ƒ I have no actual or potential conflict of interest in relation to this presentation.

Methee Chayakulkeeree Kamonwan Jutivorakul Porpon Rojanapan

ƒ Immunomodulator: A chemical agent that modifies the ƒ Vast expansion in diversity and number of available immune response or function of the immune system immunomodulatory agents in the last 2 decades (as by stimulation or inhibition) ƒ Rheumatologic diseases ƒ Hematologic malignancies ƒ Neurologic diseases ƒ Association between infections and conventional ƒ Dermatologic diseases immunomodulators or immunosuppressive agents ƒ Gastrointestinal diseases such as steroids and chemotherapeutics is well known ƒ Solid organ transplantation ƒ Characteristics of biologic agents ƒ More targeted in their effect ƒ Impact potential infectious complications ƒ Mechanism of a biologic agent – “KEY” to predict host ƒ Based on case series and case reports susceptibility to infection ƒ Interpret based on overall immunosuppressive state ƒ Eculizumab (C5 complement inhibitor) ƒ Susceptible to meningococcemia Example; ƒ Similar to congenital terminal complement deficiency ƒ Autoimmunue diseases ƒ Indication for biologic agents ƒ Presumed immune dysregulation ƒ Rituximab (anti CD-20) in lymphoma targets tumor cells ƒ Previous treatment or concurrent use of immunosuppressive ƒ Rituximab in rheumatoid arthritis targets B cells ƒ Joint prosthesis

ƒ Dose and duration ƒ Hematologic malignancies ƒ Effects of Rituximab: 6 months ƒ Abnormal immune cells function and number ƒ Effects of Eculizumab: weeks ƒ Other immunosuppressive agents ƒ Central venous catheter

ƒ Monoclonal Antibodies ƒ Biologic Agents ƒ Monoclonal Antibodies ƒ Biologic Agents ƒ TNF-Į inhibitors ƒ TNF-Į inhibitor ƒ TNF-Į inhibitors ƒ TNF-Į inhibitor ƒ Infiximab ƒ Eternacept ƒ Infiximab ƒ Eternacept ƒ Adalimumab ƒ IL-1 inhibitor ƒ Adalimumab ƒ IL-1 inhibitor ƒ Certolizumab pegol ƒ Anakinra ƒ Certolizumab pegol ƒ Anakinra ƒ Golimumab ƒ CTLA-4 fusion protein ƒ Golimumab ƒ CTLA-4 fusion protein ƒ Anti CD-20 Antibodies ƒ Abatacept ƒ Anti CD-20 Antibodies ƒ Abatacept ƒ Rituximab ƒ Belatacept ƒ Rituximab ƒ Belatacept ƒ Ofatumumab ƒ JAK inhibitors ƒ Ofatumumab ƒ JAK inhibitors ƒ Obinutuzumab ƒ Ruxolitinib (JAK 1/2) ƒ Obinutuzumab ƒ Ruxolitinib (JAK 1/2) ƒ Anti CD-52 Antibody ƒ Tofacitinib (JAK 3) ƒ Anti CD-52 Antibody ƒ Tofacitinib (JAK 3) ƒ Alemtuzumab ƒ Tyrosine Kinase Inhibitors (TKI) ƒ Alemtuzumab ƒ Tyrosine Kinase Inhibitors (TKI) ƒ Anti IL Anitbodies ƒ Imatinib, Dasatinib, Nilotinib ƒ Anti IL Anitbodies ƒ Imatinib, Dasatinib, Nilotinib ƒ Ustekinumab (IL12 and IL23) ƒ Sorafenib, Sunitinib, Pazopanib ƒ Ustekinumab (IL12 and IL23) ƒ Sorafenib, Sunitinib, Pazopanib ƒ Tocilizumab (IL6) ƒ Proteosome inhibitors ƒ Tocilizumab (IL6) ƒ Proteosome inhibitors ƒ Complement Inhibitor ƒ Bortezomib ƒ Complement Inhibitor ƒ Bortezomib ƒ Eculizumab ƒ Carfilzomib ƒ Eculizumab ƒ Carfilzomib

ƒ Immune Activating Agents ƒ Immune Activating Agents ƒ Ipilimumab (CTLA-4 inhibitor) ƒ Ipilimumab (CTLA-4 inhibitor) ƒ Pembrolizumab (PD-1 inhibitors) ƒ Pembrolizumab (PD-1 inhibitors) ƒ Rituximab, Ofatumumab, Obinutuzumab ƒ A 59-year-old male ƒ Monoclonal antibodies to CD-20, a B lymphocyte marker ƒ Diagnosed diffused large B cell lymphoma (19 June 2014) presented with tonsil enlargement and cervical lymphadenopathy ƒ Practical impact ƒ Profoundly impaired vaccine response to new and recall antigens ƒ Lymph node biopsy showed positive CD-20 ƒ Rituximab linked to hypogammaglobulinemia (esp. repeated doses ƒ Received R-CHOP 6 cycles (21 Aug 2014 - 16 Dec 2014) over months or years) ƒ Associate with hepatitis B virus reactivation (black box warning on all ƒ HBsAg-negative, antiHCV-negative agents!) ƒ June 2015 (10 months after CMT) ƒ Fever with malaise and jaundice ƒ TB 12.8 mg/dL, DB 9.4 mg/dL, AST 874 U/L, ALT 1491 U/L

Van der Kolk LE, et al. Blood 2002;100:2257-9, Ljungman P., et al. Br J Haematol 2005; 103: 96-8, Casulo C., et al. Clin Lymphom Myeloma Leuk 2013;13:106-11, Makatsori M., et al. QJM 2014;107: 821-8

Exposure Reactivated HBV infection - Perinatal Resolved HBV infection -HBsAg+ -Percutaneous -HBsAg+ Æ antiHBsAb+ -(antiHBeAb+ Æ HBeAg+) ƒ At admission -sexual -antiHBcAb+ -HBV DNA high ƒ TB 30.2 mg/dL, DB 25.5 mg/dL, AST 1462 U/L, ALT 1982 U/L -HBV DNA- -Abnormal LFTs ƒ HBsAg positive, antiHBsAb negative Anti CD-20 ƒ AntiHBcAb positive, antiHBcAb IgM-negative

ƒ antiHAV IgG positive, antiHAV IgM negative Acute HBV infection ƒ antiHCV negative -HBsAg+ -HBV DNA+ Inactive carrier ƒ HBV viral load 26,374 IU/mL -HBsAg+ -(HBeAg+ Æ antiHBeAb+) ƒ Treatment - HBV DNA low or -

ƒ Entecavir (0.5) 1 tab OD Chronic HBV infection ƒ Supportive treatment: ursolin, NAC - HBsAg+ > 6 months -antiHBcAb+ ƒ Candidate for orthotropic liver transplantation -HBV DNA+

Chronic active infection -HBsAg+ -HBV DNA+ s c

ƒ Rise in HBV DNA +/- abnormal liver test ƒ Loss of anti-HBsAb and reappearance of HBsAg ƒ Can progress to fulminant hepatic failure and death ƒ Detectable HBV DNA

ƒ Higher risk in inactive carrier > patients with resolved HBV ƒ Pattern ƒ In non-Hodgkin’s lymphoma with HBsAg+ carriers ƒ HBV DNA detectable weeks to months before reverse ƒ RCHOP: 80% reactivation seroconversion or clinical hepatitis ƒ CHOP: 55% reactivation ƒ Potential window for intervention – DNA monitoring ƒ Some patients with detectable DNA Æ spontaneously clear ƒ EARLY reactivation in HBV carriers without antiviral prophylaxis (can occur within days)

Kusumoto S., et al. CID 2015; 61:719-29, Huang Y-H., et al. JCO 013; 31: 2765-72, Hsiao L-T., et al. Medicine 2015; 94:e1321, Yeo W., et al. JCO 2009; 27:605-11, Niitsu N., et al. JCO 2010;28:5097-100 Pei s., et al. Ann Hematol 2010; 89:255-62

c

ƒ Lymphoma ƒ ALL received anti CD-20; SCREEN for HBV ƒ 24% reactivation with RCHOP ƒ Also TNF-Į inhibitors, abatacept, high dose steroid, etc… ƒ 8-12% if using detectable DNA as a criteria for reactivation ƒ If HBsAg+ Æ antiviral prophylaxis ƒ 0% reactivation with CHOP ƒ Most data on “lamivudine” ƒ Other drug are emerging; TDF ƒ Reactivation occurs later than inactive carrier ƒ 2-6 cycles of R-containing regimens and up to 12 months later ƒ Management for anti-HBcAb+ : varies ƒ Guidelines recommend antiviral prophylaxis ƒ Risk factors ƒ Recent studies showed excellent outcomes with careful monthly ƒ HBsAb < 10 IU/L monitoring of HBV DNA for up to 1 year after receiving anti CD-20 ƒ HBV DNA detected at baseline therapy ƒ More than 6 cycles of Rituximab

Kusumoto S., et al. CID 2015; 61:719-29, Huang Y-H., et al. JCO 013; 31: 2765-72, Kusumoto S., et al. CID 2015; 61:719-29, Hwang JP., et al. JCO 2015; 33:2212-20 Hsiao L-T., et al. Medicine 2015; 94:e1321, Yeo W., et al. JCO 2009; 27:605-11, Niitsu N., et al. JCO 2010;28:5097-100, Reddy KR., et al. Gastroenterol 2015; 148:215-9 Niitsu N., et al. JCO 2010;28:5097-100 ƒ A study in RA: 29,129 biologic agent treatment ƒ Increased incidence of PML in rheumatologic patients episodes ƒ Association: efalizumab, adalimumab, natalizumab, ƒ Received HZ vaccine 0.4% in 2007 to 4.1% in 2011 fludarabine, rituximab, mycophenolate, steroids, MTX ƒ 423 HZ episodes ƒ Rates per 100,000 discharge: ƒ Certolizumab 2.45 per 100 PYs (anti-TNF) ƒ SLE 4, RA 0.4, others CTD 2 (average 1 in 100,000) ƒ Rituximab 2.27 per 100 PYs ƒ 0.2% with natalizumab for multiple sclerosis or Crohn’s ƒ Golimumab 1.61 per 100 PYs (anti-TNF) ƒ 1 in 500 with efalizumab for psoriasis ƒ 57 reported cases after rituximab

Yun H. et al. Arthritis Care & Research 2015 Molly and Calabrese, Arthritis Rheumatism 2009;60:3761-5

ƒ Alemtuzumab ƒ Chronic lymphocytic leukemia ƒ 43% infection ƒ Monoclonal antibodies to CD-52, a marker on B, T and NK lymphocytes ƒ Most common – CMV reactivation/CMV diseases ƒ Others – Adenovirus, PML, VZV, fungal infection, toxoplasmosis ƒ Use in lymphoproliferative disorders and solid organ transplant ƒ Practical impact ƒ Hematopoietic Stem cell Transplant ƒ Depletion of all lymphocyte cell lines (esp. CD4+-T lymphocytes) ƒ CMV reactivation 66.7% (37% in non-alemtuzumab) ƒ Vulnerable to broad range of infections ƒ Opportunistic infections 44.4% (29.6% in non-alemtuzumab) ƒ When use in hematologic diseases Æ CMV reactivation ƒ Solid organ transplantation Æ fungal diseases

Stanley IM., et al. CID 2006:43 Infection rate in kidney transplant recipients Bacteremia 69/449 episodes(15%) ƒ Alemtuzumab – 33% Organism Percent ƒ Basiliximab (anti-CD25) – 40% S. aureus 18 ƒ Antithymocyte globulin – 36% CoNS 12 Fungal infection (most common – candidiasis) E. faecium 9.5 ƒ Alemtuzumab – 10% ƒ Basiliximab – 9% E. faecalis 7.5 P. a e r u g in o s a 8.5 Disseminated fungal infection K. pneumoniae 10 ƒ Alemtuzumab – 68%* ƒ Basiliximab – 30% E. coli 6 E. cloacae 3.5 Pancreas transplant – 6.6% (cryptococcosis, histoplasmosis, aspergillosis and candidiasis) S. marcescen 2 others 27

Safdar N., et al. Diagn Micro Infect Dis 2010:66, Nath DS, et al. Transplant Proceedings 2005; 37 Silveira FP, et al. J Infection 2006; 53

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