“aggressive” b-cell lymphoma - pathobasic...2018/09/25 · •t-cell/histiocyte-rich large...
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Pathology Stephan Dirnhofer
“Aggressive” B-cell lymphoma
Patho-Basic 25. September 2018
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Be aware - in Lymphoma
aggressive vs indolent
high grade versus low grade
large cell versus small cell
… does not mean the same!
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• Lymphoblastisches Lymphom (LBL/B-ALL)
• Burkitt Lymphom (BL)
• Grosszellige B-Zell Lymphome (DLBCL, u.a.)
• High-grade B-Zell Lymphom (HGBCL)
– HGBCL, with MYC and BCL2 and/or BCL6 rearrangements
– HGBCL, NOS
«aggressive» BCL
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• T-cell/histiocyte-rich large B-cell lymphoma
• Intravascular large B-cell lymphoma
• Primary DLBCL of the CNS
• Primary cutaneous DLBCL, leg-type
• Primary mediastinal (thymic) large B cell lymphoma
• EBV-positive DLBCL, NOS
• Large B cell lymphoma with IRF4 rearrangements
• DLBCL associated with chronic inflammation
• ALK+ large B-cell lymphoma
• Plasmablastic lymphoma
• HHV8-positive DLBCL
• Primary effusion lymphoma
• High grade B-cell lymphoma
HGBCL, with MYC and BCL2 and/or BCL6 rearrangements
HGBCL, NOS
• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and cHL
• DLBCL, NOS
- Morphological variants: Centroblastic, Immunoblastic, Anaplastic
- Molecular subtypes: GCB-type, non GCB-type (ABC-type)
Large B-cell lymphomas – WHO 2017
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6
• Most common lymphoma worldwide (30-40%)
• Heterogenous disease (morphology, phenotype, genotype, clinic)
• Majority cured by first-line treatment (R-CHOP)
• 30 - 40% of DLBCL relapse
• Relapse - worse outcome
• Identification of these patients needed
• Prognostic and/or predictive markers
Mareschal et al. 2015
DLBCL: the clinical problem
Nowakowski et al., J Natl Cancer Inst, 2016
Davies A., Hematology Am Soc Hematol Educ Program.,2017
Sehn & Cascoyne, Blood 2015
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• Cell of origin (CoO) - classification: required
• Distinguish GCB from non‐GCB type DLBCL
• Methods: GEP, IHC, Nanostring…..
• IHC: any algorithm accepted (Hans, Visco, Tally, Choi…)
DLBCL, NOS: WHO-update 2017
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COO Classification in the WHO Update 2017
“Insight into the diverseness of GCB and ABC DLBCL has led to the investigation
of more specific therapeutic strategies to mitigate the worse outcome among
those with ABC/non-GCB type DLBCL reported and prospective trials are ongoing
to determine if these therapies should be incorporated into clinical practice”.
“For this reason the revised classification will require the identification of these
two subtypes. With GEP still not a routine clinical test, the use of IHC algorithms
will be considered acceptable. While the Hans algorithm remains the most popular
and has a reasonable correlation with the GEP, other algorithms also may be used
(Visco, Choi, Tally,…)”.
Swerdlow et al. Blood 2016
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Cell of Origin – Hype index
CoO-HI
2000 2005 2008 2018
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Molecular subtypes of DLBCL: COO-classification
Nature, 2000
Wright et al., PNAS 2003 Rosenwald et al., J Exp Med 2003
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Different prognosis of ABC & GCB DLBCL (R-CHOP)
Lenz et al., NEJM, 2008
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Lymph2Cx-based COO Classification and Survival Analysis in the German HG Clinical Trails
Ricover 60 R-CHOP (>60-80 ys.)
R-MegaCHOEP (18-60 ys.)
COO may not be a prognostic marker in (all) clinical trials
Staiger et al., JCO 2017
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Reddy et al;
Cell 2017
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Reddy et al; Cell 2017
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• 304 DLBCL
• WES, CNA, SV
• Coordinate genetic signatures (consensus clustering)
• 5 DLBCL subsets: C1 - C5
2018
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Chapuy et al; Nature Medicine 2018
Outcome association of DLBCL
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• Choice of method (GEP – NanoString – HTG – IHC)
• IHC: choice of algorithm (Hans, Visco, Tally, Choi…)
• Type of tissue (CNB)
CoO-testing: Practical Problems
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CoO-testing: Concordance of IHC with GEP
• 70-90% (Hans - classifier)
• CD10 robust, MUM1 & BCL6 more variable
• High interlaboratory concordance for stainings and CoO-subtyping
de Jong D et al., J Clin Oncol 2007
Gutiérrez-García et al., Blood 2011
Lawrie et al., Histopathology 2012
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MYC FISH
BCL2 & BCL6
FISH
DLBCL, NOS
CD10
GCB type
BCL6
MUM1
ABC type
-
+ DLBCL, NOS
“ single hit”
HGBCL
“double/ triple hit”
+
- +
-
+
-
ABC type
GCB type
-
+
Large B-cell lymphoma
Diagnostic Algorithm: “large B-cell lymphoma”
modified from: Gerlach and Dirnhofer; labmed 2018
Klapper et al; Der Pathologe 2018
Scott et al; Blood 2018
Reinke et al: Virchows Archive 2018
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Do we really need CoO – classification?
21
No immediate clinical relevance
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G. Lacoboni et al., Annals of Oncology 2018 Please note, cross trial comparisons should be interpreted with caution due to differences in inclusion criteria and patient populations
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Press release available from: https://www.jnj.com/janssen-provides-update-on-imbruvica-ibrutinib-phase-3-phoenix-trial-
in-newly-diagnosed-non-germinal-center-b-cell-non-gcb-subtype-of-diffuse-large-b-cell-lymphoma-dlbcl
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R-CHOP + lenalidomide R-CHOP
(historical comparison)
GCB
Non-GCB
wait for: DLC-002 (ROBUST) trial in ABC –
DLBCL
R-CHOP +/- lenalidomide
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Outlook
• “Top down” solution
• Clinical studies will determine the further “fate” of CoO
• If “practice changing” study/studies published
– Methodological gold standard
– Proficiency testing for analytical variables
– Biopsy according to guidelines
May 30, 2018
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Cell of Origin – Hype index
CoO-HI
2000 2005 2008 2018 2025
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Thank you!
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The PHOENIX study
2014
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ABC/GCB prognostic relevance in R-CHOP
treated DLBCL – results of independent consortia
Author Method Prospective trial Prognostic
Lenz et al. (NEJM 2010)
Gene expression (Affymetrix)
No Yes
Visco et al. (Leukemia 2012)
Immuno-histochemsitry
No Yes
Copie-Bergman et al. (JCO 2009)
Immuno-histochemsitry
Yes No
Cunnigham et al. (Lancet 2013)
Immuno-histochemsitry
Yes No
Staiger et al. (JCO 2017)
Gene expression (Nanostring)
Yes No
Reddy et al. (Cell 2017)
Gene expression (RNA-Seq.)
No Yes
Slide, modified: Prof. W. Klapper, Kiel
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Impact of Concurrent Expression of MYC and BCL2
Across Studies
Authors Number of
cases
%MYC/BCL2
positive
Significance Multivariate
Johnson 2012 307 18% P<.001 Significant
Green 2012 309 29% P<.001 Significant
Horn 2013 141 28% P<.001 Significant
Hu 2013 700 34% P<.001 Significant
Valera 2013 219 58% P<.001 Significant
Perry 2014 106 17% P<.001 Significant
Scott 2015 339 31% P<.001 Significant
Ye 2015 831 17% P<.001 Significant
S. Dirnhofer, Basel MYC BCL2
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2018
• 574 DLBCL
• WES, RNA-seq., targeted amplicon resequencing, CNA
• 4 genetic subtypes (co-occurrence of genetic alterations)
MCD (MYD88 & CD79B)
BN2 (BCL6 & NOTCH2)
N1 (NOTCH1)
EZB (EZH2 & BCL2)
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Schmitz et al; NEJM 2018
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Schmitz et al; NEJM 2018
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Chapuy et al; Nature Medicine 2018
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