1. Mantle Cell Lymphoma: from
bench to clinic
Michael Wang, MD
Associate Professor
Co-Director, Clinical Trials in Lymphoma
Director, Myeloma Tissue Bank
Director, Mantle Cell Lymphoma
Program of Excellence
Departments of
Lymphoma/Myeloma ,
Stem Cell Transplantation

2. Evolution of MCL as a distinct subtype of NHL
In mid-1970s, the Rappaport classification system described MCL as a
diffuse or vaguely nodular low-grade lymphoma of intermediate differentiation.
In the 1980s, this entity was recorded as centrocytic NHL by the Kiel
classification system or was called lymphocytic lymphoma of intermediate
differentiation by Jaffe et al.
In 1982, MCL was then categorized as diffuse small-cleaved cell lymphoma
by the Working Formulation system.
In 1992, Banks and colleagues (22) coined the term mantle cell lymphoma,
establishing MCL as a distinct type of lymphoma.
In 1994, the REAL classification system, MCL.
In 2000 by the World Health Organization (WHO) classification system, MCL.
Zhou, Wang et al, Cancer, 2008

3. 0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
75-76 77-78 79-80 81-82 83-84 85-86 87-88 89-90 91-92 93-94 95-96 97-98 99-00 01-02 03-04
Year of diagnosis
Age-adjustedincidencerate(casesper100000)
>=80
50-59
70-79
60-69
<50
Age-adjusted Incidence Rates for MCL by Age
1975 and 2004
Zhou, Wang et al, Cancer, 2008

4. Biology of mantle cell lymphoma

5. A distinct subtype of non-Hodgkin’s lymphoma (NHL)
t(11; 14)(q13; q32) chromosomal translocation
Bcl-1/PRAD-1 gene with over expression of cyclin D1
MCL is derived from CD5-positive B cells within the
mantle zone (CD5+, CD23-, cyclin D1+)
A typical CD20 + B cell lymphoma, with the poorest survival among all
NHLs.
High response rate to initial treatment
Inevitable relapse.
Mantle Cell Lymphoma (MCL)

6. Treatment of Mantle-Cell Lymphoma
• No currently available treatment option is curative in
advanced MCL
• Investigational approaches
– Chemotherapy (R-CHOP, R-HCVAD, R-Bendamustine)
– Radiation
– Immunotherapy (Rituximab, thalidomide, lenalidomide, DLI, Id
Abs)
– Radioimmunotherapy (Zevalin, Bexxar)
– Stem cell transplantation (HDT with ASCT, Allogeneic BMT)
– Proteasome inhibition (bortezomib, carfilzomib)
– Other biological agents (Temsirolimus, Cal-101)
Zhou, Wang et al, American J Hematology, 2007;
Evans LS, Hancock BW. Lancet. 2003;362:139-146

7. Ten-year follow-up after intense chemoimmunotherapy
with Rituximab-HyperCVAD alternating with Rituximab-
high dose methotrexate/cytarabine (R-MA) and without
stem cell transplantation in patients with untreated
aggressive mantle cell lymphoma
Romaguera et al, British J Heme, 2008

8. Overall survival in 97 patients treated with R-
HyperCVAD alternating with R M/A
Romaguera et al, British J Heme, 2008

9. Time to Failure in 97 patients treated with
R-HyperCVAD alternating with R M/A
Romaguera et al, British J Heme, 2008

10. Overall Survival according to B2 microglobulin
(B2M)/age
High B2M is defined as 3 mg/l or more, and high age is defined as >65 years old. HH, high
B2M, high age; HL, high B2M, low age; LH, low B2M, high age; LL, low B2M, low age; E,
expected; N, number
Romaguera et al, British J Heme, 2008

11. Time to Failure according to B2 microglobulin
(B2M)/age
Romaguera et al, British J Heme, 2008

12. Overall Survival according to Mantle cell IPI
(MIPI)
Romaguera et al, British J Heme, 2008

13. Time to Failure according to Mantle cell IPI
(MIPI)
Romaguera et al, British J Heme, 2008

15. Published Response: Salvage Therapies in Relapsed/Refractory MCL
Author Regimen No. Patients CR (%) PR (%) ORR (%)
Foran19 Rituximab 35 14 23 37
Gressin20 VAD + Chlorambucil* 30 43 30 73
Kaufmann21 Rituximab + thalidomide 16 31 50 81
Dang22 Ontak 8 12.5 25 37.5
Cohen23 Cyclophosphamide + fludarabine# 30 30 33 63
Goy24 Bortezomib 29 21 21 42
O’Connor25 Bortezomib 11 9 36 45
McLaughlin26 Fludarabine + mitoxantrone +
dexamethasone
5 20 80 100
Seymour27 Fludarabine + cisplatin + cytarabine 8 88
Forstpointner28 Fludarabine + cyclophosphamide +
mitoxantrone
24 0 46 46
Forstpointner28 Fludarabine + cyclophosphamide +
mitoxantrone + rituximab
24 29 29 58
Levine29 Fludarabine + mitoxantrone + rituximab 5 80 0 80
Rummel30 Bendamustine + rituximab 16 50 25 75
Fisher31 Bortezomib 141 8 25 33
Robak32 2-CDA + rituximab or
rituximab/cyclophosphamide
9 22 45 67
* - 30% untreated # - 33% untreated
CR = complete response; PR = partial response; VAD = vincristine, doxorubicin, dexamethasone

16. Phase 2 Trial of Rituximab Plus HyperCVAD
Alternating With Rituximab Plus
Methotrexate-Cytarabine for Relapsed or
Refractory Aggressive Mantle Cell
Lymphoma
Michael Wang, MD, Luis Fayad, MD, Fernando Cabanillas, MD, Fredrick Hagemeister,
MD, Peter McLaughlin, MD, Maria A Rodriguez, MD, Larry W. Kwak, MD, Yuhong Zhou,
MD, Hagop Kantarjian, MD, Jorge Romaguera, MD
16Wang et al. Cancer. 2008

17. Results
• Patients: relapsed/refractory MCL; n=31
• Median # cycles: 5 (1-7)
• ORR 93%
• CR/uCR 45%
• PR 48%
• All 5 previously resistant to HyperCVAD had a response (1 CR,
4 CR)
• Toxicities:
– Febrile neutropenia 11%
– Grade 3/4 neutropenia 74%
– Grade 3/4 thrombocytopenia 63%
17Wang et al. Cancer. 2008

18. Failure-free survival of patients treated with
HyperCVAD
18
At median follow-up of 40 months  Median FFS 11 months
Wang et al. Cancer. 2008

20. 12%
32%
33%
37%
38%
42%
46%
48%
69%
0% 10% 20% 30% 40% 50% 60% 70% 80%
Overall Response
PCI-32765 (Wang et al 2011)
Lenalidomide (Witzig et al 2011)
Temsirolimus (Witzig et al 2005)
Bortezomib (Fisher et al 2006)
Rituximab (Foran et al 2000)
Everolimus (O' Connor et al 2011)
90Y-ibritumomab tiuxetan (Wang et al 2009)
Cladribine (Inwards et al 2008)
CAL-101 [Phase I ](Kahl et al, ICML 2011)
Single-agent activity of different agents in
Relapsed/Refractory MCL

21. Michael Wang, MD, Liang Zhang, MD, Xiaohong Han, Ph.D. Pei Lin, MD, Jorge Romaguera, MD,
Qing Yi, Ph.D., MD
Department of Lymphoma and Myeloma
Department of Pathology
The University of Texas M. D. Anderson Cancer Center,
Houston, TX 77030
A SCID-HU IN VIVO MOUSE MODEL OF
HUMAN PRIMARY MANTLE CELL
LYMPHOMA
Wang, Zhang, Lin, Yi, Clin Cancer Res, 200

22. c
Human fetal femur Patient MCL cells Tumor burden
Bone
implantation Tumor injection Tumor growth Tumor migration
Schematic presentation of MCL-SCID-hu model

23. c
Human fetal femur Patient MCL cells Tumor burden
Bone
implantation Tumor injection Tumor growth Tumor migration
Schematic presentation of MCL-SCID-hu model

24. Control CD5 CD20
A
Bone and
tumor mass
X-ray
Control 0.5M 2M 5M
Numbers of inoculated MCL cells
C
HE
CD20
D E
IHC
B
0
20
40
60
80
100
120
140
160
180
Pre-
bone
Post-
bone
4 8 12
Weeks after tumor inoculation
Human2M(ng/mL)
MCL-5M
MCL-2M
MCL-0.5M
PBS

Engraftment of primary MCL cells in SCID-hu mice.

25. PBS-SCID-huMCL-SCID-hu
LN
Spleen
ng
Liver
GI tract
Wang, Zhang, Lin, Yi, Clin Cancer Res, 2007

26. CD20 Cyclin D1
Wang, Zhang, Lin, Yi, Clin Cancer Res, 200

27. 0
5
10
15
20
25
30
0 1 2 3
Weeks after tumor inoculation
HumanM(ng/mL)
PBS Atiprimod
2
Wang, Zhang, Lin, Yi, Clin Cancer Res, 200

28. Multiple Myeloma and Mantle Cell
Lymphoma Share Similar Effective
Therapies
Multiple Myeloma Mantle Cell Lymphoma
VAD (vincristine, doxorubucin and a steroid) CHOP (vincristine, doxorubucin and
a steroid cyclophosphamide)
Modified Hyper CVAD Hyper CVAD
Thalidomide Thalidomide + Rituximab
[Kaufman et al. Blood 104 (8)2269-
71, 2004]
Bortezomib (Velcade) Bortezomib (Velcade)
Lenalidomide (Revlimid) Lenalidomide (Revlimid)
Atiprimod Atiprimod
(Wang el al, Blood 109(12):5455-
5462, 2007)
Carfilzomib (ongoing clinical trials) Carfilzomib (ongoing clinical trials)

29. Lenalidomide plus rituximab inhibited the growth of MCL cells in
SCID mice. Lenalidomide augmented the function of NK cells in vivo
A B
DC
LEN
RTX
0
1000
2000
3000
4000
5000
0 1 2 3 4 5
TumorVolume(mm
3
)
DMSO
LEN
RTX
LEN+RTX
Weeks from treatment
0
20
40
60
80
100
120
0 1 2 3 4 5 6
Weeks from treatment
%Survival
DMSO
LEN
RTX
LEN+RTX
0
5
10
15
20
25
Splenocytes NK cells
Cell(X106
)
DMSO
LEN
0
10
20
30
40
50
NK cells
%splenocytes
DMSO
LEN

30. Oral lenalidomide plus 4 doses
of rituximab induced prolonged
remissions in
relapsed/refractory
mantle cell lymphoma:
a phase I/II clinical trial
Michael Wang, Luis Fayad,
Nicolaus Wagner-Bartak,
Fredrick Hagemeister, Sattva Neelapu, Michelle
Fanale, Anas Younes,
Fernando Cabanillas, Liang Zhang,
Richard Champlin, Larry Kwak, Lei Feng,
Neda Bell, Jerome Zeldis,
and Jorge Romaguera
Departments of
Lymphoma/Myeloma ,
Radiology,
Biostatistics,
Stem Cell Transplantation
Celgene Support

31. To evaluate safety of lenalidomide in
combination with rituximab in patients with
relapsed/refractory MCL in Phase I
To determine the Maximum Tolerated Dose
(MTD) in Phase I
To confirm safety and efficacy in Phase II
Objectives

32. Study Design
Standard 3 + 3 dose-escalation with 3 pts/cohort
Doses: lenalidomide 10, 15, 20 and 25 mg orally daily 3
weeks on and 1 week off, every 28 days. Rituximab 375
mg/m2 IV weekly X 4, cycle 1 only
DLT: Grade 3 or 4 non-hematologic or Grade 4
hematologic toxicity during the first cycle
MTD: dose level prior to level in which 1/3 or 2/6 pts
experience DLT during cycle 1
An addition of 38 patients at MTD in phase II

33. Hematological Toxicity
Phase I
(N = 14, 108 cycles)
Phase II
(N = 46, 262 cycles)
All Grades Grade 3/4 All Grades Grade 3/4
Toxicity events and % of cycles
Anemia 14 (13%) 0 (0%) 57 (22%) 0 (0%)
Neutropenia 25 (23%) 12 (11%) 113 (43%) 47 (18%)
Febrile neutropenia 1 (1%) 1 (1%) 2 (1%) 2 (1%)
Thrombocytopenia 15 (14%) 5 (5%) 61 (23%) 12 (25%)
Lymphopenia 19 (18%) 3 (3%) 79 (30%) 19 (7%)

34. Non-hematological Toxicity
Phase I
(N = 14, 108 cycles)
Phase II
(N = 46, 262 cycles)
All Grades Grade 3/4 All Grades Grade 3/4
Toxicity events and % of cycles
Pruritus 15 (14%) 0 (0%) 22 (8%) 0 (0%)
Fatigue 19 (18%) 2 (2%) 56 (21%) 2 (1%)
Constipation 8 (8%) 0 (0%) 22 (8%) 0 (0%)
Neuropathy 9 (9%) 0 (0%) 38 (14%) 1 (0.4%)
Non-neutropenic
infections
14 (13%) 2 (2%, DLT) 27 (10%) 1 (0.4%)
Rash 11 (10%) 0 (0%) 32 (12%) 1 (0.4%)
Myalgia 6 (6%) 1 (1%) 29 (11%) 2 (0.8%)
Hypercalcemia 2 (2%) 1 (1%, DLT) 1 (0.4% 0 (0%)

35. Responses at MTD in Phase II
Response N=46 (%)
Overall response 26 (57)
Complete response 15 (33)
Partial response 11 (24)
Stable disease 10 (21.5)
Progressive disease
Time to first response
10 * (21.5)
2 (2-8)
* 1 patient (2%) was not evaluable for response, but counted as treatment
failure

36. Response Duration
• Median response duration = 18.9 months
(range 17–not reached)

37. Overall Survival &
Progression-free Survival
• Median PFS = 13.0 months (range 8.3–20.8)
• After a median follow-up of 23.1 months,
median OS = 25.1 months
(range 19.8–not reached)

38. Conclusions
• Oral lenalidomide plus 4 doses of rituximab is
effective and induced high quality and durable
remissions in relapsed/refractory MCL
• This combination had a very favourable toxicity
profile.
• Correlative studies in the future will provide insights
in the mechanism of synergy.
• This combination provides a solid base for future
innovative clinical trials.

39. • Human fetal bone is critical for the engraftment of primary MCL
cells in SCID-hu mice.
• Patient MCL cells grow out of human bones and form expansile
tumor masses surrounding the human bones.
• Human MCL cells home to mouse lymph node, spleen, bone
marrow, and GI tract.
• MCL-SCID-hu mouse model is useful for testing the in vivo
therapeutic efficiency of anti-MCL agent.
• This is the first in vivo model of human patient MCL.
Summary
Wang, Zhang, Lin, Yi, Clin Cancer Res, 20

40. Case Study
Mediastinal mass (left)
and abdominalmass (right)
before study therapy
Mediastinal mass (left)
and abdominal mass (right)
after 2 cycles
Resolution (CR) of
mediastinal mass (left)
after 4 cycles
and abdominal mass (right)
after 6 cycles

41. Carfilzomib
• an irreversible proteasome inhibitor with selectivity for the
chymotrypsin-like active site
• inhibits the proliferation of MCL cells in vitro and in vivo
• Unlike bortezomib, carfilzomib is good-tolerated and does not
induce severe neuropathy
• Therefore, carfilzomib can be used in higher dose than
bortezomib in vivo.

42. Preclinical Studies:
Effects of carfilzomib on cell growth
0
20
40
60
80
100
120
0 1.25 2.5 5 10 20 40 80
MINO
Jeko-1
Carfilzomib (nM)
Growth(%control)
0
20
40
60
80
100
120
0 1.25 2.5 5 10 20 40 80
PT1
PT2
PT3
Carfilzomib (nM)
Growth(%control)
0
20
40
60
80
100
120
0 1.25 2.5 5 10 20 40 80
PBMC
1
PBMC
2
Carfilzomib (nM)
Growth(%control)
0
20
40
60
80
100
120
0 1.25 2.5 5 10 20 40 80
No activation
Iono/PMA
Carfilzomib (nM)
Growth(%control)
A
B
C
D

43. CFZ induces apoptosis of MCL cells but exhibits low cytotoxicity
toward PBMCs from healthy volunteers

44. CFZ induces apoptosis in a caspase-dependent manner
0 5 10 20 (nM)
Jeko-1
0 5 10 20
MINO
cPARP
CFZ
β-actin
cCasp-3
0
20
40
60
80
100
%Apoptoticcells
MINO
Jeko-1
CFZ - - + + - -
BTZ - - - - + +
Z-VAD - + - + - +
MINO
cPARP
Jeko-1
0 6 12 24 hour0 6 12 24
CFZ (20nM)
β-actin
cCasp-9
cCasp-3
cCasp-8
CFZ - - + + + +
IETD-
CHO
- + - + + -
Z-LETD - + - + - +
3.8 5.6 17.782.5
7.2 6.7 23.978.2
MINO
Jeko-1
Annexin V
57.560.2
53.262.0
A B
C
D

45. CFZ-induced activation of mitochondrial apoptotic
signalings and inactivation of survival signalings
pAKT
pIκB
pSTAT3
MINO Jeko-1
0 6 12 24 hour0 6 12 24
CFZ (20nM)
STAT3
IκB
AKT
pBcl-2
Bcl-2
cCyto c
tCyto c
MINO Jeko-1
0 6 12 24 hour0 6 12 24
CFZ (20nM)
pJNK
JNK
β-actin
β-actin
A
B
C
MINO Jeko-1
0 6 12 24 hour0 6 12 24
CFZ (20nM) β-actin

46. Phase I/II Study of
Carfilzomib + Lenalidomide + Rituximab
in relapsed/refractory
Mantle Cell Lymphoma
Michael Wang, MD
Associate Professor
Department of Lymphoma/Myeloma
MD Anderson Cancer Center

47. Primary Objectives
• Phase 1: To determine the MTD of carfilzomib, lenalidomide and
rituximab in patients with relapsed/refractory MCL.
• Phase 2: To evaluate the response rate of carfilzomib, lenalidomide
and rituximab in patients with relapsed/refractory mantle cell
lymphoma.
Secondary Objectives
• To further evaluate the safety of carfilzomib, lenalidomide and
rituximab in combination with rituximab in patients with
relapsed/refractory mantle cell lymphoma at the MTD.
• To evaluate the survival of mantle cell lymphoma patients treated
with carfilzomib, lenalidomide and rituximab.

48. Study Design
• single-center, phase I/II clinical trial
• in patients with refractory or relapsed mantle cell lymphoma
• In part 1  MTD of this regimen will be determined using a 3+3
algorithm.
• In part 2  efficacy of this regimen will be evaluated using Simon’s
optimal 2-stage design.
• Max. 69 pt. will be enrolled on an intent-to-treat basis
• (up to 24 in phase I and 45 patients in phase II)
• Estimated time: 20 to 30 months.

49. Study rationale
• Carfilzomib: well tolerated, ORR 78% (in combination with
lenalidomide-dex)
• Effective in vitro and in vivo preclinical studies
• We hypothesized—
combining lenalidomide and carfizomib with rituximab  may
result in even higher rates as well as deeper responses in MCL
patients

50. ENDPOINT ANALYSIS
Primary endpoint:
• To evaluate the frequency and severity of adverse events in Phase I
• To evaluate the frequency and severity of adverse events at the
MTD
• To observe the rate of CR, PR, SD and PD.
Secondary endpoint:
• To observe the duration of responses, the progressions free survival
and overall survival.

51. The B-cell antigen receptor (BCR) signaling
pathway in mantle cell lymphoma (MCL) cells

52. PCI-32765 (uM)
Groeth(%ofcontrol)
0 10 20 30 40 50
0
25
50
75
100
125 Normal B cell
DB SP53
Z138
JMP1
Jeko1
Mino
Growth inhibition of MCL cell lines by PCI-32765

53. The Bruton’s Tyrosine Kinase Inhibitor PCI-32765 is
Highly Active As Single-Agent Therapy in Previously-
Treated Mantle Cell Lymphoma (MCL): Preliminary
Results of a Phase II Trial
MICHAEL (LUHUA) WANG, MD1, PETER MARTIN, MD2, KRISTIE A. BLUM, MD3, BRAD S.
KAHL, MD4, LAUREN S. MAEDA, MD5, RANJANA ADVANI5, MD, MICHAEL E.
WILLIAMS, MD6, SIMON RULE, MD7, SARA RODRIGUEZ8, CHING-FAI PANG, PHD8, ERIC
HEDRICK, MD8 AND ANDRE GOY, MD9
1Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
2Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY
3The Ohio State University, Columbus, OH
4Department of Medicine-Hematology/Oncology, University of Wisconsin, Madison, WI
5Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA
6University of Virginia, Charlottesville, VA
7Department of Haematology, Derriford Hospital, Plymouth, United Kingdom
8Pharmacyclics, Sunnyvale, CA
9John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ

54. Common Non-Hematologic AEs
(Events in > 10% of Patients Regardless of relationship to PCI-32765)
54
0% 10% 20% 30% 40% 50%
Abdominal Pain
Vomiting
Rash
Myalgia
Mucosal inflammation
Edema peripheral
Dyspnea
Nausea
Dizziness
Diarrhea
Fatigue
Grade 1
Grade 2
Grade 3
Grade 4

55. Grade 3/4 Hematologic Toxicity
(regardless of relationship to PCI-32765)
Grade 3/4 Hematology toxicity1
Total
(n=61)
Neutropenia
Febrile neutropenia
Anemia
Thrombocytopenia
Pancytopenia
Grade 3 Grade 4
2% 3%
3% 0%
3% 0%
3% 0%
0% 2%
55
1Reported as Adverse Events

56. Best Response
0%
20%
40%
60%
80%
14%
56
BTZ-naïve
(n=31)
BTZ-exposed
(n=20)
Total
(n=51)
CR
PR
SD
PD
71%
16%
13%
65%
69%
20%
15%
18%
15%
50%
16%
55%
16%
53%

57. Rapid Nodal Response Accompanied by
“Compartmental Shift” of CD19/CD5+ B-cells
57
Chang, D et al. Proc ASH 2011 Abstract 954, Tuesday 8:45 Rm 5AB
Day 22
50%
100%
150%
200%
ALC%ChangefromBaseline
Lymphocyte Count
CD5
CD5
CD19 CD19
Day 1 Day 8
Day 15
50%
100%
150%
200%
ALC%ChangefromBaseline
Lymphocyte Count
CD5
CD5
CD19 CD19
Day 1 Day 8
Day 8
50%
100%
150%
200%
ALC%ChangefromBaseline
Lymphocyte Count
CD5
CD5
CD19 CD19
Day 1 Day 8
50%
100%
150%
200%
ALC%ChangefromBaseline
Day 2
Lymphocyte Count
CD5
CD5
CD19 CD19
Day 1 Day 8

58. Subcarinal LAD: 83 x 54 mm; left inguinal LAD: 36 x 23 mm

59. Subcarinal LAD: 21 x 13 mm ; left inguinal LAD: 16 x 11 mm

60. accrue # C2 C4 C6 C8 C10 C13 C16 best response
1 SD NA SD
2 SD PD SD
3 SD SD PD SD
4 SD PR CR CR CR CR CR CR
5 PR PR CR CR CR CR CR CR
6 SD SD SD SD SD SD
7 PR PR CR CR CR CR CR CR
8 SD SD SD PR PR PR PR PR
9 SD SD PR PR PR PR PR PR
10 PR PD PR
11 PR PR CR CR CR CR CR CR
12 SD PR PR CR CR CR CR
13 SD NA SD
14 PR CR CR CR CR CR CR
15 CR CR NA CR
16 SD PR PR CR CR CR CR
17 PR PR PD PR
18 PR PR PR PR PR PR PR
19 PD PD
20 SD SD SD CR CR CR CR
21 SD PR CR NA CR
22 SD SD SD SD SD SD
23 PR PR PR PR PR
24 PR PR PR PR PR
25 PR PR PR CR CR CR CR
26 CR CR PD CR
27 PR PR CR CR CR CR
28 NE NE
29 NE NE
30 PR PR PR PR PR
31 PR PR PR PR PR

61. Day 1

62. Day 7

63. 12%
32%
33%
37%
38%
42%
46%
48%
57%
69%
0% 10% 20% 30% 40% 50% 60% 70% 80%
Overall Response
PCI-32765 (Wang et al 2011)
Lenalidomide (Witzig et al 2011)
Temsirolimus (Witzig et al 2005)
Bortezomib (Fisher et al 2006)
Rituximab (Foran et al 2000)
Everolimus (O' Connor et al 2011)
90Y-ibritumomab tiuxetan (Wang et al 2009)
Lenalidomide +Rituximab (Wang et al 2012)
Cladribine (Inwards et al 2008)
CAL-101 [Phase I ](Kahl et al, ICML 2011)
Single-agent activity of different agents in
Relapsed/Refractory MCL

64. Michael Wang, MD, Liang Zhang, MD, Xiaohong Han, Ph.D., Jorge
Romaguera, MD, Qing Yi, Ph.D., MD
Department of Lymphoma and Myeloma
The University of Texas M. D. Anderson Cancer Center,
Houston, TX 77030
Bortezomib is synergistic with rituximab and
cyclophosphamide in inducing apoptosis of
mantle cell lymphoma cells
Wang, Zhang, Han, Yang, Qian, Romaguera, Yi. Luekemia, 2

66. Acknowledgements
• All patients
• Larry Kwak, MD, Ph.D., Chairman and Professor, Department of Lymphoma/Myeloma
• Lymphoma Colleagues: Jorge Romaguera, Anas Younas, MD, Peter McLaughlin, Luis
Fayad, Frederick Hagemeister, Sattva Neelapu, Felipe Samanigo, Barbara Pro, Barry
Samuels, Michelle Finale, Maria A. Rodriguez, MD, Michelle Purdom, Crisitne
Samuel, Maria Badilo, Vivian Green, Jairo Mathews, Gloria Obundo, Michael Eckenfells.
• Myeloma Colleagues: Raymond Alexanian, Qing, Yi, Ph.D., MD, Donna Weber, MD, Sirgio
Giralt, MD, Sheeba Thomas, MD, Jatin Shah, MD, Robert Orlowski, MD, Ph.D., Jin
Yang, Ph.D. Jianfei Qian, Ph.D., Liang Zhang, MD, Ph.D.
• Colleagues from other Departments at MDACC: Richard Champlin, MD, Steven
Korblau, MD, Pei Lin, MD, Muzafar Qazibush, MD, Ph.D.
• Colleagues from other Institutions: Xianglin Du, Ph.D., Harry Wang, MS
• Fernando Cabanillas, MD
• Sister Institutions in China:
Yuhong Zhou, MD, Yuankai Shi, MD, Ph.D., Xiaohong Han, Ph.D., Jialei Wang, MD, Jin
Li, MD, Gueliang Jiang, MD, Zheng Zi Qian, MD, Huaqing Wang, MD, Yin
Wang, MD, Shishan Hao, MD, Zhen Cai, MD, Ph.D.

67. Phase II Study of Yttrium-90
Ibritumomab Tiuxetan in Patients With
Relapsed or Refractory Mantle Cell
Lymphoma
Michael Wang,Yasuhiro Oki, Barbara Pro, Jorge Enrique Romaguera, Maria Alma
Rodriguez, Felipe Samaniego, Peter McLaughlin, Frederick Hagemeister, Sattva
Neelapu, Amanda Copeland, Barry I. Samuels, Evelyne M. Loyer, Yuan Ji, and Anas
Younes
Wang et al. JCO. 2009

68. Results
• Patients Relapsed and/or refractory MCL; n=35
• # patients with prior rituximab therapy= 32 (91%)
• RR: 32%, CR: 16%; PR: 16%
• Median EFS/PFS: 6 months and OS: 21 months
• Toxicities: manageable, reversible
• Grade 3/4 neutropenia (32%) and thrombocytopenia (24%)
Median EFS
those who achieved CR/PR 28 months
those who did not respond 3 months
those with tumor <5 cm 9 months
Tumor > 5 cm 3 months
Wang et al. JCO. 2009

69. Event Free Survival (EFS) and Overall
survival (OS) in patients
Median EFS 6 months and median OS 21 months Wang et al. JCO. 2009

70. Event Free Survival According to prior
HyperCVAD and relapsed/refractory status
Wang et al. JCO. 2009

71. • 90Y–ibritumomab tiuxetan has promising activity as
a single agent in relapsed MCL, especially in
patients with a small volume disease and those who
have previously achieved CR with their last therapy.
Conclusion
Wang et al. JCO. 2009

72. International Kite