1. Low Grade Lymphomas: Treatment approaches Parameswaran Venugopal, MD Professor of Medicine Rush University Medical Center

2. SEER DATA 2015 2

3. 3

4. 4 Armitage and Weisenburger. J Clin Oncol. 1998;16:2780. Adapted from Jemal et al. CA Cancer J Clin. 2006;56:106. Relative Incidence of NHL Subtypes

5. 5 Selected Indolent B-Cell Non-Hodgkin’s Lymphoma Subtypes Indolent Non-Hodgkin’s Lymphoma * Follicular lymphoma (22%) Small lymphocytic lymphoma (6%) Marginal-zone lymphoma (6%) −Splenic MZL −Nodal MZL −Mucosa-associated lymphoid tissue Hairy cell leukemia (<1%) Waldenstrom macroglobulinemia (<1%) *% of all NHL. National Comprehensive Cancer Network. Practice Guidelines in Oncology. v.2.2006. At: http://www.cancer.gov/ cancertopics/pdq/treatment/adult-non-hodgkins/HealthProfessional/page2. Accessed May 2006. Ansell and Armitage. Mayo Clin Proc. 2005;80:1087.

6. 6 Low Grade Lymphoma  Indolent lymphoma accounts for 30%-40% of NHL cases –FL (22%), SLL (7%), MALT (8%), WM (uncommon)  Often asymptomatic  85%-90% present in stage III or IV (Ann Arbor Staging)  Long median survival (~10 years)  Advanced disease rarely curable with conventional treatments  Transformation to aggressive lymphoma often occurs –3% risk/year –30% risk over 10 years Winter et al. Hematology. 2004;203. Armitage and Weisenburger. J Clin Oncol. 1998;16:2780. Adapted from Jemal et al. CA Cancer J Clin. 2005;55:10. Al-Tourah et al. ASCO, 2006. Abstract 7510.

7. 7 Follicular Lymphoma (FL)  Most common indolent NHL, accounts for ~22% of NHL in North America  Typically advanced stage at presentation  Often asymptomatic

8. 8 FL: WHO/REAL Grading <5/hpf Grade 1 Grade 2 6-15/hpf Grade 3a Grade 3b >15/hpf Sheet

9. Diagnosis

10. 10 Follicular Lymphoma: Diagnosis  B symptoms  Physical Examination  Laboratory studies:  Biopsy of Lymph Node  Bone Marrow Biopsy  CAT Scan  PET scan

11. Treatment

12. Follicular Lymphoma Common Management Approach

13. Watch & Wait Radiotherapy Chemotherapy Monoclonal Antibodies Radioimmunotherapy Stem Cell Transplantation New Agents:

14. New Agents: Ibrutinib (Imbruvica) Idelalisib (Zydelig) Venetoclax (Venclexta) Obinutuzumab (Gazyva)

15. 15 Rituximab as a Targeted Therapy in FL  Murine/human IgG 1 kappa monoclonal antibody  Binds to CD20 antigen  Half-life (at 375 mg/m 2 ) ~76.3 hours after 1st infusion and 205.8 hours after the 4th infusion  Mechanism of action –CDC, ADCC, apoptosis, and ionizing radiation– induced cell death Murine variable regions bind specifically to CD20 on B cells Human  constant regions Human IgG 1 Fc domain works in synergy with human effector mechanisms CDC = complement-mediated cell death; ADCC = antibody-dependent cell cytotoxicity.

16. 16 Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Fc region Antigen B cell Antibody NK cell Fc receptor (Fc  RIII) Granules Pores (perforin) Granules release perforins and granzymes; cytokines secreted (eg, IFN  ) H 2 O, ions, granzymes Lysis NK = natural killer.

17. 17 Radioimmunotherapy Radionuclide Chelator Ibritumomab Tiuxetan Tositumomab

18. Targeting of B Cell Receptor Niedermeier M, et al. Blood. 2009;113(22):5549-5557.