Recognizing Biologic and Clinical Subsets in B-cell Lymphoma
Recognizing Biologic and Clinical Subsets in B-cell Lymphoma
Recognizing Biologic and Clinical Subsets in B-cell Lymphoma
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<strong>Recogniz<strong>in</strong>g</strong> <strong>Biologic</strong> <strong>and</strong> <strong>Cl<strong>in</strong>ical</strong> <strong>Subsets</strong><br />
<strong>in</strong> B-Cell <strong>Lymphoma</strong>: ASH 2010<br />
R<strong>and</strong>y D. Gascoyne, MD<br />
BC Cancer Agency<br />
Vancouver, Canada
Follicular <strong>Lymphoma</strong> (FL)
Morphologic Heterogeneity <strong>in</strong> FL<br />
Completely follicular Marg<strong>in</strong>al zone differentiation Follicular & diffuse<br />
Grade 1 FL Grade 2 FL Grade 3B FL
The Natural History of Follicular NHL is Chang<strong>in</strong>g<br />
Overall Survival on Sequential SWOG Trials<br />
100%<br />
8 0%<br />
60%<br />
40 %<br />
CHOP + Monoclonal Antibody<br />
ProMace<br />
CHOP<br />
20%<br />
0%<br />
0 2 4 6 8 10<br />
Years After Registration<br />
Fisher RI, et al. J Cl<strong>in</strong> Oncol. 2005;23:8447-8452.
Prognostic Factors <strong>in</strong> FL?<br />
IR1, IR2, <strong>in</strong>terfollicular CD4<br />
T-<strong>cell</strong>s, follicular FOXP3<br />
Treg, PD1 <strong>cell</strong>s,<br />
macrophages, mast <strong>cell</strong>s,<br />
FDCs, MVD<br />
Malignant<br />
B-<strong>cell</strong>s<br />
Treatment<br />
<strong>Cl<strong>in</strong>ical</strong> Factors<br />
BCL2/BAK ratio, MUM1, p53<br />
Ki67 rate, loss of p16,<br />
+7, +X, del1p36, del17p<br />
del6q, aUPD 1p36/16p<br />
MYC translocations<br />
Non-neoplastic<br />
<strong>cell</strong>s <strong>in</strong> the<br />
microenvironment<br />
Host (germl<strong>in</strong>e)<br />
genetics (SNPs)<br />
FcR3a, IL8, IL2, IL12B<br />
IL1RN, C1qA
Microenvironment<br />
Benign<br />
Malignant<br />
T<br />
MZ<br />
T<br />
M<br />
B<br />
T<br />
B<br />
T<br />
M<br />
M<br />
B<br />
M<br />
Fb<br />
Follicular<br />
dendritic <strong>cell</strong>s<br />
Benign<br />
B-<strong>cell</strong>s<br />
GC<br />
T-<strong>cell</strong>s<br />
Fibroblasts, reticular <strong>cell</strong>s<br />
Macrophages<br />
Vessels (endothelium & pericytes)
Probability of OS<br />
Risk of Transformation<br />
FOXP3 Patterns<br />
FL cases with a follicular pattern of Treg <strong>cell</strong>s showed <strong>in</strong>ferior OS<br />
(P < 0.0001) <strong>and</strong> a higher risk for transformation (P = 0.005)<br />
1.0<br />
1.0<br />
.8<br />
.6<br />
Diffuse (n = 64)<br />
.8<br />
.6<br />
P = 0.005<br />
Follicular (n = 38)<br />
.4<br />
.2<br />
0.0<br />
0<br />
P < 0.0001<br />
5<br />
10<br />
Follicular (n = 38)<br />
15<br />
20<br />
.4<br />
.2<br />
0.0<br />
0<br />
5<br />
10<br />
Diffuse (n = 64)<br />
15<br />
20<br />
Years<br />
Years<br />
Far<strong>in</strong>ha P, et al. Blood. 2010;115:289-295.
Probability of OS<br />
Risk of Transformation<br />
Microvessel Density<br />
Cases with <strong>in</strong>creased angiogenesis at the time of diagnosis<br />
have <strong>in</strong>ferior overall survival <strong>and</strong> are at <strong>in</strong>creased risk to<br />
transform to aggressive histology lymphomas<br />
1.0<br />
1.0<br />
.8<br />
Low MVD (n = 63)<br />
.8<br />
.6<br />
.6<br />
High MVD (n = 21)<br />
.4<br />
High MVD (n = 21)<br />
.4<br />
Low MVD (n = 63)<br />
.2<br />
0.0<br />
0<br />
P = 0.0001<br />
5<br />
10<br />
Years<br />
15<br />
20<br />
.2<br />
0.0<br />
0<br />
5<br />
10<br />
Years<br />
P = 0.012<br />
15 20<br />
Far<strong>in</strong>ha P, et al. Haematologica. Published onl<strong>in</strong>e August 26, 2010.
Follicular <strong>Lymphoma</strong> Survival from Diagnosis<br />
With <strong>and</strong> Without Transformation<br />
1.0<br />
0.8<br />
Without transformation (n = 430)<br />
0.6<br />
0.4<br />
0.2 With transformation (n = 170)<br />
0.0<br />
0<br />
P < 0.0001<br />
5<br />
10 15<br />
20<br />
Overall survival (years)<br />
Al-Tourah AJ, et al. J Cl<strong>in</strong> Oncol. 2008;26:5165-5169.
Biomarkers Predict<strong>in</strong>g FL Transformation<br />
Increased Risk<br />
Follicular lymphoma, grade 1<br />
- Chromosomal ga<strong>in</strong>s +7, +12q13-14, +18q<br />
- Chromosomal losses del1p36, del6q23,<br />
-17p13, -9p21<br />
- aUPD 1p36.3 <strong>and</strong> 16p; MYC translocations<br />
- Diffuse areas, high proliferation rate<br />
- Follicular Treg <strong>cell</strong>s, <strong>in</strong>trafollicular CD4 +<br />
T-<strong>cell</strong>s, immature FDC<br />
- Increased MVD<br />
Reduced Risk<br />
- Pure follicular architecture<br />
- Low proliferation rate (Ki67)<br />
- Mature FDC phenotype<br />
- Diffuse pattern of Treg <strong>cell</strong>s<br />
- Decreased microvessel density (MVD)<br />
Diffuse large B-<strong>cell</strong> lymphoma
The Impact of Therapy on FL<br />
CD4<br />
Intrafollicular CD4 + T-<strong>cell</strong>s<br />
Biopsies obta<strong>in</strong>ed<br />
prior to therapy<br />
reflect differences <strong>in</strong><br />
basic biology <strong>in</strong> FL<br />
Treatment<br />
CD4<br />
Interfollicular CD4 + T-<strong>cell</strong>s<br />
Uniform Rx<br />
Results are<br />
<strong>in</strong>terpretable<br />
R-Chemo<br />
Variable Rx<br />
Prognosis implies outcome follow<strong>in</strong>g<br />
therapy <strong>and</strong> treatments used are lymphotoxic <strong>and</strong><br />
differentially visited upon the neoplastic<br />
B-<strong>cell</strong>s vs immune <strong>cell</strong>s <strong>in</strong> the<br />
microenvironment<br />
Results are<br />
difficult<br />
to <strong>in</strong>terpret<br />
Rel<strong>and</strong>er T, et al. J Cl<strong>in</strong> Oncol. 2010;28:2902-2913.
The Future <strong>in</strong> FL<br />
• Develop a list of robust biomarkers that can be<br />
used at the time of diagnosis to predict the bad<br />
actors <strong>and</strong> those at-risk to transform early<br />
• Determ<strong>in</strong>e those factors of value <strong>in</strong> the current<br />
era of R-chemo<br />
• Await the biologic correlates of rituximab<br />
failure/resistance (RESORT trial, others?)<br />
• Await discovery result<strong>in</strong>g from large-scale<br />
sequenc<strong>in</strong>g efforts <strong>in</strong> FL; these data will add<br />
texture to the molecular predictors, but will<br />
require the analysis of purified FL B-<strong>cell</strong>s
Mantle Cell <strong>Lymphoma</strong>
Molecular Pathogenesis of MCL<br />
Naïve<br />
B-<strong>cell</strong><br />
Germl<strong>in</strong>e<br />
Early MCL Classical MCL Blastoid MCL<br />
CCND1<br />
ATM<br />
CHK2<br />
t(11;14)<br />
Cycl<strong>in</strong> D1 <br />
ATM<br />
CHK2<br />
INK4A/CDK4/RB<br />
ARF/MDM2/p53<br />
RB1<br />
p27<br />
Complex<br />
karyotype<br />
High proliferation<br />
Adapted from Jares P, et al. Nat Rev Cancer. 2007;7:750-762.
Proliferation Signature Average <strong>in</strong> MCL<br />
Quartile 1 Quartile 2 Quartile 3 Quartile 4<br />
Rosenwald A, et al. Cancer Cell. 2003;3:185-197.
Quantitative Measurement of Proliferation<br />
Predicts Length of Survival Follow<strong>in</strong>g<br />
Diagnosis of Mantle Cell <strong>Lymphoma</strong><br />
5.07 X 10 -9<br />
Rosenwald A, et al. Cancer Cell. 2003;3:185-197.
The Future <strong>in</strong> MCL<br />
• Proliferation rema<strong>in</strong>s the cornerstone of<br />
outcome prediction <strong>in</strong> MCL<br />
• Next-generation sequenc<strong>in</strong>g may reveal<br />
important <strong>in</strong>sights <strong>in</strong> MCL biology <strong>and</strong> should<br />
provide new targets for therapy <strong>and</strong><br />
improvements to outcome prediction
Diffuse Large B-Cell <strong>Lymphoma</strong><br />
(DLBCL)
Morphological Heterogeneity <strong>in</strong> DLBCL<br />
Centroblastic Immunoblastic Plasmablastic<br />
PMBCL Anaplastic T-Cell/Histiocyte-Rich
Dissect<strong>in</strong>g a Cancer <strong>in</strong>to Molecularly <strong>and</strong> <strong>Cl<strong>in</strong>ical</strong>ly<br />
Significant Subgroups Based on Gene Expression Profil<strong>in</strong>g<br />
DLBCL treated<br />
with CHOP<br />
Rosenwald A, et al. N Engl J Med.<br />
2002;346:1937-1947.
Genetic Alterations are Characteristic of Molecular<br />
Subtypes of DLBCL<br />
DLBCL treated<br />
with R-CHOP<br />
GCB<br />
DLBCL<br />
ABC<br />
DLBCL<br />
PMBCL<br />
c-rel amplification (2p)<br />
BCL2 translocation<br />
BCL6 translocation<br />
Constitutive NF-B<br />
16% 0% 25%<br />
42% 0% 0%<br />
11% 22% 0%<br />
- + +<br />
MYC translocation<br />
14%<br />
9% 0%<br />
Ga<strong>in</strong>/amp chromosome 9p<br />
0% 6% 43%<br />
Lenz G, et al. Proc Natl Acad Sci<br />
USA.2008;105:13520-13525.
Mutations of Specific Genes Dist<strong>in</strong>guish the Molecular<br />
Subtypes of DLBCL<br />
DLBCL treated<br />
with R-CHOP<br />
GCB<br />
DLBCL<br />
ABC<br />
DLBCL<br />
PMBCL<br />
EZH2 mutations* 22% 0% 0%<br />
CARD11 mutations<br />
TNFAIP3 mutations<br />
4% 10% 0%<br />
2% 24% 0%<br />
BLIMP1 mutations<br />
0%<br />
24% 0%<br />
STAT6 mutations<br />
0% 0% 36%<br />
CD79b mutations † 21%<br />
0% 0%<br />
*Mor<strong>in</strong> RD, et al. Nat Genet.<br />
2010;43:181-185; † Davis RE,<br />
et al. Nature. 2010;463:88-92.
Cell-of-Orig<strong>in</strong> Dist<strong>in</strong>ctions Reveal Different Survival<br />
Characteristics <strong>in</strong> DLBCL Treated With R-CHOP<br />
DLBCL treated<br />
with R-CHOP<br />
3-year<br />
Survival<br />
PMBCL<br />
GCB DLBCL<br />
ABC DLBCL<br />
90%<br />
85%<br />
56%<br />
Lenz G, et al. N Engl J Med. 2008;359:2313-2323.
Prognostic Factors <strong>in</strong> DLBCL?<br />
Malignant<br />
B-<strong>cell</strong>s<br />
Treatment<br />
MYC translocations,<br />
BCL2 with MYC levels,<br />
GCB vs ABC,<br />
HIF1, EBV, CD5, loss of<br />
HLA-DR, p53 mutations,<br />
p16 loss, IBL<br />
morphology<br />
Stomal-1, stromal-2,<br />
MVD, macrophages<br />
<strong>Cl<strong>in</strong>ical</strong> Factors<br />
Non-neoplastic<br />
<strong>cell</strong>s <strong>in</strong> the<br />
microenvironment<br />
Host (germl<strong>in</strong>e)<br />
genetics (SNPs)<br />
IL10, IL8RB, IL4R<br />
IL1A, TNF
GCB vs Non-GCB DLBCL by<br />
Immunohistochemistry<br />
+<br />
GCB<br />
-<br />
GCB<br />
CD10<br />
-<br />
BCL6<br />
MUM1<br />
+ +<br />
-<br />
Non-GCB<br />
Non-GCB<br />
Hans CP, et al. Blood. 2004;103:275-282.
Develop New <strong>and</strong> Improved Immunohistochemistry Profiles<br />
93%<br />
81%
Cell-of-Orig<strong>in</strong> Phenotype: GCB<br />
CD10<br />
FOXP1<br />
GCET1<br />
BCL6<br />
MUM1<br />
Choi WW, et al. Cl<strong>in</strong> Cancer Res. 2009;15:5494-4402.
Cell of Orig<strong>in</strong> Phenotype: Non-GCB<br />
CD10<br />
FOXP1<br />
GCET1<br />
BCL6<br />
MUM1<br />
Choi WW, et al. Cl<strong>in</strong> Cancer Res. 2009;15:5494-4402.
A Bayesian Classifier to Estimate the<br />
Probability That a<br />
<strong>Lymphoma</strong> is ABC vs GCB DLBCL<br />
15-20% unclassified<br />
Non-GCB<br />
GCB<br />
Wright G, et al. Proc Natl Acad Sci USA. 2003;100:9991-9996.
The Hans Classifier – Controversies <strong>in</strong><br />
the CHOP <strong>and</strong> R-CHOP Era<br />
Hans, et al. Blood 2003<br />
Berglund, et al. Mod Pathol 2005<br />
Haarer, et al. Arch Pathol Lab Med 2006<br />
Muris, et al. J Pathol 2006<br />
Sjo, et al. Eur J Haematol 2007<br />
van Imhoff, et al. J Cl<strong>in</strong> Oncol 2007<br />
Nyman, et al. Blood 2007<br />
Amara, et al. Mod Pathol 2008<br />
Fu, et al. J Cl<strong>in</strong> Oncol, 2008 (R-CHOP)<br />
Colomo, et al. Blood 2003<br />
Nyman, et al. Blood 2007 (R-CHOP)<br />
De Paepe, et al. J Cl<strong>in</strong> Oncol 2005<br />
Dupuis, et al. Haematologica 2007<br />
Natkunam, et al. J Cl<strong>in</strong> Oncol 2008 (R-CHOP)<br />
Veelken, et al. Ann Oncol 2007<br />
Amen, et al. Histopathology 2007<br />
Wilson, et al. J Cl<strong>in</strong> Oncol 2008 (DA-EPOCH-R)<br />
Ott, et al. Blood (epub 2010) (R-CHOP)<br />
Survival association<br />
yes<br />
yes<br />
yes<br />
yes<br />
yes<br />
yes<br />
yes<br />
yes<br />
yes<br />
no<br />
no<br />
no<br />
no<br />
no<br />
no<br />
no<br />
no<br />
no
We Studied 135 Patients With de novo DLBCL<br />
Treated With R-CHOP Us<strong>in</strong>g a TMA <strong>and</strong><br />
Performed MYC FISH With a Breakapart Probe<br />
Normal MYC signal<br />
MYC translocated<br />
Savage KJ, et al. Blood. 2009;114:3533-3537.
Cumulative Survival<br />
MYC Translocations <strong>in</strong> de novo DLBCL<br />
Affect PFS/OS <strong>in</strong> Patients Treated With R-CHOP<br />
1.0<br />
1.0<br />
.9<br />
.8<br />
MYC Translocation – (n = 123)<br />
.8<br />
MYC Translocation – (n = 123)<br />
.7<br />
.6<br />
.6<br />
MYC Translocation + (n = 12)<br />
.5<br />
.4<br />
.4<br />
.3<br />
.2<br />
MYC Translocation + (n = 12)<br />
.2<br />
.1<br />
0.0<br />
0.0<br />
0<br />
2<br />
4<br />
6<br />
8<br />
10<br />
0<br />
2<br />
4<br />
6<br />
8<br />
10<br />
Progression free survival (y)<br />
Overall survival (y)<br />
Savage KJ, et al. Blood. 2009;114:3533-3537;<br />
Barrans S, et al. J Cl<strong>in</strong> Oncol. 2010;28:3360-3365.
Patterns of BM Involvement <strong>in</strong> DLBCL<br />
LN<br />
CD20<br />
Concordant<br />
Discordant<br />
CD20<br />
CD20
Overall Survival for 795 Patients<br />
With DLBCL Treated With R-CHOP<br />
Negative BM (n = 670)<br />
Discordant BM (n = 58)<br />
Concordant BM (n = 67)<br />
Sehn LH, et al. Submitted (2010).
Progression-Free Survival for 795 Patients<br />
With DLBCL Treated With R-CHOP<br />
Negative BM (n = 670)<br />
Discordant BM (n = 58)<br />
Concordant BM (n = 67)<br />
Sehn LH, et al. Submitted (2010).
The Future <strong>in</strong> DLBCL<br />
• Cell-of-orig<strong>in</strong> dist<strong>in</strong>ctions are important <strong>in</strong> R-<br />
CHOP treated patients <strong>and</strong> are beg<strong>in</strong>n<strong>in</strong>g to be<br />
used to stratify patients <strong>in</strong> phase III cl<strong>in</strong>ical trials<br />
test<strong>in</strong>g novel agents<br />
• MYC translocations <strong>and</strong> concordant BM<br />
<strong>in</strong>volvement are reliable predictors of treatment<br />
failure <strong>in</strong> de novo DLBCL<br />
• Next-generation sequenc<strong>in</strong>g will add texture to<br />
this list <strong>and</strong> identify those patients need<strong>in</strong>g<br />
targeted approaches based on their mutational<br />
profile at diagnosis
Conclusions<br />
• There are reliable biomarkers predictive of<br />
decreased survival <strong>and</strong> risk of transformation <strong>in</strong> FL,<br />
but these need to be studied <strong>in</strong> the current era of<br />
treatment with R-chemo<br />
• Beyond the proliferative rate, MCL is <strong>in</strong> desperate<br />
need of novel biomarker discovery<br />
• Cell-of-orig<strong>in</strong> dist<strong>in</strong>ctions, MYC, <strong>and</strong> concordant BM<br />
<strong>in</strong>volvement appear to be cl<strong>in</strong>ically relevant <strong>in</strong><br />
DLBCL; further mean<strong>in</strong>gful progress must await the<br />
publication of the mutational l<strong>and</strong>scape of this<br />
tumor