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?

agoy@hackensackUMC.org

MCL – Clinical Course – EU MCL Network

CR-CRu 20-25%

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

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

MCL – Management – 1st Challenge

Decide when to treat and recognize “indolent” MCL

MIPI

Ki-67

Hoster, Blood Jan 2008Determann, Blood Dec 2007

Indolent?

MCL – Management – 1st Challenge

Decide when to treat and recognize “indolent” MCL

Fernandez, Can Res, Feb 2010

MCL – Management – 1st Challenge

Recognize “indolent” MCL iMCL vs. cMCL

Fernandez, Can Res, Feb 2010

MCL – Important Steps – Induction Therapy

Geisler, Leuk Lymphoma, Aug 2009

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

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

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

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)

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

MCL – Important Steps- Induction Impact Prior to ASCT

Geisler, Blood, July 2008

< 60y vs. > 60y / same benefitMCL 2: 55% CR-CRu post induction

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

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

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

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

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%)

MCL - Important Steps - R/AraCInduction Impact

Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151

HD AraC translates into > OS as well

MCL – Important Steps

Benefit in all MIPI groups: TTF ITT

Hermine O, et al. ASH 2012. Abst # 151

Ki67 in low MIPI

MCL – Important Steps

Hermine O, et al. ASH 2012. Abst # 151

MCL – Important Steps

Hermine O, et al. ASH 2012. Abst # 151

Remission duration based on clinical and mol response after induction

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

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%)

MCL – Important Steps – ASCT remains relevant in the R-chemo Era

TTF w/ R-CHOP vs. R-CHOP/R-DHAPASCT

Hoster, AH 2008

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

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

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)

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?

Thank you!

agoy@HackensackUMC.org