Double hit lymphomas What are they and how should they be managed?

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Double hit lymphomasWhat are they and how should
they be managed?

• John P. Leonard, M.D.
• Richard T. Silver Distinguished Professor of
  Hematology and Medical Oncology
• Associate Dean for Clinical Research
• Vice Chairman, Department of Medicine

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Disclosures

• Consulting advice
• Seattle Genetics, Abbott, Sanofi Aventis,
  Repligen, Johnson and Johnson, Pharmacyclics,
  Amgen, Biotest, Millenium, Celgene, Helsinn, GSK,
  Hospira, Boehringer Ingelheim, Genentech, Onyx,
  Teva, Medimmune, Gilead, Spectrum, Emergent, Cell
  Therapeutics

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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

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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

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Chromosomal breakpoints in DLBCL
Aukema et al, Blood 2011
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Chromosomal breakpoints in DLBCL
Study N MYC 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
Aukema et al, Blood 2011
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MYC B cell lymphomas by histology(Mitelman
database)
Aukema et al, Blood 2011
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Caveats in understanding clinical characteristics
and outcomes in double hit lymphoma

• Selection biases of series
• Where from?
• What patients included?
• Variability in molecular testing
• Challenges and changes in morphologic/pathologic
  classification
• Non-uniform therapy
• Single vs multicenter
• Retrospective

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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
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Clinical features of double hit lymphoma
Study N DH/ total N () DH w prior iNHL Med age St III/IV LDH gt Nl BM CNS gt 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
Aukema et al, Blood 2011
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Treatment and outcome double hit lymphoma
Study No. of DH/tot () Treatment Regimen Overall RR Median survival, y
Bertrand 2007 10/17 (59) NA 50 lt 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 lt 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 2009 19/19 (100) CycloBEAP CHOP hi dose MTX CHOP R-CHOP 89 1.5
Snuderl 2010 20/20 (100) R-ICE/SCT CHOP R-CHOP CODOX-M/IVAC EPOCH-R 50 0.38
Tomita 2009 27/27 (100) CHOP CODOX-M/IVAC HyperCVAD 26 0.5
Aukema et al, Blood 2011
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CHOP/CHOEP/R-CHOP and MYC rearranged DLBCL
EFS
OS
Klapper et al, Leukemia 2008
Savage et al, Blood 2009
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R-CHOP and MYC rearranged DLBCL
35 (14) with MYC rearrangements 19 also had
t(1418) 3 also had BCL6 7 triple
hit Therefore most MYC are double or
triple hit
EFS
OS
Barrans et al, JCO 2010
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R-CHOP and MYC rearranged DLBCLInteraction with
IPI and age
EFS
OS
Barrans et al, JCO 2010
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FISH DH DLBCL and treatment with R-CHOP
EFS
OS
Green et al, JCO 2012
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IHC score DH DLBCL and treatment with R-CHOP
EFS
OS
One point for findings above median IHC BCL2
gt 70 MYC gt 40
Green et al, JCO 2012
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R-CHOP and MYC/BCL2 (IHC)
EFS
OS
Johnson et al, JCO 2012
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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
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C-MYC and DH/TH DLBCL and outcomes

• Generally retrospective analyses
• Non-comparative studies
• Less favorable outcome than other DLBCL with
  R-CHOP
• Risk seems to be beyond age, IPI
• Also less favorable at progression
• Rearrangements noted
• BCL2 31
• BCL6 18
• C-MYC 13
• C-MYC worse PFS and OS

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C-MYC and DH/TH DLBCL and treatment options

• R-CHOP (nothing to date shown to be better)
• AutoSCT consolidation
• Significant number dont 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

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CODOX-M/IVAC and aggressive B cell lymphoma
EFS
B cell lymphoma, Ki67 gt95 Mixture of BL and
DLBCL Low and high risk by IPI All 4 DH
patients died within 5 mo
OS
Mead et al, Blood 2008
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DA-R-EPOCH and MYC DLBCL
9 MYC DLBCL 99 MYC- DLBCL Similar risk by
IPI High RR/PFS in BL How many had DH?
EFS
OS
Dunleavy et al, Lugano 2011
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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