1. MCL: Should all Eligible patients with MCL receive HDT-ASCT upfront?
Andre Goy, MD
Cancer Center Director
Lymphoma Division Head
John Theurer Cancer HUMC, NJ
Chief Science Officer Research / Innovation RCCA
Professor of Medicine at Georgetown

2. MCL – Clinical Course – EU MCL Network
CR-CRu 20-25%

3. MCL: High-Dose Therapy as Consolidation
CHOP-> ASCT >CHOP-IFN
69 / 75 pts
Response
IFN
arm
ASCT arm
p value
Med DOR
3.7y
1.6 y
0.0004
ITT med TTF
1.4y
2.6y
0.0001 OS
5.4 y
7.5
0.075
Dreyling M, et al. Blood. April 2005 3 3 3

4. MCL – Management – 4 Phases
BEFORE
Induction
Consolidation
Maintenance
Salvage
More chemo…?
Very short response
to salvage chemo
even with HDT-ASCT
CVP, CHOP, FC, CBL
Nothing or HDT-ASCT
Nothing or IFN
Frequent chemoresistance

5. MCL – Management – 1st Challenge
Decide when to treat and recognize “indolent” MCL
MIPI
Ki-67
Indolent?
Hoster, Blood Jan 2008
Determann, Blood Dec 2007

6. MCL – Management – 1st Challenge
Decide when to treat and recognize “indolent” MCL
Fernandez, Can Res, Feb 2010

7. MCL – Management – 1st Challenge
Recognize “indolent” MCL iMCL vs. cMCL
Fernandez, Can Res, Feb 2010

8. MCL – Important Steps – Induction Therapy
Geisler, Leuk Lymphoma, Aug 2009

9. MCL – Important Steps – Rituximab Impact
Meta analysis showed > OS with R-chemo
Elderly “real world” / TTNT med 11 ms,
med OS 27 vs 37 ms
Schulz, J Natl Cancer Inst, May 2007
Griffith et al, Blood 2011; SEER data

10. MCL – Important Steps- Rituximab / R-chemo
Response
CHOP
R-CHOP p
ORR
74%
94%
0.005 CR 7%
34%
TTF
14 ms
21 ms
0.01
59 / 62 pts
PFS
TTNT OS
Rituximab increases ORR, CR rate but med 25%!!!
Lenz, JCO, March 2005; Hoster ASH 2008
Schulz, J Natl Cancer Inst, May 2007; Griffith et al, Blood 2011; SEER data

11. MCL: ASCT remains Relevant in R-chemo Era
ASCT vs. Maint IFN in R-chemo era
Pooled younger / older HDT /vs. stand + maint IFN
ASCT remains relevant in the R-chemo era
Hoster, ASH 2008 11 11 11

12. DIT/ASCT Have Also an Impact Outside of Clinical Trials
167 MCL pts NCCN database – frontline R-chemo - NOT on trial
PFS OS
3y PFS R-CHOP 18%
3 times < to any dose-intensive strategy (56-58%)
OS K-M p
R-HyperCVAD vs R-CHOP
P < .04
R-CHOP/ASCT vs R-CHOP
P < .20
R-HyperCVAD vs R-CHOP/ASCT
TP = .64
When pooling DI-HDT pts / R-CHOP >>> PFS and OS (p=0.001)
LaCasce A, et al. Blood, 2012 Mar 1;119(9):2093-9

13. MCL - Important Steps - Induction Impact Prior to ASCT
EFS
(R)-CHOP-DHAP  ASCT OS
Tripled CR rate after R-DHAP
(12% vs. 61%)
Med EFS: 84 ms vs. 51 ms prior to rituximab
Delarue, Blood Jan 2013 13 13 13

14. MCL – Important Steps- Induction Impact Prior to ASCT
MCL 2: 55% CR-CRu post induction
< 60y vs. > 60y / same benefit
Geisler, Blood, July 2008

15. MCL – Important Steps- Induction Impact Prior to ASCT
Median follow-up of 6·5 years
More than 70% of patients with low-intermediate MIPI-B were alive
at 10 years
Geisler, Br JnlHeamatol, Aug 2012
Geisler, Blood Feb 2010
Geisler, Br JnlHeamatol, Aug 2012

16. MCL - Important Steps - Induction Impact Prior to ASCT
Multicenter setting
Med age 56 y (32-65)
Median OS and median response duration BOTH not reached at 10 years
Geisler, Blood Feb 2010

17. MCL - Important Steps - R/AraC Induction Impact
Study
Therapy
5-Yr EFS, %
GITIL[2]
(R) HDS-ASCT*
61%
MDACC [3,4]
R-HyperCVAD
60% / FFS
CALGB
R-Maxi CHOP-MTX / VP16-AraC/ CBV- ASCT
56% / PFS
EU (GELA)
R-CHOP/DHAP- TAM ASCT
65% / TTF
R-CHOP 2y PFS 25% !!
1. Cortelazzo S, et al. ASH Abstract 1282.
2. Romaguera JE, et al. J ClinOncol. 2005;23: Fayad L, et al. Clin Lymphoma Myeloma. 2007;8, Delarue, Blood Jan 2013

18. MCL - Important Steps - R/AraC Induction Impact
AraC benefit confirmed in randomized trial
MCL Younger
< 65 years R
Dexa
BEAM
Cyclo
TBI + Autograft
P B S C harvest
Ara-C, Melphalan
3-monthly follow-up 1 9 5 13 17
week
R-CHOP/R-DHAP alternating 3-weekly
R-CHOP 3-weekly
MRD
MRD 2-3 monthly intervals
Hermine et al, ASH 2010 abst # 110

19. MCL - Important Steps - R/AraC Induction Impact
212 pts R-CHOP/ 208 pts R-CHOP/DHAP
No diff between arms in pts characteristics or % pts going ASCT (77% / 79%)
months
TTFT (Primary endpoint)
Remission Duration after ASCT
w/ med follow up 51 ms,
TTF 46 vs 88 ms, p0.038
w/ med follow up 51 ms,
remission duration 49 vs 84 ms, p
Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151

20. MCL - Important Steps - R/AraC Induction Impact
HD AraC translates into > OS as well
Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151

21. MCL – Important Steps Benefit in all MIPI groups: TTF ITT
Ki67 in low MIPI
Hermine O, et al. ASH Abst # 151

22. MCL – Important Steps
Hermine O, et al. ASH Abst # 151

23. Remission duration based on clinical and mol response after induction
MCL – Important Steps
Remission duration based on clinical and mol response after induction
Hermine O, et al. ASH Abst # 151

24. EU - MCL Younger Pts - Results
Impact of ASCT on MRD status
R-CHOP
R-DHAP PB BM 25 50 75
100
% MRD negative
54%
70%
p = 0.04
p = 0.01
36%
60%
82%
73%
87% ns *
Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151

25. MCL – Younger Pts – Frontline Summary
Arm R-CHOP-DHAP leads to > outcome TTF, DOR and now OS
Due to higher and earlier rate of CR-CRu and molecular CR in HD AraC arm POST induction ++
Med OS AraC arm NR vs 82 ms, p 0.045
Parameter
R-CHOP/R-DHAP
R-CHOP p
CR-CRu
55%
40%
p=0.0028
Mol CR
83%
51%
p <
Post ASCT similar CR-CRu (79/82%)
Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151

26. MCL – Important Steps – ASCT remains relevant in the R-chemo Era
TTF w/ R-CHOP vs. R-CHOP/R-DHAPASCT
Hoster, AH 2008

27. MCL – Important Steps – DIT/ASCT remains relevant in the R-chemo Era
“Longest mileage”
Cost

28. MCL - DIT/HDT-ASCT - Summary
Med OS improvement recognized mostly due to long unprecedented PFS > 5y with DIT and /or HDT-ASCT (40% MCL are <60y)
Achieving a deep and early response in MCL matters
A CR  translates into >> outcome
Molecular CR ++ might become new surrogate endpoint

29. MCL – DIT-ACST Remains the Best Option in R-Chemo Era
Clearly subset of MCL that are more indolent (nonnodal leukemic phase, hypermutated & SOX11 -ve)
Novel therapies very promising
Platform for combinations (improve mol CR) and /or maintenance post therapy
Alternative to chemotherapy (in elderly)

30. MCL – Management – DIT/ASCT Fit Pts
NOW
and FORWARD
Induction
Induction: R-chemo with cytarabine
Mol CR as a new endpoint?
Beyond standard chemo in MCL
Consolidation
Still longest PFS
Will MOL CR early still need ASCT?
Maintenance
Still late relapses
Novel therapies?
PCR based?
Salvage
Role of HDT/ASCT debated
Novel therapies combos?
Mini allo? CAR?

31. Thank you!