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NCCN Flash Updates: NCCN Guidelines Updated for Prevention and Treatment of Cancer-Related Infections

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®),  and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) for Prevention and Treatment of Cancer-Related Infections. These NCCN Guidelines^® are currently available as Version 1.2023.

Link directly to the Updates section of the NCCN Guidelines: Prevention and Treatment of Cancer-Related Infections

INF-1

• Bullet added to Intermediate, Disease/Therapy Examples and Antimicrobial Prophylaxis: CAR T-cell therapy

INF-2

• Disease/Therapy Example modified: Significant acute GVHD (especially grade 3/4) receiving IST
• Antifungal prophylaxis for MDS and AML modified: Voriconazole, fluconazoleisavuconazole, an echinocandin, amphotericin B products, orfluconazole (if mold activity not needed) (all category 2B)
• Antifungal prophylaxis for significant acute GVHD (especially grade 3/4) modified: Voriconazole, echinocandin, amphotericin B products, or isavuconazole (all category 2B)
• Footnote h modified: All three agents in the echinocandin class (micafungin, caspofungin, and anidulafungin) are considered by many to be interchangeable. Echinocandins are active against candida and aspergillus.

INF-3

• Footnote k modified: HSV prophylaxis is indicated in seropositive children. In pediatrics, HSV prophylaxis is indicated and seropositive children and prophylaxis for VZV not routinely given unless there is a history of recurrent zoster infections or after 1st zoster episode while on myelosuppressive therapy, even if they are seropositive or vaccinated
• Footnote removed: For pediatric patients, prophylaxis for VZV is not routinely given unless there is a history of recurrent zoster infections or after first zoster while on myelosuppressive therapy, even if they are children who are seropositive or vaccinated.

INF-4

• Allogenic HCT pathway added: for prophylaxis
• Allogenic HCT pathway added: for preemption, weekly quantitative CMV viral load by PCR testing
• Footnotes modified:
  • a: Categories of risk are based on several factors, including underlying malignancy, whether disease is in remission, duration of neutropenia, prior exposure to chemotherapy, recipient or donor CMV status, and intensity of IST. For infection concerns and recommended prophylaxis for immune-targeted agents, see INF-A.
  • r: Typically therapy is initiated with oral valganciclovir unless there are absorption or toxicity issues and it would be continued at a minimum until a negative polymerase chain reaction (PCR). However, some centers prefer ganciclovir over valganciclovir. Choice of agent may depend on institutional preference and/or concern for myelosuppression and nephrotoxicity.
  • s: Consider testing for letermovirdrug resistance if clinically significant breakthrough infection is detected.

INF-5

• HBV positive, therapy considerations modified: Consult with an expert in hepatitis treatment to determine possible antiviral prophylaxis/ treatment
• Footnotes
  • Removed: Chronic hepatitis based on biopsy or active viral replication (ie, high levels of HBsAg+ and/or HBeAg+ or increasing HBV viral load). Biopsy should be performed if clinical suspicion of disease. In case of cirrhosis, reconsider decision for transplant.
  • z: Duration of therapy may depend on various factors and typically needs to be continued beyond the completion of immunosuppression.For example, in patients receiving rituximab, the risk of reactivation continues after treatment is concluded and is increased if treatment is halted too early.

• Foonotes added
  • w: See current HIV management Guidelines https://www.iasusa.org/resources/ guidelines/ and https://clinicalinfo.hiv.gov/en/guidelines and https://clinicalinfo.hiv.gov/en/guidelines
• aa: Hepatitis B Virus Screening and Management for Patients With Cancer Prior to Therapy: ASCO Provisional Clinical Opinion Update | Journal of Clinical Oncology (ascopubs.org)

INF-6

• Disease/Therapy Examples bullet added: CAR T-cell Therapy
• Footnote dd modified: TMP/SMX, when appropriately dosed, may have activity against other pathogens including Nocardia, Toxoplasma, and Listeria. Atovaquone may have activity against Toxoplasma.

INF-7

• Pneumococcal vaccination, bullet removed: Pneumococcal antibody responses to some serotypes in PCV7 and PCV13 were decreased following co-administration of the meningococcal conjugate vaccine, MenACWY-D, PCV-7, and PCV13. Therefore, PCV7 and PCV13 should not be given with MenACWY-D but can be given with MenACWY-CRM.
• Recombinant Zoster Vaccine: The administration of recombinant zoster vaccine (RZV) is recommended for adult patients aged ≥50 years and those ≥18 years who are at increased risk for herpes zoster (HZ) disease. For patients who have previously received the live-attenuated herpes zoster vaccine (ZVL), RZV should be given at least 2 months after the last ZVL dose
• Footnotes
  • ii modified:For prevention of infection in cancer survivors, including vaccination recommendations, see the NCCN Guidelines for Survivorship. For recommendations regarding COVID-19 vaccinations, please see the NCCN website for COVID-19 resources. See Management of Concurrent COVID-19 and Cancer in Patients (COV-1).
  • jj modified: Age-appropriate vaccines are recommended. High-dose flu vaccine is recommended for patients ≥65 years of age. See CDC website for more updated recommendations
  • ll added: Pneumococcal antibody responses to some serotypes in PCV13 were decreased following co-administration of the meningococcal conjugate vaccine, MenACWY-D, and PCV13. Therefore, PCV13 should not be given with MenACWY-D but can be given with MenACWY-CRM. Similar precautions should be used for PCV15.

INF-8

• Pneumococcal vaccination, bullets modified:
  • 3 doses of PCV1315 or PCV1520, 4–8 weeks apart.
  • Upon completion of PCV1315 or PCV1520 series, PPSV23, 4–8 weeks after last PCV dose.
• Measles/Mumps/Rubella (MMR), recommended timing after HCT modified: ≥24 months (may vaccinate earlier when risk:benefit ratio suggests)
• Footnotes
  • mm modified: For patients with GVHD, PCV 15, or PCV 20 may be considered instead of PPSV23 as a fourth dose. CDC is currently evaluating use of primary series of PCV20 and PCV15 post-HCT.
  • tt added: DTaP isnot approved for use in ages >7 (FDA/ACIP-approved 3-dose series for ≥7 year olds is Tdap/Td/Td vs. considerations of Tdap/Tdap/Tdap). Other than 3 doses of DTaP as stated, 3 doses of Tdap, or 1 dose of Tdap followed by 2 doses of Td are also acceptable options.
  • uu added: Emerging therapies such as CAR-T appear to behave similar to patients who have undergone allogenic transplant in terms of vaccine boosting recommendations.

INF-A 1 of 13

• Table 1 extensively revised.

INF-A 6 of 13

• Table 2 extensively revised.

INF-A 9 of 13

• Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor agent added: Tremelimumab-actl
• Programmed death-1 (PD-1) inhibitors,
  • Nivolumab, major uses modified: Cancers of colorectal, squamous cell of head/neck, liver, urothelial, esophageal, gastric; NSCLC, SCLC, RCC, melanoma, Hodgkin lymphoma
  • Pembrolizumab, major uses modified: Cancers of cervical... SCLC, RCC, Hodgkin lymphoma, thymic LBCL, melanoma; other solid tumors
  • Agents modified:
    • Cemiplimab-rwlc
    • Dostarlimab -gxly

INF-A 12 of 13

• Footnotes added:
  • g: Consider monitoring and/or prophylaxis for opportunistic fungal infections
  • h: Many of these agents can cause QTc prolongation
  • i: Agents listed in this table may be used either as monotherapy or in combination regimens. Please refer to the full prescribing information and/or other cancer-specific NCCN Guidelines for the appropriate use of these agents.

FEV-1

• Initial evaluation
  • Sub-bullet 3 modified: History of prior significantPrior documented infections in the last 3 months
  • Bullet 2 modified: Epidemiologically relevant exposures (eg, marijuana or cigarette smoking, vaping, injection drug use)
• Microbiologic evaluation
  • Bullet 1 modified: Blood culture x at least 2 sets (one set = 2 bottles)
  • Sub-bullet 1 modified: One peripheral + one catheter (preferred but not required)

FEV-4

• Follow-up, bullet 2 modified: Daily assessment (clinic or home visit) for the first 72 hours to assess response, toxicity, and compliance adherence; if responding, then telephone follow-up daily thereafter

FEV-5

• Page title modified: Initial Inpatient Empirin Therapy for Uncomplicated Fever and Neutropenia
• Lower pathway added: Follow-up (FEV-4)
• Footnote k modified: For severe beta-lactam allergy, consider vancomycin and aztreonam while further evaluation is carried out with ID/allergy consultation.

FEV-7

• Abdominal pain, treatment modifications, bullet 1 modified: Consider adding anaerobic therapy
• Footnote removed: Lab studies include CMV antigens/PCR and abdominal/pelvic CT.

FEV-8

• CDI resolved, subsequent treatment removed:
  • Consider continuing vancomycin or fidaxomicin when diarrhea recurs
  • Consider continuing prophylactic vancomycin during antibiotic use
• Footnote s added: If continuing antibiotics, may consider secondary prophylaxis.

FEV-9

• Page extensively revised.

FEV-10

• Cellulitis/skin and soft tissue infections, treatment modifications modified: Add Gram-positive active agents (consider for MRSA)
• Vesicular lesions, evaluation modified: Aspiration or scraping for VZV or HSV PCR/DFA, and/or herpes virus cultures if PCR unavailable
• CNS symptoms, treatment modifications, bullet 2 modified: Empiric therapy of meningitis should include coverage of Pseudomonas aeruginosa, Gram-positive bacteria including and Listeria. and MDR Gram-negative rods

FEV-11

• Results of daily monitoring, lower pathway modified: Not responding/ Clinically worsening (persistently febrile/bacteremic)

FEV-12

• Suggested minimum duration
  • Sub-bullet 3 modified: S. aureus: typically requires 4 weeks after first negative blood culture; ID consult advisedstrongly recommended
  • Sub-bullet 5 modified: Catheter removal favored for bloodstream infections with Candida or other yeasts... Bacillus spp., atypical nontuberculous mycobacteria...
  • Sub-bullet 7 modified: Mold (eg, Aspergillus): minimum of 12 weeks
• Footnote m modified: See Antiviral Agents (FEV-C) for dosing, spectrum, and specific comments/cautions. The antivirals are not equal in terms of efficacy, side effects, and resistance.

FEV-A 1 of 3

• Daptomycin
  • Dose modified: 6–10 mg/kg/day IV with higher doses indicated for specific infections
  • Spectrum, bullet 2 modified: Has in vitro activity against VRE but is not FDA-approved for this indication
• Footnote modified: Higher doses of daptomycin (8–102 mg/kg) are recommended for certain bloodstream infections (eg, enterococci). ID consult is strongly recommended.

FEV-A 3 of 3

• Levofloxacin/Moxifloxacin
  • Spectrum, bullet 4 modified: Moxifloxacin is more active against anaerobes than other fluoroquinolones, but has insufficient activity against some gram-negativeorganisms, including Pseudomonas
  • Comments/cautions, bullet removed: Preferred dose for Pseudomonas coverage
• Footnote h added: There are multiple new agents that may be useful against multiply drug-resistant bacteria including ceftolozane-tazobactam, ceftazidime/avibactam, meropenem-vaborbactam, Imipenem/cilastatin/relebactam, andcefiderocol. These agents have variable spectrum and activity and should only be used with expert consultation.

FEV-B 1 of 5

• Fluconazole, dose modified: In adults with normal renal function: typical dosing is 400 mg IV/PO daily. May vary dependingon indication and Candida susceptibility.

• Itraconazole, comments/cautions bullet removed: Consult ID
• Itraconazole, comments/cautions bullet 3 modified: A new formulation, SUBA-itraconazole, has improved absorption
• Footnote a modified: Azoles inhibit fungal cell membrane synthesis and inhibit cytochrome P450 isoenzymes that may lead to impaired clearance of other drugs metabolized by this pathway. Fluconazole is a less potent inhibitor of cytochrome P450 isoenzymes than the mold-active azoles. QTc prolongation and interactions have been reported with all azole antifungals except isavuconazole. With broad use, anti microbial resistant organisms may emerge and may have implications for future activity of these agents.
• Footnote b modified: TDM is an ongoing area of research; TDM should be considered in consultation with ID specialists. (See Discussion). TDM is routinely used in managing.

FEV-B 2 of 5

• Posaconazole
  • Dose, bullet removed: Oral suspension if used as prophylaxis: 200 mg TID, if used as treatment: 200 mg QID
  • Comments/cautions, bullet modified: Tablets are better absorbed, though it should be taken with foodand preferred, except in circumstances where alternative dosing is needed.
  • Comments/cautions, bullet added: IV formulation should be used with caution in patients with significant renal dysfunction.

FEV-B 3 of 5

• Amphotericin B lipid complex, dose modified: 3–5 mg/kg IV daily
• Spectrum, bullet 2 modified: Several species of fungi may be intrinsically resistant to amphotericin (see Discussion) (eg, Scedosporium, Lomentospora)
• Comments/cautions, bullet 4 added: Slowing the rate of infusion is an additional way to manage amphotericin infusion reactions.
• Footnotes removed:
  • Broad spectrum of antifungal activity. Significant infusional and renal toxicity, though less so with lipid formulations.
  • Slowing the rate of infusion is an additional way to manage amphotericin infusion reactions.

FEV-B 4 of 5

• Spectrum, bullet 4 modified: Not reliable or effective against most other fungal pathogens (eg, Trichophyton, Cryptococcus, ZygomycetesMucorales)

FEV-C 1 of 4

• Ganciclovir, typical dosing, bullet 1 modified: Preemptive therapy for CMV: 5 mg/kg every 12 h for 2 wks; if CMV remains detectable, further ID evaluation may be required
• Ganciclovir, typical dosing, bullet 2 modified: Treatment: CMV disease (5 mg/kg every 12 h for 2 wksfor induction followed by 5 mg/kg daily for at least an additional 2 wksmaintenance and resolution of all symptoms). Consider adding intravenous immunoglobulin (IVIG) for CMV pneumonia.
• Valganciclovir, typical dosing, bullet modified: Preemptive therapy for CMV: Induction with 900 mg PO BID for at least 2 wksfor induction and until negative test; consider additional 900 mg PO daily for at least 7 daysfor maintenance after a negative test. for maintenance

FEV-C 2 of 4

• Foscarnet, typical dosing
  • Bullet 1 modified: Prophylaxis for CMV: 60 mg/kg IV every 8–12 h for 7 d induction, followed by 90–120 mg/kg IV daily until day 100for maintenance after HCT.
  • Bullet 2 modified: Preemptive therapy for CMV: Induction for 2 wks; either 60 mg/kg IV every 8 h or 90 mg/kg IV every 12 h.

• Bullet 3: Therapy: Acyclovir-resistant HSV (40 mg/kg every 8 h for 7–10 days); CMV disease (90 mg/ kg every 12 h for 2 wksinduction followed by 90–120 mg/kg daily for at least an additional 2–4 wksmaintenance and resolution of all symptoms). Consider adding IVIG for CMV pneumonia.

• Letermovir
  • Typical dosing, bullet 1 modified: Primary prophylaxis for CMV seropositive recipients (R+) who undergo allogeneic HCT: 480 mg PO daily or daily IV infusion over 1 h beginning between Day 0 and 28 post-transplantation and continue for 100 days post-transplant.
  • Comments/cautions, bullet 2 modified: Has multiple drug interactions, including azoles, cyclosporine, and tacrolimus; see package insert. (TDM is important)
  • Comments/cautions, bullet 3 modified: Not active against other herpes group viruses (including HSV and VZV). Acyclovir is also needed for HSV and VZV.
• Maribavir, comments/cautions, bullet 6 modified: Monitor for drug interactions (may increase level of immunosuppressants such as cyclosporine, tacrolimus, sirolimus, etc.)

FEV-C 3 of 4

• Intravenous immunoglobulin (IVIG), comments/cautions, bullet 2 modified: CMV-specific IVIG is not more efficacious than standard IVIG. IVIG use as an antiviral is controversial.
• Ribavirin, comments/cautions, bullet 2 modified: Experience in immunocompromised adultsadults who are immunocompromised with RSV disease is limited., but should be considered given potential morbidity and mortality associated with RSV infection.

COV-2

• Footnote c added: If feasible, consider doingtest-based strategy with 2 negative tests separated by 24 hours.

COV-4

• Significant exposure to SARS-CoV-2 recommendations, bullet 2 modified: While the CDC does not recommend quarantine or routine empiric transmission-based isolation precautions of peoplewho have been exposedare up-to-date on COVID-19 vaccination, patients who are immunocompromised who are at high risk for severe COVID-19 (Table 2) and have had a significant exposure to a person with known SARS-CoV-2 infection should consider quarantining for 14 days after last exposure.

Updates in Version 1.2023 of the NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections from Version 3.2022 include:

COV-6

• Antiviral options, bullet removed: Monoclonal antibodies
• Comments, bullet 3 removed: Monoclonal antibody therapy (that is active against circulating SARS-CoV-2 variants)
• Comments, sub-bullet 5 removed: Effective monoclonal antibody therapy depends upon the current and predominant circulating SARSCoV-2 variant and may quickly change.
• Comments, sub-bullet 6 removed: Several Emergency Use Authorizations (EUAs) for monoclonal antibody products have been suspended due to circulating viral variants becoming resistant.
• Comments, sub-bullet 7 removed: See real-time updated monoclonal antibody treatment options active against current viral variants from the NIH or IDSA COVID-19 webpage.
• Comments, sub-bullet 9 added: Please see table 5 for recommendations regarding the use of contraception
• Comments, bullet 5 removed: Patients should use effective contraception while taking molnupiravir and for at least 4 days after last dose to avoid pregnancy.

• Footnote e modified: Monoclonal Antibody therapy should not be used as an alternative to COVID-19 vaccination. Patients who receive monoclonal antibody therapy should still receive the COVID-19 vaccine series; however, monoclonal antibody treatment can interfere with vaccine-generated immunologic response COVID-19 vaccination can be given at any interval following receipt of passive antibody therapy. A person should wait 2 weeks after COVID-19 vaccination before receiving tixagevimab/cilgavimab for pre-exposure prophylaxis. Note that COVID-19 vaccination status should not affect decisions regarding the use or timing of monoclonal antibody therapy for treatment of breakthrough COVID-19 disease. All monoclonal antibody FDA approvals have been suspended due to emergence of viral resistance as availability of mAB for treatment depends on susceptibility to circulating strains.
• Footnote h added: This is a rapidly changing field. Here are links to routinely updated guidance. See NIH and IDSA guidelines for updated information: NIH and IDSA.

COV-7

• Patient hospitalized for non–COVID-19 indication but with acute symptomatic COVID-19
  • Antiviral options, bullet removed: Monoclonal antibodies
  • Comments, bullet removed: Monoclonal antibodiese (mild to moderate disease, Table 2)
  • Comments, sub-bullet removed: Effective monoclonal antibody therapy depends upon the current and predominant circulating SARS-CoV-2 variant that may quickly change.
  • Comments, sub-bullet removed: See real-time updated treatment monoclonal antibody treatment options active against identified viral variants from the NIH or IDSA COVID-19 webpage.
  • Comments, bullet 2 modified: Consider high-titer COVID-19 convalescent plasma if effective monoclonal antibody therapy is not available. Pre-BA plasma may not be as effective.

COV-8

• Persistent symptomatic COVID-19 infection
  • Antiviral options modified: Combination of antiviral (remdesivir or nirmatrelvir/ritonavir) and passive immunotherapy (COVID-19 convalescent plasma or monoclonal antibodiesd,e,11) via investigational useRemdesivir or nirmatrelvir/ritonavir. Immunotherapy (COVID-19 convalescent plasma or monoclonal antibodies) may be added in combination.
  • Comments, sub-bullet removed: Monoclonal antibodiesd (depending upon predominant circulating viral variants)

COV-9

• Remdesivir, comments, bullet 6 added: Can be extended up to 10 days
• Molnupiravir, comments, bullet 5 modified: May cause fetal harm. Patients of childbearing potential should use contraception during treatment and 4 days after treatment. Patients should use contraception during treatment and at least 3 months after treatment. Patients who may become pregnant should use reliable contraception during therapy and for 4 days after the last dose of molnupiravir. Sexually active males with partners who may become pregnant should also use effective contraception during therapy and for at least 3 months after the last molnupiravir dose.

COV-10

• Monoclonal antibodies removed:
  • Bebtelovimab
  • Tixagevimab/cilgavimab (Current EUA only for preexposure prophylaxis)

Updates in Version 1.2023 of the NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections from Version 3.2022 include:

• Monoclonal antibody guidance added: None available at this time, please see: NIH Guidelines IDSA Guidelines

COV-11

• Baricitinib, comments, bullet 6 added: Concurrent disease or treatment-associated immunosuppression
• Footnote removed: Sotrovimab, casirivimab/imdevimab, and bamlanivimab/etesevimab have historically been used, but are no longer recommended for use.

COV-A 3 of 4

• Reference removed: Luitel P, Vais D, Gidron A. Successful treatment of persistent coronavirus disease 2019 infection in a patient with hypogammaglobulinemia with REGN-COV2: A Case Report Open Forum Infect Dis 2021;8:ofab335.

 

 

 

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