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4/23/2012
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Great Debates / Updates in Hematologic Malignancies
“Should an asymptomatic MCL patient w/ low tumor burden be
observed or receive immediate treatment?”
Great Debates / Updates in Hematologic Malignancies
April 2012, New York, New York
Andre Goy, MDCancer Center Director
Lymphoma Division Head John Theurer Cancer Center @ HUMC, NJ
Acknowledgements
Organizers
Co‐investigators
Colleagues
Patients enrolled in trials
AND Supporting staff…
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MCL – Evolving Landscape
– Overall survival of MCL has improved over the last 2 decades
– Intensive approaches have led to very durable PFS– Intensive approaches have led to very durable PFS
– AraC containing regimens lead to very high CR rate and mol CR rate which impact outcome
– Emerging novel therapies and maintenance strategies will play a g g p g p ybigger role
– Burden or symptoms NOR clinical prognostic factors truly help yet our decisions
MCL ‐ Can we stratify patients based on Symptoms and /or Tumor burden?
– What is low tumor burden? (no good cut‐off)
– Early stage / most MCL are advanced stages (PBL flow +ve)
– ½ to 2/3 pts with MCL even with high tumor burden or blastoid histology have no B symptoms
– What are the other prognostic factors to help decide on RX?
– Can we identify more a “biologically” indolent MCL?
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MCL – Early Stage MCL
26 pts Stage I‐II A MCL British Columbia 1984‐2000Treated w/ RT / Chemo alone orCMT
Leitch H A et al. Ann Oncol 2003;14:1555-1561
MCL – Early Stage MCL
19 pts ‐ Princess Margaret ‐ 1990‐2007, all CMT
PFS OS
Bernardet al, ICML 2011, poster 232
Early stage MCL: rare, some very long term disease‐free Outcome is better in stage I AND use of radiation
MOST relapses are systemic
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MCL – Most MCL Present with Advanced Stage
6% NHL and M:F ratio = 3:1
Typically advanced stage +++ Typically advanced stage +++
> 90% extra‐nodal involvement: BM, blood, liver, GI ++
> 80% circulating tumor cells
B symptoms: 1/3 to ½ cases
Fisher RI, et al. Ann Oncol. 1996;7(suppl 6):S35-S39.Armitage JO, et al. Oncology (Williston Park). 1998;12(10 suppl 8):49-55Ferrer et al, Cancer June 2007
Most MCL @ DIAGNOSIS have an “indolent” presentation / aysmptomatic
MCL Advanced Stage Has Poor Outcome
PFS OS
MCL MCL
Fisher RI, et al. Blood Feb, 89, 1995, 3909-3918
MCL has clearly different outcome than other “indolent” MCL
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MCL: OS Has ImprovedKLSG 150 pts (75‐86) vs GSLG 350 pts (96‐04)
(non‐blastoid variants)
KLSG: mostly CBL‐P, COPGSLG: anthracyclines, R, HDT
5y OS 22% vs 47% p < 0.0001
Herrmann, J ClinOncol, Vol 27, Feb 2009: pp. 511‐518
Med OS more than doubled in 30y: from 2.1 to 4.8y!
MCL – Reasons for Improvement of OS
– Better recognition MCL
– Supportive care
– Introduction of dose‐intensive strategies and MAb(rituximab)which have led to long progression‐free intervals
Development of novel therapies in the relapse setting for a– Development of novel therapies in the relapse setting for a disease otherwise typically chemoresistant (none before mid 2000’s)
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MCL ‐ In favor of Dose‐Intensive or HDT‐ASCT Frontline
Comparison conv RX and HDT
CHOP/R‐CHOP
R‐CHOP
CHOP
64 pts / arm 69 / 75 pts
ASCT
IFN
ASCT > CHOP‐IFN R‐CHOP‐AraC‐ASCT
160 pts
63%
15%
p < .0001
PFS PFS EFS
“Historical controls” “Only RCT”
MCL‐2 (n = 160)
MCL‐1 (n = 41)
“HDT AraC containing regimens”
MCL – Impact of Dose‐intensive Approaches Frontline
167 MCL pts NCCN database – frontline R‐chemo ‐ NOT on trial
PFS OS
LaCasce A, et al. Blood, 2012 Mar 1;119(9):2093‐9
OS K-M p
R-HyperCVAD vs R-CHOP P < .02
R-CHOP/ASCT vs R-CHOP P < .20
R-HyperCVAD vs R-CHOP/ASCR TP = .64
3y PFS R‐CHOP 18% 3 times <to any dose‐
intensive strategy (56‐58%)
Ongoing intergroup study R‐HyperCVAD vs BR‐ACST
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Comparison of Dose‐Intensive / HDT in MCL
AraC‐containing induction regimens for MCL
Study Therapy N Age limit, Yrs
5-Yr EFS, % 5-Yr OS, % Follow-up, Mos
Nordic[1] MCL-2
(R + Maxi-CHOP +
HD AraC+
Maint R
160 < 66 63% 74% 40
GITIL[2] (R) HDS-ASCT* 77 < 61 61% 74% 50
MDACC [3,4]
R-HyperCVAD
97 Up to 80
(1/3 > 65)
48%/FFS 65% 50
≤ 65 60%/FFS 76% 50≤ 65 60%/FFS 76% 50
CALGB R-Maxi CHOP-MTX / VP16-AraC/ CBV
78 18-69 56%/PFS 64% 50
EU
Younger pts
R-CHOP/DHAP- TAM ASCT 208 <65 65% TTF 78% 32
1. Geisler CH, et al. ASH 2007. Abstract LB1. 2. Cortelazzo S, et al. ASH 2007. Abstract 1282.3. Romaguera JE, et al. J Clin Oncol. 2005;23:7013‐7023. 4. Fayad L, et al. Clin Lymphoma Myeloma. 2007;8(suppl 2):S57‐S62.
*4 MDS and 3 solid tumors R‐CHOP PFS 25% @2y
In EU ‐MCL Younger Protocol Design
Ara‐C, MelphalanTBI + Autograft
R‐CHOP/R‐DHAP alternating 3‐weekly
MCL Younger< 65 years
R
P B S Charvest
g
3‐monthly follow‐up
1 95 13 17week
3‐weekly
3‐monthly follow‐upP B S Charvest
MRD MRD 2‐3 monthly intervals
DexaBEAM
CycloTBI + Autograft
harvest y p
1 95 13 17week
R‐CHOP 3‐weekly
Hermine et al, ASH 2010 abst # 110
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In EU ‐MCL Younger PEP: TTFT
212 pts R‐CHOP/ 208 pts R‐CHOP/DHAP
(63% low risk MIPI / 14% high risk)
N diff b t i t h t i ti % t i ASCT (77% / 79%)No diff between arms in pts characteristics or % pts going ASCT (77% / 79%)
TTFT
months
Hermine et al, ASH 2010 abst # 110
In EU ‐MCL Younger – HDT – Summary
R-CHOP
R-CHOP/
R-DHAP
CR 54 26% 72 36% p=0.032
CR or CRu 83 40% 111 55% p=0.0028
CR or CRu or PR 186 90% 188 94% p=0.14
No difference in ORR (97%) or CR-CRu (79/82%) post ASCT
Hermine et al, ASH 2010 abst # 110
Relapse after CR-CRu-PR 49 23% 22 10%
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MCL: HDT/ASCT Impact of Minimal Residual Disease
EU St d / 65 HDT ASCT / l d t i l MRD
RQ-PCR (IgH or t(11;14)) / clonotypic PCR +++
After R‐CHOP induction
EU Study / <65 HDT‐ASCT / pooled trials – MRD post ASCT
After R‐CHOP/R‐DHAP induction
MRD status after induction is an independent prognostic factor in MCL
Pott et al, ASH 2010, abst # 965
MCL: HDT/ASCT Impact of Minimal Residual Disease
MRD kinetics showed that Ara‐C induction is responsible for the better outcome and not the conditioning regimen
* 0 0001R-CHOP R-DHAP
50
75
100
D negative
p = 0.03 p = 0.008
82%
90%
77%
88%
ns ns
* *
* *
D negative
*p < 0.0001
50
75
100
83%
*
Pott et al, ASH 2010, abst # 965
PB BM PB BM0
25
% M
R
51%
70%
33%
61%% M
R
53%
R‐CHOPR‐CHOP/R‐DHAP
0
25 51%
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Impact of Minimal Residual Diseasein BOTH Younger and Elderly MCL pts
RQ-PCR (IgH or t(11;14)) / clonotypic PCR +++
259 pts / MRD studies in 2 randomized trials in EU
Pott C et al, Blood, 2010 Apr 22;115(16):3215‐23
MCL: HDT/ASCT Impact of Minimal Residual Disease
RQ-PCR (IgH or t(11;14)) / clonotypic PCR +++
259 pts / MRD studies in 2 randomized trials in EU
PBL
Pott C et al, Blood, 2010 Apr 22;115(16):3215‐23
BM
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MCL – Impact of DEEP Early response
– Achieving a CR in frontline in MCL impacts outcome +++
– Molecular CR has huge impact on outcome
– Likely higher chance to achieve molecular CR with low tumor burden (MCL highest % of secondary cytogenetic abnormalities among NHL)
– Recent strategies with maintenance (MR) showed a benefit in OS!
MCL – Impact of Maintenance Therapy
EU Pts 470 MCL >60‐65yr pts / FCR x6 vs R-CHOP x 8 + IFN vs maintenance rituximab (q 2ms) POD
OS after R‐CHOP inductionDOR after R‐CHOP induction
Maintenance rituximab improved OS in responsive pts after R‐CHOP!
Kluin-Nelemans JC, et al. ASH 2011. Abstract 439 and ICML 2011
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Rituximab w/ Chemo Improves OS in MCL
Cochrane meta-analysis of rituximab impact in FL and MCL
Schultz H et al. JNCI 2007 May 2;99(9):706-14
Evolving Management of MCL
Chemo alone ASCT Nothing More chemo ?“Before” Chemo alone ASCT NothingIFN
More chemo…?Very short response
to salvage chemoeven with HDT-ASCT
Before
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Evolving Management of MCLBortezomib
BendamustineNew Mab
LenalidomideBTKi (PCI-32765)
PI3K (CAL-101 AMG 479
Chemo ImmunotherapyR-chemo + BTZ
RIT
ASCT
RituximabLenalidomide?
BTZ?
PI3K (CAL-101, AMG 479mTORi
DAC CMC-544CDKi
HDACi (comb)Bcl-2 inhibitorsHSP inhibitors
“Now”
Chemo alone ASCT IFN ? More chemo…?“Before”
In Spite of Clear Improvement in OS Still NO Consensus
Cornell 1997‐ 2007117 path cases
1/3 observed > 3ms Med time to 1st RX 12ms
(4 128 ms)(4‐128 ms)
Martin et al, J Clin Oncol. 2009 Mar 10;27(8):1209-13
Clin data on 75 pts (42%) / Mostly CHOP‐like
regimens…
Med OS 7.1 y Observation group Med age 58 vs 65y
25% pts had localized stage I‐II MCL14% vs 61% ECOG >0
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Delayed Therapy in MCL?
OS calculated from time to 1st therapy
Martin, P. et al. J Clin Oncol; 27:1209-1213 2009
Most RX were CHOP‐like regimens / shorter DOR?
> 80% MCL acquire second genetic abnormalities
Disparities among studies might reflect heterogeneity of the disease
MCL – Can we Stratify Pts Beyond Tumor Burden and Symptomatic? MIPI
Clinical Prognostic Index: MIPI(455 pts ½ CHOP, 1/3 R‐chemo, 17% ACST)
Probability of Overall Survival
LR, median not reached
IR, median = 51
HR median = 290 1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Validated in both standard and DIT
(2/4 factors ECOG and age impact enrollment in HDT approaches
Months Since Registration
P HR, median = 29
0.0
0.1
0 12 24 36 48 60 72 84 96
Hoster E, et al. Blood. 2008;111:558‐565
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MCL – A Growing Number of Prognostic Variables Beyond MIPI
2 microglobulin (≥ 3mg/l > LDH?)
Blastoid variant (5‐15%)
Growing molecular heterogeneity (p53, CGH, miRNA, secondary genetic defects ++)
RQ‐PCR signature (not validated)
Hoster E, et al. Blood. 2008;111:558‐565
Q g ( )
Proliferation index: Ki67 +++
MCL – Proliferation Shows MCL …..“Spectrum of Diseases . .”
MCL gene expression / proliferation signature
GEP: proliferation signature quantitative integrator of oncogenic events predicts survival in MCL
High
Poor Prognosis Favorable
Favorable
Favorable
High Low0 6
0.8
1.0
iliby
All Cases
P = 5.07 x 10‐9
Rosenwald A, et al. Cancer Cell. 2003;3:100‐102.
g
MCL IHC Ki‐67
Hartmann E et al. Jnl Clin Oncol, Vol 26, 2008, 4966‐4972
Median OS varies from 0.7‐8.0 yrs!
0
0.20.4
0.6
0 12 14
Probab
i
108642
OS (Yrs)
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MCL – Concept of “Indolent” iMCL
iMCL cMCL
Non nodal presentation (higher leukemic
phase and splenomegaly
no/minimal lymphadenopathy)
Classical presentation, including
lymphadenopathy
>> Hypermutated mutations (> 5%) Much less commonly mutated
Non complex karyotypes >>>> % genomic imbalances
Gene signatures (13 genes diff)
SOX11 ( l ) ti
SOX11 more commonly positive ?
SOX11 (more commonly) negative
Indolent course >>W & W? More aggressive
Fernandez et al, Cancer Research 70, 1408, Feb 2010.
MCL – As “Spectrum of Diseases .”
„indolent“ MCL (15%) „classical“ MCL (80%) „transformed“ (5%)
Jares, Nature Review 2007
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MCL – Evolving Landscape
– Overall survival of MCL: 5y OS 22% (1975‐85) to 47% (1996‐2004)
– Improvement due to dose‐intensive approaches, AraC containing regimens and Mab (rituximab) (not yet to novel therapies then…)
– Early CR and molecular CR have huge impact on outcome (likely easily achievable in low tumor burden?)y )
– Emerging novel therapies and maintenance strategies will play a bigger role
MCL ‐ Can we stratify patients based on Symptoms and /or Tumor burden?
– Tumor burden or symptoms (mostly asymptomatic at baseline) OR clinical prognostic factors DO NOT truly help yet our decisions
– There is a GREAT heterogeneity within MCL
Subset of truly indolent iMCL (W&W for years ”CLL like”)
Others spectrum of disease / W&W is relative (not same as FL Others = spectrum of disease / W&W is relative (not same as FL ++) future biological stratification??
– Non cytotoxic based options in elderly / low risk pts currently being tested
