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Treatment approaches to non-Hodgkin’s l ymphoma in elderly patients

Treatment approaches to non-Hodgkin’s l ymphoma in elderly patients. Larry W. Kwak, M.D., Ph.D. Chairman, Department of Lymphoma/Myeloma Justin Distinguished Chair in Leukemia Research Co-Director, Center for Cancer Immunology Research MD Anderson Cancer Center.

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Treatment approaches to non-Hodgkin’s l ymphoma in elderly patients

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  1. Treatment approaches to non-Hodgkin’s lymphoma in elderly patients Larry W. Kwak, M.D., Ph.D. Chairman, Department of Lymphoma/Myeloma Justin Distinguished Chair in Leukemia Research Co-Director, Center for Cancer Immunology Research MD Anderson Cancer Center

  2. Refractory/Relapsed DLBCL: Therapy for “Non-Transplant Candidates” • Poor disease control and substantial morbidity. • Goal is generally palliative • Gemcitabine based • Low dose oral chemotherapy • “hyperfractionatedcytoxan” • Rituximab • Radiation • New drugs

  3. Novel Anti-CD20 MoAbs for Relapsed/Refractory Indolent Lymphoma Morschhauser. Ann Oncol. 2010 (Epub ahead of print); Morschhauser. J Clin Oncol. 2009;27: 3346; Negrea. ASH. 2009 (abstr 3757); Hagenbeek. ASH. 2009 (abstr 935); Hagenbeek. Blood. 2008;111:5486; Salles. ASH. 2009 (abstr 1704).

  4. Brentuximab Vedotin: Mechanism of Action Brentuximab vedotin (SGN-35) antibody-drug conjugate (ADC) monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-CD30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released G2/M cell cycle arrest MMAE disruptsmicrotubule network Apoptosis With permission from Chen R et al. Proc ASH 2010; Abstract 283.

  5. Brentuximab Vedotin (SGN-35) for Rel/Ref Systemic ALCL Shustov, ASH 2010 # 961 (Oral) In terms of response, ALK (+) = ALK (–) “B” symptom resolution = 82% Peripheral neuropathy = 38% (median time to resolution 5.4 weeks)

  6. Novel Therapeutics for NHLs Mahadavan and Fisher. JCO 29: 1876, 1884, 2011.

  7. Tumor Cells IL-6 TNF IL-1 Tumor Stroma ICAM-1 Blood Vessels NFAT IL-2 IFN  PKC IL-2 NK Cells VEGF bFGF CD28 PI3K CD8+ T Cells Dendritic Cells Lenalidomide: Targeting the Tumor Cell and Its Microenvironment Chng. Cancer Control.2005;12:91; Drach. Expert Rev Cancer. 2005;5:477.

  8. Lenalidomide/Rituximab for Untreated Stage II-IV iNHL: Response Rates by Subtype

  9. Rituximab Plus Lenalidomide 20 mg daily for 21 days, off 7 days X 6, and if CR, reduce to 10 mg

  10. Lenalidomide + Rituximab for Ref/Rel DLBCL

  11. Lenalidomide for Ref/Rel DLBCL: Response by Molecular Subtype • 40 patients • GCB 23 • Non-GCB 17 • PFS (p=0.004) • Non-GCB 6.2 months • GCB 1.7 months Hernandez-Ilizaliturri et al. Cancer 2011

  12. Lenalidomide vs Investigators Choice for Ref/Rel DLBCL: Study Design lenalidomide n=25 lenalidomide n=25 lenalidomide n=74 Stage 2 N = 148 or 296 Selected Type(s) Non-GCB R R Inv. Choice n=25 Inv. Choice n=25 Inv. Choice n=74 DLBCL Stratify by IHC GCB R ? ? Stage 1 N = 100 If lenalidomide is superior to investigator’s choice in either or both subtype(s) then that subtype(s) will be tested in Stage 2. 13

  13. Small Molecule Inhibitors: Responses for Various Lymphoma Subtypes

  14. Results of Activation of the B-Cell Receptor and Targets for Manipulation CAL-101 fostamatinib PCI-32765 ? enzastaurin ? temsirolimus everolimusdeferolimus bortezomibcarfilzomib

  15. O N H 2 N N N N N O PCI-32765: A Novel Small Molecule Inhibitor of Btk in the BCR Pathway • Forms a specific and irreversible bond with cysteine-481 in Btk • Potent Btk inhibition • IC50 = 0.5 nM • Orally available • Once daily dosing results in 24-hr sustained target inhibition

  16. Phase I PCI-32765 for Recurrent NHL and CLL: Response in 48 Evaluable Patients ORR (evaluable) 52% ORR (ITT) 45% *2 CLL pts had nodal response with lymphocytosis

  17. Phase I PCI-32765 for Recurrent NHL and CLL: Hematologic Tolerability (N=56) • No hepatic or renal toxicities • No evidence of cumulative hematologic toxicity Percent

  18. Interim Results of an International, Multicenter, Phase 2 Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Relapsed or Refractory Mantle Cell Lymphoma (MCL): Durable Efficacy and Tolerability With Longer Follow-up Michael Wang, MD1, Simon Rule, MD2, Peter Martin, MD3, Andre Goy, MD4, Rebecca Auer, MD5, Brad S. Kahl, MD6, WojciechJurczak, MD7, RanjanaAdvani, MD8, Jorge Romaguera, MD1, Jesse McGreivy, MD9, Fong Clow, ScD9, Michelle Stevens-Brogan9, Lori Kunkel, MD9, Kristie A. Blum, MD10 1 Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; 2 Department of Haematology, Derriford Hospital, Plymouth, United Kingdom; 3 Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY; 4 John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ 5 Department Haemato-oncology, Barts Health NHS Trust, London, United Kingdom ; 6 Department of Medicine-Hematology/Oncology, University of Wisconsin, Madison, WI; 7 Department of Haematology, Jagiellonian University, Krakow, Poland; 8 Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA 9 Pharmacyclics, Inc., Sunnyvale, CA; 10 The Ohio State University, Columbus, OH

  19. Best Response(Efficacy Population n=110, Median Follow-up 9.2 mo) 72% 68% Percent of patients (%) 66% Bortezomib-naïve(n=63) Bortezomib-exposed(n=47) Total(n=110)

  20. Current Active Trials with Ibrutinib

  21. PI3K Promotes Survival/Growth of Cancer Cells LYMPH NODE MALIGNANT B-CELL

  22. Single-Agent CAL-101 for R/R MCL, iNHL, and CLL: Best Tumor Volume Response

  23. ORR with CAL-101 for R/R iNHL Overall Response Rate Compared to Those with Other Drugs PFS results are as good or better with CAL-101

  24. CAL-101 for R/R NHL: Cumulative Adverse Events • Grade 3-4 events were usually related to underlying disease or prior therapy • Reversible Gr 3-4 ALT/AST elevations were not associated with increased bilirubin or decreases in liver synthetic function • No obvious pattern of drug-related symptomatic adverse events

  25. Department of Lymphoma/Myeloma Disease –specific Working Groups Larry W. Kwak, M.D., Ph.D. Chairman, Lymphoma/Myeloma Michael Wang, M.D. Nathan Fowler, M.D. Co-Directors Lymphoma Clinical Research Robert Orlowski, M.D., Ph.D. Director Myeloma Clinical Research Multiple myeloma Low Grade lymphoma T cell lymphoma Large Cell lymphoma Mantle cell lymphoma Hodgkins Phase I D. Weber J. Shah S. Thomas M. Wang R. Alexanian Q. Yi L. Fayad A. Rodriguez F. Hagemeister J. Westin M. Wang J. Romaguera M. Fanale F. Hage- meister N. Fowler F. Samaniego S. Neelapu L. Fayad L. Kwak M. Fanale N. Fowler J. Shah J. Westin Y. Oki M. Fanale Burkitt HIV Brain Testicular M. Fanale N. Fowler

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