DOUBLE HIT AND OTHER MOLECULARLY DEFINED LARGE CELL LYMPHOMAS

DOUBLE HIT AND OTHER MOLECULARLY DEFINED LARGE CELL LYMPHOMAS

Morton Coleman, M.D.Director, Center for Lymphoma and Myeloma

New York-Presbyterian Hospital Weill Cornell Medical Center

Clinical Professor of Medicine

Weill Cornell Medical College

Chairman, Medical Affiliates Board

Lymphoma Research Foundation

Morton Coleman, M.D.Director, Center for Lymphoma and Myeloma

New York-Presbyterian Hospital Weill Cornell Medical Center

Clinical Professor of Medicine

Weill Cornell Medical College

Chairman, Medical Affiliates Board

Lymphoma Research Foundation

Chromosomal translocations in lymphoma and MYC

40% of B cell lymphomas have recurrent reciprocal translocations– May be subtype specific– Often oncogene plus Ig loci enhancer t(8;14)(q24;q32) – lymphoma initiating in BL MYC breakpoints may be secondary events in other

lymphomas At diagnosis or at progression In MYC+ DLBCL and DH lymphoma, often non Ig-MYC

breakpoints

“Double hit”

Chromosomal breakpoints in DLBCL

Aukema et al, Blood 2011

Chromosomal breakpoints in DLBCL

Aukema et al, Blood 2011

Study NMYC+ total %

MYC+ SH %

BCL2/ MYC+ DH %

BCL6/ MYC+ DH %

BCL2/ BCL6/

MYC+ TH %

All DH and TH %

Barrans 2010 245 14% 2% 8% 1% 3% 12%

Obermann 2009

220 4% 3% 0 0 0 1%

Yoon 2008 137 7% 7% 1% 1% 1% 3%

Tibiletti 2009 74 16% 4% 7% 7% 1% 12%

Copie-Bergman 2009

68 3% 3% 0 0 0 0

Van Imhoff 2006

58 15% 8% 5% 2% 0 7%

Savage 2009 135 9% 7% 2% NA NA NA

Klapper 2008 117 8% NA NA NA NA NA

What is a “double hit” lymphoma?

Recurrent breakpoints activating multiple oncogenes, one being MYC

BCL2+/MYC+ most common

BCL6, CCND1 and BCL3 may also occur

Can also have “triple hit”

B cell lymphoma, unclassifiable, with features intermediate between diffuse

large B cell lymphoma and Burkitt lymphoma

WHO 2008 classification 35-50% of cases have a MYC translocation,

15% have a BCL2 translocation Increasing incidence with age Many are DH

Immunophenotype of “double hit” lymphoma

CD10+, GCB phenotype

Lack MUM1/IRF4

BCL2 + in 95% of cases

High proliferative index – median 90% Ki67+

Aukema et al, Blood 2011

Clinical features of “double hit” lymphoma

Aukema et al, Blood 2011

StudyN DH/

total N (%)

DH w prior iNHL

%

Med age

St III/IV %

LDH > Nl

%

BM + %

CNS + %

> 1 ENS %

IPI Hi/HiI

%

Bertrand 2007

10/17 (59%)

10% 58 70% NA NA NA NA 56%

Johnson 2009

54/54 (100%)

46% 62 76% 50% 71% NA 35% 70%

Kanungo 2006

14/14 (100%)

None 55 NA 93% 79% 21% 57% NA

Le Gouill 2007

16/16 (100%)

25% 61 100% 100% 94% 50% 88% 81%

Macpherson 1999

15/39 (38%)

46% 65 92% 80% 69% NA 62% 90%

Niitsu 2009 19/19 (100%)

None 61 100% 100% 84% 21% 63% 89%

Snuderl 2010

20/20 (100%)

15% 64 95% 100% 59% 45% 30% 85%

Tomita 2009 27/27 (100%)

17% 51 96% 93% 65% 9% 65% 87%

Treatment and outcome “double hit” lymphoma

Aukema et al, Blood 2011

StudyNo. of

DH/tot (%)Treatment Regimen

Overall RR %

Median survival, y

Bertrand 2007 10/17 (59%) NA 50% < 1

Johnson 2009 54/54 (100%)

R-CHOP; HDC +/- SCT; CHOP; P

NA R-CHOP, 1.4; HD, 0.26; CHOP, 0.42

Kanungo 2006

14/14 (100%)

CT-NOS; CT and BMT NA < 1

Le Gouill 2007 16/16 (100%)

R-CHOP; CHOP; HDC+/- SCT (incl.allo)

75% 0.42

Macpherson 1999

15/39 (38%) CHOP-like; HDC +/- SCT; P NA 0.21

Niitsu

200919/19

(100%)CycloBEAP; CHOP + hi dose

MTX; CHOP; R-CHOP89% 1.5

Snuderl 2010 20/20 (100%)

R-ICE/SCT; CHOP; R-CHOP; CODOX-M/IVAC; EPOCH-R

50% 0.38

Tomita

200927/27 (100%)

CHOP; CODOX-M/IVAC; HyperCVAD

26% 0.5

CHOP/CHOEP/R-CHOP and MYC rearranged DLBCL

Klapper et al, Leukemia 2008

EFS

OS

Savage et al, Blood 2009

BCL-2 and MYC rearranged “double hit”

lymphomas

Johnson et al, Blood 2009

EFS

OS

55 cases (BCCA) outof 1260

57% C-MYC + at dx43% at transformation

R-CHOP and MYC rearranged DLBCL

Barrans et al, JCO 2010

EFS

OS

35 (14%) with MYC rearrangements

19 also had t(14;18)

3 also had BCL6

7 “triple hit”

Therefore most“MYC+” are “double”or “triple” hit

R-CHOP and MYC rearranged DLBCL

Interaction with IPI and age

Barrans et al, JCO 2010

EFS

OS

C-MYC in relapsed DLBCL

BioCoral study – relapsed DLBCL

Rearrangements noted– BCL2 31%– BCL6 18%– C-MYC 13%

C-MYC worse PFS and OS

Thieblemont et al, JCO 2011

C-MYC and DH/TH DLBCL and treatment options

R-CHOP (nothing to date shown to be better)

AutoSCT consolidation– Significant number don’t get to SCT

Intensive BL type regimens

R-EPOCH

Less favorable outcome than other DLBCL with R-CHOP– Risk seems to be beyond age, IPI

Less favorable at progression

Rearrangements noted– BCL2 31%– BCL6 18%– C-MYC 13%

C-MYC worse PFS and OS

CODOX-M/IVAC and aggressive B cell lymphoma

Mead et al, Blood 2008

EFS

OS

B cell lymphoma,Ki67 >95%

Mixture of BL and DLBCL

Low and highrisk by IPI

All 4 DH patientsdied within 5 mo

DA-R-EPOCH and MYC+ DLBCL

Dunleavy et al, Lugano 2011

EFS

OS

9 MYC+ DLBCL

99 MYC- DLBCL

Similarrisk by IPI

High RR/PFS inBL

Phase II study of dose adjusted R-EPOCH in previously untreated BL and

c-MYC + DLBCL

Inclusion criteria– Burkitt lymphoma or B-cell lymphoma,

unclassifiable, with features intermediate between Diffuse Large B-cell lymphoma and Burkitt Lymphoma

– c-MYC + DLBCL– c-MYC+ plasmablastic lymphoma

NCT01092182

Approach to “variant” DLBCL GCB vs non-GCB

– R-CHOP is standard– Various randomized trials underway

MYC+, DH, TH– Consider FISH for MYC, BCL2, BCL6– Less favorable with R-CHOP– Unclear if other approaches better– Prospective studies underway– Analysis needs incorporation in clinical trials

Intensive BL type regimens

R-EPOCH

Less favorable outcome than other DLBCL with R-CHOP– Risk seems to be beyond age, IPI

Less favorable at progression

Rearrangements noted– BCL2 31%– BCL6 18%– C-MYC 13%

C-MYC worse PFS and OS

Acknowledgment

Clinical Research Jia Ruan, M.D., Ph.D.Richard Furman, M.D.John P. Leonard, M.D.Peter Martin, M.D.Maureen Joyce, R.N.Patricia Glenn, R.N.Jamie KetasJessica HansenKaren WeilJennifer O’LoughlinRebecca Elstrom

Biostatistician

Ken Chueng, Ph.D. (Columbia)

Madhu Mazumdar, Ph.D. (Cornell)

Translational Core Maureen Lane, Ph.D. (Cornell)Maureen Ward

Laboratory Research Ari Milneck, M.D., Ph.D.(Cornell)Katherine Hajjar, M.D. (Cornell)Shahin Rafii, M.D. (Cornell)

Lymphoma Research Foundation

ASCO Foundation (YIA, CDA)

NIH / NHLBI