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
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Mantle Cell Lymphoma: from bench to clinic Michael Wang, MD Associate Professor Co-Director, Clinical Trials in Lymphoma Director, Myeloma Tissue Bank.
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Mantle Cell Lymphoma: from bench to clinic
Michael Wang, MD
Associate ProfessorCo-Director, Clinical Trials in Lymphoma
Departments of Lymphoma/Myeloma ,Stem Cell Transplantation
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, American J Hematology, 2007; Evans LS, Hancock BW. Lancet. 2003;362:139-146
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
Overall survival in 97 patients treated with R-HyperCVAD alternating with R M/A
Romaguera et al, British J Heme, 2008
Time to Failure in 97 patients treated with R-HyperCVAD alternating with R M/A
Romaguera et al, British J Heme, 2008
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
Time to Failure according to B2 microglobulin (B2M)/age
Romaguera et al, British J Heme, 2008
Overall Survival according to Mantle cell IPI (MIPI)
Romaguera et al, British J Heme, 2008
Time to Failure according to Mantle cell IPI (MIPI)
Romaguera et al, British J Heme, 2008
Published Response: Salvage Therapies in Relapsed/Refractory MCL
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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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,
Lenalidomide plus rituximab inhibited the growth of MCL cells in SCID mice. Lenalidomide augmented the function of NK cells in vivo
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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
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
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
* 1 patient (2%) was not evaluable for response, but counted as treatment failure
Response Duration
• Median response duration = 18.9 months (range 17–not reached)
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)
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.
• 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
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
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.
Preclinical Studies: Effects of carfilzomib on cell growth
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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
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.
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.
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
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.
The B-cell antigen receptor (BCR) signaling pathway in mantle cell lymphoma (MCL) cells
PCI-32765 (uM)
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Growth inhibition of MCL cell lines by PCI-32765
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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Common Non-Hematologic AEs (Events in > 10% of Patients Regardless of relationship to PCI-32765)
Abdominal Pain
Vomiting
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Myalgia
Mucosal inflammation
Edema peripheral
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Grade 1Grade 2Grade 3Grade 4
Grade 3/4 Hematologic Toxicity(regardless of relationship to PCI-32765)
• 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,
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
Event Free Survival (EFS) and Overall survival (OS) in patients
Median EFS 6 months and median OS 21 months Wang et al. JCO. 2009
Event Free Survival According to prior HyperCVAD and relapsed/refractory status
Wang et al. JCO. 2009
• 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.