Transcript Slide 1

Mantle Cell Lymphoma:
Approach to Induction Therapy
Mitchell R. Smith M.D., Ph.D.
Director, Lymphoid Malignancy Program
Cleveland Clinic
Mantle Cell Lymphoma
IMMUNOPHENOTYPE
 CD19/20/22+
 CD5+
 Negative for CD10, CD23
DETECTION t(11;14)
 FISH > 95%
 Cytogenetics 70%
 PCR 40%
Small subset cyclin D1-ve overexpress cyclin D2, D3
Wlodarska I, et al. Blood. 2008;111:5683-5690.
Fu K, et al. Blood. 2005;106:4315-4321. Herens C, et al. Blood. 2008;111:1745-1746.
Mantle Cell Lymphoma:
Clinical Summary
• High response rate to chemotherapy, but short duration
• Better response duration, but not curable, even with RHyperCVAD/R-MA or HDC/ASCT
• Optimal treatment regimen remains unclear
• Promising recent advances in biology and treatment
• Goals and selection of treatment depend on:
– Is MCL aggressive, since it has “short” median survival?
– Is MCL indolent, since not curable with CHOP-like regimens?
What is expected survival in MCL?
1990s Data
Median OS ~ 3yr
Armitage and Weisenburger JCO 1998
What is expected survival in MCL?
1.0
Survival probability
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
1
2
3
4
5
6
7
8
9
10
Years
GLSG Data (1996-2004)
MEDIAN OS ~ 5 yr
Herrmann et al. ASH, 2006: A2446
Proliferation correlates with MCL outcome
KI-67
Katzenberger et al Blood 2006
Proliferation correlates with MCL outcome
Proliferation Gene Expression Signature
Lowest
quartile
Rosenwald, A et al Cancer Cell 2003
MCL IPI = MIPICLINICAL
44% of Pts
35%
21%
CLINICAL FACTORS
Age
PS (0,1 vs 2-4)
LDH
WBC
BIOLOGIC FACTOR
Ki67 adds additional
prognostic value
Hoster et al Blood 2008;111:558-565
R-CHOP vs CHOP for Untreated MCL:
TTF and OS
Time to Treatment Failure
Overall Survival
100
75
Percent Alive
Percent Failure-Free
100
R-CHOP (35/62)
50
R-CHOP (52/62)
75
CHOP (49/60)
50
P=.93
CHOP (24/60)
25
25
0
0
0
1
2
3
Years
4
0
1
2
Years
Data confounded by post-induction IFN or SCT
Lenz et al. JCO 23: 1984-1992, 2005.
3
4
Rituximab Effect on MCL Overall
Survival: Meta-analysis
MCL
Schultz et al. J Natl Can Inst. 2007
To improve on (R)-CHOP in MCL

Intensify induction therapy
– R-HyperCVAD/R-MA
– Rituximab + High Dose Cytarabine
– Add “Novel” agents to CHOP
e.g. antibody, bortezomib, temsirolimus, lenalidomide

As response rate already high, add consolidation
– Rituximab maintenance
– Radioimmunotherapy
– High dose therapy/autologous stem cell rescue
– Allogeneic stem cell transplant
– “Novel” agents:
e.g. target other surface markers, proteosome, mTOR,
immunomodulation, BCR signaling
NCCN GUIDELINES:
MCL Frontline therapy

CHOP  rituximab
– older patients who cannot tolerate more intensive therapy

R-HyperCVAD/R-HDMtx+Ara-C (< 60-65?)

R-EPOCH

Modified R-HyperCVAD (part A) + rituximab maintenance
– in patients > 65 yrs

Nordic regimen (R-Maxi-CHOP alt R-HiDAC → autoSCT)

Cladribine + rituximab

Clinical trial

Observation for selected stage III-IV patients
CONSOLIDATION

Clinical trial

HDC/auto SCT
“Aggressive” Therapy
HDC/SCT prolongs remission, but does not cure, MCL
Dreyling M, ASCO Educ Book 2006
R-HyperCVAD/MA in MCL
FFS and OS in 97 patients at MDACC
5 toxic deaths +
3 MDS + 1 AML
Romaguera et al JCO 2005
R-HyperCVAD/MA in MCL
FFS by Age
1.0
•••••
Survival probability
.
0.8.
<= 65 yrs
0.6.
> 65 yrs
0.4
% of Patients
> 65 yrs - 32 pts, 19 failed
<65 24 “failed” of 65)
>65 19 “failed” of 32) 50
<= 65 yrs - 65 pts, 24 failed
0.2
p = 0.03
P=0.03
0
0
10
20
30
40
50
Months from start of treatment
For patients >65 years old vs patients ≤65, P=0.03.
Updated from Romaguera et al. J Clin Oncol. 2005;23:7013.
60
70
80
R-HyperCVAD/R-MA initial treatment of MCL
Gruppo Italiano Studio Linfomi
Median Age 57 (29-66)
MIPI
Low
60%
Int
31%
High
9%
Completed all Rx = 22 (37%)
Deaths on RX
=3
Merli et al Brit J Haematology 156)3): 346-353, 2012
Phase 2 R- HyperCVAD/R-MA Front-Line MCL:
SWOG 0213
Median age: 57 yrs (eligible if < 70)
88% RR (58% CR/CRu; 30% PR)
Grade 3 or 4 ANC 85%; platelets 87%
100%
80%
60%
40%
Progression 1-Year
At Risk or Death Estimate
HCVAD MTX/Ara-C + rituximab
49
13
89%
20%
0%
0
1
2
3
Years from Registration
Epner et al. ASH, 2007. Abstract 387 Courtesy of Dr. Epner
4
5
Initial therapy for MCL patients < 65:
NCCN NHL Database Analysis
PROGRESSION-FREE SURVIVAL
©2012 by American Society of Hematology
LaCasce A et al BLOOD 2012; 119:2093
Initial therapy for MCL patients < 65:
NCCN NHL Database Analysis
OVERALL SURVIVAL
©2012 by American Society of Hematology
LaCasce A et al BLOOD 2012; 119:2093
MCL Younger Trial: Study Design
Eligibility criteria:
• Treatment naive
• Ann Arbor stage
II-IV MCL
• Age < 65 years
• Eligible for highdose therapy
• ECOG PS < 2
R
A
N
D
O
M
I
Z
E
Primary endpoint: TTF
Control Arm
R-CHOP × 6
Stem cell
mobilization
Experimental
Alternating (2 + 1)
R-CHOP/R-DHAP→
Stem cell
mobilization
Myeloablative
Regimen
TBI 12 Gy
Cyclophosphamide
60 mg/kg × 2
ASCT
Myeloablative
Regimen
TBI 10 Gy
Cytarabine 1.5 g/m2 × 4
Melphalan 140 mg/m2
ASCT
R-CHOP
R-CHOP/R-DHAP
Median age (yrs)
55
56
Male
78%
79%
Stage 4
85%
79%
MIPI Lo/Int/Hi
61/25/14%
62/23/15%
% Transplanted
72%
73%
Hermine et al. ASH 2010; abstract 110.
MCL Younger Trial: Efficacy
R-CHOP
(n = 206)
R-CHOP/R-DHAP
(n = 199)
P
Complete response/CRu
83 (40%)
111 (55%)
P = .0028
Complete response/CRu/PR
186 (90%)
188 (94%)
P = .14
Response Rates After ASCT (CR)
97% (63%)
(n = 131)
97% (65%)
(n = 129)
29%
76%
65%
88%
(n = 212)
(n = 208)
49
22
49 months
Not reached
48 months
(n = 133)
Not reached
(n = 133)
Response Rates After Induction
Molecular CR (MRD- by RQ-PCR)*
After Induction
After ASCT
Time to Treatment Failurea
Relapse events after CR/CRu/PR
Median
Remission Duration After ASCTb
Overall Survivalc
HR 0.68;
P = .0382
P = .0059
P = .37
a
Median follow-up: 32 months
Median follow-up: 30 months
c Median follow-up: 33 months, median OS not reached in either arm
b
Hermine et al. ASH 2010; abstract 110.
Pott et al ASH 2010; abstract 965.
Nordic Lymphoma study group
Maxi-CHOP/R-HiDAC → ASCR → R
Age  65
Median age 56
Geisler CH et al Blood 2008
“Less Aggressive” Therapy
Less Intense Regimens for MCL
Bendamustine is active
R-CHOP vs R-bendamustine in MCL
German Study Group Indolent Lymphomas (StiL)
Progression- free survival
1.0
0.9
N = 93
Probability
0.8
0.7
0.6
0.5
B-R
0.4
Bendamustine 90 mg/m2 days 1, 2
Rituximab 375 mg/m2 day1, q 28d
0.3
CHOP-R
0.2
0.1
0.0
0
12
24
36
48
courtesy of Dr. M. Rummel
Less Intense Regimens for MCL
R-CHOP followed by Radioimmunotherapy
R-CHOP Followed by 90Y-Ibritumomab in
Untreated Mantle Cell Lymphoma
(E1499)
Patients with
previously
untreated MCL,
stage II-IV (N=56)
R-CHOP
CR
3-5 weeks
PR
SD
Primary end point: PFS
Secondary end points: ORR, toxicity
R-CHOP: R (375 mg/m2); CHOP (q21 × 4)
*0.3 mCi/kg for patients with platelet 100-149,000.
Smith et al. J Clin Oncol 2012 in press.
R (250 mg/m2)
+ imaging with
111In-Ibritumomab
tiuxetan
1 week
R (250 mg/m2) +
90Y-Ibritumomab
tiuxetan (0.4 mCi/kg
or 0.3* mCi/kg)
E1499: R-CHOP → 90Y-Ibritumomab in MCL:
PFS (top) and OS (bottom); right panels by age < 65 vs ≥ 65
Median Overall PFS = 28 months
PFS
OS
Age ≥ 65
Age ≥ 65
MEDIAN FOLLOW-UP 41 MONTHS
Smith et al J Clin Oncol 2012 in press
Less Intense Regimens for MCL
Omitting High dose MTX/ARA-C from RHyperCVAD/R-MA
And adding Rituximab maintenance
R-HyperCVAD Part A + Rituximab Maintenance
in Untreated MCL: PFS and OS
OS
100
100
80
% of patients alive
% of patients progression-free
Progression-Free Survival
median PFS 37
months
60
40
20
Median OS not
reached
80
60
40
20
0
0
0
10
20
30
40
Months
50
60
0
10
Median follow up 37 months
Kahl et al. Ann Oncol. 2006
20
30
40
Months
50
60
Less Intense Regimens for MCL
Bortezomib is active in MCL
Can we incorporate bortezomib in frontline
regimens?
VcR-CVAD → R in Untreated MCL: E1405

Add bortezomib to modified R-HyperCVAD (part A)

Add maintenance rituximab

90% RR in previously untreated MCL

69% CR or CRu

Toxicity manageable
– Grade 3 or 4 toxicity primarily hematologic
– Neurotoxicity tolerable

Ongoing follow-up to define durability of responses
with rituximab maintenance
Cladribine  rituximab in Untreated MCL
(CDA 5 mg/m2 d 1-5)
Therapy
Trial
N
RR
CR/PR
TTP (mos)
CDA
CDA
CDA + rituximab
Rummel et al
Inwards et al
Inwards et al
Leuk Lymph 1999
Cancer 2008
Cancer 2008
12
26
29
58%
81%
66%
42%/39%
52%/14%
14.6
12.1
Randomized Phase 2 Intergroup Trial: Initial Therapy of
Mantle Cell Lymphoma in patients < age 65
Randomized phase II, N ~ 160; 80 eligible per arm
R
E
G
I
S
T
R
A
T
I
O
N
R-Benda x 6
HD Cy SCC
R-HCVAD/MTX/AraC X 4*
ASCT
ASCT
HD Cy= cyclophosphamide
1.5 g/m2
SCC= stem cell collection
* SCC after cycle 3
35
Randomized Phase 2 Intergroup Trial: Initial Therapy of
Mantle Cell Lymphoma in patients  age 60
Randomized phase II, N ~ 328; 82 eligible per arm
R
E
G
I
S
T
R
A
T
I
O
N
BR x 6
Rituximab
BVR x 6
Rituximab
BR x 6
Lenalidomide
+ Rituximab
BVR x 6
Lenalidomide
+ Rituximab
B=bendamustine, V=bortezomib
36
Mantle Cell Lymphoma Treatment: 2012

Therapy guided by patient age/comorbidities and pace of disease

Watch and wait for selected patients

CLINICAL TRIAL ACCRUAL IS CRITICAL!

Initial therapy in young/fit patient
– R-HyperCVAD/R-MA (? X 8 or x4 → HDC/ASCR)
– R-CHOP (alt with R-DHAP?) → HDC/ASCR
–
? Role of HiDAC

Initial therapy in older/less fit patient
– R-bendamustine
– R-C(H)OP
– (Vc)R-CVAD → R
– rituximab “maintenance” under investigation

New agents promising
Mantle Cell Lymphoma
CONCLUSIONS

Overall Survival is improving

Risk stratification is improving

Treatment outcomes are improving

Does dose-intense therapy yield best outcomes?

Cure remains elusive

Better understanding of MCL biology needed to
improve targeted therapies: more effective and
less toxic