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![Page 1: Andre Goy, MD Cancer Center Director Lymphoma Division Head John Theurer Cancer Center @ HUMC, NJ Chief Science Officer Research / Innovation RCCA Professor.](https://reader033.fdocuments.us/reader033/viewer/2022050908/56649c855503460f9493bf64/html5/thumbnails/1.jpg)
Andre Goy, MDCancer Center Director
Lymphoma Division Head John Theurer Cancer Center @ HUMC, NJ
Chief Science Officer Research / Innovation RCCAProfessor of Medicine at Georgetown
MCL: Should all Eligible patients with MCL receive HDT-ASCT upfront?
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MCL – Clinical Course – EU MCL Network
CR-CRu 20-25%
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MCL: High-Dose Therapy as Consolidation
CHOP-> ASCT >CHOP-IFN
69 / 75 pts
Dreyling M, et al. Blood. April 2005
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
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MCL – Management – 4 Phases
Induction Consolidation Maintenance Salvage
BEFORE
CVP, CHOP, FC, CBL
Nothing or HDT-ASCT Nothing or IFN
More chemo…?Very short response to salvage
chemoeven withHDT-ASCT
Frequent chemoresistance
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MCL – Management – 1st Challenge
Decide when to treat and recognize “indolent” MCL
MIPI
Ki-67
Hoster, Blood Jan 2008Determann, Blood Dec 2007
Indolent?
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MCL – Management – 1st Challenge
Decide when to treat and recognize “indolent” MCL
Fernandez, Can Res, Feb 2010
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MCL – Management – 1st Challenge
Recognize “indolent” MCL iMCL vs. cMCL
Fernandez, Can Res, Feb 2010
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MCL – Important Steps – Induction Therapy
Geisler, Leuk Lymphoma, Aug 2009
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MCL – Important Steps – Rituximab Impact
Meta analysis showed > OS with R-chemo
Schulz, J Natl Cancer Inst, May 2007 Griffith et al, Blood 2011; SEER data
Elderly “real world” / TTNT med 11 ms, med OS 27 vs 37 ms
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MCL – Important Steps- Rituximab / R-chemo
Response
CHOP R-CHOP p
ORR 74% 94% 0.005
CR 7% 34% 0.00024
TTF 14 ms 21 ms 0.01
Lenz, JCO, March 2005; Hoster ASH 2008Schulz, J Natl Cancer Inst, May 2007; Griffith et al, Blood 2011; SEER data
PFS TTNT OS
Rituximab increases ORR, CR rate but med PFS @2y 25%!!!
59 / 62 pts
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MCL: ASCT remains Relevant in R-chemo Era
ASCT vs. Maint IFN in R-chemo era
Hoster, ASH 2008
ASCT remains relevant in the R-chemo era
Pooled younger / older HDT
/vs. stand + maint IFN
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DIT/ASCT Have Also an Impact Outside of Clinical Trials
167 MCL pts NCCN database – frontline R-chemo - NOT on trial
LaCasce A, et al. Blood, 2012 Mar 1;119(9):2093-9
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
PFS OS
3y PFS R-CHOP 18% 3 times < to any dose-
intensive strategy (56-58%)
When pooling DI-HDT pts / R-CHOP >>> PFS and OS (p=0.001)
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MCL - Important Steps - Induction Impact Prior to ASCT
(R)-CHOP-DHAP ASCT
Tripled CR rate after R-DHAP (12% vs. 61%)
Med EFS: 84 ms vs. 51 msprior to rituximab
EFS
Delarue, Blood Jan 2013
OS
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MCL – Important Steps- Induction Impact Prior to ASCT
Geisler, Blood, July 2008
< 60y vs. > 60y / same benefitMCL 2: 55% CR-CRu post induction
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MCL – Important Steps- Induction Impact Prior to ASCT
Geisler, Blood Feb 2010Geisler, Br JnlHeamatol, Aug 2012
Median follow-up of 6·5 years
More than 70% of patients with low-
intermediate MIPI-B were aliveat 10 years
Geisler, Br JnlHeamatol, Aug 2012
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MCL - Important Steps - Induction Impact Prior to ASCT
Geisler, Blood Feb 2010
- Multicenter setting - Med age 56 y (32-65)-Median OS and median response duration BOTH not reached at 10 years
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MCL - Important Steps - R/AraCInduction Impact
1. Cortelazzo S, et al. ASH 2007. Abstract 1282.2. Romaguera JE, et al. J ClinOncol. 2005;23:7013-7023. 4. Fayad L, et al. Clin Lymphoma Myeloma. 2007;8, Delarue, Blood Jan 2013
R-CHOP 2y PFS 25% !!
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
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MCL - Important Steps - R/AraCInduction Impact
MCL Younger< 65 years
R
DexaBEAM
CycloTBI + Autograft
P B S Charvest
Ara-C, MelphalanTBI + Autograft
3-monthly follow-up
1 95 13 17week
R-CHOP/R-DHAP alternating 3-weekly
1 95 13 17week
R-CHOP 3-weekly
3-monthly follow-upP B S Charvest
MRD MRD 2-3 monthly intervals
Hermine et al, ASH 2010 abst # 110
AraC benefit confirmed in randomized trial
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MCL - Important Steps - R/AraCInduction Impact
Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151
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
0.0001
212 pts R-CHOP/ 208 pts R-CHOP/DHAP No diff between arms in pts characteristics or % pts going ASCT (77% / 79%)
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MCL - Important Steps - R/AraCInduction Impact
Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151
HD AraC translates into > OS as well
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MCL – Important Steps
Benefit in all MIPI groups: TTF ITT
Hermine O, et al. ASH 2012. Abst # 151
Ki67 in low MIPI
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MCL – Important Steps
Hermine O, et al. ASH 2012. Abst # 151
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MCL – Important Steps
Hermine O, et al. ASH 2012. Abst # 151
Remission duration based on clinical and mol response after induction
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EU - MCL Younger Pts - Results
Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151
R-CHOP R-DHAP
PB BM PB BM0
25
50
75
100%
MR
D n
egat
ive
54%
70%
p = 0.04 p = 0.01
36%
60%
82% 82% 73%
87%
ns ns
* *
* *
Impact of ASCT on MRD status
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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=0.0028Mol CR 83% 51% p < 0.0001
Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151
Post ASCT similar CR-CRu (79/82%)
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MCL – Important Steps – ASCT remains relevant in the R-chemo Era
TTF w/ R-CHOP vs. R-CHOP/R-DHAPASCT
Hoster, AH 2008
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MCL – Important Steps – DIT/ASCT remains relevant in the R-chemo Era
CHOP
R-CHOP
R-CHOP-ASCT
R-CHOP-DHAP-ASCT
R-HyperCAVD
0 10 20 30 40 50 60 70 80 90 100
TTF
TTF
CHOP
R-CHOP
R-CHOP-ASC
T
R-CHOP-DHAP-A
SCT
R-Hyp
erCAVD
0%
20%
40%
60%
80%
100%
120%
ORR
CR
Mol CR
• “Longest mileage”• Cost
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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
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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)
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MCL – Management – DIT/ASCT Fit Pts
Induction
NOW and FORWARD
Mol CR as a new
endpoint?Beyond standard
chemo in MCL
Induction: R-chemo with
cytarabine
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?