Andre Goy, MD, Chairman and Chief of Lymphoma, John Theurer Cancer Center at Hackensack University Medical Center - Treatment of Large Cell Lymphoma Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

1. Treatment of Large Cell Lymphoma
Andre Goy, MD
Chairman / Director John Theurer Cancer Center
Lymphoma Program Head
Professor of Medicine UMDNJ

2. Early Stage DLBCL

3. Early Stage DLBCL (SWOG)
8 CHOP vs 3 CHOP + IFXRT
200 pts per arm / stage I (2/3 pts) / stage II 1/3 pts
100
90
CHOP plus radiotherapy
80
70
60
% Survival
50
CHOP alone
40
30
20
P = 0.02
10
0
0 1 2 3 4 5 6 7 8
Year post randomization
5y OS 72% vs 82% for CMT
Miller, NEJM July 1998

4. CHOP alone vs CHOP + IFXRT in
Stage I-II DLBCL > 60y (GELA)
290 pts per arm / Med flup 7y
PFS OS
5y NO difference / Prognostic factor: Stage II <
Bonnet JCO, March 2007

5. Localized DLBCL
Controversy on number of cycles
and need for radiation consolidation
Radiation improved local control and often > PFS
Difference in OS debated
Bindra & Yahalom, Expert Rev Anticancer Ther, 2011 Sep;11(9):1367-78.

6. MINT Trial – R-CHOP / CHOP for Young
Patients with good-prognosis DLBCL
18–60 y with 0 or 1 risk factor according to the aa-IPI,
stage II–IV disease or stage I-bulky
420 pts each arm / Median follow-up of 6 years
Rituximab obviously improves all subgroups /
Pts with IPI = 0, no bulk > 90%
Pfreundschuh, Lancet Oct 2011

7. - R-Chemo is also > in early stage DLBCL
- Impact of bulky disease is reduced by
R-chemo but remains prognostic
- Do we still need XRT in R-chemo era?

8. Can PET Scan Help?
Stage I/II, no B symp, mass ≤10 cm (Vancouver)
65 patients
Sehn L, ICML 2011, abst # 28

9. Can PET Scan Help?
Stage I/II, no B symp, mass ≤10 cm (Vancouver)
PET –ve excellent outcome / PET +ve high relapse
rate of distant relapse  NEED other approaches
Ongoing GELA study / PET to decide 6 vs 4 cycles
Sehn L, ICML 2011, abst # 28

10. Issues with Early Stage DLBCL
- Problem is series vary I, II and BULK or not
- Most relapses are distant relapses
Are late and distant relapses a reflection of
inadequate systemic therapy?

11. GELA – ACBVP vs CHOP + IFRT
Previously untreated patients < 61 years old / Stage I or II aggressive lymphoma
320 pts each arm / No IPI risk factors / Median follow-up of 7.7 years
5y EFS 82% for chemo alone vs 74% for CMT /
also > in PFS and OS
(similar In bulky or non-bulky)
Reyes, NEJM, March 2005

12. DLBCL – Early Stage
- Very limited disease (stage I / non bulky):
 R-CHOP x 3 w/wo XRT (3 +1 if PET –ve?)
 R-CHOP (6/6 vs 4/6) FLYER study Germany
- Stage I bulky / IE or II non bulky
 R-CHOP x 6 / limit nb cycles + XRT?
 6 R-CHOP-21 vs 6 R-CHOP-14
(UNFOLDER)
 6 v 4 R-CHOP if PET –ve (GELA)

13. Advanced Stage
DLBCL

14. Established Superiority of R-CHOP vs CHOP
MInT[1] British Columbia[2]
1.0
R- 1.0
0.8 Chemo Post-rituximab
0.8
0.6 0.6
GELA
0.4 Chemo
0.4
1.0 Pre-rituximab
0.2 0.2
P = .000000007 P=.0001
0 0.8
0
0 5 10 15 20 25 30 35 40 45 50 0.6 R-CHOP
0 1 2 3 4
Months Years
0.4 CHOP
0.2 RICOVER 60[5]
1.0 ECOG 4494[3] P < .0001
0 R-CHOP-14
0.8 Maintenance 0 1 2 3 4 5 6 7 8 9 10
Years
0.6
CHOP-14
0.4
Observation
0.2 CHOP
R-CHOP P = .000025
0.0
0 1 2 3 4 5 0 5 10 15 20 25 30 35 40 45
Years Months
Confirmed by multiple studies even in < 60y
1. Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391. 2. Sehn L, et al. ASH 2003.
Abstract 88. 3. Habermann T, et al. J Clin Oncol. 2006;24:3121-3127. 4. Coiffier B, et al.
ASCO 2007. Abstract 8009. 5. Pfreundschuh M, et al. Lancet Oncol. 2008;9:105-116.

15. R-CHOP-21
is The “Standard”
How can we improve?

16. DLBCL: Current Challenges w/R-CHOP
GELA 98-05 - median follow-up time of 10 years
80%
of drop
1st 3 years 40% at 10 y
still NED in
R-CHOP
½ failures occur in 1st 12 to 18ms
Poor outcome of early relapse (<1y)
 target for improvement +++
Coiffier et al, Blood June 2010

17. DLBCL: Strategies to improve / R-CHOP
Nb cycles / 6 vs 8 cycles
RICOVER trial (q2kws)
Dose-intensity
“More“ chemo R-CHOP-14 vs 21
Continuous infusion
R-EPOCH
Consolidation w/
DI / HDT-ASCT upfront
Prediction response on PET
Pts stratification ++
New combinations / R-CHOP + X
Revisit maintenance strategies

18. Adjust Number of cycles:
6 vs 8 Cycles (R)-CHOP-14 (RICOVER)
RICOVER Trial: 6 vs 8 CHOP-14 ± R in DLBCL > 60y (GHGLSG) / > 800 pts
Regimen 6 cycles 8 cycles
FFTF
CHOP 53% 58%
R-CHOP 70% 70%
PFS according to mid-therapy restaging
100
90 CR CRu PR
80
70
60
%
50
40 8 R-CHOP 14 8 R-CHOP 14 8 R-CHOP 14
30 6 R-CHOP 14 6 R-CHOP 14 6 R-CHOP 14
20
10 0 20 40 60 0 20 40 60 0 20 40 60
0 Months Months Months
NO benefit from 8 cycles
Schubert J, et al. ASH 2007. Abstract 788
Pfreundshuh M. Lancet Oncol. 2008;9:105-116. No benefit from XRTBulk in CR-CRu

19. R-CHOP-21 vs R-CHOP-14
UK NCRI Phase III Trial
R-CHOP-21
CHOP-21: 8 cycles
Newly diagnosed Rituximab x 8
CD20+ve R
DLBCL
R-CHOP-14 CHOP-14 x 6
Rituximab x 8
Stratified by age, IPI Lenograstim dasy 4-12
1080 pts, 540 / arm / 119 sites / May 2005 Nov 2008
Primary endpoints: OS
Cunningham D et al, , ASCO 2011, abst # 8000.

20. R-CHOP-21 vs R-CHOP-14
UK NCRI Phase III Trial
Recruitment by age
450
52%
400
350
Patients recruited
300
250
200
150
100
50
0
<30 30-39 40-49 50-59 60-69 70-79 80+
Age range
No difference clinical parameters btw both arms
2/3 stage III-IV / 50% bulky
Cunningham D et al, , ASCO 2011, abst # 8000.

21. R-CHOP-21 (8) vs R-CHOP-14 (6)
UK NCRI Phase III Trial
DLBCL, age >18, Bulky IA (>10cm), IB, II, III, IV
PFS OS
ORR 88% for RCHOP-21 vs 90% for RCHOP-14
Radiological CR 47% in both arms
No difference in ORR, CR rate, PFS or OS
Cunningham D et al, , ASCO 2011, abst # 8000.

22. R-CHOP-21 vs R-CHOP-14
UK NCRI Phase III Trial
Higher % neutropenia and F/N in R-CHOP21
reflects the primary prophylaxis with G-CSF in R-CHOP14
Cunningham D et al, , ASCO 2011, abst # 8000.

23. R-CHOP-21 vs R-CHOP-14
UK NCRI Phase III Trial
OS by phenotype
1.0
0.9
0.8
Probability
0.7
0.6
0.5
0.4 p=0.2082
0.3
Events Totals
0.2
non GC 63 271
0.1 GC 53 289
0.0
0 1 2 3 4 5 6
No difference in bulky, IPI, KI-67 (MIB-1), LDH, etc..
Cunningham D et al, , ASCO 2011, abst # 8000.

24. R-CHOP-21 vs R-CHOP-14 (8 cycles)
GELA Trial
Interim analysis
• 60 to 80 y 200 pts
• Stage II to IV
• AA IPI 1,2 or 3 Med flup 39 ms
Update ICML Lugano
R-CHOP14 R-CHOP21
CR + CRu 71% 73%
PR 16 % 12 %
ORR 87 % 85 %
Delarue et al, ASH 2009: abst # 406 Delarue, ICML 2011 abst # 124

25. R-CHOP-21 vs R-CHOP-14 (8 cycles)
GELA Trial
EFS OS
3y-EFS : 57% vs 60% 3y-OS : 70% vs 73%
No benefit ORR, CR, EFS, PFS or OS
Delarue, ICML 2011 abst # 124 Delarue et al, ASH 2009: abst # 406

26. Continuous Infusion – R-EPOCH
Phase II Study of dose-adjusted R-EPOCH in DLBCL
72 pts stage II or more, med age 50, 40% had a high-intermediate or high IPI
IPI score / PFS (P = .007)
Risk 5y PFS
Low-risk 91%
Low-interm 90%
High-interm 67%
High risk 47%
LNH98-5:
R-CHOP
high risk
5y EFS 47%
Ongoing randomization R-CHOP-21 vs R-EPOCH (CALGB) w/ GEP
Wilson WH, et al. J Clin Oncol. 2008;26:2717-2724.

27. More Intensive Induction Regimens?
LNH 03-2B Trial
380 pts / young pts IPI ≥ 1
MTX R-IFM-VP16 Ara-C
R-ACVBP 14
0 2 4 6 10 14 24 Wks
R 4 IT-MTX
0 3 6 9 12 15 18 21 Wks
R-CHOP 21
*No radiotherapy in both arms
NO ASCT
Recher Blood Nov 2010 abst # 109

28. More Intensive Induction Regimens?
LNH 03-2B Trial
3-y PFS 87% in R-ACVBP arm 3-y OS was 92% R-ACVBP
vs 73% in R-CHOP arm and 84% (R-CHOP arm
R-ACVBP significantly improves EFS, PFS, DFS and overall survival
Recher Blood Nov 2010 abst # 109

29. Consolidation w/ HDT – ASCT
Meta analysis 15 large randomized studies with chemo vs ASCT in DLBCL frontline
2728 pts
In pre rituximab era multiple studies conducted  NOT conclusive
Greb, Cancer Treatment Reviews (2007) 33, 338-346

30. Consolidation w/ HDT – ASCT Upfront
In Rituximab Era
DLCL04 Trial
R-CHOP-14 vs R-mega CHOP  consolidation or not w/HDT-ASCT /
High risk DLBCL pts AAIPI 2-3 /188 pts / arm
2y PFS no HDT-ASCT: 59% 2y OS: no difference
vs 72% for HDT-ASCT
Vitolo, ICML 2011 abst # 72

31. Consolidation w/ HDT – ASCT Upfront
In Rituximab Era
GOELAMS Trial 075
R-CHOP-14 x 8 vs HDT (CCEP/MC/DHAP) induction
followed by BEAM ASCT / 340 pts
1,0
Cumulative Survival
0,8
0,6
R-CHOP
0,4 R-HDT
p= 0.03
0,2
3y EFS R-CHOP 56 %
3y EFS R-HDT 41 %
0,
0 10 20 30 40 50 60 70
Months
3y PFS 81 % vs 79 % / No diff in OS or by IPI
LeGouill ASCO 2011 abst # 8003

32. Consolidation w/ HDT – ASCT Upfront
In Rituximab Era
DSHNHL Trial
8 CHOEP + 6 R vs 4 MegaCHOEP+ 6R
MegaCHEOP increasing dose  3 ASCR / 130 pts /arm / young pts high risk
R-MegaCHOEP not > (CR rate and PFS) and >> toxicity
Schmitz, ICML 2011 abst # 73

33. Consolidation w/ HDT – ASCT Upfront
In Rituximab Era
S9704 Trial (SWOG + Canada)
Bulky stage II, III, and IV H-Int / High IPI DLBCL
Hypothesis: is HDT-ASCT > after 5 CHOP+/- R?
Stiff, ASCO 2011 abst # 8001

34. Consolidation w/ HDT – ASCT Upfront
In Rituximab Era
S9704 Trial (SWOG + Canada)
Bulky stage II, III, and IV H-Int/High IPI diffuse
Outcome ASCT arm Conventional Hazard ration P-value
% arm
2-year PFS 69 56 1.72 .005
2-year OS 74 71 1.24 .16
HDT-ASCT improved PFS even for pts who received R-CHOP but no diff OS
(except in AN UNPLANNED
subset analysis > for high
risk pts)
Stiff, ASCO 2011 abst # 8001

35. Consolidation w/ DI / HDT – ASCT
Upfront??
• Rituximab is likely to decrease potential differences
between conventional and high-dose regimens
• Lack of impact on OS means it does not matter if pts
receive HDT-ASCT
HDT should not be part of routine upfront consolidation
A subset of high risk pts might benefit from DI / HDT approaches
upfront (difficult to identify)

36. Can we identify high risk
patients upfront
/ early on??

37. Adjust Response Based on PET
Can we use
functional imaging
to detect
chemosensitivity
in-vivo?

38. Early Interim PET in Lymphoma
No event in PET-ve group
PET after 4th cycle PET after 1st cycle
PET+ve
Interim-
PET +
Spaepen et al, Ann Oncol 13: 1356, Kostakoglu et al, Cancer 107: 2678,
2002 2006
PET after 3rd cycle PET after 2nd cycle
Mikhaeel et al, Ann Oncol 16: 1514, 2005 Haioun et al, Blood 106: 1376, 2005
Strong predictor if NEGATIVE
Issues: consistency / false +ve / NEED BIOPSY
ΔSUV (drop ≥70%) might be better predictor?

39. Early Interim PET in Lymphoma
• Evidence that pts benefit from having their treatment
adapted based on early FDG-Pet is limited and
conflicting (need better standardization interpretation)
• Most data so far „adjusting“ based on PET were pre
Rituximab
• Ongoing risk-adapted studies / still pending
Ongoing studies FDG-PET remains investigational
Haouin, ICML 2011 abst # 139
Moskowitz, ICML 2011 abst # 140 Djor, ICML 2011 abst # 132

40. Risk Adapted Therapy
Patients
stratification ++

41. CLINICAL Prognostic Factors – IPI (APLES)
Risk Group Risk CR, 5-Yr OS,
Factors, % %
n
Patients (all ages)
 Low 0-1 87 73
 Low intermediate 2 67 51
 High intermediate 3 55 43
 High 4-5 44 26
Patients 60 yrs of age or younger
 Low 0 92 83
 Low intermediate 1 78 69
 High intermediate 2 57 46
 High 3 46 32
Prognostic models CAN BE INFLUENCED by EVOLVING therapies
Shipp et al, NEJM 1993

42. Revised IPI (R-IPI)
365 pts DLBCL R-CHOP
PFS Overall Survival
R-IPI cannot predict population < 50% OS @ 5y!
IPI still debated in the R-chemo era
Other factors: beta-2microglobulin, BM+, bulky NOT included!
Sehn et al, Blood, 2007 Bari A et al, Ann Oncol 2010;21:1486-1491
Ziepert et al, JCO May 2010

43. Impact of biological
heterogeneity of DLBCL

44. Cellular Origin of B-cell Lymphomas
Classification of lymphomas based on B-cell differentiation steps
and molecular (oncogenic) features
Kuppers et al, Nat Rev Cancer,

45. DLBCL Subtypes Resemble Stages
of B-cell Differentiation and Activation
2 main molecular
subtypes of DLBCL
correspond to different
cell of origin
GC- ABC-
DLBCL DLBCL
Alizdeh et al, Nature 2000. Kuppers et al, Nat Rev Cancer,

46. Primary Mediastinal Large Cell lymphoma
(PMBL) Have Distinct GEP
A group of 46 genes allowed to separate PMBL signature overlaps
PMBL from other DLBCL w/ classical Hodgkin lymphoma
Rosenwald et al, J Ex Med, Sept 2003

47. 3 Main Subtypes of DLBCL
w/ Different Outcome
Rosenwald et al, J Ex Med, Sept 2003

48. Distinction ABC / GC remains
after R-CHOP in DLBCL
Non GC subtype still worse outcome
Rosenwald A, et al. N Engl J Med. 2002;346:1937-1947 Lenz et al, NEJM, Nov 2008

49. Definition of ABC and GC Subtypes by IHC
Hans algorithm
GCB GCB
+ -
CD 10+
MUM-1
+
-
Bcl-6
+ Non-GCB
- Non-GCB
GCB Non-GCB
76% 34%
Choi model addition of GCET-1 (GC) and FOXP-1 (ABC)
Hans, CP, et al. Blood. 2004;103:275-282. Choi et al, Clin CA Res, Nov 2009.

50. Stromal Signatures in DLBCL
GEP on lymph node biopsies of 233 pts treated w/ R-CHOP
Stroma 1:
extra-cellular
matrix, myeloid,
macrophages
Stroma 2:
endothelial,
angiogenesis
signature
Lenz G et al. N Engl J Med 2008;359:2313-2323
Also predictive for PFS

51. Evolving COMPLEXITY
Of Signatures in DLBCL
Other Mutations
Genomic
MicroRNAs (MYC, double-
hit, CGH)
Epigenetic
SNPs (Histones,
methylation)

52. GROWING awareness of
molecular Heterogeneity of
DLBCL
BUT
not yet ready for routine clinical
decisions

53. What Happen After R-CHOP
(Relapse / refractory setting)?

54. Guideline Recommendations for
Treatment of Relapsed DLBCL
 Second-line therapy in  Second-line therapy for
candidates for high- patients who are not
dose therapy + ASCT candidates for high-dose
– DHAP ± rituximab therapy
– ESHAP ± rituximab – Clinical trial
– GDP ± rituximab – Rituximab
– GemOx ± rituximab – CEPP ± rituximab
– ICE ± rituximab – PEPC
– miniBEAM ± rituximab – EPOCH ± rituximab
– MINE ± rituximab
NCCN clinical practice guidelines in oncology: non-Hodgkin’s lymphomas. v.1.2011.

55. PARMA Study: Bone Marrow
Transplantation vs Salvage Chemotherapy
Transplantation
100 100 Conventional treatment
80 80
EFS (%)
OS (%)
60 60
40 40
20 20
P = .001 P = .038
0 0
0 15 30 45 60 75 90 0 15 30 45 60 75 90
Mos After Randomization Mos After Randomization
All PRE rituximab
Philip T, et al. N Engl J Med. 1995;333:1540-1545.

56. CORAL – Relapse / Refractory DLBCL
2 questions: Salvage regimen and benefit of maintenance post ASCT
R
A
Patients with A N Rituximab
R-ICE
relapsed/refract S D q2 m x 6
ory C O
CD20+ DLBCL, T M
R-DHAP I Observation
< 65 years
Z
E
N =400 patients
OS PFS
R-ICE and R-DHAP : similar activity
C. Gisselbrecht et al. JCO Sept 2010

57. CORAL – Relapse / Refractory DLBCL
Impact of prior Rituximab Impact of early relapse
Prior rituximab exposure
and relapse within 12 ms of diagnosis
 3y PFS 23% after HDT-ASCT
C. Gisselbrecht et al. JCO Sept 2010

58. BIO- CORAL Study
Paired biopsies showed no diff in GC / non-GC over time and by GEP
Hans algorythm
GC
Non GC
R-ICE R-DHAP
52%
31%
27% 32%
3 years 3 years
p = NS p = 0.04
p = NS
Difference in outcome confirmed when based on GEP +++
Thieblemont et al. ASH 2010, abt # 993

59. CORAL – Update on Maintenance
post ASCT
At 45 months, mobilization-adjusted ORR comparable after induction therapy
• ORR 51.5% for R-ICE vs 56.5% for R-DHAP (NS)
• EFS 29% vs 33% (NS)
• OS 48% vs 51% (NS)
Outcome R- No further P-value
4- years % maintenance treatment
EFS 55 53 .7435
PFS 55 57 .8314
OS 64 67 .7547
R-maintenance is not superior to observation after salvage  ASCT
(except in women > > PFS @2y and > OS for MR (p= 0.0066)
Gisselbrecht ASC0 2011, abst # 8004

60. Effect of R-CHOP Induction Debated
Moore ICML 2011, abst # 76

61. Salvage after R-CHOP
• Primary failures to R-CHOP do VERY POORLY +++
• Early failures to R-CHOP do worse than late failures
(>1y) but if chemosensitive should be transplanted
• Need for new strategies / (new combinations /
allogenic TH2)

62. Special Considerations
in the Treament of DLBCL

63. R-Mini-CHOP in > 80y
Life expectancy of an 80y person is 9 years!
 >80 y - Stage I-X to IV  150 pts 51 males 99 females
 R-mini-CHOP:  38 GELA centers
cyclophosphamide: 400 mg/m2
doxorubicine: 25 mg/m2  108 pts completed 6 cycles
vincristine: 1 mg total dose D1
 ORR 74% / CR-CRu 63%
 6 cycles q21d / GCSF optional
 2y OS 59% / PFS 48%
 Primary endpoint efficacy / OS
 30 deaths: 1/3 tox / 1/3 NHL /
1/3 other
Elderly w/ good PS can still do well with reduced dose R-CHOP
Schmitz N, et al. ASH 2010. Abstract 112.

64. Location: Testes Lymphoma - IELSG-10
(CONSORT Trial)
Fifty-three patients (22-79) with untreated stage I or II PTL
R-CHOP-21 + IT MTX + XRT (controlateral testis)
Cumulative incidence of CNS relapse
at 5 years was only 6%
(up to 35% in prior studies)
Is IT only sufficient?
Common brain parenchymal relapses
> Outcome /
historical controls
Vitolo, JCO July 2011

65. CNS Disease in DLBCL
 CNS involvement in DLBCL  CNS disease developed in
poor prognosis ++ 56 patients (2.5%) @ median:
7.0 mos; range, 0.2-85.0 mos
 Few data available on impact of
systemic therapy on CNS
events in DLBCL  CNS disease reduced in
patients with IPI 0 or 1 receiving
 2797 patients ≥ 60 yrs DLBCL rituximab
in the DSHNHL and MInT trials
– 2196 pts received CHO(E)P ±
R for 6-8 courses or  NOT for high risk pts
MegaCHOEP + R
Current prophylaxis (IT MTX) – not needed in “low risk” /
NOT “helpful” in high risk  redefine risk factors? HD MTX?
Peyrade, et al. ASH 2010. Abstract 853

66. Can we add to R-CHOP?

67. DLBCL: Add Mab (anti CD22) to R-CHOP
R-CHOP-21 + Epratuzumab 360 mg/m2 on day 1 of each cycle
107 pts
ER-CHOP feasible / appears to improve EFS comp to historical controls
Micallef et al, Blood Oct 2011

68. DLBCL: Add Mab to R-CHOP
Therapy type Drug / Rationale / design
Anti CD20 GA-101 / Ofatumumab
RIT R-CHOP  RIT
HDT RIT salvage
Anti-angiogenesis?? Bevacizumab
MAIN trial stopped
Anti VGEF (aflibercept)
Anti CD30 Brentuximab vedotin 64% CR rate
in CD30+ve lymphomas

69. DLBCL – Novel Therapies
New biologicals: small molecules
Therapy type Drug Comments
Rationale / design Efficacy / Toxicity
Proteasome Strong rationale for R-CHOP-Bz
inhibitors combinations
R-EPOCH-Bz
mTOR inhibitors RAD-001 (Everolimus) ORR 30% / DOR ≈ 6ms
PILLAR 2 trial: rand maintenance in CR post
R-CHOP
IMiDs Lenalidomide NHL-003 trial ORR 31%
Median of 3 prior RX (1-10)
R2-CHOP Len 265 days 1-10 / 30 pts
ORR 100% / CR rate 83%
++ MAINT post R-CHOP in > 60y (REMARC)
PKCβ inhibitor Enzastaurin Maintenance post R-CHOP / suggest > PFS
Other HDAC inhibitors Ongoing

70. Validation of NFKB Target in ABC DLBCL
Differential efficacy of Bortezomib + chemotherapy within molecular
subtypes of DLBCL
Rationale for ongoing trial R-CHOP +- Bortezomib in ABC-DLBCL
(PYRAMID Trial)
Dunleavey, Blood June 2009

71. Differences in responses to Lenalidomide
monotherapy in relapsed/refractory
GCB vs. Non GCB DLBCL
P=
% of response
0.004
P = 0.006
ORR 8.7% in GC vs. 53% in non-GCB DLBCL treated
with lenalidomide-monotherapy (n=40) (p = 0.006)
No differences in the median number or treatments, IPI score, histology, stage or
other demographic characteristics @ time lenalidomide Rx btw the two groups
Hernandez-Ilizaliturri, et al, Cancer April 2011

72. Targeting BCR Pathway in Lymphoma
BCR-associated kinases are targets of new drugs in
preclinical and clinical development
Inhibitor Activity
in DLBCL
Syk (spleen 5/23 responded
tyrosine ORR: 22%
kinase)
Fostamatinib
Btk (Bruton’s ORR 29%
tyrosine ? More CR in
kinase) PCI- ABC
32765
PI3K inhibitor Activity in CLL,
CAL-101 MCL, FL
1 Quiroga MP, et al. Blood 114(5):1029-37, 07/2009
From: Nat Rev Immunol 2:945 2 Niedermeier M, et al. Blood 113(22):5549-57, 5/2009

73. DLBCL: Strategies to improve / R-CHOP
6 cycles enough!
R-CHOP-14 vs 21
“More“ chemo no difference
Patients stratification will
Continuous infusion
R-EPOCH?
help develop novel
? Subset benefit from
strategies in DE-(RE)FINED
HDT-ASCT upfront
New combinations
subsets of pts
R-CHOP + X
NEW maintenance strategies
Prediction response on PET?
Patients stratification ++

74. DLBCL: Considerable Progress!
BEFORE
ASCT No
CHOP-21 HDT / ASCT
Debated? maintenance
Induction Consolidation Maintenance Relapse
New Mab
NOW
DAC
R-CHOP-21 No HDT/ASCT New Lenalidomide
+++ Subset of pts? agents ?? BTZ
SYK
BTKi