double-hit lymphomas...definition: aggressive lymphomas with myc and bcl2 or less frequently bcl6...

ESMO

DOUBLE-HIT LYMPHOMAS

Professor Dr. med. Georg Lenz

Director Department of

Hematology and Oncology

Universitätsklinikum Münster, Germany

Definition of double-hit lymphomas

Introduction in the biology of MYC

Impact on the prognosis of affected patients

Therapeutic implications

Summary

OVERVIEW

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?

Squamous cell carcinoma

Ovarian cancer

Pancreatic cancer

Malignant lymphoma

MYC IS DEREGULATED IN

DIFFERENT CANCERS

Slide courtesy of German Ott

MYC regulates roughly 15% of all genes

BIOLOGIC ROLE OF MYC


MYC dimerizes with MAX to bind specific DNA sequences known as E-boxes




MYC can activate or repress gene expression


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.



MYC can activate or repress gene expression

Different genetic aberrations deregulate MYC expression


DIFFUSE LARGE B-CELL LYMPHOMA

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

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.

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.


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.

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



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.

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.

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.

DLBCLs WITH MYC



Barrans S, et al., J Clin Oncol, 28(20), 2010:3360–5. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.

74% of cases with MYC

rearrangement had concurrent

t(14;18)

26% of cases with MYC

rearrangement had a BCL6

translocation

DLBCLs WITH MYC



Barrans S, et al., J Clin Oncol, 28(20), 2010:3360–5. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.

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

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

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.

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

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.

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.


MYC-R

GCB ABC

Slide courtesy of Kieron Dunleavy.

BCL-2-R

MYC-R

HighBCL-2expression

HighMYCexpression

GCB ABC

Double-hitlymphomas

Slide courtesy of Kieron Dunleavy.

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.

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.

THERAPEUTIC IMPLICATIONS

ARE MORE INTENSIVE REGIMENS BETTER THAN R-CHOP?

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

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

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.

DA-EPOCH-R IN MYC-R DLBCL

N=52

*Of 31 cases tested.


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%

PROGRESSION-FREE SURVIVAL –

ALL PATIENTS


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

PFS – IMPACT OF BCL2-R (DHL)


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

PFS – IMPACT OF BCL2 IHC


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–

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.

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.

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.

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

THANK YOU!

double-hit lymphomas...definition: aggressive lymphomas with myc and bcl2 or less frequently bcl6...

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