12
Evaluation
+M3
+M7
C3
ARM 2: Observation
+M12
Coral Study:
Patient Characteristics
• Chemotherapy:
CHOP-like
85%
ACVB-like
rituximab
13%
62%
23%
─Local radiation
• Age-adjusted IPI
(PS, stage, LDH)
• Prior CR/CRu
progression on Rx
0,1
2,3
50%
50%
65%
11%
CORAL: main results
CR
Overall
Response
ICE DHAP
36% 40%
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 RDHAP (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
100
Eligible for intensive salvage
50
Response to second line therapy
25
Able to proceed to ASCT
20
Long-term survivors
10