Integration and Automation in Practice: CI/CD in Mule Integration and Automat...
Dr. Campo MCL
1. Biology and Pathology of
Mantle Cell Lymphoma
Elias Campo
Hospital Clinic, University of Barcelona
2. Mantle Cell Lymphoma
1.0
0.8
Probability
0.6
Cyclin D1 0.4
0.2
0.0
0 2 4 6 8
Years
Complete Response 25% (6-50%)
14 der(14) 11 der(11) Duration of CR 1.5 yrs (0.5-2.5 yrs)
Median Survival 3-4 years
IGH/CCND1
3. Improvement in Survival of Patients
with non-blastoid MCL
1996 to 2004
1975 to 1986
• New diagnostic tools and management measures
• Application of new therapeutic regimens
Herrmann, A. et al. J Clin Oncol; 27:511-518 2009
4. MCL Pathogenesis
• Cell Cycle Dysregulation
• Dysruption of DNA damage
response pathway
• Cell survival pathways
12. Molecular Pathogenesis in MCL
Early Classical Blastoid
Naive B
MCL MCL MCL
lymphocyte
t(11;14) ATM p16/CDK4/Rb Bcl-2/other
ARF/MdM2/p53
Cyclin D1 CHK2
Increased High Cell
Rb p27 Genomic Proliferation Survival
Instability
Jares P et al Nat Rev Cancer 2007
13. IGH Somatic Hypermutations in 807 MCL
Highly mutated 111 (13%)
Minimally/borderline mutated 458 (57%)
Truly Unmutated 238 (30%)
Hadzidimitriou A et al Blood 2011
14. MCL: From Naive to an Antigen Selected Cell ?
UnMutated-MCL
T Cell-Independent Response
Naïve Boderline Mutated-MCL
V D J cμ cγ
Antigen Selection
Ig Somatic Mutations
Class Switch
HyperMutated-MCL
23. MCL with Indolent Clinical Behavior
OS from diagnosis OS from treatment
Martin P et al JCO 2009
24. Conventional vs Indolent MCL
Clinical Characteristics
Clinical data Conventional Indolent
MCL (15) MCL (12)
Chemotherapy 15 0
Median Follow-up 15 m (0.5 - 79) 70 m (25-121)
5-year Overall Survival 49% 100%*
ECOG≥2 70% 0+
Intermediate/High MIPI 46% 0+
Lymphadenopathy (>1cm) 15/15 2/12+
Lymphocytosis (≥5x109/L) 9/11 4/9
+ p <0.05
* p=0.002 Fernandez V et al Cancer Res 2010
25. iMCL and cMCL Have a Distinct Gene Expression Signature
Supervised analysis
Indolent and
conventional MCL
LGALS3BP
CSNK1E
SOX11
KIAA1909
FARP1
PON2
CNN3
DBN1
HDGFRP3
CDK2AP1
HMGB3
SETMAR
CNR1
RNGTT
Fernandez V et al Cancer Res 2010
27. Can SOX11 expression recognize a subtype of MCL with
different clinicopathological features and outcome?
Clinical data SOX11 - SOX11 +
(n = 15) (n = 97)
High MIPI 33% 46%
Lymphn nodes (>1cm) 53% 99% *
Splenomegaly 92% 48%*
WBC ≥ 10x109/L 57% 18%*
Lymphocytosis (≥5x109/L) 83% 24% *
Ki67 high >50% 20% 28%
Adriamycin-Regimens 67% 72%
Complete Response 40% 54%
5-year OS (%) 78% 36%*
+ p <0.01 Fernandez V et al Cancer Res 2010
28. Overall Survival in MCL patients according to SOX11 Expression
1
SOX11 negative (N=15; dead: 4)
.8
.6
Sox11 -
.4
PROBABILITY
SOX11 positive (N=97; dead: 68)
.2 Sox11 +
0
0 2 4 6 8 10 12 14 16
YEARS
P< 0.001
Fernandez V et al Cancer Res 2010
33. Conclusions
- MCL pathogenesis integrates alterations in cell cycle, DNA damage
response and survival pathways that may be targeted by new
therapies
- Antigen selection may play a role in the pathogenesis of at least a
subgroup of MCL
- Cyclin D1 negative MCL can be recognized by SOX11 expression
and seem to have similar clinical and genetic characteristics to
conventional MCL.
- Some MCL have an indolent clinical course and may benefit of a
more conservative clinical management. A subset of them seems to
correspond to a different biological subtype.
- We may recognize early steps in MCL lymphomagenesis that
should be managed with caution.
34. Acknowledgments
Hospital Clínic-University National Institute of Health
of Barcelona Bethesda
Adrian Wiestner
Silvia Bea Wyndham Wilson
Cristina Royo Elaine Jaffe
Alba Navarro
Guillem Clot
Alejandra Martinez Institute of Pathology-Würzburg
Eva Giné Elena Hartmann
Gonzalo Gutierrez Andreas Rosenwald
Verònica Fernàndez
Dolors Colomer
Abteilung für Klinische-Pathologie-
Neus Villamor
Stuttgart
Pedro Jares
German Ott
Armando Lopez-Guillermo
University Hospital
Schleswig-Holstein-Kiel
Chistiane Pott Addenbrooke’s Hospital-Cambridge
Itziar Salverria Nicola Trim
Reiner Siebert
Wendy Erber
University Hospital Munich-
Grosshadern-Munich S. Orsola-Malpighi Hospital-Bologna
Martin Dreyling Claudio Agostinelli
Stefano A Pileri