Ne New biologics: Wh What are they? Peter Chin-Hong MD Professor - PDF document

10/11/19 Disclosures • Research support from Karius Ne New biologics: Wh What are they? Peter Chin-Hong MD Professor of Medicine UCSF October 2019 1 2 Autoimmune disease and cancer increase with age Learning objectives After attending this presentation, learners will be able to: • List the types of conditions for which biologic agents may be prescribed for Rheumatoid arthritis Crohn disease Vasculitis Psoriasis • Explain the mechanism of action in general of these agents to a patient in Ulcerative colitis your practice so that he or she may understand why certain opportunistic infections and other complications may arise • Describe the array of infectious and other complications that may arise Lymphoma with these agents • Design strategies that you can use in clinic to prevent infectious and other complications in your patients Melanoma Prostate cancer Lung cancer Leukemia Slide 4 of 36 3 4 1

10/11/19 Immunobiologics treat autoimmune disease and cancer What is a “biologic”? ▪ Any biologically derived product TNF-α inhibitors ▪ Binds or interferes with a specific molecular target Infliximab Adalimumab Monoclonal antibodies Etanercept Receptor analogues Crohn disease Rheumatoid arthritis Vasculitis Psoriasis Chimeric small molecules Ulcerative colitis Anti-CD20 ▪ Abbreviations placed at the ends of the names of Rituximab therapeutic agents convey specific information relating to their structure: Lymphoma "-cept" refers to fusion of a receptor to the Fc part of human IgG1 Checkpoint block "-mab" indicates a monoclonal antibody (mAb) Ipilimumab "-ximab" indicates a chimeric mAb "-zumab" indicates a humanized mAb CAR-T cells Melanoma Prostate cancer Leukemia Lung cancer Slide 5 of 36 Slide 6 of 36 5 6 Type of immune defect related to drugs used Who is the most immune suppressed? Humoral immunity • Rituximab (anti-CD20) •Hyposplenism •CVID (low IgG) Innate Cell- Heme malignancy/stem cell transplant (PMNs) mediated immunity immunity Organ transplant • Solid organ transplant Autoimmune disease treatment • Cancer chemoRx • Stem cell transplant HIV Solid tumor treatment • Chronic gran dz (CGD) • TNF-α inhibitors Congenital/acquired immune deficiency • Steroids Hyposplenism • Other biologics Slide 11 of 36 Slide 7 of 36 7 8 2

10/11/19 How is this different from HIV immunosuppressed Case patients? ▪ 56 year-old woman with Crohn disease managed with infliximab and 6-MP HIV Non-HIV ▪ Presents to ED complaining of Immune Death of shortness of breath x 3 weeks Heterogeneous CD4 + T-cells defect ▪ What else do you want to know? OI risk No reliable tests CD4 + count stratification available Slide 10 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard Slide 9 of 36 9 10 Case Case ▪ 56 year-old woman with Crohn ▪ 56 year-old woman with Crohn disease managed with disease managed with infliximab and 6-MP infliximab and 6-MP ▪ Presents to ED complaining of ▪ Presents to ED complaining of shortness of breath x 3 weeks shortness of breath x 3 weeks ▪ PPD negative prior. Lives in ▪ CXR shows patchy infiltrates New York . Came back 4 weeks ago from a trip to Puerto Rico ▪ What do you check next? where she visited family and helped with property clean up Slide 11 of 36 Slide 12 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard Case courtesy Dr. Camille Kotton, MGH/Harvard 11 12 3

10/11/19 56 yo with Crohn disease on infliximab, short of breath Case What do you check next? ▪ 56 year-old woman with Crohn disease managed with infliximab and 6-MP A. Chest CT ▪ Presents to ED complaining of B. Interferon gamma release shortness of breath x 3 weeks assay (IGRA) ▪ Urinary histoplasma antigen C. Sputum AFB x 3 positive. Chest CT: symmetric D. Tuberculin Skin Test (TST) nodules E. Repeat CXR Diagnosis: Acute histoplasmosis Slide 13 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard Slide 14 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard 13 14 MOA TNF-α inhibitors: tuberculosis ▪ Post-marketing survey of TB cases following release of infliximab (1998-2001) ▪ 70 cases of TB ▪ Median time to diagnosis: 12 weeks (range 1-52) ▪ TB characteristics ▫ Extrapulmonary disease: 57% ▫ Disseminated disease: 24% Keane J. NEJM. 2001 Scott DL et al, NEJM Aug 17, 2006 CXR showing disseminated TB in patient on infliximab Slide 15 of 36 Slide 16 of 36 15 16 4

10/11/19 TNF-α inhibitors: mycobacteria and fungi Case ▪ 42 year-old male with Crohn ▪ Survey of serious infection on disease x 3 years, started on TNF-α inhibitors in the US infliximab after persistent ▫ Non-tuberculous mycobacteria: 32 diarrhea 5 months prior ▫ TB: 17 ▪ Admitted with 3 weeks ▫ Histoplasmosis: 56 shortness of breath, low grade ▪ FDA alert 2008: 256 cases of temps, dry cough. No help with histoplasmosis in patients on amoxicillin x 1 week TNF-α inhibitors ▪ What is your differential diagnosis? Endemic mycoses in the US Winthrop KL. CID. 2008 Case courtesy Dr. Ivan Hung, University of Hong Kong Slide 18 of 36 Slide 17 of 36 17 18 Case 42 y-o Crohn disease fevers, cough, short of breath ▪ 42 year-old male with Crohn What diagnostic tests do you send? disease x 3 years, started on infliximab after persistent A. Chest CT diarrhea 5 months prior B. Chest CT and Sputum AFB x 3 ▪ Admitted with 3 weeks and culture shortness of breath, low grade C. Chest CT, Sputum AFB x 3 and temps, dry cough. No help with culture and Respiratory virus panel amoxicillin x 1 week D. Chest CT, Sputum AFB x 3 and ▪ What diagnostic tests do you culture, Respiratory virus panel and send? Sputum DFA for PCP Slide 19 of 36 Case courtesy Dr. Ivan Hung, University of Hong Kong Slide 20 of 36 Case courtesy Dr. Ivan Hung, University of Hong Kong 19 20 5

10/11/19 Case Case ▪ Sputum AFB negative x 3 ▪ 74 year-old HIV-negative man ▪ Sputum AFB Cx negative with interstitial lung disease and chronic lymphocytic leukemia ▪ Respiratory virus PCR negative on idelalisib ▪ Chest CT: ground glass opacities ▪ BAL DFA+ P. jiroveci ▪ Admitted with progressive ▪ HIV Ab positive shortness of breath on exertion and dry cough for 1 month ▪ Diagnosis: Pneumocystis pneumonia ▪ Treated with clindamycin and ▪ Diagnosis: Pneumocystis primaquine (TMP/SMX allergic) pneumonia ▪ Started ART Case courtesy Dr. Ivan Hung, University of Hong Kong Case courtesy Dr. Jen Mulliken, UCSF Slide 21 of 36 Slide 22 of 36 21 22 Biologics and PCP Case – (not so surprising) follow-up ▪ Retrospective analysis of 2198 patients (across 8 studies) with relapsed CLL or NHL ▪ Patients on idelalisib +/- co- therapy (ritux or ritux/benda) ▪ PCP RR: 12.5 ▪ Median time to PCP: 141 days ▪ No standard PCP prophylaxis guidance Coccidiodomycosis Sehn LH, Blood, 2016 Furman, NEJM, 2014 Slide 24 of 36 Slide 23 of 36 23 24 6

10/11/19 MOA Case ▪ 69 year-old HIV-negative woman with low grade lymphoma, treated only with rituximab (anti-CD20) ▪ Months after treatment, develops slowly progressive mental status changes ▪ CSF PCR positive for JC virus and MRI consistent with PML ▪ Diagnosis: Progressive Multifocal Leukoencephalopathy (PML) Case courtesy Dr. Camille Kotton, MGH/Harvard Slide 25 of 36 Maloney DG, NEJM, May 24, 2012 Slide 26 of 36 25 26 Biologics and viral infections Cancer immunotherapy in the beginning ▪ Hepatitis B reactivation Reactivation with TNF-α inhibitors reported Rituximab – common ▪ JC virus (progressive multifocal leukoencephalopathy) Natalizumab – must check JCV IgG Rituximab – reports, less common ▪ Varicella zoster virus Langer-Gould A. NEJM, 2005 Slide courtesy Dr. Gabe Mannis, UCSF Slide 27 of 36 Slide 28 of 36 27 28 7

10/11/19 How Jimmy Carter beat How Jimmy Carter beat cancer cancer TIME TIME January 20, 2017 January 20, 2017 New immunotherapy drug New immunotherapy drug behind Jimmy Carter’s behind Jimmy Carter’s cancer cure cancer cure The Guardian The Guardian December 6, 2015 December 6, 2015 Slide 29 of 36 Slide 30 of 36 29 30 Checkpoint blockade: a billion dollar industry ▪ Block the inhibitory receptor with monoclonal antibodies (CTLA-4, PD1) ▪ Target the immune system – not the cancer ▪ May lead to autoimmune disease & immune-related adverse events ▪ Infection risk may increase as immune suppression used to Skin and hair depigmentation after treating melanoma treat complications of therapy with anti-CTLA-4 Gandhi L et al, NEJM, April 16, 2018 Del Castillo M et al, CID, 2016 Slide 31 of 36 Slide 32 of 36 31 32 8