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Mantle Cell Lymphoma: from bench to clinic

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.

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Mantle Cell Lymphoma: from bench to clinic

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  1. 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

  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. Age-adjusted Incidence Rates for MCL by Age 1975 and 2004 Zhou, Wang et al, Cancer, 2008

  4. Biology of mantle cell lymphoma

  5. Mantle Cell Lymphoma (MCL) 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.

  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 chemoimmunotherapywith Rituximab-HyperCVADalternating 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

  14. Published Response: Salvage Therapies in Relapsed/Refractory MCL

  15. Phase 2 Trial of Rituximab Plus HyperCVADAlternating 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, YuhongZhou, MD, HagopKantarjian, MD, Jorge Romaguera, MD Wang et al. Cancer. 2008

  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% Wang et al. Cancer. 2008

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

  18. Single-agent activity of different agents in Relapsed/Refractory MCL

  19. A SCID-HU IN VIVO MOUSE MODEL OF HUMAN PRIMARY MANTLE CELL LYMPHOMA 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 Wang, Zhang, Lin, Yi, Clin Cancer Res, 2007

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

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

  22. CD23 CD19 Numbers of inoculated MCL cells C A Control 0.5M 2M 5M Bone and tumor mass Control CD5 CD20 X-ray B HE  D E IHC CD20 Engraftment of primary MCL cells in SCID-hu mice.

  23. MCL-SCID MCL-SCID-hu PBS-SCID-hu LN Spleen BM Liver GI tract CD20 staining Wang, Zhang, Lin, Yi, Clin Cancer Res, 2007

  24. Cyclin D1 CD20 Wang, Zhang, Lin, Yi, Clin Cancer Res, 2007

  25. 2 Wang, Zhang, Lin, Yi, Clin Cancer Res, 2007

  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 steroidcyclophosphamide) 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. A B RTX LEN D C Lenalidomide plus rituximab inhibited the growth of MCL cells in SCID mice. Lenalidomide augmented the function of NK cells in vivo

  28. Oral lenalidomide plus 4 doses of rituximab induced prolongedremissions in relapsed/refractorymantle cell lymphoma:a phase I/II clinical trial Departments of Lymphoma/Myeloma , Radiology, Biostatistics, Stem Cell Transplantation Celgene Support 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

  29. Objectives • 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

  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. Hematological Toxicity

  32. Non-hematological Toxicity

  33. Responses at MTD in Phase II * 1 patient (2%) was not evaluable for response, but counted as treatment failure

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

  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. Conclusions • Oral lenalidomide plus 4 doses of rituximabis 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. Summary • 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. Wang, Zhang, Lin, Yi, Clin Cancer Res, 2007

  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. 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, carfilzomibis good-tolerated and does not induce severe neuropathy • Therefore, carfilzomib can be used in higher dose than bortezomibin vivo.

  40. Preclinical Studies: Effects of carfilzomib on cell growth B A D C

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

  42. CFZ induces apoptosis in a caspase-dependent manner MINO Jeko-1 0 5 10 20 CFZ 0 5 10 20 (nM) A B cCasp-3 cPARP β-actin CFZ (20nM) MINO Jeko-1 0 6 12 24 0 6 12 24 hour cCasp-3 C cCasp-8 3.8 5.6 82.5 60.2 17.7 57.5 MINO cCasp-9 7.2 6.7 78.2 62.0 23.9 53.2 Jeko-1 cPARP D β-actin Annexin V

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

  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. 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. 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. 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. 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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