2018 BMT Pharmacists Conference

Infection Prophylaxis in the HCT patient

Melissa D. Johnson, PharmD, AAHIVP Associate Professor of Medicine Duke University Medical Center Liaison Clinical Pharmacist Duke Antimicrobial Stewardship Outreach Network Durham, North Carolina [email protected] @idpharmacist Disclosures

• Research grants: Merck, Charles River Laboratories Objectives

• Assess the factors influencing risk of infection in hematopoietic cell transplant recipients • Compare and contrast current, recently approved and emerging antimicrobials for prophylaxis in hematopoietic cell transplant recipients • Discuss recent studies evaluating antimicrobials for prophylaxis in hematopoietic cell transplant recipients • Identify important monitoring parameters and supportive strategies for prophylaxis in hematopoietic cell transplant recipients Hematopoietic Cell Transplantation Transplant Variables and Infection Risk

• Underlying disease Pre-Tx Stem cells • Type of transplant Therapy +/- GVHD Autologous, Allogeneic • HLA matching Conditioning • Conditioning regimen Engraftment • Source of stem cells • Graft manipulation • Graft versus host disease • Donor & recipient age Bacterial

Viruses Fungal

INFECTIOUS PATHOGENS

Respiratory Pneumocystis Viruses

Other Case Question 1

• 37-year-old male with AML Initial presentation: • 45,000 WBC, normal cytogenetics, FLT3/ITD genes (+), NPM1 (-) Treatment plan: Standard induction followed by allogeneic hematopoietic peripheral blood stem-cell transplant

• Which of the following pathogens is he at greatest risk of infection from during the post-transplant, pre-engraftment period? a. Mucorales spp. b. Pneumocystis jirovecii c. E. coli d. Varicella zoster virus Allogeneic HCT

Pre Post Late Phase Engraftment Engraftment

PERIODS OF RISK

Bacterial

Viral

Fungal

Figure adapted from: Tomblyn M. et al. Biol Blood Marrow Transplant. 2009;15(10):1143–1238. Risks for bacterial infection in HCT

• Pre-engraftment & early post-engraftment Neutropenia Gram Positive Mucosal breakdown Gram Negative

Indwelling CVCs Bloodstream, Lungs, GI tract

• Late phase GVHD Hypoglobulinemia Encapsulated bacteria CVCs Bacterial Percent of HCT Recipients Experiencing Infection 6 collaborating transplant centers Infections 2006-2011 in HCT 0 10 20 30 40 50 60

BSI

444 HCT patients C. diff Matched, unrelated 55% Matched, related 40% Mismatched 6% Pneumonia Peripheral blood cells 87% BMT 12% UCT 1% T cell depleted <1% UTI Myeloablative 72% Sinusitis

93% of patients experienced an infection

Schuster MG et al. Open Forum Infect Dis 2017;4:1-7. 231 Bacteremias in HCT Recipients in 6 collaborating transplant centers Bacterial 2006-2011 Infections 55% 21% in HCT Gram Positive Gram Negative 140

120

100 444 HCT patients Matched, unrelated 55% 80 Matched, related 40% Mismatched 6% 60 Peripheral blood cells 87% BMT 12% 40 UCT 1%

T cell depleted <1% Episodes of Number 20 Myeloablative 72%

0

VRE CoNS MSSA MRSA E. coli other GP E faecium E faecalis beta strep C. freundiiE. cloacae B. cepaciaOther GN A. baumanii P. aeruginosaK. pneumoniaS. maltophilia Polymicrobial

Schuster MG et al. Open Forum Infect Dis 2017;4:1-7. 231 Bacteremias in HCT Recipients in 6 collaborating transplant centers Bacterial 2006-2011 Infections 55% 21% in HCT Gram Positive Gram Negative 140

120 Mortality within 7 days of bacteremia: 100 444 HCT patients 13% vs 45% (p=0.02) Matched, unrelated 55% 80 Matched, related 40% Mismatched 6% 60 Peripheral blood cells 87% BMT 12% 40 UCT 1%

T cell depleted <1% Episodes of Number 20 Myeloablative 72%

0

VRE CoNS MSSA MRSA E. coli other GP E faecium E faecalis beta strep C. freundiiE. cloacae B. cepaciaOther GN A. baumanii P. aeruginosaK. pneumoniaS. maltophilia Polymicrobial

Schuster MG et al. Open Forum Infect Dis 2017;4:1-7. Bacterial 146 Bacterial Infection Episodes in 104 haplo-HCT with post-transplant Cyclophosphamide & PBSC Infections June 2009-June 2015 in HCT 43% 39% Gram Positive Gram Negative

40 104 T-cell replete 35 haploidentical peripheral 30 blood HCT 25 Myeloablative 41% Nonmyeloablative 59% 20 15 No FQ prophylaxis used 10 5 0

62% of patients VRE MRSA CoNS Strep C. diff experienced a bacterial GP Rod S. aureus infection Enterococcus P.aeruginosa S. maltophilia S. pneumoniae Anaerobic GNR C. diff: 13% Enterbacteriaceae

Slade M et al. Transpl Infect Dis 2017; 19:e12629. Pros/Cons of Prophylaxis

Pros Cons • Reduction of infection • C. difficile infection Fewer documented • Change in microbiota, yeast infections overgrowth Fewer bacteremias • Antibiotic exposure à development of resistant • Reduction of fever pathogens • Mortality benefit Up to 30% multi-drug All-cause & infection- resistant isolates in those receiving fluoroquinolone related prophylaxis

Febrile episode NNT= 5 (leukemia/HCT) • Side effects Bacterial infection NNT= 6 (leukemia/HCT) • Drug interactions Mortality NNT=43 (leukemia/HCT)

Leibovici L et al. Cancer 2006. 107(8): 1743-1751. Ideal Bacterial Prophylaxis in HCT

• Broad spectrum of activity Includes P. aeruginosa, Enterobacteriaceae Low propensity to induce resistance • Good safety profile • Available IV/PO • Few drug interactions Prophylaxis: Bacterial Pathogens

• Fluoroquinolones high-risk, expected durations of Example Protocol for Bacterial Prophylaxis* prolonged and profound neutropenia Type Recommendation Auto Ciprofloxacin 500 mg PO BID with conditioning through 3 (ANC ≤100 cells/mm for >7 days) duration of neutropenia or until IV antibiotics started for febrile neutropenia; start on first day of conditioning • B-I recommendation from IDSA, 2-A regimen NMA Allo Ciprofloxacin 500 mg PO BID with conditioning through recommendation from NCCN duration of neutropenia or until IV antibiotics started for febrile neutropenia; start on first day of conditioning Intermediate risk: autologous HCT regimen; continue/resume until 6 months post-transplant MA Allo Ciprofloxacin 500 mg PO BID with conditioning through (matched duration of neutropenia or until IV antibiotics started for sibling and febrile neutropenia; start on first day of conditioning MUD) regimen Bulk of data with levofloxacin and MA Cord Ciprofloxacin 500 mg PO BID with conditioning through duration of neutropenia or until IV antibiotics started for ciprofloxacin febrile neutropenia; start on first day of conditioning regimen; continue/resume until 6 months post-transplant GVHD Penicillin VK 500 mg PO BID (if chronic GVHD on any immunosuppression) for coverage against Streptococcus Timing of discontinuation not pneumoniae systematically studied

Freifeld AG et al. Clin Inf Dis 2011;52:e56-e93; NCCN Practice Guidelines in Oncology v.1.2018. *Duke University Medical Center, Adult Stem Cell Transplantation Infection Prophylaxis Case Question 2

• 37-year-old male with AML Initial presentation: • 45,000 WBC, normal cytogenetics, FLT3/ITD genes (+), NPM1 (-) Treatment plan: Standard induction followed by allogeneic hematopoietic peripheral blood stem-cell transplant

• Which of the following agents has the most data to support its use as bacterial prophylaxis during the pre- engraftment period for allogeneic HCT? a. Cefiderocol b. Amoxicillin/clavulanate c. Penicillin d. Ciprofloxacin Newer antibiotics in development Phase III/recently approved

Activity vs Resistant Pathogens Novel Features Name Route(s) CRAB CRPA CRE OPP Class Target Mechanism No X-R Meropenem + IV + - - +/- vaborbactam Delafloxacin IV + PO - - - - Cefiderocol IV - - - +/- Eravacycline IV + PO - - - - Imipenem - IV - - - - relebactam Omadacycline IV + PO - - - - Plazomicin IV - - - - Aztreonam- IV - - - - Avibactam Finafloxacin IV - - - - Murepavidin IV + + + + CRAB= Carbapanem Resistant Acinetobacter baumanii CRPA= Carbapenem Resistant Pseudomonas aeruginosa CRE= Carbapenem Resistant Enterobacter spp. OPP= Other important pathogen Adapted from: World Health Organization; 2017 (WHO/EMP/IAU/2017.11). Licence: CC BY-NC-SA 3.0 IGO X-R= Cross resistance Fungal Infections 100 in HCT 90 80 70 60 50 40 30 20 10 0 Medicine Heme-Malig HCT SOT Solid Tumor HIV Surgery Invasive Candidiasis Invasive Aspergillosis Mucormycosis Cryptococcosis

Azie et al. Diag Micro Infect Dis. 2012;73:293-300 Proven/Probable Invasive Fungal Infections in HCT (N=444)

Type of Infection Site of Infection 20 30 18 16 25 14 20 12 10 15 8 6 10 4 5 2 0

Number of infections of Number 0

CNS Mixed Candida Sinusitis Exophiala Aspergillus Mucorales Alternaria Pneumonia Bloodstream Disseminated

Pneumocystis jiroveci

Schuster MG et al. Open Forum Infect Dis 2017;4:1-7. Fungal Infections in HCT Timeline

Early IFI Late IFI Very Late IFI

Fusarium Mucormycosis Aspergillus Candida

0 60 120 180 240 300 360

Days following transplantation

Horan J., Perfect J and Alexander B. Invasive Fungal Disease in the Transplant Population: Overview. In: Principles and Practices of Transplant Infectious Diseases. Eds: Safdar A. Risks for IFI in HCT : Pre-Engraftment

Risk Factor Details Transplant Related Donor HLA similarity Autologous < Allogeneic (MRD < MMRD/URD) Stem cell source Peripheral blood < bone marrow < cord blood; increased risk with T-cell depleted and CD34 selected cells Conditioning regimen NMA < MA in early infections, NMA ≥ MA in late infections Post-Transplant Related Neutropenia Especially in early risk period Viral illness CMV (most commonly associated), RSV, parainfluenza, +/- influenza

GVHD Both acute (particularly grade III-IV) and chronic GVHD

Horan J, Perfect J and Alexander B. Invasive Fungal Disease in the Transplant Population: Overview. In: Principles and Practices of Transplant Infectious Diseases. Eds: Safdar A. Duration of Neutropenia in Allo HCT

Myeloablative Myeloablative Cord blood Myeloablative Bone marrow Peripheral blood Non-myeloablative Non- Myelotoxic myeloablative Non-myelotoxic

Duration of neutropenia

Duration of neutropenia is a MAJOR driver of the risk for invasive mold disease

Martino R et al. Blood. 2006;108:2928-2936. Risks for IFI in HCT : Pre-Engraftment

History of invasive mold Risk Factor Details disease Antifungal Transplant Related Prophylaxis Donor HLA similarity Autologous < Allogeneic (MRD < MMRD/URD) Stem cell source Peripheral blood < bone marrow < cord blood; increased risk with T-cell Environmental depleted and CD34 selected cells Conditioningexposure regimen NMA < MA in early infections, NMA ≥ MA in late infections Post-Transplant Related Neutropenia LocalEspecially in early risk period Viral illness CMV (mostEpidemiology commonly associated), RSV, parainfluenza, +/- influenza GVHD GVHD Both acute (particularly grade III-IV) and chronicProphylaxis GVHD Comorbidities

Horan J, Perfect J and Alexander B. Invasive Fungal Disease in the Transplant Population: Overview. In: Principles and Practices of Transplant Infectious Diseases. Eds: Safdar A. Timeline and Risk Factors for Invasive Fungal Infection in Allo-HCT

T-CELL DEPLETION CMV REACTIVATION

EXPOSURE EXPOSURE

MUCOSITIS GVHD

NEUTROPENIA NEUTROPENIA

Pre-engraftment Post-engraftment

Atalla A et al. Transpl Infect Dis. 2015;17:7-13. Systemic Antifungal Agent Pipeline

Isavuconazole

Posaconazole IV Posaconazole Posaconazole Anidulafungin DR

Voriconazole Micafungin ABLC Caspofungin Itraconazole Terbinafine L-AmB

5FC Amphotericin B Fluconazole

1950 1960 1970 1980 1990 2000 2010 2020 Systemic Antifungal Agent Pipeline

MAT2203

CD101 SCY078 F-901318 MGCD290 Isavuconazole VT1129 VT1161 Posaconazole IV Posaconazole Posaconazole Anidulafungin DR

Voriconazole Micafungin ABLC Caspofungin Itraconazole Terbinafine L-AmB

5FC Amphotericin B Fluconazole

1950 1960 1970 1980 1990 2000 2010 2020 Case Question 3

• 37-year-old male with AML Initial presentation: • 45,000 WBC, normal cytogenetics, FLT3/ITD genes (+), NPM1 (-) Treatment plan: following standard induction, is now ready for allogeneic hematopoietic peripheral blood stem-cell transplant

• Which of the following agents has been evaluated in randomized clinical trials as antifungal prophylaxis in HCT? a. Itraconazole b. Micafungin c. Isavuconazole d. Caspofungin Comparative Clinical Trials: FDA Indications

AmB/ Infection LFAB Anid Cas Mica Flu Itra Vori Posa Isa Invasive ü ü ü ü ü ü Candidiasis

Aspergillosis ü salvage salvage ü ü

Mucormycosis* ü ü

Prophylaxis ü ü ü ü ü ü

Neutropenic ü ü ü ü Fever

Green=FDA indication Black= clinical trials * No randomized, comparative clinical trials http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ Wingard JR et al. Blood. 2010 Dec 9;116(24):5111-8. Winston DJ et al. Am J Med. 2000;108(4):282-9. Boogaerts M et al. Ann Intern Med. 2001 Sep 18;135(6):412-22. Micafungin vs Fluconazole Prophylaxis in Allo-HCT

• Mica (50 mg/d) vs Fluconazole (400 mg/d) until engraftment

Micafungin Fluconazole p n=425 n=457 Aspergillosis 0.2% 1.5% 0.07 Candidiasis 0.9% 0.4% 0.44 Total Invasive fungal diseases 12% 2% 0.35 Empiric antifungal therapy 15% 21% 0.02

Van Burik JA et al. Clin Infect Dis. 2004;39:1407-1416. Voriconazole vs Fluconazole Prophylaxis in Allo-HCT

•Open label, fluconazole (n=295) vs voriconazole (n=305) •Prophylaxis from conditioning to D+100 or beyond •Composite endpoint: tolerate drug for ≥100 d and survived without invasive fungal disease (IFD) until D+180

Proven / probable IFD Vori n=305 Fluco n=295 p Study period(180 days) Total 7.3% 11.2% 0.12 Aspergillosis 2.9% 5.7% 0.09

* screening: galactomannan 2x/w for 60 days (and 1x/w until D+100 or 2x/w if GVHD)

Wingard JR et al. Blood. 2010;116:5111-5118. Posaconazole vs fluconazole in GVHD

• March 1999-Feb 2003 IFIs During the Fixed Treatment • Acute GVHD (II-IV), chronic GVHD or Period corticosteroidsProven (≥ or 1 Probable mg/kg/day IFIs acute, ≥ 10 0.8 mg/kg/day chronic), ATG, or ≥ 2 9 immunosuppressive treatments 8 • Posaconazole suspension 200 mg TID 7 or fluconazole 400 mg daily 6 5 • Up to 112 days 4 Percent 3 Time to IFI longer & deaths due to 2 IFI lower for posaconazole 1 (p= 0.048 & 0.046) 0 posaconazole fluconazole

OR 0.56 (0.30-1.07)

Ullmann AJ, et al. N Engl J Med 2007; 356: 335-347. Challenges with fungal prophylaxis in HCT

• Drug-drug interactions • Variable pharmacokinetics • Drug penetration • Poor absorption • Diagnostic difficulty Mixed infection Immune reconstitution • Development of resistance • Toxicities Cytochrome P450 & PgP Effects With Azoles

Site Fluconazole Itraconazole Voriconazole Posaconazole Isavuconazole CYP3A4 Inhibitor ++ +++ ++ - +++ ++ ++ Substrate 0 +++ + 0 +++ CYP2C8/9 Inhibitor ++ + ++ 0 0 Substrate 0 0 + 0 0 CYP2C19 Inhibitor + 0 ++ 0 0 Substrate + 0 +++ 0 0 PgP Substrate + ++ 0 ++ 0 Inhibitor 0 ++ 0 ++ +

Chau MM et al. Intern Med J. 2014;44:1364-1388. Dodds Ashley ES et al. Clin Infect Dis. 2006;43:S28-S39. Cresemba Prescribing Information. Northbrook, IL: Astellas Pharma US; 2015. Effects of Newer Azoles on Immunosuppressants

CYP3A4 Voriconazole Posaconazole Isavuconazole substrate (tablet) (oral suspension) (capsule) Midazolam ­ 10 ­ 5 ­ 2 (3A4 Probe) Cyclosporine ­ 1.7 ­ 1.7 ­ 1.3 Sirolimus ­ 11 ­ 9 ­ 2 Tacrolimus ­ 3 ­ 4.6 ­ 2.3

Townsend R et al. 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Copenhagen, Denmark; 25–28 April, 2015. P0216. New interactions… new headaches?

• Midostaurin 3A4 inhibitors may increase midostaurin levels • Ketoconazole (400 mg QD x 10 days): increased AUC 10x • Itraconazole (100 mg BID, days 22-28): increased day 28 trough by 2x Midostaurin inhibits CYP 2C19, 2D6, 2C9, 1A2, 2C8, 2E1 and induces CYP 3A, 2C19, 2C9, 1A2, 2B6, 2C8

Novartis Pharmaceuticals Corp. Rydapt Package insert. 2017. Bloodstream Concentrations of Azoles in Samples Sent for TDM UTHSC Reference Laboratory Jan 2001-April 2013

With Permission, Wiederhold NP et al. Antimicrob Agents Chemother. 2014;58:424-431. TDM: When and What Target?

Goal trough Time to Goal trough Antifungal concentration steady- First Trough Level concentration When To Recheck Level Drug for state for treatment prophylaxis* During second week of therapy to reconfirm

4 – 7 Day 2-5 At 3-5 days if change in dose Voriconazole 1-2 >2 to ≤ 4-6 days (or after 5th dose) IV to PO switch Change in clinical condition New interacting drugs started/stopped 4 – 7 If pre-dose trough is low, change Posaconazole Day 7-8 0.7 ≥ 1 formulation/dose & recheck 5-7 days days later Change in oral absorption ~ 7 Itraconazole Day 5-7 ≥ 0.5 and ≤ 4 1 – 2 Change in dose days New interacting drugs Change in clinical condition

**by HPLC

Triazole TDM. ECIL6 meeting, Sept 2015. https://www.ebmt.org/Contents/Resources/Library/ECIL/Documents/2015%20ECIL6/ECIL6-Triazole-TDM-07-12-2015- Lewis-R-et-al.pdf Ashbee HR et al. J Antimicrob Chemother. 2014 May;69(5):1162-76. doi: 10.1093/jac/dkt508 Real World Experience: Posaconazole Tablets

• 157 patients, prophylaxis Hematologic malignancies & allo HCT with GVHD • Posaconazole DR tablets • Subtherapeutic trough concentrations: 18% (n=28) • Risk factors:

N (%) p value Diarrhea 24 (83%) <0.001 Proton pump inhibitor 27 (93%) 0.016 Weight >90 kg 14 (48%) 0.047

Tang LA et al. J Antimicrob Chemother 2017. 72(10): 2902-2905 Fungal Infections in HCT: Example Protocol*

Risk Group Fungal Prophylactic Regimen

Autologous Fluconazole 400mg QD through engraftment

Non-myeloablative allo MRD, MMRD, MUD and Voriconazole 200mg BID through day +100 UCT Myeloablative allo Voriconazole 400mg QD through day +100 MRD, MMRD, URD

Myeloablative allo - UCT Voriconazole 200mg BID through day +100

Posaconazole 200mg TID (alt: voriconazole + inhaled Graft-versus-host disease ABLC) MMRD – mismatched related donor, MRD – matched related donor, MUD – matched unrelated donor, UCT – umbilical cord transplant

*Duke University Medical Center, Adult Stem Cell Transplantation Infection Prophylaxis Guidelines Systemic Antifungal Agent Pipeline

MAT2203

CD101 SCY078 F-901318 MGCD290 Isavuconazole VT1129 VT1161 Posaconazole IV Posaconazole Posaconazole Anidulafungin DR

Voriconazole Micafungin ABLC Caspofungin Itraconazole Terbinafine L-AmB

5FC Amphotericin B Fluconazole

1950 1960 1970 1980 1990 2000 2010 2020 Pneumocystis • Allogeneic HCT risk 5-15% with median onset day jirovecii +90 (prior to routine prophylaxis) in HCT • Shift with prophylaxis to late complication • Risks include steroid receipt, T-cell depletion • Reactivation >> new infection • Tropism for lungs, rare disseminated infection • Retrospective evaluation at DUMC database query for all positive pneumocystis PCR results from 1/2011 to 10/2013 5 cases (2 auto/3 allo) Allo HCT cases either on suboptimal or no prophylaxis, NMA conditioning regimens inclusive of alemtuzumab, onset day + 195-432

DeCastro N et al. BMT 2005;36:879-883. Cordonnier C et al. J Antimicrob Chemother 2016. 71(9): 2379-2385. PCP Prophylaxis options

Agent Comments Usual Dose & AEs Toxo activity? Cost Route Trimethoprim- Drug of choice SS QD* or DS PO Skin rash Yes low sulfamethoxazole 85% reduction in PCP TIW or QD* Leukopenia (RR 0.15, 95% CI: 0.04-0.62) Hyperkalemia NNT: 19 (95% CI 17-42) Hypersensitivity Dapsone Avoid if G6PD deficient 100 mg PO QD Hemolysis Only if given with low Methemoglobinemia pyrimethamine Hypersensitivity Atovaquone 1 study (autologous HCT) 1500 mg PO QD GI unclear high similar outcomes Pentamidine Rate of PCP higher than 300 mg inhaled Bronchospasm, cough, no low TMP/SMX (9.1% vs 0%) monthly nausea IV has been studied in children

*Daily dosing preferred to prevent Toxoplasma gondii

Maertens J et al. J Antimicrob Chemother 2016. 71(9): 2397-2404. Stern, A. Cochrane Database of Systematic Reviews. Oct 2014. DOI: 10.1002/14651858.CD005590.pub3 Colby C, et al. Bone Marrow Transplantation 1999;24(8):897-902. Example protocol: PCP prophylaxis in HCT

• Autologous: not routine • Allogeneic Septra DS 1 tablet PO BID during conditioning (through Day -2) and resumes after engraftment or Day +30 (whichever comes first) at 1 SS tablet PO daily or other standard regimen for at least 6 months (longer if on immunosuppression) Alternatives: dapsone 100mg/day, atovaquone 1500mg/day, inhaled pentamidine

*Duke University Medical Center, Adult Stem Cell Transplantation Infection Prophylaxis Guidelines Viral Infections in HCT

Pre Post Late Phase Engraftment Engraftment

HSV CMV

Respiratory & Enteric Viruses VZV Other viruses ~HHV-6

EBV PTLD

Figure adapted from: Tomblyn M. et al. Biol Blood Marrow Transplant. 2009;15(10):1143–1238. Other viruses in HCT

Risk Factors Comments Antivirals with activity HHV-6 UCT, T-cell depletion Viremia common post- Ganciclovir Myeloablative conditioning allo HCT (~40-60%) Foscarnet Unrelated or HLA-mismatched +/- cidofovir donors Adenovirus T-cell depleted grafts Often asymptomatic Cidofovir HLA mismatch Reduce Under study: GVHD (Grade III-IV, steroid therapy) immunosuppression brincidofovir

RSV Lymphopenia Seasonal, incubation 4-6 Ribavirin (+/- IVIG) GVHD days Myeloablative conditioning Unrelated or HLA-mismatched donors BK virus Myeloablative conditioning Viruria common cidofovir BK viremia/viruria Viremia ~33% of MA-HCT Possibly: brindcidofovir Unrelated donor recipients, median 41 days; hemmorhagic cystitis 14%

DeVincenzo JP. N Engl J Med. 2014;371(8):711-22. Olson AL et al. Biol Blood Marrow Transplant 2014;20:787-93. Shah JN. Blood. 2011 Mar 10;117(10):2755- 63. Satyanarayana G, et al. Transpl Infect Dis. 2014 Aug; 16(4): 521–531. Viral HSV • Risk early post-transplant Infections • Clinical presentation in HCT • Mucositis /esophagitis most common • Visceral, neurologic and ocular less common • Emergence of Resistance (3.5-10%)

VZV • Risk late post-transplant • Clinical presentation • Cutaneous most common • Visceral, neurologic and ocular less common • Rare resistance • Consider prophylaxis for at least 6-12 months after autologous HCT, 1 yr after allogeneic HCT Viral Prophylaxis in HCT

During neutropenia and longer depending on risk

Example Protocol for HSV/VZV Prophylaxis in HCT* Type Recommendation Autologous HCT Acyclovir 400 mg PO BID with conditioning through duration of neutropenia (Day +30) if HSV+ or VZV+; Acyclovir 800 mg PO BID Day +30 through +365 if VZV+ Allogeneic HCT Acyclovir 400 mg PO BID with conditioning through duration of neutropenia (Day +30) if HSV+ or VZV+ Acyclovir 800 mg PO BID Day +30 through +365 if VZV+ (or until 6 months after immunosuppression is discontinued)

NCCN Practice Guidelines in Oncology v.1.2018. *Duke University Medical Center, Adult Stem Cell Transplantation Infection Prophylaxis Guidelines CMV • Infection vs. disease • Primary infection (R-) vs reactivation (R+) Viral • Overall risk: R(+) > R(-) • Seropositive recipients Infections • ~80% reactivation in allo HCT without prophylaxis in HCT • Possible benefit of D+/R+ • Seronegative recipients • D-/R-: lowest overall risk • D+/R-: >30-40% develop primary CMV infection • Low risk of disease with pre-emptive therapy • Mortality due to bacterial and fungal infections higher in D+/R- • Possible indirect immunomodulating effects of primary CMV • Other risks: transplant type (auto/allo), donor type, stem cell source, conditioning regimen, GVHD • Allogeneic >>> autologous • Specific high risk seropositive autologous HCT recipients • TBI, CD-34 selected graft, recent alemtuzumab or fludarabine

Nichols et al. JID 2002;185:273-282. ; Boeckh M et al. Blood 2004;103:2003-8.; Boeckh M et al. J Clin Invest 2011;121:1673-80. Overview of Antiviral Agents with CMV activity

Mechanism Features Side Effects Resistance Mutations Ganciclovir Nucleoside analog IV & PO Myelosuppression, renal UL97 Poor bioavailability toxicity UL54 Valgancyclovir L-valyl ester of ganciclovir PO Myelosuppression, renal UL97 toxicity UL54 Foscarnet Pyrophosphate analog; IV Renal impairment, UL54 inhibits viral DNA Penetrates CSF headache, seizures, less polymerase marrow toxicity Cidofovir Nucleotide analog IV Renal toxicity (AN, ARF), UL54 anemia, rash, headache, GI Letermovir Interferes with viral pUL56 IV & PO; IV in GI (dose-limiting), UL56 gene product hydroxypropyl-b- peripheral edema, cough cyclodextrin Maribavir Benzimidazole nucleoside; PO Taste disturbance, skin rash UL97 Competitive inhibitor of (upstream) pUL97 protein Brindcidofovir Lipid antiviral conjugate IV & PO Abdominal pain, aphthous UL54 linked to cidofovir stomatitis CMV Monitoring/Prophylaxis in HCT

• Universal prophylaxis vs pre-emptive monitoring

Example Protocol for CMV Monitoring in HCT* Autologous No routine monitoring Allogeneic Pre-emptive monitoring • Weekly CMV PCR from week 1 post-transplant thru at least day +100 or discharge home • Continued monitoring indefinitely if ongoing immunosuppression, cGVHD

*Duke University Medical Center, Adult Stem Cell Transplantation Infection Prophylaxis Guidelines CMV Prophylaxis with Letermovir

• Allogeneic HCT, CMV +, undetectable CMV DNA, initiated within 28 days after HCT • Letermovir (480 mg daily) vs. placebo, 2:1 through week 14 (~100 days) Letermovir 240 mg daily if receiving cyclosporine A Oral or IV (In hydroxypropyl-b-cyclodextrin) • Primary Endpoint: clinically significant CMV infection through Week 24 • Preemptive therapy triggers: Through week 14 After week 14 High risk: CMV >150 copies/mL CMV > 300 copies/mL Low risk: CMV > 300 copies/mL

Marty FM, Ljungman P, Chemaly RF, et al. N Engl J Med 2017;377:2433-44. Outcomes at 14 Weeks

60

50

40 of of Patients 30

20

Proportion 10

0 Overall Clin Sig Infection Preemptive Therapy CMV disease Letermovir Placebo Difference: -31.3% (-39.9 to -22.6) p<0.001

Marty FM, Ljungman P, Chemaly RF, et al. N Engl J Med 2017;377:2433-44. Outcomes at 24 Weeks

All cause mortality: Letermovir 10.2% vs 15.9% p=0.03

70

60

50 of of Patients 40

30

20

Proportion 10

0 Overall Clin Sig Infection Preemptive Therapy CMV disease Letermovir Placebo Difference: -23.5% (-32.5 to -14.6) p<0.001

Marty FM, Ljungman P, Chemaly RF, et al. N Engl J Med 2017;377:2433-44. Adverse Events • Similar overall • Any difference in adverse event in safety population, by system:

System Letermovir Placebo Difference N, % N, % %, (95% CI) Cardiac disorders 47 (12.6) 12 (6.3) 6.4 (1.1, 11.0) Ear/Labrynth disorders 17 (4.6) 2 (1.0) 3.5 (0.5, 6.3)

No clear association of cardiac AEs and drug exposure

Marty FM, Ljungman P, Chemaly RF, et al. N Engl J Med 2017;377:2433-44. Supplementary Information. How will this impact our CMV prophylaxis?

• All allogeneic transplant recipients or risk-stratify? • Continuing long term? • Viral load monitoring? • Other settings? Case Question 4

• 37-year-old male with AML Initial presentation: • 45,000 WBC, normal cytogenetics, FLT3/ITD genes (+), NPM1 (-) received MUD PB HCT, CMV R+ (D+) and is 1 month post-HCT. He initially received prophylaxis with ciprofloxacin, voriconazole & acyclovir. He has recently added TMP/SMX SS tablet QD to voriconazole & acyclovir, and has a new rash. • What are some of the considerations for monitoring prophylaxis in this patient? a. Voriconazole concentrations do not need monitored b. Renal function and electrolytes should be assessed in a patient receiving acyclovir & TMP/SMX c. Rash is rarely caused by any of the agents in his regimen d. There is no need to monitor CMV DNA at this stage Vaccination Post HCT Vaccine Earliest Time Number of Doses Recommended if not previously administered or not current Haemophilus influenza b 6 months 3 Hepatitis A 6 months 2 Hepatitis B 6 months 3 3* DTaP, DT, Td, Tdap 6 months *If ≥ 7 years, could also do one dose Tdap, then 2 doses DT or Td Influenza, inactivated 4 months 1 Pneumococcal conjugate (PCV 13) 3 months 3 Pneumococcal polysaccharide (PPSV 23) ≥ 12 months post if no GVHD 1 (booster if ≥ 65 years) Polio, inactivated 3 3 NOT Recommended Influenza, live attenuated

Measles-mumps-rubella-varicella, live Measles**-mumps-rubella, live **If seronegative, ≥ 24 months after 1 (adult) or 2 (children) transplant, no GVHD, not on Varicella**, live immunosuppressants 2 Only if patient not current with recommendations for doses of immunocompetent persons of similar risk/age Human Papilloma Virus 6 3

Wingard JA. Up To Date, 2018. Carpenter PA. Blood 2016. 127: 2824-2832. Defer “early” vaccinations

• Anti-CD20 monoclonal antibody <6 months prior • Moderate or severe GVHD • Quiescent GVHD and CD4 count ≤ 200/uL with CD19 ≤ 20/uL • Received IVIG <2 months prior & CD4 count ≤ 200/uL with CD19 ≤ 20/uL

• “2-1-8 rule” for live vaccines • ≥ 2 years post HCT • ≥ 1 year off all immunosuppressive therapy • ≥ 8 months after any IVIG dose

Carpenter PA. Blood 2016. 127: 2824-2832. Herpes Zoster (Shingles) Vaccines

• Zoster Vaccine Live (Zostavax) Live attenuated virus vaccine, adults ≥ 50 years of age, single dose ACIP: “immunocompetent adults aged ≥60 years” by 6 years postvaccination, vaccine effectiveness against herpes zoster is <35%

• Recombinant Zoster Vaccine (Shingrix) 2-dose, subunit vaccine (non-live) containing recombinant glycoprotein E in combination with a novel adjuvant (AS01B) Adults ≥ 50 years of age ACIP: “immunocompetent adults ≥ 50 years of age” • Allowed for immunocompromised patients receiving <20 mg/day of prednisone or equivalent or using inhaled or topical steroids ZOE HSCT: Allogeneic HCT; efficacy ~68%

Dooling KL et al. MMWR. January 26, 2018 / 67(3);103–108 https://www.gsk.com/en-gb/media/press-releases/new-data-supports-the-safety-and-efficacy-of-gsk-s-shingrix-in-preventing-shingles-in-autologous- haematopoietic-stem-cell-transplant-patients/ Conclusions

• There are risk factors and characteristic periods of risk for HCT patients that predispose them to bacterial, fungal, viral & other pathogens • While trials in some areas are limited, available data and published guidelines can aid in selection of appropriate prophylactic agents for HCT patients • Monitoring of toxicities, drug interactions, drug concentrations and ongoing host immunosuppression are important to ensuring optimal prophylaxis Questions? [email protected]