1. Highlights from Lugano: The 12th International Conference on Malignant Lymphoma
Franco Cavalli, M.D., F.R.C.P.

2. Main novelties in ICML structure
Plenary session: the 3 abstracts with the highest score
Clinical case discussions
USA (Mayo) vs. France

3. Abstracts: the top 10 nations
USA
151
Italy 62
France
Germany 56
Japan 35
Spain 33 UK 31
Korea 24
Denmark 17
Switzerland

4. 12-ICML, Workshop on June 18th
“Identification of diffuse large B-cell lymphoma subtypes: a way towards tailored treatment”
Report at today by M. Shipp

5. Report of the ESO Workshop - “Molecular Heterogeneity and Tailored Treatment of Diffuse Large B-cell Lymphoma”
Where are we now?
Molecular signatures revealed by gene expression profiling, copy number analysis and deep sequencing
Current approaches to translate molecular signatures into diagnostic assays
What are the targets and pathways?
Cell surface molecules, B-cell receptor signaling, Toll-like receptor signaling, NFkB pathway, p53/ cell cycle deregulation, Metabolic programs, Apoptotic blocks, Epigenetic modifications, BCL6
How do we develop robust assays that capture molecular heterogeneity and design informative targeted clinical trials?
Molecular signaling and genetic alterations
Targeted therapies
Organization and collaboration

6. What We Know in June 2013
Predicting treatment failure and primary refractory R-CHOP status represent an unmet clinical need.
Cell-of-origin distinctions are biologically & clinically relevant.
We have a reasonable approximation of the mutational landscape in DLBCL.
Clinical assays will need to be robust, reproducible and applicable to formalin-fixed paraffin-embedded tissue.

7. What We Know in June 2013
MYC translocations are found in ~ 10% of all de novo DLBCL cases. Associated with inferior outcome with R-CHOP.
~ 50% MYC+ cases are double + triple-hit lymphomas (MYC + BCL2/6 translocations).
~ 3x as many cases express both proteins (DHIT IHC/MYC & BCL2). Independent predictor of survival and maybe enriched in the ABC subtype.

8. What We Don’t Know in June 2013
With the exception of TP53* and FOXO1#, survival impact of any other recurrent mutations in DLBCL
Overlap/exclusivity of most recurrent mutations
Systematic integration of copy-number alterations, mutations and epigenetic data, pathway perturbations
*Hu-Monette et al, Blood; 120: (2012)
#Trinh et al, Blood; 121: (2013)

9. Next Steps Workshop report
Working group to define a battery of robust tests to capture genetic heterogeneity
Working group to develop structures for clinical analysis of targeted agents in molecularly defined patient subgroups
Input and participation welcome!

10. Follow-up of the (11-ICML and )12-ICML Workshops On Lymphoma Staging and Restaging in the PET-CT Era
Organizing committee:
T.A. Lister, B.D. Cheson, R.I. Fisher, S.F. Barrington, E. Zucca

11. “Accepted” Modification of Staging System
PET/CT (with 5-point scale) is accepted as “best” staging (for all PET avid lymphomas)
The 5-point scale will be used until more quantitative measures are available and validated
CT to assess response in non-avid histologies or where PET was negative prior to treatment
A and B no longer need be applied
Symptoms are frequently neither recorded nor accurate and not included in most prognostic systems and nowadays they very infrequently impact on choice of treatment. Hence, anatomic stage is sufficient
Preference to maintain Ann Arbor Stage (PET legitimized)
BM and other extranodal sites:
need for BM biopsy in HD only if PET not performed
not complete agreement for the indication to BM biopsy in DLBCL
Spleen: “normal” size cannot be defined, FDG avidity defines involvement
CR: lesions do not have to completely disappear but should no longer be FDG avid
Surveillance with PET or CT indicated only in circumstances of high expectation of progression that would mandate therapy
Routine surveillance discouraged in clinical practice for all histologies
number of scans to assess for progression in clinical trials should be minimized

12. Next Steps Further discussion and data collection
Tumour bulk (currently unidimensional)
Bidimensional vs. uni-dimensional measurements
Staging/Response manuscript to be submitted for publication once issues have been resolved
manuscripts on validity of uni-dimensional criteria and PET standardization need to be published first

13. Marginal zone lymphomas
International Extranodal Lymphoma Study Group - IELSG 19 Randomised Study
E. Zucca, 12-ICML, Hematol Oncol (suppl 1):97. Abs 007

14. Response to Treatment
International Extranodal Lymphoma Study Group - IELSG 19 Randomised Study
Response ORR 110 (85%) 124 (95%) 104 (79%) CR* 80 (62%) 104 (80%) 73 (55%) PR 30 (23%) 20 (15%) 31 (23%) SD 11 (8%) 1 (<1%) 15 (11%) PD 7 (5%) 4 (3%) 9 (7%) NA 2 (1.5%) 2 (1.5%) 4 (3%)
* R-Chl vs. Chl, P= R-Chl vs. R, P<0.001; Chl vs. R, P= 0.372
E. Zucca, 12-ICML, Hematol Oncol (suppl 1):97. Abs 007

15. Event-Free Survival
International Extranodal Lymphoma Study Group - IELSG 19 Randomised Study
Log-rank HR 95% C.I.
R vs. Chl, P= ( )
R-Chl vs. Chl, P= ( )
R-Chl vs. R, P= ( )
5-year EFS (95%CI):
Chlorambucil , 52% (42%-60%)
R-Chlorambucil, 70% (61%-77%)
Rituximab, 51% (40%-61%)
E. Zucca, 12-ICML, Hematol Oncol (suppl 1):97. Abs 007

16. R-Bendamustine as First Line Treatment for MALT Lymphoma
A. Salar, 12-ICML, Hematol Oncol (suppl 1): Abs 100

17. Evidence that alloHCT can improve the natural course of poor-risk CLL:
Final results from a retrospective donor vs.
no donor comparison
P Dreger, I Herth, A Benner, S Dietrich, M Rieger, U Hegenbart, P Stadtherr, A Bondong, TH Tran, T Zenz, AD Ho
Department Medicine V, University of Heidelberg
Abstr. 059, 12-ICML
12-ICML,

18. (primary endpoint; study population: matches vs controls, n=97)
OS from 3-month landmark after start of search by compatible donor availability
(primary endpoint; study population: matches vs controls, n=97)
Median
follow-up
28 months
12-ICML,

19. Event Free Survival (ITT population; N=683)
Rituximab maintenance (qd 2m for 2y) or not
after R-CHOP-like regimens for DLBCL
Overall Survival (ITT population)
Event Free Survival (ITT population; N=683) 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Time [months] 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 AA 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Time [months] 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84 87 90 93 96 99
Rituximab
maintenance
Observation
Rituximab
maintenance
Observation
Austrian study group
27 countries,
N=683
p = 0.067
Jaeger at al, Abstr 119, 12-ICML, Lugano 2013

20. Retrospective study of patients with DLBCL treated in the R-era in the NCCN centres (n=841)
48% had stage I-II
23% had bulky disease
35% of cohort received RT
119 deaths :
88 in CHOP-R and 31 CHOP-R+ RT
Dabaja at al, Abstr 121, 12-ICML, Lugano 2013

21. Bulky Disease: RTx per protocol
The best arm of the RICOVER 60 trial (R-CHOP14 x6 + 2R + RT to bulk)
was compared to a subsequent cohort in which no RT was given
Bulky Disease: RTx per protocol
EFS
PFS OS
88% [95%-CI: 80-95]
90% [95%-CI: 84-97]
80% [95%CI: 71-89]
62% [95%-CI: 46-78]
65% [95%-CI: 49-81]
54% [95%-CI: 38-71]
p=0.001
p<0.001
p=0.001
months
RICOVER-60
(n=67)
RICOVER-60-no-RX
(n=36)
Zwick at al, Abstr 122, 12-ICML, Lugano 2013

22. Bulky Disease: PR after R-CHOP-14
The result seems to be due mainly to the effect of RT
in patients with only PR after systemic therapy
EFS
PFS OS
p<0.001
p=0.025
p=0.019
months
RICOVER-60
(n=84)
RICOVER-60-no-RX
(n=27)
Zwick at al, Abstr 122, 12-ICML, Lugano 2013

23. British Columbia: since 2005 end-of-treatment PET is performed to all DLBCL
If PET is +, RT is recommended if feasible
Positive PET (n=82 / 249)
22 (27%) no XRT
13 multiple sites not amenable, 7 physician choice, 2 biopsy negative
12/22 (55%) relapsed
Sehn at al, Abstr 123, 12-ICML, Lugano 2013 23

24. PROGRESSION-FREE SURVIVAL
Survival curves according to PET positivity
and performed RT
PROGRESSION-FREE SURVIVAL
OVERALL SURVIVAL
Percent Survival
Time (years)
Negative (n=167)
Positive- XRT (n=60)
Positive- No XRT (n=22)
Time (years)
Percent Survival
Positive- No XRT (n=22)
Negative (n=167)
Positive- XRT (n=60)
Sehn at al, Abstr 123, 12-ICML, Lugano 2013

25. Autologous transplant for elderly: Japanese registry
484 pts over 60
Rel/refr DLBCL who received autologous transplant
Non-relapse mortality by age group
P=0.598
Chihara at al, Abstr 21, 12-ICML, Lugano 2013

26. Survival curves according to age group
2-yr OS for over 70:
46% (29-61)
Progression free survival
Overall survival
2-yr PFS for over 70:
42% (25-57)
P=0.04
Chihara at al, Abstr 21, 12-ICML, Lugano 2013

27. Results of autologous transplant according to age Canadian GDP vs
Results of autologous transplant according to age Canadian GDP vs. DHAP trial
Random Assignment
N = 619
Age <60 (n = 442)
Median age 51.2
Range 19-59
Age > 60 (n = 177)
Median age 63.7
Range
GDP 222
DHAP 220
GDP 88
DHAP 89
Chemotherapy
ITT population
50.3% transplanted
49.8% transplanted
Davison at al, Abstr 22, 12-ICML, Lugano 2013

28. Survival curves of study patients divided by age group
Event free survival
Overall survival
Percentage
Age <60
Age >60
Time from randomization (months)
Percentage
Age <60
Age ≥ 60
Time from randomization (months)
P=0.42
P=0.43
Davison at al, Abstr 22, 12-ICML, Lugano 2013