Mantle Cell Lymphoma: from bench to clinic

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  • The BCR signaling pathway is initiated through phosphorylation of the coreceptorsIg-α and Ig-β, which recruit the tyrosine kinase Syk, a kinase that phosphorylates several downstream kinases, including Bruton tyrosine kinase (Btk) and phosphatidylinositol-3-kinase (PI3K). Activation of PI3K and phospholipase C (PLC) activates protein kinase C-beta (PKC-β), leading to activation of Akt, extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK) and NF-κB. B-cell activating factor (BAFF) and CD40 enhance the BCR signaling pathway to activate several transcription factors, such as nuclear factor of activated T cells (NFAT) and nuclear factor-κB (NF-κB). In addition, Btk may play a role in the pathogenesis of MCL by regulating integrin-mediated migration and adhesion through regulation of chemokine and receptors, such as CXCL12, CXCL13, CXCR4, CXCR5, and VLA-4. BLNK = B-cell linker protein; DAG = diacylglycerol.
  • PCI-32765 effectively inhibited the growth of Mino, Z138, JMP1, Jeko and DB SP53 MCL cell lines in a dose-dependent manner. There was no effect on the growth of normal B cells.
  • Mantle Cell Lymphoma: from bench to clinic

    1. 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. 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. 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. 4. Biology of mantle cell lymphoma
    5. 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. 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. 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. 8. Overall survival in 97 patients treated with R- HyperCVAD alternating with R M/A Romaguera et al, British J Heme, 2008
    9. 9. Time to Failure in 97 patients treated with R-HyperCVAD alternating with R M/A Romaguera et al, British J Heme, 2008
    10. 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. 11. Time to Failure according to B2 microglobulin (B2M)/age Romaguera et al, British J Heme, 2008
    12. 12. Overall Survival according to Mantle cell IPI (MIPI) Romaguera et al, British J Heme, 2008
    13. 13. Time to Failure according to Mantle cell IPI (MIPI) Romaguera et al, British J Heme, 2008
    14. 14. 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
    15. 15. 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
    16. 16. 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
    17. 17. 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
    18. 18. 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
    19. 19. 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
    20. 20. c Human fetal femur Patient MCL cells Tumor burden Bone implantation Tumor injection Tumor growth Tumor migration Schematic presentation of MCL-SCID-hu model
    21. 21. c Human fetal femur Patient MCL cells Tumor burden Bone implantation Tumor injection Tumor growth Tumor migration Schematic presentation of MCL-SCID-hu model
    22. 22. 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.
    23. 23. PBS-SCID-huMCL-SCID-hu LN Spleen ng Liver GI tract Wang, Zhang, Lin, Yi, Clin Cancer Res, 2007
    24. 24. CD20 Cyclin D1 Wang, Zhang, Lin, Yi, Clin Cancer Res, 200
    25. 25. 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
    26. 26. 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)
    27. 27. 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
    28. 28. 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
    29. 29. 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
    30. 30. 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
    31. 31. 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%)
    32. 32. 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%)
    33. 33. 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
    34. 34. Response Duration • Median response duration = 18.9 months (range 17–not reached)
    35. 35. 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)
    36. 36. 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.
    37. 37. • 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
    38. 38. 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
    39. 39. 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.
    40. 40. 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
    41. 41. CFZ induces apoptosis of MCL cells but exhibits low cytotoxicity toward PBMCs from healthy volunteers
    42. 42. 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
    43. 43. 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
    44. 44. 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
    45. 45. 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.
    46. 46. 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.
    47. 47. 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
    48. 48. 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.
    49. 49. The B-cell antigen receptor (BCR) signaling pathway in mantle cell lymphoma (MCL) cells
    50. 50. 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
    51. 51. 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
    52. 52. 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
    53. 53. 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
    54. 54. 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%
    55. 55. 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
    56. 56. Subcarinal LAD: 83 x 54 mm; left inguinal LAD: 36 x 23 mm
    57. 57. Subcarinal LAD: 21 x 13 mm ; left inguinal LAD: 16 x 11 mm
    58. 58. 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
    59. 59. Day 1
    60. 60. Day 7
    61. 61. 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
    62. 62. 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
    63. 63. 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.
    64. 64. 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
    65. 65. 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
    66. 66. Event Free Survival (EFS) and Overall survival (OS) in patients Median EFS 6 months and median OS 21 months Wang et al. JCO. 2009
    67. 67. Event Free Survival According to prior HyperCVAD and relapsed/refractory status Wang et al. JCO. 2009
    68. 68. • 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
    69. 69. International Kite

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