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
1010
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