mantle cell lymphoma: from bench to clinic
DESCRIPTION
Mantle Cell Lymphoma: from bench to clinic. Departments of Lymphoma/Myeloma , Stem Cell Transplantation. Michael Wang , MD Associate Professor Co-Director, Clinical Trials in Lymphoma Director, Myeloma Tissue Bank Director , Mantle Cell Lymphoma Program of Excellence. - PowerPoint PPT PresentationTRANSCRIPT
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Mantle Cell Lymphoma: from bench to clinic
Michael Wang, MD
Associate ProfessorCo-Director, Clinical Trials in Lymphoma
Director, Myeloma Tissue BankDirector, Mantle Cell Lymphoma
Program of Excellence
Departments of Lymphoma/Myeloma ,Stem Cell Transplantation
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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
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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-
adju
sted
inci
denc
e ra
te (c
ases
per
100
000
)
>=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
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Biology of mantle cell lymphoma
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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 treatmentInevitable relapse.
Mantle Cell Lymphoma (MCL)
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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
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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
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Overall survival in 97 patients treated with R-HyperCVAD alternating with R M/A
Romaguera et al, British J Heme, 2008
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Time to Failure in 97 patients treated with R-HyperCVAD alternating with R M/A
Romaguera et al, British J Heme, 2008
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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
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Time to Failure according to B2 microglobulin (B2M)/age
Romaguera et al, British J Heme, 2008
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Overall Survival according to Mantle cell IPI (MIPI)
Romaguera et al, British J Heme, 2008
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Time to Failure according to Mantle cell IPI (MIPI)
Romaguera et al, British J Heme, 2008
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Published Response: Salvage Therapies in Relapsed/Refractory MCL
Author Regimen No. Patients CR (%) PR (%) ORR (%)
Foran19 Rituximab 35 14 23 37Gressin20 VAD + Chlorambucil* 30 43 30 73Kaufmann21 Rituximab + thalidomide 16 31 50 81Dang22 Ontak 8 12.5 25 37.5
Cohen23 Cyclophosphamide + fludarabine# 30 30 33 63Goy24 Bortezomib 29 21 21 42O’Connor25 Bortezomib 11 9 36 45McLaughlin26 Fludarabine + mitoxantrone +
dexamethasone5 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 75Fisher31 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
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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
Wang et al. Cancer. 2008
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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%
Wang et al. Cancer. 2008
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Failure-free survival of patients treated with HyperCVAD
At median follow-up of 40 months Median FFS 11 months
Wang et al. Cancer. 2008
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0% 10% 20% 30% 40% 50% 60% 70% 80%
12%
32%
33%
37%
38%
42%
46%
48%
69%
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
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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, 2007
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c
Human fetal femur Patient MCL cells Tumor burden
Bone implantatio
nTumor injection Tumor growth Tumor migration
Schematic presentation of MCL-SCID-hu model
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c
Human fetal femur Patient MCL cells Tumor burden
Bone implantatio
nTumor injection Tumor growth Tumor migration
Schematic presentation of MCL-SCID-hu model
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Control CD5 CD20
A
Bone and tumor mass
X-ray
Control 0.5M 2M 5MNumbers of inoculated MCL cells
C
HE
CD20
D E
IHC
B
020406080
100120140160180
Pre-bone
Post-bone
4 8 12
Weeks after tumor inoculation
Hum
an
2 M (n
g/m
L) M CL-5MM CL-2MM CL-0.5MPBS
Engraftment of primary MCL cells in SCID-hu mice.
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PBS-SCID-huMCL-SCID-hu
LN
Spleen
CD20 staining
MCL-SCID
Liver
GI tract
Wang, Zhang, Lin, Yi, Clin Cancer Res, 2007
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CD20 Cyclin D1
Wang, Zhang, Lin, Yi, Clin Cancer Res, 2007
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0
5
10
15
20
25
30
0 1 2 3
Weeks after tumor inoculation
H
uman
M (n
g/m
L) PBS Atiprimod 2
Wang, Zhang, Lin, Yi, Clin Cancer Res, 2007
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Multiple Myeloma and Mantle Cell Lymphoma Share Similar Effective
TherapiesMultiple 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)
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Lenalidomide plus rituximab inhibited the growth of MCL cells in SCID mice. Lenalidomide augmented the function of NK cells in vivo
A B
DC
LENRTX
0
1000
2000
3000
4000
5000
0 1 2 3 4 5
Tum
or V
olum
e (m
m3 )
DMSOLENRTXLEN+RTX
Weeks from treatment
0
20
40
60
80
100
120
0 1 2 3 4 5 6
Weeks from treatment
% S
urvi
val
DMSOLENRTXLEN+RTX
0
5
10
15
20
25
Splenocytes NK cells
Cel
l (X1
06 )
DM SOLEN
0
10
20
30
40
50
NK cells
% s
plen
ocyt
es
DMSOLEN
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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
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To evaluate safety of lenalidomide in combination with rituximab in patients with relapsed/refractory MCL in Phase ITo determine the Maximum Tolerated Dose (MTD) in Phase ITo confirm safety and efficacy in Phase II
Objectives
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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
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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%)
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Non-hematological ToxicityPhase 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%)
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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
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Response Duration
• Median response duration = 18.9 months (range 17–not reached)
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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)
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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.
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• 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, 2007
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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
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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.
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Preclinical Studies: Effects of carfilzomib on cell growth
0 1.25 2.5 5 10 20 40 800
20
40
60
80
100
120
MINOJeko-1MAVER
Carfilzomib (nM)
Gro
wth
(% c
ontro
l)
0 1.25 2.5 5 10 20 40 800
20
40
60
80
100
120
PT1PT2PT3
Carfilzomib (nM)
Gro
wth
(% c
ontr
ol)
0 1.25 2.5 5 10 20 40 800
20
40
60
80
100
120
PBMC1
Carfilzomib (nM)
Gro
wth
(% c
ontr
ol)
0 1.25 2.5 5 10 20 40 800
20
40
60
80
100
120
No activationIono/PMAAnti CD3/CD28
Carfilzomib (nM)
Gro
wth
(% c
ontr
ol)
A
B
CD
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CFZ induces apoptosis of MCL cells but exhibits low cytotoxicity toward PBMCs from healthy volunteers
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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
Se-ries1
0
20
40
60
80
100MINOJeko-1
% A
popt
otic
cel
ls
CFZ - - + + - -BTZ - - - - + +
Z-VAD - + - + - +MINO
cPARP
Jeko-1 0 6 12 24 hour 0 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
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CFZ-induced activation of mitochondrial apoptotic signalings and inactivation of survival signalings
pAKT
pIκB
pSTAT3
MINO Jeko-1 0 6 12 24 hour 0 6 12 24
CFZ (20nM)
STAT3
IκB
AKT
pBcl-2
Bcl-2
cCyto c
tCyto c
MINO Jeko-1 0 6 12 24 hour 0 6 12 24
CFZ (20nM)
pJNKJNK
β-actin
β-actin
A
B
C
MINO Jeko-1 0 6 12 24 hour 0 6 12 24
CFZ (20nM) β-actin
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Phase I/II Study of Carfilzomib + Lenalidomide + Rituximab
in relapsed/refractory Mantle Cell Lymphoma
Michael Wang, MDAssociate Professor
Department of Lymphoma/MyelomaMD Anderson Cancer Center
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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.
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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.
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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
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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.
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The B-cell antigen receptor (BCR) signaling pathway in mantle cell lymphoma (MCL) cells
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PCI-32765 (uM)
Gro
eth
(% o
f con
trol
)
0 10 20 30 40 500
25
50
75
100
125 Normal B cellDB SP53Z138JMP1Jeko1Mino
Growth inhibition of MCL cell lines by PCI-32765
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The Bruton’s Tyrosine Kinase Inhibitor PCI-32765 isHighly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II TrialMICHAEL (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, TX2Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY3The Ohio State University, Columbus, OH4Department of Medicine-Hematology/Oncology, University of Wisconsin, Madison, WI5Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA6University of Virginia, Charlottesville, VA7Department of Haematology, Derriford Hospital, Plymouth, United Kingdom8Pharmacyclics, Sunnyvale, CA9John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ
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54
Common Non-Hematologic AEs (Events in > 10% of Patients Regardless of relationship to PCI-32765)
Abdominal Pain
Vomiting
Rash
Myalgia
Mucosal inflammation
Edema peripheral
Dyspnea
Nausea
Dizziness
Diarrhea
Fatigue
0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50%
Grade 1Grade 2Grade 3Grade 4
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Grade 3/4 Hematologic Toxicity(regardless of relationship to PCI-32765)
Grade 3/4 Hematology toxicity1 Total(n=61)
NeutropeniaFebrile neutropeniaAnemiaThrombocytopeniaPancytopenia
Grade 3 Grade 42% 3%3% 0%3% 0%3% 0%0% 2%
55
1Reported as Adverse Events
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Best Response
0%
20%
40%
60%
80%
14%
56
BTZ-naïve(n=31)
BTZ-exposed(n=20)
Total(n=51)
CRPR
SD
PD
71%
16%13%
65% 69%
20%15% 18%
15%
50%
16%
55%
16%
53%
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Rapid Nodal Response Accompanied by “Compartmental Shift” of CD19/CD5+ B-cells
57Chang, D et al. Proc ASH 2011 Abstract 954, Tuesday 8:45 Rm 5AB
Day 22
C1D1
C1D8
C1D15
C1D22
C2D1
C3D1
C4D1
C5D1
C6D1
C7D22
50%
100%
150%
200%
ALC
% C
hang
e fro
m B
asel
ine
Lymphocyte Count
CD
5
CD
5CD19 CD19
Day 1 Day 8
Day 15
C1D1
C1D8
C1D15
C1D22
C2D1
C3D1
C4D1
C5D1
C6D1
C7D22
50%
100%
150%
200%
ALC
% C
hang
e fro
m B
asel
ine
Lymphocyte Count
CD
5
CD
5CD19 CD19
Day 1 Day 8
Day 8
C1D1
C1D8
C1D15
C1D22
C2D1
C3D1
C4D1
C5D1
C6D1
C7D22
50%
100%
150%
200%
ALC
% C
hang
e fro
m B
asel
ine
Lymphocyte Count
CD
5
CD
5CD19 CD19
Day 1 Day 8
C1D1
C1D8
C1D15
C1D22
C2D1
C3D1
C4D1
C5D1
C6D1
C7D22
50%
100%
150%
200%
ALC
% C
hang
e fro
m B
asel
ine
Day 2Lymphocyte Count
CD
5
CD
5CD19 CD19
Day 1 Day 8
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Subcarinal LAD: 83 x 54 mm; left inguinal LAD: 36 x 23 mm
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Subcarinal LAD: 21 x 13 mm ; left inguinal LAD: 16 x 11 mm
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accrue # C2 C4 C6 C8 C10 C13 C16 best response1 SD NA SD2 SD PD SD3 SD SD PD SD
4 SD PR CR CR CR CR CR CR
5 PR PR CR CR CR CR CR CR6 SD SD SD SD SD SD
7 PR PR CR CR CR CR CR CR8 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 CR13 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 PR19 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
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Day 1
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Day 7
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0% 10% 20% 30% 40% 50% 60% 70% 80%
12%
32%
33%
37%
38%
42%
46%
48%
57%
69%
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
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Michael Wang, MD, Liang Zhang, MD, Xiaohong Han, Ph.D., Jorge Romaguera, MD, Qing Yi, Ph.D., MD
Department of Lymphoma and MyelomaThe 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, 2007
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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.
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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
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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
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Event Free Survival (EFS) and Overall survival (OS) in patients
Median EFS 6 months and median OS 21 months Wang et al. JCO. 2009
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Event Free Survival According to prior HyperCVAD and relapsed/refractory status
Wang et al. JCO. 2009
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• 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
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International Kite Festival, Weifang, China, 2004