double-hit lymphomas...definition: aggressive lymphomas with myc and bcl2 or less frequently bcl6...
TRANSCRIPT
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ESMO
DOUBLE-HIT LYMPHOMAS
Professor Dr. med. Georg Lenz
Director Department of
Hematology and Oncology
Universitätsklinikum Münster, Germany
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Definition of double-hit lymphomas
Introduction in the biology of MYC
Impact on the prognosis of affected patients
Therapeutic implications
Summary
OVERVIEW
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Definition: aggressive lymphomas with MYC and BCL2 or less frequently BCL6
translocations
However, some studies have not even looked for BCL6 translocations
Currently it does not refer to lymphomas in which MYC translocations occur with
other chromosomal translocations
The term “double hit” implies that these lymphomas harbour only two genetic
aberrations
WHAT ARE DOUBLE
HIT LYMPHOMAS?
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Squamous cell carcinoma
Ovarian cancer
Pancreatic cancer
Malignant lymphoma
MYC IS DEREGULATED IN
DIFFERENT CANCERS
Slide courtesy of German Ott
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MYC regulates roughly 15% of all genes
BIOLOGIC ROLE OF MYC
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MYC regulates roughly 15% of all genes
MYC dimerizes with MAX to bind specific DNA sequences known as E-boxes
BIOLOGIC ROLE OF MYC
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MYC regulates roughly 15% of all genes
MYC dimerizes with MAX to bind specific DNA sequences known as E-boxes
MYC can activate or repress gene expression
BIOLOGIC ROLE OF MYC
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MYC CONTROLS DIFFERENT
BIOLOGIC PROCESSES
Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature, Nat Rev Cancer, Analysis of genomic targets reveals complex functions
of MYC. Patel JH, et al., Copyright 2004.
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MYC regulates roughly 15% of all genes
MYC dimerizes with MAX to bind specific DNA sequences known as E-boxes
MYC can activate or repress gene expression
Different genetic aberrations deregulate MYC expression
BIOLOGIC ROLE OF MYC
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DIFFUSE LARGE B-CELL LYMPHOMA
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8–10% OF ALL DLBCLs ARE
CHARACTERISED BY
MYC TRANSLOCATIONS
Hecht JL, et al., J Clin Oncol, 18(21), 2000:3707–21. Reprinted with permission. © 2000 American Society of Clinical Oncology. All rights reserved
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GENE EXPRESSION PROFILING
DIFFERENTIATES BURKITT LYMPHOMA
FROM MOLECULAR DLBCL SUBTYPES
From N Engl J Med, Dave SS, et al., Molecular diagnosis of Burkitt's lymphoma, 354:2431–42. Copyright © 2006 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.
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DLBCLs WITH MYC
TRANSLOCATIONS SHOW A GENE
EXPRESSION PROFILE OF DLBCLs
From N Engl J Med, Dave SS, et al., Molecular diagnosis of Burkitt's lymphoma, 354:2431–42. Copyright © 2006 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.
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p=0.016
p=0.006
DLBCLs WITH MYC
REARRANGEMENT ARE CHARACTERISED
BY INFERIOR SURVIVAL AFTER R-CHOP
Republished with permission of American Society of Hematology, from Blood, Savage K, et al., 114-17, 2009, permission conveyed through Copyright Clearance Center, Inc.
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Incidence 8.8%
Characterised by high
proliferation
Increased risk of
CNS relapse
3/12 cases with MYC
rearrangement had
concurrent t(14;18)
DLBCLs WITH MYC
REARRANGEMENT ARE CHARACTERISED
BY INFERIOR SURVIVAL AFTER R-CHOP
p=0.016
p=0.006
Republished with permission of American Society of Hematology, from Blood, Savage K, et al.;114-17, 2009, permission conveyed through Copyright Clearance Center, Inc.
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DLBCLs WITH MYC AND BCL2
TRANSLOCATIONS ARE CHARACTERISED
BY INFERIOR SURVIVAL
Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature, Leukemia, Clinical features and prognosis of de novo diffuse large B-cell
lymphoma with t(14;18) and 8q24/c-MYC translocations, Niitsu N, et al.,Copyright 2009.
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DLBCLs WITH SINGLE MYC OR
DOUBLE HIT ARE CHARACTERISED
BY INFERIOR SURVIVAL
Republished with permission of American Society of Hematology, from Blood, Copie-Bergman C, et al., 126, 22; 2015, permission conveyed through Copyright
Clearance Center, Inc.
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DLBCLs WITH MYC
REARRANGEMENT ARE CHARACTERISED
BY INFERIOR SURVIVAL AFTER R-CHOP
Barrans S, et al., J Clin Oncol, 28(20), 2010:3360–5. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.
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74% of cases with MYC
rearrangement had concurrent
t(14;18)
26% of cases with MYC
rearrangement had a BCL6
translocation
DLBCLs WITH MYC
REARRANGEMENT ARE CHARACTERISED
BY INFERIOR SURVIVAL AFTER R-CHOP
Barrans S, et al., J Clin Oncol, 28(20), 2010:3360–5. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.
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RELAPSED DLBCL CASES WITH
MYC REARRANGEMENT ARE
CHARACTERISED BY INFERIOR SURVIVAL
Republished with permission of American Society of Hematology, from Blood, Cuccuini W, et al., 119, 20; 2012, permission conveyed through Copyright Clearance Center, Inc.
Progression free survival Overall survival
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17% (28/161) of patients have MYC rearrangement
75% (21/28) harbour one or more concurrent translocation (BCL2, BCL6)
MYC+ patients have advanced aaIPI, elevated LDH
RELAPSED DLBCL CASES WITH
MYC REARRANGEMENT ARE
CHARACTERISED BY INFERIOR SURVIVAL
Republished with permission of American Society of Hematology, from Blood, Cuccuini W, et al., 119, 20; 2012, permission conveyed through Copyright Clearance Center, Inc.
Progression free survival Overall survival
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TRANSLOCATION PARTNERS
MIGHT IMPACT PROGNOSIS
Pedersen MO, et al., Eur J Haematol 2014;92(1):42–8. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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MYC EXPRESSION IS DETECTABLE
IN A RELATIVELY HIGH FRACTION
OF DLBCL CASES
RICOVER DATA
MYC FISH R 36/407 (8.8%)
MYC only 14/35 (40%)
MYC/additional break 21/35 (60%)
MYC IHC+ (>40%) 90/283 (31.8%)
Horn H, et al., Blood 2013;121(12):2253–63
Courtesy of German Ott
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DLBCL REPRESENTS A
HETEROGENEOUS DISEASE WITH
DISTINCT MOLECULAR SUBTYPES
Nogai H, et al., J Clin Oncol, 29(14), 2011:1803–11. Reprinted with permission. © 2011 American Society of Clinical Oncology. All rights reserved.
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ABC AND GCB DLBCL HAVE
SIGNIFICANTLY DIFFERENT SURVIVAL
RATES FOLLOWING R-CHOP
From N Engl J Med, Lenz G, et al., Stromal gene signatures in large-B-cell lymphomas, 359, 2313–23 Copyright © 2008 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.
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MYC-R
GCB ABC
Slide courtesy of Kieron Dunleavy.
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BCL-2-R
MYC-R
HighBCL-2expression
HighMYCexpression
GCB ABC
Double-hitlymphomas
Slide courtesy of Kieron Dunleavy.
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DLBCL CASES THAT EXPRESS
BOTH MYC AND BCL2 ARE CHARACTERISED
BY ADVERSE PROGNOSIS
Johnson NA, et al., J Clin Oncol, 30(28), 2012:3452–9. Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved.
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DLBCL CASES THAT EXPRESS
BOTH MYC AND BCL2 ARE CHARACTERISED
BY ADVERSE PROGNOSIS
Johnson NA, et al., J Clin Oncol, 30(28), 2012:3452–9. Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights reserved.
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DOUBLE EXPRESSERS ARE
CHARACTERISED BY INCREASED
CNS RELAPSE RISK
Republished with permission of American Society of Hematology, from Blood, Savage KJ, et al., 127, 18; 2016, permission conveyed through Copyright Clearance Center, Inc.
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THERAPEUTIC IMPLICATIONS
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ARE MORE INTENSIVE REGIMENS BETTER THAN R-CHOP?
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Dose mg/m 2 /day
Etoposide Vincristine
Doxorubicin
Cyclophosphamide Prednisone
50 0.4 10
750 60 BID
Days 1-4
Day 5 Days 1-4
Treatment Days
Infusional Agents
Bolus Agents
Biologic Agents
Filgrastim 5 (mg/kg) Days 6 ! ANC recovery
Dose-Adjusted EPOCH-R Chemotherapy
Pharmacodynamic Dose Adjustment
Rituximab 375 Day 1
DOSE-ADJUSTED-EPOCH-R
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DA-EPOCH-R IN MYC-R AND
MYC– DLBCL
*Fisher’s Exact Test
Dunleavy K, et al. Lugano, 2011.
Median f/up
4 yearsP=0.59
1 3 5 7 9 11 13
Time (years)
Pro
gres
sion
-fre
e su
rviv
al (
%)
0
20
40
60
80
100
MYC-R
MYC-neg
Total
samples
FISH: N=108
MYC-R MYC-
9 (8%) 99 (92%)
Low IPI 4 (44%) 56 (57%)
High IPI 5 (56%) 43 (43%)
*P=0.51
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Untreated patients
Age ≥18 years
De-novo DLBCL (transformed excluded) or BCL-U
MYC-R + by FISH or cytogenetics
DA-EPOCH-R IN MYC-R DLBCL
Dunleavy K, et al., Blood 2014;124:395. Presented at American Society of Hematology Annual Meeting 2014.
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DA-EPOCH-R IN MYC-R DLBCL
N=52
*Of 31 cases tested.
Dunleavy K, et al., Blood 2014;124:395. Presented at American Society of Hematology Annual Meeting 2014.
Characteristics %
Median (range) age (years) 61y (29-80y)
Male sex 71%
Stage III or IV 73%
High LDH 59%
CNS disease 6%
IPI score
0–2
3–5
35%
65%
Histology
DLBCL
BCL-U
86%
14%
MYC+ by FISH or cytogenetics
BCL2+ by FISH
BCL2– High by IHC
100%
45%*
56%
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PROGRESSION-FREE SURVIVAL –
ALL PATIENTS
Dunleavy K, et al., Blood 2014;124:395. Presented at American Society of Hematology Annual Meeting 2014.
6 12 180 24 30 36 42 48 54
Time (months)
Sur
viva
l (%
)
0
10
20
30
40
50
60
70
80
90
100
Median f/up
14 months
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PFS – IMPACT OF BCL2-R (DHL)
Dunleavy K, et al., Blood 2014;124:395. Presented at American Society of Hematology Annual Meeting 2014.
6 12 180 24 30 36 42 48 54
Time (months)
Sur
viva
l (%
)
0
10
20
30
40
50
60
70
80
90
100
BCL2-R
Median f/up
14 months
Cases that underwent a consolidative
transplant were censoredP=0.23
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PFS – IMPACT OF BCL2 IHC
Dunleavy K, et al., Blood 2014;124:395. Presented at American Society of Hematology Annual Meeting 2014.
Median f/up
14 months
Cases that underwent a consolidative
transplant were censoredP=0.044
6 12 180 24 30 36 42 48 54
Time (months)
Sur
viva
l (%
)
0
10
20
30
40
50
60
70
80
90
100
BCL2+
BCL2–
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META-ANALYSIS ON DOSE
INTENSIFICATION IN DOUBLE
HIT LYMPHOMAS
Howlett C, et al., Br J Haematol 2015;170(4):504–14. Reprinted with permission © 2015 John Wiley & Sons Ltd.
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META-ANALYSIS ON DOSE
INTENSIFICATION IN DOUBLE
HIT LYMPHOMAS
Howlett C, et al., Br J Haematol 2015;170(4):504–14. Reprinted with permission © 2015 John Wiley & Sons Ltd.
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INTENSIFICATION MIGHT IMPROVE
OUTCOME OF PATIENTS WITH
DOUBLE HIT LYMPHOMA
Landsburg DJ, et al., J Clin Oncol, 35(20), 2017:2260–7. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.
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ASCT DOES NOT SEEM TO
IMPROVE OUTCOME OF PATIENTS
WITH DOUBLE HIT LYMPHOMA
Landsburg DJ, et al., J Clin Oncol, 35(20), 2017:2260–7. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.
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Double hit lymphomas are still not completely defined and understood
MYC-positive and double hit lymphomas seem to be characterised by
adverse survival
DA-EPOCH-R might overcome therapeutic dilemma of MYC-positive and double
hit lymphomas
Incorporation of novel agents into molecularly defined subsets of DLBCL is crucial
to improve prognosis of affected patients
CONCLUSIONS
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THANK YOU!