1. Mantle Cell Lymphoma: Approach to Induction Therapy
Mitchell R. Smith M.D., Ph.D.
Director, Lymphoid Malignancy Program
Cleveland Clinic

2. Small subset cyclin D1-ve overexpress cyclin D2, D3
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: Fu K, et al. Blood. 2005;106: Herens C, et al. Blood. 2008;111: 2 2

3. Mantle Cell Lymphoma: Clinical Summary
High response rate to chemotherapy, but short duration
Better response duration, but not curable, even with R- HyperCVAD/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? 3

4. What is expected survival in MCL?
1990s Data Median OS ~ 3yr
Armitage and Weisenburger JCO 1998

5. What is expected survival in MCL?
GLSG Data ( )
MEDIAN OS ~ 5 yr
Herrmann et al. ASH, 2006: A2446

6. Proliferation correlates with MCL outcome KI-67
Katzenberger et al Blood 2006

7. Proliferation correlates with MCL outcome Proliferation Gene Expression Signature
Lowest
quartile
Rosenwald, A et al Cancer Cell 2003

8. MCL IPI = MIPICLINICAL CLINICAL FACTORS Age PS (0,1 vs 2-4) LDH WBC
BIOLOGIC FACTOR
Ki67 adds additional
prognostic value
44% of Pts
35%
21%
Hoster et al Blood 2008;111:

9. R-CHOP vs CHOP for Untreated MCL:
TTF and OS
Time to Treatment Failure
Overall Survival
100 75 50 25
100 75 50 25
R-CHOP (52/62)
R-CHOP (35/62)
Percent Alive
CHOP (49/60)
Percent Failure-Free
P=.93
CHOP (24/60) 4 3 2 1 4 3 2 1
Years
Years
Data confounded by post-induction IFN or SCT
Lenz et al. JCO 23: , 2005.

10. Rituximab Effect on MCL Overall Survival: Meta-analysis
Schultz et al. J Natl Can Inst. 2007 10

11. 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

12. 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
HDC/auto SCT

13. “Aggressive” Therapy

14. HDC/SCT prolongs remission, but does not cure, MCL
Dreyling M, ASCO Educ Book 2006

15. 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

16. R-HyperCVAD/MA in MCL FFS by Age Months from start of treatment .
> 65 yrs - 32 pts, 19 failed
<= 65 yrs - 65 pts, 24 failed
p = 0.03
<= 65 yrs
> 65 yrs
R-HyperCVAD/MA in MCL FFS by Age
1.0
0.8
0.6
Survival probability
0.4
<65 24 “failed” of 65)
>65 19 “failed” of 32) 50
% of Patients
0.2
P=0.03 10 20 30 40 50 60 70 80
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.

17. 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): , 2012

18. 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
20%
HCVAD MTX/Ara-C + rituximab 49 13
89% 0% 1 2 3 4 5
Years from Registration
Epner et al. ASH, Abstract 387 Courtesy of Dr. Epner

19. 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

20. 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

21. MCL Younger Trial: Study Design
Myeloablative Regimen
TBI 12 Gy
Cyclophosphamide 60 mg/kg × 2
Control Arm
R-CHOP × 6
Stem cell mobilization R A N D O M I Z E
Eligibility criteria:
Treatment naive
Ann Arbor stage II-IV MCL
Age < 65 years
Eligible for high-dose therapy
ECOG PS < 2
ASCT
Experimental
Alternating (2 + 1)
R-CHOP/R-DHAP→
Stem cell mobilization
Myeloablative Regimen
TBI 10 Gy
Cytarabine 1.5 g/m2 × 4
Melphalan 140 mg/m2
ASCT
Primary endpoint: TTF
R-CHOP
R-CHOP/R-DHAP
Median age (yrs) 55 56
Male
78%
79%
Stage 4
85%
MIPI Lo/Int/Hi
61/25/14%
62/23/15%
% Transplanted
72%
73%
Hermine et al. ASH 2010; abstract 110. 21

22. MCL Younger Trial: Efficacy
R-CHOP
(n = 206)
R-CHOP/R-DHAP
(n = 199) P
Response Rates After Induction
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)
Molecular CR (MRD- by RQ-PCR)*
After Induction
29%
76%
After ASCT
65%
88%
Time to Treatment Failurea
(n = 212)
(n = 208)
Relapse events after CR/CRu/PR 49 22
Median
49 months
Not reached
HR 0.68;
P = .0382
Remission Duration After ASCTb
48 months
(n = 133)
P = .0059
Overall Survivalc
P = .37
a Median follow-up: 32 months
b Median follow-up: 30 months
c Median follow-up: 33 months, median OS not reached in either arm
Hermine et al. ASH 2010; abstract 110.
Pott et al ASH 2010; abstract 965. 22

23. Nordic Lymphoma study group Maxi-CHOP/R-HiDAC → ASCR → R
Age  65
Median age 56
Geisler CH et al Blood 2008

24. “Less Aggressive” Therapy

25. Less Intense Regimens for MCL
Bendamustine is active

26. R-CHOP vs R-bendamustine in MCL German Study Group Indolent Lymphomas (StiL)
Progression- free survival
1.0
0.9
N = 93
0.8
0.7
0.6
Probability
0.5
B-R
Bendamustine 90 mg/m2 days 1, 2 Rituximab 375 mg/m2 day1, q 28d
0.4
0.3
CHOP-R
0.2
0.1
0.0 12 24 36 48
courtesy of Dr. M. Rummel

27. Less Intense Regimens for MCL
R-CHOP followed by Radioimmunotherapy

28. R-CHOP Followed by 90Y-Ibritumomab in Untreated Mantle Cell Lymphoma (E1499)
Patients with previously untreated MCL, stage II-IV (N=56) CR PR SD
R (250 mg/m2) + imaging with 111In-Ibritumomab tiuxetan
R (250 mg/m2) + 90Y-Ibritumomab tiuxetan (0.4 mCi/kg or 0.3* mCi/kg)
R-CHOP
3-5 weeks
1 week
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 ,000.
Smith et al. J Clin Oncol 2012 in press.

29. 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
Age ≥ 65
Age ≥ 65 OS
MEDIAN FOLLOW-UP 41 MONTHS
Smith et al J Clin Oncol 2012 in press

30. Less Intense Regimens for MCL
Omitting High dose MTX/ARA-C from R- HyperCVAD/R-MA
And adding Rituximab maintenance

31. R-HyperCVAD Part A + Rituximab Maintenance in Untreated MCL: PFS and OS
Progression-Free Survival OS
100
100
Median OS not reached 80 80
median PFS 37 months 60 60
% of patients progression-free
% of patients alive 40 40 20 20 10 20 30 40 50 60 10 20 30 40 50 60
Months
Months
Median follow up 37 months
Kahl et al. Ann Oncol. 2006

32. Less Intense Regimens for MCL
Bortezomib is active in MCL
Can we incorporate bortezomib in frontline regimens?

33. 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

34. Cladribine  rituximab in Untreated MCL (CDA 5 mg/m2 d 1-5)
Therapy
CDA
CDA + rituximab
Trial
Rummel et al
Leuk Lymph 1999
Inwards et al
Cancer 2008 N 12 26 29 RR
58%
81%
66%
CR/PR
42%/39%
52%/14%
TTP (mos)
14.6
12.1

35. Randomized phase II, N ~ 160; 80 eligible per arm
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 A O N
ASCT
R-Benda x 6
HD Cy SCC
R-HCVAD/MTX/AraC X 4*
ASCT
HD Cy= cyclophosphamide 1.5 g/m2
SCC= stem cell collection
* SCC after cycle 3 35

36. Randomized Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma in patients  age 60
Randomized phase II, N ~ 328; 82 eligible per arm
Rituximab R E G I S T A O N
BR x 6
Rituximab
BVR x 6
Lenalidomide
+ Rituximab
BR x 6
Lenalidomide
+ Rituximab
BVR x 6
B=bendamustine, V=bortezomib 36

37. 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

38. 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