Mantle Cell Lymphoma: from bench to clinic Michael Wang, MD Associate Professor Co-Director,...

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

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

0

0.5

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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

Ag

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70-79

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Age-adjusted Incidence Rates for MCL by Age 1975 and 2004

Zhou, Wang et al, Cancer, 2008

Biology of mantle cell lymphoma

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)

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

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


Time to Failure in 97 patients treated with R-HyperCVAD alternating with R M/A


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


Time to Failure according to B2 microglobulin (B2M)/age


Overall Survival according to Mantle cell IPI (MIPI)


Time to Failure according to Mantle cell IPI (MIPI)


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

Wang 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%


18

Failure-free survival of patients treated with HyperCVAD

At median follow-up of 40 months Median FFS 11 months


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

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

c

Human fetal femur Patient MCL cells Tumor burden

Bone implantatio

nTumor injection Tumor growth Tumor migration

Schematic presentation of MCL-SCID-hu model

Control CD5 CD20

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Bone and tumor mass

X-ray

Control 0.5M 2M 5M

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HE

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Post-bone

4 8 12

Weeks after tumor inoculation

Hum

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2 M (

ng/m

L) M CL-5M

M CL-2M

M CL-0.5M

PBS

Engraftment of primary MCL cells in SCID-hu mice.

PBS-SCID-huMCL-SCID-hu

LN

Spleen

CD20 staining

MCL-SCID

Liver

GI tract


CD20 Cyclin D1


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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)

Lenalidomide plus rituximab inhibited the growth of MCL cells in SCID mice. Lenalidomide augmented the function of NK cells in vivo

A B

DC

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RTX

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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

An addition of 38 patients at MTD in phase II

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%)

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%)

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

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


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

0 1.25 2.5 5 10 20 40 800

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

CFZ induces apoptosis in a caspase-dependent manner

0 5 10 20 (nM)

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cCasp-9

cCasp-3

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CFZ - - + + + +IETD-CHO - + - + + -

Z-LETD - + - + - +

3.8 5.6 17.782.5

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CFZ-induced activation of mitochondrial apoptotic signalings and inactivation of survival signalings

pAKT

pIκB

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MINO Jeko-1

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STAT3

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JNK

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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

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

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

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%

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

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Day 1 Day 8

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Day 8

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Day 1 Day 8

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CD

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5CD19 CD19

Day 1 Day 8

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

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

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 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 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

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

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, 2007

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.

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

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


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


• 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


International Kite Festival, Weifang, China, 2004

Mantle Cell Lymphoma: from bench to clinic Michael Wang, MD Associate Professor Co-Director,...

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