Prevention and Treatment of Cancer-Related Infections, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology

During Neutropenia

Patients with cancer and chemotherapy-induced neutropenia are at risk for severe bacterial infections. Fluoroquinolones are the most commonly used prophylactic antibacterial agents in adults with chemotherapy-induced neutropenia.

Two large, randomized, placebo-controlled studies showed the benefit of levofloxacin prophylaxis in neutropenia at different levels of risk for infectious complications.^5,6 The main advantage of levofloxacin prophylaxis (in patients with intermediate and higher risk of infections) with chemotherapy-induced neutropenia was a reduction in clinically significant bacterial infections, including gram-negative rod bacteremia.⁵ In contrast, the main advantage of prophylaxis in lower risk neutropenia was a small, but statistically significant, reduction in fever and hospitalization for neutropenic fever.⁶ Neither study conducted a systematic long-term evaluation of antimicrobial resistance. The NCCN panel considers that reduction in the incidence of significant infections is a more clinically meaningful endpoint than reduction in the incidence of neutropenic fever. Using prevention of neutropenic fever as the primary endpoint in this study by Cullen et al⁶ 1,000 hypothetical patients with low risk of infections would have to receive prophylaxis during each cycle of chemotherapy-induced neutropenia to benefit only 44 patients.

In a single-center randomized study in patients undergoing high-dose therapy followed by autologous HCT (n=157), patients were randomized to receive prophylaxis (with oral ciprofloxacin 500 mg twice daily and intravenous vancomycin 1,000 mg once daily) or no prophylaxis; all patients received antifungal prophylaxis with fluconazole.⁷ Empirical therapy (comprising amikacin, ceftazidime, and full-dose vancomycin) was initiated when neutropenic fever developed. The use of antibacterial prophylaxis significantly reduced the incidences of neutropenic fever (56% vs 91%; P<.001) and bacteremia (6% vs 35%; P=.005) compared with no prophylaxis, but at the expense of decreased response to first-line empirical therapy (66% vs 84%; P=.025). Among the patients who received prophylaxis and developed neutropenic fever, 34% required second-line therapy that included a carbapenem, suggesting that these patients developed infections resistant to the prophylactic regimen. Duration of hospitalization and overall survival rates were similar between study arms. These results led the study investigators to conclude that routine antibacterial prophylaxis was not recommended in patients undergoing high-dose therapy and autologous HCT.⁷ It should be noted, however, that the prophylactic regimen in this study included vancomycin (albeit at a lower dose) and is not supported by the NCCN or IDSA panels for use as either antimicrobial prophylaxis or standard initial empirical therapy for fever and neutropenia.⁸

In a systematic review and meta-analysis by Gafter-Gvili et al (based on 109 trials, n=13,579 patients) comparing antibacterial prophylaxis with placebo, no intervention, or prevention with another agent in patients with afebrile neutropenia, the use of antibacterial prophylaxis was found to significantly reduce the risk of all-cause mortality (risk ratio, 0.66; 95% CI, 0.55–0.79) as well as infection-related deaths (risk ratio, 0.61; 95% CI, 0.48–0.77) compared with placebo or no intervention.⁹ The use of prophylaxis also significantly reduced the incidence of fever and clinically or microbiologically documented infections. Although no significant differences in all-cause or infection-related mortality were seen between prophylactic quinolones or trimethoprim/sulfamethoxazole (TMP/SMX), the use of quinolones was associated with decreased drug resistance and fewer adverse events that subsequently reduced the incidence of drug discontinuation.⁹

A systematic review and meta-analysis evaluated the risks associated with colonization and infections by fluoroquinolone-resistant bacteria.¹⁰ Most of the studies (48 of 56 trials) included patients with hematologic malignancies or HCT recipients. Results of the analysis (based on 56 trials, n=7,878 patients; data on colonization by resistant bacteria based on 27 trials) showed that quinolone prophylaxis was associated with an increase in colonization with quinolone-resistant organisms compared with placebo or no intervention, although the increase was not statistically significant (relative risk [RR], 1.68; 95% CI, 0.71–4.00). However, no difference was observed in the incidence of infections caused by quinolone-resistant organisms (RR, 1.04; 95% CI, 0.73–1.50), regardless of whether these were resistant gram-negative or gram-positive bacteria.¹⁰ Moreover, in an analysis of trials comparing quinolones with TMP/SMX (11 trials), prophylaxis with quinolones was associated with fewer incidents of colonization and infections by resistant bacteria (those resistant to the prophylactic agents) compared with the use of TMP/SMX.¹⁰ This analysis suggests that prophylaxis with quinolones does not appear to increase the rate of infections by resistant organisms.

A 2017 prospective intercontinental study assessed gram-negative rod resistance to fluoroquinolones, noncarbapenem β-lactams (including ceftazidime, cefepime or β-lactam/β-lactamase inhibitors), and carbapenems (meropenem/imipenem/doripenem) in HCT recipients. Of 655 gram-negative rod bacteremia episodes, half were found to be fluoroquinolone and noncarbapenem resistant. The total resistance rates were higher in patients with allogeneic HCT than in those with autologous HCT. Risk factors for fluoroquinolone resistance in allogeneic HCT included prolonged neutropenia and breakthrough on fluoroquinolones. Mortality was found to be significantly more common in infections caused by resistant bacteria.¹¹

A 2018 meta-analysis of studies published in the years 2006–2014 assessed the role of fluoroquinolone prophylaxis during neutropenia in consideration of increasing antibiotic resistance globally.¹² The meta-analysis found no effect of the background rate of fluoroquinolone resistance on the efficacy of fluoroquinolone prophylaxis. However, in a few studies, fluoroquinolone prophylaxis resulted in an increased colonization or infection with fluoroquinolone- or multidrug-resistant strains. Fluoroquinolone prophylaxis had no effect on mortality, but it reduced the rate of bloodstream infections and episodes of fever.¹²

An important consideration for those with low risk with short durations of neutropenia is whether fluoroquinolone prophylaxis is of greater benefit than outpatient fluoroquinolone treatment of fever and neutropenia, should it occur. Both the NCCN Guidelines and IDSA⁸ panels recommend oral fluoroquinolone-based regimens as outpatient empirical therapy for neutropenic fever in adults who meet criteria for a low risk of complications. Fluoroquinolone prophylaxis may preclude its subsequent use as empirical therapy for neutropenic fever in the same patient. The modest difference in rates of hospitalization for suspected infection in levofloxacin compared with placebo recipients (15.7% vs 21.6%, respectively) may be offset by exclusion of outpatient oral empirical therapy in patients receiving fluoroquinolone prophylaxis. To limit antibacterial use, Cullen et al¹³ have suggested prophylaxis with levofloxacin on cycle 1 of myelosuppressive cancer chemotherapy and only in subsequent cycles if a febrile episode occurs.

The decision whether to use antibacterial prophylaxis and the selection of the specific agent requires a balance between expected benefit and risk (explained in greater detail in a review by Hoffman et al¹⁴). The concept of risk applies to immediate adverse effects of the drug (eg, rash, gastrointestinal intolerance), the potential for selection for resistant pathogens that can harm the individual receiving prophylaxis, and the risk of resistant organisms to a specific population of patients (eg, those being treated at a cancer center). Thus, the emergence of multidrug-resistant organisms, disruption of the microbiome, and antibiotic toxicities must be considered when choosing an antimicrobial prophylactic agent. The link between fluoroquinolone use and severe Clostridium difficile as well as methicillin-resistant S. aureus infections provides an additional cautionary note regarding excess use of fluoroquinolones.^15–18

NCCN Recommendations for Antibacterial Prophylaxis

Antibacterial prophylaxis is not recommended for patients with a low risk of overall infection (see Figure 3). In patients with neutropenia who are at lower risk of infectious complications (a category that includes most patients with solid tumor malignancies), the main benefit of antibacterial prophylaxis is a reduction in fever rather than in documented infections. In patients with neutropenia expected to last <7 days who are not receiving immunosuppressive regimens (eg, systemic corticosteroids), the panel suggests no antibiotic prophylaxis.⁸ In patients deemed at intermediate or high risk, the NCCN Guidelines panel advises that fluoroquinolone prophylaxis (levofloxacin is preferred) be considered in patients with an expected duration of neutropenia (absolute neutrophil count [ANC] ≤500 neutrophils/mcL or ≤1,000 neutrophils/mcL and a predicted decline to ≤500/mcL over the next 48 hours) for >7 days. This is in agreement with the recommendations of the IDSA guidelines for the use of antimicrobial agents in patients with neutropenia with cancer.⁸ For patients with intolerance to fluoroquinolone, TMP/SMX or an oral third-generation cephalosporin may be considered.

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INF-1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections, Version 3.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 9; 10.6004/jnccn.2024.0056

Clinical practice guidelines have also been developed for systemic antibacterial prophylaxis in pediatric patients with cancer and those undergoing HCT.¹⁹ The panel for these guidelines recommends consideration of antibacterial prophylaxis in children with acute myeloid leukemia and relapsed acute lymphoblastic leukemia receiving intensive chemotherapy expected to result in severe neutropenia (ANC <500/mcL) for at least 7 days. The panel recommends against the routine use of antibacterial prophylaxis for children undergoing induction chemotherapy for ALL, autologous HCT and allogeneic HCT. A strong recommendation against its routine use was made for children whose therapy is not expected to result in prolonged severe neutropenia. If used, prophylaxis with levofloxacin is recommended as a preferred option during severe neutropenia.¹⁹

Prophylaxis for Pneumococcal Infection

Prophylaxis for pneumococcal infection is advised in allogeneic HCT recipients. Patients undergoing allogeneic HCT are at an increased risk for pneumococcal sepsis due to functional asplenia and impaired B-cell immunity. Pneumococcal sepsis is most common in the late transplant period, between 3 months to several years after HCT.^20,21 IST for graft-versus-host disease (GVHD) delays reconstitution of B-cell immunity and significantly increases the risk of posttransplant pneumococcal sepsis.^21,22

The NCCN Guidelines panel advises that penicillin prophylaxis be initiated at 3 months after HCT and be continued until at least 1 year after transplant in patients with GVHD. Patients should receive prophylaxis regardless of prior administration of pneumococcal vaccines.²³ Prophylaxis should be continued in patients with chronic GVHD until IST has been discontinued. Posttransplant pneumococcal infection is generally community acquired, and the frequency of resistance to antibiotics reflects regional susceptibility patterns. In some regions as many as 35% of pneumococcal isolates have intermediate- or high-level resistance to penicillin,²⁴ and cross-resistance to other classes of antibiotics is common. Breakthrough pneumococcal sepsis in HCT recipients receiving penicillin prophylaxis is well described.²⁵ Thus, in areas with a significantly higher frequency of penicillin-resistant pneumococcal isolates, alternative agents should be considered based on local susceptibility patterns. Daily TMP/SMX used as prophylaxis for PJP is likely to be protective against pneumococcal disease but depends on local susceptibility patterns. In high-risk populations (eg, allogeneic HCT recipients with GVHD), prophylaxis with penicillin and TMP/SMX should be considered. Vaccination with pneumococcal vaccine is also strongly recommended (see “Vaccination,” page 633) 3 to 6 months post-HCT.

Azoles

Azoles are among the most commonly used medications for the prevention and treatment of fungal infections. Early-generation azoles such as ketoconazole are used less commonly now because of toxicity, drug interactions, and limited spectrum of activity. Some “first-generation” triazoles (ie, fluconazole and itraconazole) are used widely due to their low cost and minimal toxicity but are limited by increasing resistance among Candida species and lack of activity against most molds. Several “second-generation” triazoles (eg, voriconazole and posaconazole) have been subsequently developed. These drugs extend the spectrum of activity of triazoles to include potent activity against many molds (importantly, activity differs within the class) but can also have complicated drug interactions and distinct toxicities and remain extremely costly with extended use.

Prophylaxis with voriconazole was compared with fluconazole in a large, randomized, double-blind study that included serum galactomannan surveillance in allogeneic HCT recipients (n=600).²⁶ Patients were randomized to receive study drugs for 100 days or for 180 days in the higher risk cohort of patients. No difference was noted in the primary endpoint (invasive fungal infection-free survival rate at 180 days) between the fluconazole and voriconazole prophylaxis arms (75% vs 78%, respectively), but a trend for reduced incidence of Aspergillus infections (17% vs 9%), reduced incidence of invasive fungal infections (11% vs 7%), and less frequent use of empirical antifungal treatment (30% vs 24%) was noted in the voriconazole arm, although the differences were not statistically significant. No differences in relapse-free and overall survival rates, nor incidence of severe adverse events were seen between treatment arms.²⁶

In a multicenter randomized trial, prophylaxis with posaconazole in patients with neutropenia with acute myeloid leukemia or myelodysplastic syndromes receiving induction or reinduction chemotherapy significantly reduced the rate of invasive fungal infections during the treatment period (2% vs 8%; P<.001) and during the 100 days following randomization (5% vs 11%; P=.003). Posaconazole prophylaxis also reduced the incidence of invasive aspergillosis (1% vs 7%; P<.001) and was associated with a significant survival benefit (P=.04) compared with the fluconazole/itraconazole arm.²⁷ Data from a prospective, randomized study showed that posaconazole was as effective as fluconazole in allogeneic HCT recipients with severe GVHD and reported reduced incidence of invasive aspergillosis and overall invasive fungal infections in patients receiving posaconazole compared with those receiving fluconazole.²⁸ Posaconazole is equally effective compared with fluconazole as primary therapy for oropharyngeal candidiasis.²⁹ Moreover, in a 2021 phase III randomized controlled trial, posaconazole was found to be noninferior to voriconazole as primary therapy for invasive aspergillosis, and participants had fewer treatment-related adverse events in the posaconazole group than in the voriconazole group.³⁰

A 2020 systematic review and meta-analysis of 69 randomized clinical trials compared prophylaxis with various antifungal agents in patients with hematologic disease or who received HCT. Posaconazole prophylaxis significantly reduced invasive fungal infections (RR, 0.57; 95% CI, 0.42–0.79) and invasive aspergillosis (RR, 0.36; 95% CI, 0.15–0.85) compared with placebo. Additionally, voriconazole was associated with a significant reduction in invasive candidiasis (RR, 0.15; 95% CI, 0.09–0.26) compared with placebo. However, patients taking posaconazole had a higher incidence of withdrawal due to adverse effects.³¹

Isavuconazonium sulfate is a second-generation azole that was approved in March 2015 for the treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazonium sulfate may be considered for antifungal prophylaxis when standard therapy is contraindicated, due to drug interactions or the risk of QT interval corrected for heart rate (QTc) prolongation.³²

Toxicities and Drug-Drug Interactions of Azoles

Experience to date suggests that fluconazole and posaconazole are generally well tolerated and serious adverse events, primarily liver toxicity, are rare. Toxicities for voriconazole include neurologic and ophthalmic adverse events. In the context of renal dysfunction, accumulation of cyclodextrin vehicle may occur when the intravenous formulation is used. Data suggest that long-term use of voriconazole may be associated with severe photosensitivity and other adverse events including cutaneous malignancies, elevated serum fluoride levels, and periosteitis.^33–37 Itraconazole may be associated with hepatic toxicity and gastrointestinal intolerance³⁸ and is contraindicated in patients with a decreased cardiac ejection fraction or a history of congestive heart failure based on its negative inotropic properties. It can also increase cyclophosphamide metabolites, which in turn are associated with hyperbilirubinemia and nephrotoxicity during the early transplant period.³⁹ Fluconazole, itraconazole, posaconazole, and voriconazole may cause QTc prolongation. Conversely, isavuconazonium sulfate has been associated with dose-dependent QTc shortening in healthy individuals.

Azole-associated drug–drug interactions are common clinical occurrences. Both the addition and withdrawal of azoles can result in either increased uptake of these other drugs or subtherapeutic exposure and potential transplant rejection or GVHD. Several studies demonstrate the interaction of azoles with hepatic enzymatic pathways. Administration of itraconazole with medications that are metabolized by the 3A4 isoenzyme can increase plasma concentrations causing QTc prolongation and ventricular tachyarrhythmias.⁴⁰ These findings reinforce a note of caution about itraconazole (and by extension, fluconazole, voriconazole, isavuconazonium sulfate, and posaconazole), with regard to potential serious drug–drug interactions through inhibition of the cytochrome P450 3A4 isoenzyme. Additionally, fluconazole and voriconazole have demonstrated inhibition of CYP2C9 and CYP2C19 enzymes and high interpatient variability of genetic CYP2C19 polymorphisms that may also affect dosing.

The potential for QTc prolongation is a concern exacerbated by the combination of azoles and other drugs (eg, fluoroquinolones, macrolides, ondansetron) and with some chemotherapies (eg, nilotinib for chronic myeloid leukemia, panobinostat for myeloma). Itraconazole and posaconazole are also known inhibitors of gastric P-glycoprotein, which can increase systemic levels of drugs that are affected by this transport system. The list of drug–drug interactions is expansive and continues to grow. Although azoles may be necessary for antifungal therapy, they should only be incorporated into treatment after consultation with an infectious disease expert.

Therapeutic Drug Monitoring of Azoles

Therapeutic drug monitoring (TDM) for the pharmacokinetic evaluation of antifungal agents provides guidance for achieving adequate plasma drug concentration while reducing toxicity.

TDM should be considered for patients receiving triazoles; there is no current evidence to support the use of TDM for the evaluation of polyenes or echinocandins. Fluconazole and isavuconazonium sulfate are the 2 triazoles that do not require TDM. Fluconazole has linear pharmacokinetics that eliminate the need for TDM,^41–45 though patients in renal failure should receive a modified dose. Studies intended to define a therapeutic range for isavuconazonium sulfate have not been performed; thus, TDM is not routinely recommended for isavuconazonium sulfate. TDM should be considered for posaconazole, voriconazole, and itraconazole. Variability of therapeutic drug levels may be affected by the route of drug administration, drug formulation, timing of monitoring, location of the infection, and intrinsic patient factors (ie, age, weight).

There are 3 formulations of posaconazole: oral suspension, delayed-release tablet, and intravenous solution. Pharmacokinetic studies with the oral suspension of posaconazole in healthy individuals showed that administration with or after a high-fat meal, or with any meal or nutritional supplement, greatly enhanced its absorption up to 400%.⁴⁶ The plasma concentration of posaconazole can be reduced by proton pump inhibitors due to the increase in gastric pH when given orally.⁴⁶ Subtherapeutic concentrations and breakthrough fungal infections have been reported.^47,48 As reviewed by Brüggemann et al⁴⁹ a substantial list of drug interactions with azole antifungal drugs can result in subtherapeutic effects or toxicity. The delayed-release (DR) tablet formulation of posaconazole was approved in 2013 and has improved absorption and more predictable bioavailability. Gastric pH does not affect plasma concentration of DR posaconazole,⁵⁰ nor does it have the same interaction with proton pump inhibitors or metoclopramide.⁵¹ The intravenous formulation has also demonstrated similar pharmacokinetics and safety compared with the DR tablet.⁵² A target concentration of posaconazole for prophylactic TDM of >0.7 mcg/mL is supported by individual studies^48,53,54 as well as 2 phase III studies;^27,28 however, doses as low as 0.5 mcg/mL have also been reported as effective.^48,54–58 TDM may not be necessary when using either the DR tablet or intravenous formulation in the prophylactic setting because data indicate that a dose of 300 mg/day results in at least 0.5 mcg/mL in >95% of patients. Treatment of an established infection is recommended to have a trough concentration >1 mcg/mL with potentially higher doses based on the pathogen minimal inhibitor concentrations and concerns for resistance.^59,60

Studies of itraconazole demonstrate a significant rate of breakthrough infections when plasma drug concentrations are <0.5 mcg/mL;^61,62 however, increased mortality was observed at plasma drug concentrations >5 mcg/mL.^63,64 Targeting a lower itraconazole plasma concentration for prophylaxis and a higher dose if an active infection is being treated may be beneficial. Studies suggest that trough concentrations of itraconazole between 1 and 2 mcg/mL have shown the best therapeutic responses for invasive infections,^65–68 while a trough concentration of >0.5 mcg/mL may be sufficient for prophylaxis. Currently, an upper limit of 17 mcg/mL measured by bioassay has been suggested,⁶⁹ but studies for the upper limit have not been extensive. Itraconazole solution should be given either 1 hour before or 1 hour after meals based on the 43% increase in bioavailability in patients who fasted,⁷⁰ while the capsule formulation should be given with a full meal. An alternative formulation, SUBA-itraconazole (for “super bioavailability”), addresses the absorption concerns of conventional itraconazole formulations with enhanced bioavailability that allows for lower dosing, while achieving similar serum concentrations. SUBA-itraconazole is FDA approved for the treatment of blastomycosis, histoplasmosis, and aspergillosis.^71,72

Target voriconazole trough values between 0.5 and 4 mcg/mL have been proposed in clinical studies.^73–80 Although 0.5 mcg/mL is a suggested target for prophylaxis, a higher range of 1 to 4 mcg/mL may be necessary for active disease and for patients with disease that has a poor prognosis. Higher concentrations may also benefit the patients who are immunocompromised by reducing breakthrough infection.^81,82 Trough concentrations ≥4 mcg/mL have correlated with toxicity in various studies.^{73,77,80,83–87} Voriconazole bioavailability was lowered by about 22% when taken with food and by 34% when given with a high-fat meal.⁸⁸ Therefore, voriconazole should be given either 1 hour before or 1 hour after meals.

Studies have shown a general consensus regarding a minimal level of plasma concentration necessary for the triazoles, though the lack of prospective studies has limited the adoption of formal monitoring standards. The Society of Infectious Diseases Pharmacists has published its guidelines for the use of TDM of antifungal agents based on available literature.⁸⁹ Consideration of TDM is recommended by the NCCN panel in conjunction with involvement of an infectious disease expert.

Amphotericin B Formulations

Amphotericin B formulations are broad-spectrum antifungal agents that bind to ergosterol in the fungal cell membrane, leading to the formation of pores in the membrane and subsequent cell death. The original formulation, amphotericin B deoxycholate (AmB-D), was associated with dose-limiting toxicities including infusion-related reactions and nephrotoxicity. Three lipid-associated formulations, amphotericin B lipid complex, liposomal amphotericin B (l-AmB), and amphotericin B colloidal dispersion, have since been developed to have reduced toxicity. When available, amphotericin B lipid complex, and l-AmB are preferred over AmB-D.

Low-dose amphotericin B formulations have been studied in patients at high risk and have been shown to provide protection against invasive molds, although no survival benefit in randomized studies was seen when compared with fluconazole.^38,90,91 Based on the toxicity of amphotericin B products and the availability of safer and equally effective alternative agents, amphotericin B products are considered a category 2B recommendation for prophylaxis. If an amphotericin B product is used, a lipid formulation is generally preferred because of less infusional and renal toxicity compared with conventional amphotericin B. Use of the lipid formulation is particularly important for patients at high risk for renal failure, such as patients with pre-existing renal disease, HCT recipients, and patients who are concurrently receiving other nephrotoxic agents.^92,93

Aerosolized delivery of amphotericin B products has been considered for several years with the advantage of local delivery to the lungs while simultaneously avoiding systemic toxicity. A randomized, placebo-controlled trial found that aerosolized l-AmB was useful for preventing invasive pulmonary aspergillosis in patients with prolonged neutropenia.⁹⁴ Limitations to the use of aerosolized amphotericin B for prophylaxis relate to the variability of this treatment due to different nebulizers and amphotericin B formulations, the lack of dosing optimization, and a dearth of direct comparative data with systemically administered mold-active azoles or echinocandins.⁹⁵

Echinocandins

Echinocandins are a class of antifungal agents that disrupt the integrity of the fungal cell wall through noncompetitive inhibition of β-(1,3)-D-glucan synthase, an enzyme involved in the biosynthesis of β-(1,3)-D-glucan, which is a component specific to the cell wall of many fungi. Echinocandins have fungicidal activity against Candida species and are fungistatic toward Aspergillus species. Combination therapy with amphotericin B or triazoles has been proposed to improve activity against molds; however, clinical evidence for this remains quite limited. Advantages of this family of antifungals are the relatively low toxicity profiles and limited drug-drug interactions. Though echinocandins demonstrate activity against Candida species that are resistant to other antifungal agents,⁹⁶ there is limited or no activity against dimorphic fungi. Four echinocandins are approved for use: caspofungin, micafungin, anidulafungin, and rezafungin. Caspofungin, micafungin, and anidulafungin are all approved for the treatment of esophageal candidiasis, while rezafungin is approved for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Caspofungin and anidulafungin have additional indications for the treatment of candidemia and other infections caused by Candida species. Caspofungin is indicated for treatment of candidal pleural space infections, empirical treatment of fungal infections in neutropenia, and treatment of invasive aspergillosis in patients who are refractory to or intolerant of other antifungal agents. Micafungin has the additional indication for prophylaxis of candidal infections in patients receiving HCT.

Caspofungin was evaluated in a double-blind study including 128 patients with esophageal candidiasis.⁹⁷ Patients received either caspofungin or AmB-D. Two doses of caspofungin were evaluated (50 mg or 70 mg intravenously once daily) with a greater response in the patients given the higher dose (96% vs 85%). Both groups treated with caspofungin had a better response than patients receiving amphotericin B (78%). At the 2-week follow-up, a greater percentage of patients remained negative for candidiasis with the caspofungin treatment (89% in the 70 mg group, 74% in the 50 mg group, and 63% in the amphotericin B group). Furthermore, drug-related adverse events were lower with caspofungin (7%, 4%, and 24%, respectively). Several studies have evaluated the role of caspofungin in the treatment of invasive aspergillosis in patients refractory to or intolerant of other antifungals, supporting its recommendation in this capacity.^98,99

Micafungin is an echinocandin approved for prophylaxis against Candida infections in patients undergoing HCT. In a randomized, double-blind trial of autologous and allogeneic HCT recipients, the success rate with micafungin was superior to fluconazole (80% vs 73.5%; absolute difference +6.5%; 95% CI, 0.9%–12%; P=.03) based on prespecified criteria for treatment success (absence of suspected, proven, or probable invasive fungal infections during treatment period and absence of proven or probable infection during the 4-week period after treatment).¹⁰⁰ The duration of this study encompassed the neutropenic period, but not the period after neutrophil recovery when GVHD would be expected to occur. The frequency of breakthrough candidemia was similar in both arms, but there was a trend to fewer episodes of invasive aspergillosis in allogeneic HCT recipients receiving micafungin. Survival and drug-related toxicity were similar between treatment arms.¹⁰⁰ Micafungin has shown activity in the treatment of aspergillosis in patients refractory to or intolerant of other antifungal agents.^101–103

Anidulafungin has been shown to be an effective antifungal agent against Candida infection in several studies. A randomized double-blind study in 601 patients with esophageal candidiasis demonstrated noninferiority of intravenous anidulafungin to oral fluconazole (97.2% vs 98.8%, respectively) and lower adverse effects (9.3% vs 12.0%) and recurring infections at the 2-week follow-up (64.4% vs 89.5%).¹⁰⁴ In a smaller study of 19 patients with triazole-refractory mucosal candidiasis, anidulafungin treatment resolved infection in 18 of the patients.¹⁰⁵ A larger phase III trial similarly showed superiority of anidulafungin compared with fluconazole in the treatment of candidemia and invasive candidiasis (75.6% vs 60.2%).¹⁰⁶ The response at 2-week follow-up was 64.6% in the anidulafungin group versus 49.2% in the fluconazole group.

Rezafungin was evaluated in a phase III multicenter, double-blind randomized trial.¹⁰⁷ In this trial, 199 patients with candidemia or invasive candidiasis were randomly assigned to either the rezafungin group (50%) or to the caspofungin group (50%). Rezafungin was found to be noninferior to caspofungin in the treatment of candidemia and invasive candidiasis (59% vs 61%, respectively) as well as for 30-day all-cause mortality (24% vs 21%, respectively).

NCCN Recommendations for Antifungal Prophylaxis

CYP3A4 inhibition by azoles can lead to toxicity when administered with several classes of drugs used in cancer therapy, including proteasome inhibitors, tyrosine kinase inhibitors, and vinca alkaloids.¹⁰⁸ Thus, mold-active azoles should be stopped several days before the potential interacting drug is given. These azoles should also not be started until the other agent has been discontinued and sufficient time has elapsed for the drug to be eliminated. Due to variations in drug pharmacokinetics, firm recommendations regarding a minimum time from drug discontinuation to azole administration cannot be made, though some institutions consider waiting at least 10 days following administration of these classes of drugs. Use of echinocandin prophylaxis may be considered in the place of azoles. Consultation with pharmacology and infectious disease experts is recommended.

The NCCN Guidelines panel recommends posaconazole (category 1) for antifungal prophylaxis in neutropenia with acute myeloid leukemia and myelodysplastic syndromes receiving induction or reinduction chemotherapy (Figure 4).⁸ The role of antifungal prophylaxis in patients with acute leukemia receiving consolidation chemotherapy has not been adequately evaluated. Voriconazole, isavuconazole, fluconazole, echinocandin, or amphotericin B products are all category 2B recommendations in this disease setting. Antifungal prophylaxis should be continued until resolution of neutropenia.

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INF-2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections, Version 3.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 9; 10.6004/jnccn.2024.0056

In patients with mucositis receiving autologous HCT, antifungal prophylaxis with fluconazole or echinocandin (both category 1) is recommended until resolution of neutropenia. No prophylaxis is recommended in autologous HCT recipients without mucositis.

The NCCN panel recognizes that strong evidence exists for the use of fluconazole or echinocandin as prophylaxis in neutropenic allogeneic HCT recipients (category 1).⁸ However, it should be noted that fluconazole use can predispose patients to colonization and bloodstream infection by fluconazole-resistant Candida strains.^109,110 Posaconazole as prophylaxis has not been evaluated during the neutropenic period after conditioning in allogeneic HCT recipients; thus, the safety of this approach is unknown. Drug–drug interactions during conditioning for HCT, specifically with posaconazole, itraconazole, or voriconazole, complicate treatment of fungal infections in these patients. Prophylaxis may need to be tailored after consultation with an infectious disease expert. Posaconazole, isavuconazole, voriconazole, echinocandins, and amphotericin B products are all considered category 2B recommendations. Antifungal prophylaxis should be considered until at least day 75 or count recovery (ANC >500) after allogeneic HCT.^8,111–113

Patients with hematologic malignancies are at high risk of developing invasive fungal disease. The German Society of Hematology and Medical Oncology strongly recommends administration of antifungal prophylaxis in patients with hematologic malignancies with prolonged neutropenia (ie, <500 cells/mcL for >7 days) with posaconazole as the drug of choice for mold-active prophylaxis.¹¹³

Although many centers reasonably use antifungal prophylaxis in non-neutropenic allogeneic HCT recipients with GVHD, this practice was only evaluated in a single, properly designed study. In the prospective, randomized, double-blind study, posaconazole was compared with fluconazole as prophylaxis in allogeneic HCT recipients with severe GVHD requiring intensive IST.²⁸ Inclusion criteria included grade 2 to 4 GVHD, chronic extensive GVHD, or intensive IST consisting of either high-dose corticosteroids, antithymocyte globulin, or a combination of two or more immunosuppressive agents or types of treatment. Prophylaxis with posaconazole resulted in reduced incidences of invasive aspergillosis, total invasive fungal infections while on treatment, and deaths attributed to fungal infection.²⁸ Posaconazole is recommended (category 1) as prophylaxis in patients with GVHD receiving intensive IST, as defined by the inclusion criteria in this trial, although the benefit/risk ratio of mold-active prophylaxis in patients receiving less intensive IST has not been established.

Patients with chronic severe neutropenia (ANC <500 neutrophils/mcL) due to an underlying disease (such as aplastic anemia) are at substantial risk for invasive aspergillosis.¹¹⁴ Although this population has not been evaluated in clinical trials of antifungal prophylaxis, some panel members advise the use of a prophylactic mold-active agent (eg, posaconazole or voriconazole).

Secondary antifungal prophylaxis is defined as administration of antifungal therapy in a patient with a prior fungal infection to prevent recrudescence. The panel recommends secondary prophylaxis with an appropriate antifungal agent in patients with prior chronic disseminated candidiasis¹¹⁵ or with invasive filamentous fungal infection¹¹⁶ during subsequent cycles of chemotherapy or HCT. In patients with invasive aspergillosis before HCT, antifungal therapy for >1 month and resolution of radiologic abnormalities correlate with a lower likelihood of posttransplant recurrence of infection.¹¹⁷ Secondary prophylaxis with a mold-active agent is advised for the entire period of immunosuppression.

Herpes Simplex Virus

HSV is an important pathogen in patients who develop neutropenia and mucositis. HSV infections primarily result from reactivation of latent virus. The presence of latent HSV can be determined by pretreatment HSV serology. Reactivation and infection with HSV occur in 60%–80% of HCT recipients and patients (without prophylaxis) with acute leukemia undergoing induction or reinduction therapy who are seropositive for HSV.^118–120 Among allogeneic HCT recipients, HSV disease is most likely to occur within the first month posttransplant, but may occur in later stages during intense immunosuppression.^121,122 Although disseminated HSV infection is uncommon, infection from viral reactivation is frequently associated with increased mucosal damage, resulting in increased pain, limited ability to maintain oral hydration and nutrition, and an increased risk of bacterial and fungal superinfections.

NCCN Recommendations for HSV Prophylaxis

Antiviral prophylaxis against HSV is advised during the period of neutropenia in patients who are HSV-seropositive who are receiving chemotherapy (induction or consolidation) for acute leukemia, and during neutropenia and possibly longer in allogeneic and autologous HCT recipients depending on the degree of immunosuppression (Figure 5). A longer period of prophylaxis should be considered in allogeneic HCT recipients with GVHD or with frequent HSV reactivations before transplantation.¹²³ Acyclovir, valacyclovir, or famciclovir are the initial agents of choice for HSV prophylaxis.^8,124 Foscarnet is typically reserved for patients with acyclovir-resistant HSV infection.^8,124 In patients receiving antiviral prophylaxis with ganciclovir or foscarnet for prevention of CMV reactivation, additional prophylaxis with acyclovir is not necessary given that these agents are active against HSV.¹²⁴ However, it is required in patients receiving CMV prophylaxis with letermovir as this agent lacks activity against HSV.

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INF-3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections, Version 3.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 9; 10.6004/jnccn.2024.0056

HSV and herpes zoster infections are common in patients with chronic lymphocytic leukemia treated with the CD52 monoclonal antibody alemtuzumab. For these patients, antiviral prophylaxis is advised until at least 2 months after completion of alemtuzumab therapy and until CD4+ cell counts are ≥200 cells/mcL.¹²⁵

Prophylaxis against HSV should be considered in other patients at intermediate risk for HSV reactivation, including those with hematologic malignancies with prolonged neutropenia or those receiving high-dose corticosteroids or T-cell–depleting agents (eg, fludarabine). Once a patient has had HSV reactivation requiring treatment, the panel recommends HSV prophylaxis for that patient during all future episodes of neutropenia induced by cytotoxic therapy. HSV prophylaxis is also indicated in children who are seropositive for the virus.

Varicella Zoster Virus

Impaired cellular immunity is the principal risk factor for VZV disease. In allogeneic HCT recipients with a history of VZV infection, about 30% have reactivation of VZV disease without antiviral prophylaxis.¹²⁶ In patients with a history of chicken pox, oral acyclovir administered from 1 to 2 months until 1 year after allogeneic HCT significantly decreased the incidence of VZV disease compared with placebo (5% vs 26%, respectively).¹²⁶ The frequency of VZV disease in the postprophylactic period was similar between the groups and predominantly occurred in patients who required systemic immunosuppression. This prolonged course of acyclovir prophylaxis is likely to also prevent HSV reactivations. Subsequent studies have consistently demonstrated the benefit of long-term antiviral prophylaxis against VZV disease in recipients of allogeneic HCT. Patients who received anti-VZV prophylaxis with acyclovir or valacyclovir for 1 year post-HCT had significantly reduced VZV disease compared with those who did not receive long-term prophylaxis (9% vs 25%; P<.001); no evidence of rebound VZV disease was observed.¹²⁷ Long-term (1 year postallogeneic HCT) prophylaxis with lower doses of acyclovir or valacyclovir was associated with a higher cumulative incidence of VZV reactivation.^128,129

NCCN Recommendations for VZV Prophylaxis

The NCCN Guidelines panel recommends prophylaxis against VZV for at least 1 year after allogeneic HCT in patients seropositive for VZV pretransplant (Figure 5) and recommends considering the extension of prophylaxis in patients who continue to receive systemic IST. Although higher doses are necessary, the same agents used as HSV prophylaxis are also active against VZV. For pediatric patients, prophylaxis for VZV should not be routinely given unless there is a history of recurrent zoster infections or incidence of first zoster infection while on myelosuppressive therapy, even if they are seropositive or vaccinated.

Among recipients of autologous HCT, HSV reactivation is more likely to occur in the early neutropenic phase, whereas the risk of VZV reactivation extends through the first year.¹³⁰ Thus, VZV prophylaxis for at least 6 to 12 months posttransplant should be considered in autologous HCT recipients. Prophylaxis against VZV should be considered in other patients at intermediate risk for viral reactivation, including patients with hematologic malignancies with prolonged neutropenia or those receiving T-cell–depleting agents (eg, fludarabine, alemtuzumab). Bortezomib is associated with an increased risk of VZV reactivation during active therapy^131–134; carfilzomib may also be associated with VZV reactivation. Prophylaxis with acyclovir, valacyclovir, or famciclovir should be protective and can be considered in these settings.^135,136 As previously discussed, among patients with chronic lymphocytic leukemia receiving alemtuzumab treatment, antiviral prophylaxis is recommended until 2 months after completion of treatment and until the CD4+ cell counts reach 200 cells/mcL or more.¹²⁵

Cytomegalovirus

CMV infections most frequently occur in patients with cancer who undergo allogeneic HCT or who receive alemtuzumab therapy or other T-cell depleting therapies. CMV is a common cause of opportunistic infections during the early postengraftment phase following allogeneic HCT, but can also occur in the late postengraftment phase (particularly for patients with GVHD during the latter phase).^121,122 Infection can result from viral reactivation (in patients who are immunocompromised CMV-seropositive) or primary infection (in CMV-seronegative). The risk for CMV reactivation and disease is highest among HCT recipients with CMV-seropositive status prior to transplant.¹³⁷ Among patients who are CMV-seropositive undergoing allogeneic HCT (with graft sources from peripheral blood, bone marrow, or umbilical cord blood), the incidence of CMV reactivation ranged from 50% to 60% (with CMV disease in about 10%–30% of seropositive recipients) even with routine surveillance and antiviral prophylaxis or pre-emptive therapy.^137–140

In a randomized phase II prophylaxis trial, oral letermovir was administered to allogeneic HCT recipients with CMV-seropositive status daily at 60 mg, 120 mg, or 240 mg for 12 weeks posttransplant. The incidence of prophylaxis failure (defined as discontinuation of the study drug because of CMV detection, end-organ disease, or any other cause) was significantly lower in the letermovir groups than in the placebo group (32% for the 120 mg group, 29% for the 240 mg group vs 64%). Moreover, letermovir was well tolerated, with no indication of hematologic toxicity or nephrotoxicity.¹⁴¹ In a randomized, double-blind, phase III trial, prophylaxis with daily oral or intravenous dose of letermovir, 480 mg/day (or 240 mg/day in patients taking ciclosporin), was administered to recipients of allogeneic HCT for 14 weeks after transplantation. Fewer patients developed clinically significant CMV infection in the letermovir group than in the placebo group (38% vs 61% in placebo; P<.001). The frequency of adverse events, like vomiting and edema, were mildly higher in the letermovir group.¹⁴² Despite the lower toxicity profile of letermovir compared with other CMV-targeted drugs, rapid emergence of resistant mutants under letermovir has been described in cases where treatment is interrupted or underdosed,¹⁴³ or in patients with other risk factors.^144,145

Valganciclovir and ganciclovir are the agents of choice for first-line pre-emptive therapy; foscarnet is more commonly used for patients who cannot tolerate ganciclovir or for second-line pre-emptive therapy.¹²⁴ Foscarnet and ganciclovir had similar efficacy as pre-emptive CMV therapies in recipients of allogeneic HCT, but ganciclovir was associated with a higher rate of early discontinuation because of neutropenia or thrombocytopenia.¹⁴⁶ Although ganciclovir had a higher rate of early discontinuation, there remains a paucity of data to recommend foscarnet as first-line treatment of CMV.^147–149

Pharmacokinetic studies have demonstrated the feasibility and safety of using oral valganciclovir, a prodrug of ganciclovir, in place of ganciclovir in patients who underwent allogeneic HCT.^150,151 Oral valganciclovir used as pre-emptive anti-CMV therapy was shown to have acceptable oral bioavailability and was safe and effective in controlling CMV infection in allogeneic HCT recipients, including patients with grades 1 and 2 gastrointestinal GVHD.^{150,152–154} Thus, valganciclovir is a highly acceptable oral option for pre-emptive therapy for CMV in the absence of substantial gastrointestinal GVHD. Reports of higher rates of CMV disease with oral valganciclovir compared with intravenous ganciclovir in patients with hepatic dysfunction restricted approval for solid tumor transplant patients by specifically excluding liver transplant patients.^155,156 It is postulated that hepatic dysfunction allows bioabsorption of valganciclovir but decreases cleavage of the valine ester, thereby limiting conversion to the active form.¹⁵⁶

Cidofovir has been evaluated as both primary and secondary pre-emptive therapy in recipients of allogeneic HCT.^157–160 In a retrospective study of recipients of allogeneic HCT (n=82) treated for CMV disease (n=20), primary pre-emptive therapy (n=24) or secondary pre-emptive therapy (n=38) with cidofovir demonstrated an observed response in 50% of patients treated for CMV disease (mainly CMV pneumonia) and in 62% of patients treated with primary pre-emptive therapy.¹⁵⁹ Moreover, secondary pre-emptive therapy with cidofovir resulted in a response rate of 66% in patients where disease progressed or relapse occurred (defined as continued presence or recurrence of pp65 antigenemia or viral DNA after at least 1 week of antivirals) following initial pre-emptive therapy with ganciclovir, foscarnet, or a combination of these agents.¹⁵⁹

For CMV infections that are refractory or resistant to available antivirals (valganciclovir, ganciclovir, foscarnet, cidofovir), maribavir has shown promise in some studies. In a phase II, randomized, double-blind trial, ≥400 mg of maribavir twice daily was found to be active against refractory or resistant CMV infections in transplant recipients, with a higher proportion of patients experiencing undetectable CMV DNA within 6 weeks of treatment compared with placebo.¹⁶¹ Dysgeusia was the most common treatment-related adverse event. In another phase III randomized trial, maribavir was superior to other anti-CMV agents in HCT and solid organ transplant recipients, with 56% of patients experiencing CMV viremia clearance under maribavir compared with 24% under other agents (P<.001). Maribavir was also associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and with less neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%).¹⁶² On the other hand, in another phase III randomized double-blind trial, noninferiority of maribavir to valganciclovir for the primary endpoint of confirmed CMV viremia clearance was not achieved based on the prespecified noninferiority margin (69.6% vs 77.4%).¹⁶³ However, maribavir demonstrated comparable CMV viremia clearance to valganciclovir during posttreatment follow-up (52.7% vs 48.5%), with fewer discontinuations due to neutropenia.

Late CMV disease, defined as occurring after day 100 of HCT, remains a persistent problem in the era of CMV prophylaxis and pre-emptive therapy. CMV infections are also common among patients with lymphoproliferative malignancies, patients receiving T-cell suppressive therapy with purine analogs, and patients receiving alemtuzumab therapy, and occurs most frequently between 3 to 6 weeks after initiation of therapy when T-cell counts reach a nadir.^164–169 Several studies of alemtuzumab in patients with chronic lymphocytic leukemia have demonstrated the effectiveness of using routine CMV monitoring coupled with pre-emptive anti-CMV therapy with ganciclovir in preventing overt CMV disease.^{164–166,170} A small randomized study in patients with lymphoproliferative disease treated with alemtuzumab-containing regimens (n=40) showed that upfront CMV prophylaxis with oral valganciclovir significantly reduced the incidence of CMV reactivation compared with oral valacyclovir (0% vs 35%; P=.004).¹⁶⁷

NCCN Recommendations for CMV Prophylaxis

Based on the available data that predict the risk of CMV disease, the NCCN Guidelines panel recommends routine surveillance for CMV reactivation after allogeneic HCT, consisting of weekly monitoring by PCR, especially during alemtuzumab therapy and at least 2 months after completion of treatment.¹⁷¹ On confirmation of CMV viremia (defined as PCR positivity for CMV in ≥2 consecutive samples obtained 1 week apart), the panel recommends pre-emptive therapy with oral valganciclovir, intravenous ganciclovir or intravenous foscarnet for at least 2 weeks and until CMV is no longer detectable (Figure 6).

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INF-4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections, Version 3.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 9; 10.6004/jnccn.2024.0056

In cases of ganciclovir-resistant CMV or when ganciclovir is not tolerated (eg, ganciclovir-induced myelosuppression), intravenous foscarnet or intravenous cidofovir may be used. Additionally, in cases of posttransplant CMV infection that is refractory to ganciclovir/valganciclovir, foscarnet, or cidofovir, oral maribavir may be used. However, infectious disease consult is highly recommended due to the possibility of drug resistance or interaction. Primary prophylaxis with oral or intravenous letermovir may be considered for CMV-seropositive recipients who undergo allogeneic HCT, with a dose reduction recommended if coadministered with cyclosporine due to drug interactions. In patients receiving allogeneic HCT, the strategy of CMV surveillance testing by PCR followed by pre-emptive anti-CMV therapy for a positive result is favored over universal long-term prophylaxis. Some centers consider the use of letermovir through day 100 post-HCT and continue CMV surveillance for patients at high risk for CMV reactivation. In certain circumstances, up to day 200 can be considered.¹⁷² Letermovir lacks HSV and VZV coverage and HSV/VZV prophylaxis should be continued.

Surveillance should typically occur for at least 3 to 6 months posttransplant and during chronic GVHD requiring IST. Higher risk transplant subgroups may exist and require different management strategies. Note that the CD4+ count will be reduced by systemic corticosteroids and by other lymphocyte-depleting agents. The majority of cases of late CMV disease occur within the first year of transplant and <5% occur after the second year.¹⁷³ Therefore, the value of CMV surveillance beyond 2 years after HCT is unknown but can be considered in patients with significant chronic GVHD. There is debate about how to treat patients after a negative test for CMV. There are not enough data to determine whether patients should be transitioned to surveillance or continue with chronic maintenance therapy, and if so, for how long. The benefits must be weighed against the potential toxicity associated with long-term antiviral use. Ganciclovir and valganciclovir are associated with bone marrow suppression that may increase the risk of common opportunistic infections. Foscarnet can cause nephrotoxicity and electrolyte abnormalities but is tolerated.^146,174 Cidofovir can be associated with substantial nephrotoxicity; although less frequent, ocular toxicity has been reported.^159,160 Acyclovir and valacyclovir have excellent safety profiles but are only weakly active against CMV and are not recommended as prophylaxis or treatment of CMV infection.

For the prevention and treatment of CMV pneumonitis, adjunctive intravenous immunoglobulin (IVIG) can be administered; however, IVIG is generally not recommended for prophylactic use except in limited situations due to cost and the limited evidence of activity of this treatment. Although no optimal dosing regimen has been determined, IVIG is commonly administered every other day for 3 to 5 doses. CMV-specific IVIG has not been shown to be any more efficacious than standard IVIG.

Hepatitis B Virus

The risk factors for HBV infection include personal or parental history of an intermediate to high prevalence of HBV infection in one’s birthplace (defined as a prevalence of hepatitis B surface antigen [HBsAg] positivity in >2% of the population); household and sexual contact with HBsAg+ persons; individuals with multiple sexual partners or history of sexually transmitted diseases; individuals who have been inmates of correctional facilities; patients with chronically elevated aspartate aminotransferase or alanine aminotransferase levels; patients with a history of injection drug use; males who have sex with other males; and patients positive for HCV or HIV.

A positive HBsAg is associated with active infection or a window period before the development of protective immunity in patients exposed to HBV. An individual who has been vaccinated for HBV typically has the following serology: negative HBsAg, positive hepatitis B surface antibody (HBsAb), and negative hepatitis B core antibody (HBcAb).¹⁷⁵ False-negative HBsAg results may occur in patients with chronic liver disease.¹⁷⁶ HBsAb positivity is generally equated with protective immunity, although reactivated HBV disease may occur in the setting of significant immunosuppression in individuals who are HBcAb-positive.¹⁷⁷ A patient with resolved hepatitis B infection will be HBcAb positive but HBsAg negative. As mentioned above, some patients with cancer are at increased risk for HBV reactivation due to profound immunosuppression stemming from cytotoxic regimens, high-dose corticosteroids, tyrosine kinase inhibitors, anti-CD20/CD52 monoclonal antibodies, and/or the underlying malignancy (eg, leukemia, lymphoma).

Patients with malignancies who are HBsAg positive and/or HBcAb positive are at risk for HBV reactivation with cytotoxic chemotherapy. Approximately 20%–50% of patients with HBsAg positivity and 3%–45% with HBcAb positivity develop HBV reactivation.^{175,178–187} The risk of HBV reactivation for patients who are HBsAg negative, HBcAb positive varies widely based on the virological profile, disease, and immunosuppressive regimen. Serum HBV DNA testing before the start of therapy may help define their risk of reactivation. If viremic, they may receive similar prophylaxis as patients who are HBsAg positive.¹⁸⁸ Complications of HBV reactivation can range from self-limited hepatitis to fulminant hepatic failure and death.^{187,189–193} HBV reactivation can lead to early discontinuation or delayed initiation of treatment.^194,195 A systematic review and meta-analysis by Zhang et al.¹⁹⁶ revealed that patients with B-cell non-Hodgkin lymphoma (NHL) who are HBsAg+ had worse prognosis and higher incidence of hepatic dysfunction during chemotherapy. In a meta-analysis and evaluation of the United States FDA safety reports, it was reported that HBcAb positivity correlated with increased incidence of rituximab-associated HBV reactivation.¹⁷⁹ After allogeneic HCT, loss of HBV-specific immunity may occur (ie, loss of HBsAb and development of HBsAg and HBV PCR positivity). This has been observed in up to 40% of susceptible individuals in one report¹⁹⁷ and may be confused with hepatic GVHD. A retrospective study showed that recipients of allogeneic HCT who were HBsAg negative but HBcAb positive had a high risk of seroconversion to HBsAg positivity and HBV reactivation (subsequently leading to hepatitis) following allogeneic HCT.¹⁹⁸

There are several nucleos(t)ide analogs approved by the FDA for the prevention and treatment of HBV. Historically, data supporting the use of these analogs have been based on lamivudine, a reverse transcription inhibitor. In a meta-analysis of clinical trials evaluating lamivudine prophylaxis in patients with HBsAg-positive lymphoma treated with IST, prophylaxis resulted in a significant reduction in HBV reactivation (risk ratio, 0.21; 95% CI, 0.13–0.35) and a trend for reduced HBV-related deaths (risk ratio, 0.68; 95% CI, 0.19–2.49) compared with no prophylaxis.¹⁹⁹ However, despite its initial effectiveness, virologic breakthrough was high, with reports of resistance in 80% of patients after 5 years of therapy.²⁰⁰ Thus, lamivudine monotherapy has fallen out of favor. Studies suggest one of the newer agents (such as entecavir or tenofovir) may be preferable or combination therapy may have a possible role for patients with lamivudine-resistant HBV infections.^201–203

As of 2015, tenofovir is available in 2 different prodrug forms, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (AF). Tenofovir AF has greater plasma stability than TDF, allowing use of a lower dose and lesser systemic exposure to the drug.²⁰⁴ TDF has demonstrated superior antiviral efficacy compared with adefovir in a phase III randomized double-blind study in patients with chronic HBV infection, making tenofovir preferred over adefovir in this setting.²⁰⁵ Two randomized, phase III, double-blind studies comparing tenofovir AF to TDF in patients with HBeAg-negative²⁰⁶ or HBeAg-positive²⁰⁷ chronic HBV infection showed that the efficacy of tenofovir AF was noninferior to TDF, with better bone and renal safety for tenofovir AF. Although these data support the use of tenofovir for HBV infection, limited data are available regarding its use in patient populations with cancer. A systematic review and meta-analysis showed that in patients with HBV-associated hepatocellular carcinoma, tenofovir was associated with better overall survival and reduced late recurrence compared with entecavir.²⁰⁸ No detectable resistance to TDF was reported in patients with chronic hepatitis B after 6 years of treatment.²⁰⁹ In another study, sequencing of the HBV polymerase/reverse transcription indicated sequence changes at polymorphic sites, though none resulted in drug resistance.²¹⁰ In total, there were only 16 cases of virologic breakthrough, 12 of which were associated with nonadherence to study medication. Resistance for TDF remained undetectable throughout a 5-year span. By comparison, lamivudine resistance was calculated to be 24% in the first year, and this number steeply climbed to 70% by year 5.²¹⁰

Entecavir has shown improved antiviral activity compared with adefovir in randomized open-label studies in patients with chronic hepatitis B.²¹¹ A few small case studies have evaluated entecavir in the prevention²¹² or treatment of HBV in patients with cancer (reviewed by Liu et al.²¹³). Entecavir had a low drug resistance of 1.2% at 5 years²¹⁴ compared with adefovir, which had an intermediate resistance that increased from 0% in the first year to 29% by year 5.^205,215,216

In addition to drug resistance, the safety profile of the nucleos(t)ide analogs should affect drug selection. Nephrotoxicity has been seen with adefovir^217,218 and tenofovir (specifically TDF).²¹⁹ No significant side effects have been reported with lamivudine or entecavir; however, it is recommended that all patients be monitored for lactic acidosis and severe hepatomegaly with steatosis.

NCCN Recommendations for HBV Prophylaxis

Risk-based screening is recommended by ASCO²²⁰ and the American Association for the Study of Liver Disease (AASLD).²²¹ Although it is possible that risk-based screening may be more cost-effective than universal screening, there are currently no validated risk tools that could easily be implemented into clinical practice. Furthermore, <60% of patients with HBV infection may have obvious risk factors,²²² and only 10%–35% of these patients may be aware of their own HBV infection.^223,224 Therefore, any patient expected to receive IST or chemotherapy should be screened. Implementation of universal screening, as recommended by the CDC, should be considered.²²⁵

In patients undergoing intensive IST, including HCT, both patient and donor should be screened for HBV, HCV, and HIV prior to treatment. Evaluation of HBsAg, HBcAb, and HBsAb should be considered at baseline.^124,175 Vaccination against HBV should be strongly considered in patients who are HBV-naïve (ie, negative for HBsAg, HBsAb, and HBcAb) (see later section on “Vaccination”).^124,175 In patients who are HBV-naïve undergoing allogeneic HCT, grafts from donors who are HBsAg-positive or HBV DNA-positive should be avoided wherever possible. Donors who have not been exposed to HBV should be considered for HBV vaccination before hematopoietic cell collection.

In individuals who are HBsAg-positive or HBcAb-positive, baseline quantitative PCR for HBV DNA should be obtained. In allogeneic HCT candidates with evidence of active HBV infection (chronic hepatitis based on biopsy or positive HBsAg or high levels of HBV DNA), transplant procedure should be delayed when possible, and antiviral therapy should be given for 3 to 6 months prior to conditioning.¹²⁴ In HCT candidates who are HBsAg-positive or HBcAb-positive but without evidence of active HBV replication, antiviral prophylaxis should be considered (starting shortly before the transplant procedure). All allogeneic HCT recipients should continue surveillance for at least 12 months after transplant or during GVHD (Figure 7). For details on the management of HBV infection in patients with B-cell NHL, see the NCCN Guidelines for B-Cell Lymphomas (available at NCCN.org)

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INF-5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections, Version 3.2024.

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The optimal choice of antiviral agents for prophylaxis (or pre-emptive approaches) will primarily be driven by institutional standards. The NCCN panel recommends consultation with an expert in hepatitis treatment to determine appropriate antiviral prophylaxis for patients who test positive for HBV. Preferred agents for HBV prophylaxis are entecavir and tenofovir. Although data were originally obtained with lamivudine, entecavir and tenofovir are preferred, especially when treating patients with active HBV infections due to the low threshold of resistance with lamivudine. Monitoring of HBsAg and HBV DNA and transaminases should be considered for patients without active HBV infection who are not receiving prophylaxis.

Hepatitis C Virus

Studies for HCV reactivation in patients with cancer are not as expansive as studies for hepatitis B; however, an increase in mortality was reported in patients with cancer who had HCV infection compared with patients with cancer who were HCV negative.²²⁶ A review by Yazici et al²²⁷ summarized studies of HCV reactivation in patients receiving targeted therapies, and the data correlated an increase in HCV reactivation with these therapies.²²⁷ Differences in outcomes between patients who are HCV positive with cancer versus HCV positive without cancer were reported to include higher occurrence of occult infection, higher risk of developing early cirrhosis, higher rate of fibrosis progression, development of viral reactivation, and poorer virologic outcomes (reviewed by Borchardt et al).²²⁸ The guidelines from the joint IDSA and AASLD panels for the testing, management, and treatment of hepatitis C recommend that treatment of HCV be considered for patients with chronic HCV with a life expectancy of >12 months.²²⁹

NCCN Recommendations for HCV Screening and Management

All patients who are expected to receive chemotherapy or IST should be screened for HCV. The data are limited regarding the treatment of HCV in patients with cancer, but it is generally not recommended that HCV treatment and cancer therapy be given concurrently.²²⁸ The IDSA/AASLD guidelines can provide additional guidance for antiviral therapy, but an infectious diseases consult is necessary to evaluate the use of concomitant or sequential anti-HCV and cancer therapy.²²⁹ Monitoring of ALT levels and HCV viral load monthly, or as clinically indicated, should be initiated as part of surveillance (Figure 7). For details on the management of HCV infection in patients with HCV-associated lymphomas, see the NCCN Guidelines for B-Cell Lymphomas (available at NCCN.org).

Human Immunodeficiency Virus

The CDC surveillance report estimates that 1.1 million persons are living with HIV in the United States. This includes the estimated 166,000 persons whose infection has not yet been diagnosed.²³⁰ There is support for HIV testing in all patients treated for cancer.²³¹ Patients who are HIV-positive and have cancer are classified as having either AIDS-defining cancer (ADC) or non–AIDS-defining cancer (NADC). ADC includes Kaposi sarcoma, NHL, and cervical cancer. There is a higher incidence of these cancers in those who are HIV-positive than in those who are HIV-negative.²³²

The incidence of NADC is increasing, likely due to the longer life expectancy of patients with HIV resulting from the advancement of treatment options.²³³ Patients with HIV and NADC were shown to have an overall worse cancer outcome when compared with patients who are HIV-negative with the same cancer.²³⁴ However, improvement in outcome was seen when patients with HIV received highly active antiretroviral therapy.²³⁵ There should be caution regarding the concomitant administration of select antiretroviral therapies (including the protease inhibitors and non-nucleoside reverse transcription inhibitors) with cancer therapy as adverse events through cytochrome P450 3A4 have been documented.²³⁶ A publication from MD Anderson Cancer Center retrospectively evaluated the use of HIV screening in patients before systemic cancer therapy.²³⁷ Of the 18,874 patients in this study, 3,514 patients tested positive for HIV at the initiation of systemic cancer therapy. Patient histories indicated a higher incidence in patients with sexually transmitted disease (37.7% vs 18.5%; P<.001) or a history of illegal drug use (46.2% vs 18.6%; P<.001). Patients screened for HIV included 12.1% of patients with NADC and 9.4% of patients with cervical cancer. Interestingly, a significantly higher percentage (88.4%) of patients with NHL were screened for HIV, which may be partially attributed to clinician education of the role of HIV in these patients.²³⁷

NCCN Recommendations for HIV Screening

In 2006, the CDC published recommendations for routine HIV testing in all patients (13–64 years of age) in the health care setting.²³⁸ The testing is intended to be voluntary and conducted only with consent from patients. Under these guidelines, patients are informed either verbally or in written format that HIV testing will be conducted unless the patient declines testing (opt-out screening). The CDC recommends that patients at high risk for HIV infection be screened at least annually.²³⁸ The implementation of these guidelines is largely dependent on institutional practices and the prevalence of undiagnosed HIV infections in specific institutions. However, the NCCN panel strongly encourages concordance with the CDC recommendations.

In addition to the CDC recommendations, the NCCN panel emphasizes that all patients receiving chemotherapy or IST be screened for HIV.²³¹ Patients coinfected with hepatitis pose an additional complication. Select antiretroviral therapies including the integrase strand inhibitors and nucleoside/nucleotide reverse transcription inhibitors have demonstrated fewer drug–drug interactions compared with the protease inhibitors and non-nucleoside reverse transcription inhibitors. However, consultation with an infectious disease expert is necessary for treatment of HIV in patients with cancer as therapies continuously evolve. HIV viral load should be monitored monthly during therapy and then as clinically indicated (Figure 7; see also NCCN Guidelines for Cancer in People with HIV, available at NCCN.org).

Screening for Other Viruses

Rapid PCR panels should be considered for detection of respiratory viruses including respiratory syncytial virus (RSV), influenza, parainfluenza virus, adenovirus, rhinovirus, and metapneumovirus in patients with cough and/or shortness of breath that might indicate a viral infection. Ribavirin and IVIG have been proposed as antiviral therapies^239–243; however, data are not sufficient to provide recommendations.

RSV is a major cause of severe infection in patients who are immunocompromised, with mortality rates ≤80% in HCT recipients.^244,245 Progression of RSV to the lower respiratory tract occurs in ≤50% of patients receiving HCT or chemotherapy.^246–248 The virulent nature of RSV requires hospitalization for treatment. Treatment options are limited to ribavirin and adjunctive IVIG. There is a diversity of practice among the institutions for the treatment of RSV disease. Based on limited data^249–251 and strong panel disagreement regarding the use of ribavirin and the best method of delivery, ribavirin has been designated a category 3 recommendation. Recommendations for inhaled versus oral ribavirin should be based on the individual institution.

Rapid screening tests are available for detection of influenza. Clinical benefit is highest when treatment is initiated within the first 48 hours of influenza symptoms, although benefits can still be seen when initiated after the 48-hour window.²⁵² During the influenza season, consider empirical antiviral therapy for patients within 48 hours after symptoms develop that are suggestive of influenza (eg, high fever, coryza, myalgia, dry cough), especially during community outbreaks. Both the IDSA (2007) and CDC guidelines (2011) recommend antiviral treatment with the neuraminidase inhibitors oseltamivir or zanamivir, which are active against both influenza A and B viruses.^253,254 Both agents are approved by the FDA for the treatment of influenza within 48 hours of symptomatic onset; the indicated duration of treatment is 5 days. However, longer courses of treatment (eg, 10 days) and treatment until resolution of symptoms can be considered in those who are immunocompromised, though this is controversial. Some centers have used higher doses (eg, 150 mg twice a day) of oseltamivir in these patients with mixed results. Pandemic influenza does not have a predictable seasonal pattern and may spread in the community concurrently with a seasonal influenza strain. Antiviral susceptibility of influenza strains is variable and cannot be predicted based on previous influenza outbreaks. In cases of seasonal influenza and pandemic strains, it is necessary to be familiar with susceptibility patterns and guidelines on appropriate antiviral treatment.²⁵⁵ There are limited data on the activity of peramivir; with comparable clinical outcomes observed in comparison with oseltamivir.^256,257 Peramivir, available as an intravenous injection, can be considered for patients who cannot absorb oral oseltamivir or tolerate oseltamivir or inhaled zanamivir.

A few small case studies showed limited efficacy of baloxavir, a polymerase inhibitor active against both influenza A and B viruses, in immunocompromised patients with oseltamivir- or peramivir-resistant influenza.^258–260 However, due to limited data and emergence of resistant strains,^260,261 this option is not routinely recommended by the CDC.

BK virus is a common polyomavirus that remains dormant in the kidney and urinary tract. In immunosuppressed individuals, BK virus can reactivate. Patients undergoing allogeneic HCT are particularly vulnerable to BK virus, and the development of hemorrhagic cystitis and additional complications such as ureteral stenosis.^262,263 Supportive care remains the mainstay of management. While cidofovir demonstrates effectiveness as a treatment option for BK virus, renal toxicity is a significant complication.²⁶⁴ There is currently a lack of data to support recommendations on the treatment of BK virus. Expert consensus on management has been published for pediatric HCT recipients.²⁶⁵

COVID-19 screening, prophylaxis, and treatment is a complex and rapidly evolving area. Please see the CDC guidelines for latest recommendations.

Influenza Vaccine

Influenza infections cause significant morbidity and mortality in patients with cancer. Among bone marrow transplant recipients, influenza accounts for about 10%–40% of all community-acquired viral respiratory infections.^282–284 An increase in both the incidence and duration of influenza infections has been observed in patients with cancer who are immunosuppressed compared with healthy controls.^285,286 During community outbreaks, influenza infections may represent a significant proportion of fever and neutropenia episodes.²⁸⁷ Influenza infections in patients with cancer who are severely immunocompromised are often associated with hospitalizations, delays in potentially life-saving chemotherapy, and occasionally death.^285–287 As a result, annual vaccination against influenza with the inactivated influenza virus is recommended for all individuals at increased risk due to immunosuppression.²⁸⁸ A randomized study of 97 patients receiving cytotoxic chemotherapy (3-week cycles) for solid tumors found that the immunogenicity of the influenza vaccine was similar when administered at the time of chemotherapy administration (day 1) or within the cytopenic period (day 11).²⁸⁹ The Advisory Committee on Immunization Practices (ACIP) for the CDC guidelines includes health care professionals and household members or caregivers in their target group for annual immunization to prevent transmission of influenza to patients at high risk.²⁸⁸

The intranasal vaccine should be avoided in patients with immunosuppression, because a LAIV is still capable of replication, which could theoretically lead to infection in immunocompromised individuals.^288,290 Because no data are available assessing the risk for person-to-person transmission of the LAIV from vaccine recipients to immunosuppressed contacts, the CDC recommends that inactivated influenza vaccine should be used in household contacts, health care workers, and others who have close contact with patients who are severely immunocompromised (ie, persons requiring a protected environment). Persons with close contact to patients with a lesser degree of immunosuppression (eg, patients receiving chemotherapy or corticosteroids, patients with HIV) may receive the LAIV.^288,290

There are not yet sufficient data for the panel to recommend the high-dose influenza vaccine over the standard-dose influenza vaccine. Preliminary data have shown that the high-dose influenza vaccine is safe for patients with cancer and may show more immunogenicity compared with the standard-dose influenza vaccine for this patient population.^291,292 A randomized, single-blind, controlled trial of influenza vaccine in autologous HCT recipients found comparable seroprotection and seroconversion rates against all influenza strains with both the high-dose and the standard-dose vaccines when used as part of a 2-dose regimen.²⁹³ Further data are needed to assess whether the high-dose influenza vaccine confers a clinical benefit compared with the standard-dose vaccine for patients with cancer.

Pneumococcal Vaccine

The pneumococcal conjugate vaccine can be given in newly diagnosed adults with hematologic or solid tumor malignancies following assessment of their immune status. The conjugate pneumococcal vaccine (PCV20) should be administered to newly diagnosed adults with cancer who are pneumococcal vaccine-naïve. Alternatively, PCV15 can be given, followed by the polysaccharide pneumococcal vaccine (PPSV23) at least 8 weeks later. Additional PPSV23 is not needed for those receiving PCV20. For patients who have previously received PPSV23, PCV20 (preferred) or PCV15 can be given. Patients who have previously received PCV13 only can receive PCV20 (rather than PPSV23) at least 1 year later. Patients who have previously received PCV13 and 1 to 2 doses of PPSV23 can receive PCV20 at least 5 years later.

A phase III randomized controlled clinical trial found that PCV15 had a comparable safety profile to PCV13 in allo-HCT recipients and induced comparable immune responses to PCV13.²⁹⁴ Based on CDC recommendations, vaccination with the conjugated 20-valent or 15-valent vaccine 3 to 6 months after HCT is recommended. If PCV20 is used, 4 doses should be administered. The first 3 doses are generally 1 to 2 months apart, with the fourth dose 6 months after the third dose. There is no need to give PPSV23. If PCV15 is used, 3 doses should be administered, followed by PPSV23 6 to 12 months post primary series. Following the primary series of 3 PCV doses, a dose of the PPSV23 to broaden the immune response might be given. For patients with chronic GVHD in whom PPSV23 might not be as effective, a fourth dose of PCV20 or PCV15 should be considered instead of PPSV23. Patients with asplenia should receive the pneumococcal vaccine. According to the ACIP Vaccine Recommendations and Guidelines for Altered Immunocompetence, the pneumococcal vaccine should be administered at least 2 weeks before elective splenectomy. Penicillin prophylaxis is advised in patients who are asplenic to prevent pneumococcal disease.^295,296

Meningococcal Conjugate Vaccine

The meningococcal vaccine is recommended for patients with increased risk for meningococcal disease including patients with persistent complement component deficiency, patients taking eculizumab, and patients with anatomic or functional asplenia. The ACIP recommends that asplenic persons be immunized with the meningococcal vaccine. The meningococcal vaccine should be administered at least 2 weeks before elective splenectomy. Patients at increased risk for meningococcal disease should receive quadrivalent conjugate vaccine series (MenACWY) and monovalent meningococcal serogroup B vaccine series. Patients at risk include those with persistent complement component deficiencies, those taking a complement C5 inhibitor (eg, eculizumab, ravulizumab), or those with anatomic or functional asplenia. MenACWY vaccine is given in 2 doses ≥8 weeks apart; serogroup B vaccine is available in a 2-or 3-dose series, depending on the vaccine formulation used. The meningococcal vaccine is recommended 6 to 12 months after HCT. Booster doses can be considered in those that remain at risk for meningococcal disease. This includes revaccination every 5 years with MenACWY vaccine, while for MenB vaccine, 1 booster dose is recommended 1 year after primary series with revaccination every 2–3 years if risk remains.

Human Papillomavirus Vaccine

The HPV vaccine is a recombinant 3-dose vaccine that is recommended for patients ≤26 years of age, and can be considered for those up to age 45. The lower age limit for this vaccine is 9 years of age. Although it does not treat existing HPV infection or disease, HPV vaccination is still recommended in individuals with prior HPV since it can still provide protection against HPV serotypes not already acquired.

Haemophilus Influenzae Type b Vaccine

Immunization of adults with the pediatric H. influenzae type b (Hib) vaccine is considered optional because of limited data on efficacy in older children and adults, although studies suggest good immunogenicity in patients who are immunocompromised. The Hib vaccine is recommended 6 to 12 months post-HCT. For patients with planned splenectomy, immunization is ideally performed at least 2 weeks in advance. If this is not feasible, immunization is advisable after splenectomy, because such patients are still capable of mounting a protective antibody response.

Varicella/Zoster Vaccines

The recombinant zoster vaccine (RZV) should be given to patients 50 to 70 days after autologous HCT. RZV may be considered after allogeneic HCT; however, its efficacy in allogeneic HCT, in the presence of GVHD, or during ongoing immunosuppression has not been established. The CDC recommends administration of RZV for patients aged ≥50 years, and those ≥18 years who are at increased risk for herpes zoster. The RZV vaccine is given in 2 doses 2 to 6 months apart. For adults who are immunocompromised and aged ≥18 years, a second dose can be given 1 to 2 months after the first dose if they will benefit from a shorter vaccination schedule. For patients who have previously received the live-attenuated herpes zoster vaccine, RZV should be given at least 2 months after the last live-attenuated herpes zoster dose.

COVID-19 Vaccine

The NCCN Guidelines recommend COVID-19 vaccination for all persons with cancer or who have been previously treated for cancer. According to the CDC, individuals aged ≥6 months who are moderately or severely immunocompromised (including recipients of HCT) and not previously vaccinated against COVID-19 should get 2 or 3 doses of the same brand of updated COVID-19 vaccine. Additionally, updated vaccines should be administered at least 2 weeks before initiation or resumption of immunosuppressive therapies. The NCCN Guidelines recommend vaccination with COVID-19 vaccine 6 months post-HCT, with a consideration for early vaccination at 3 months during community outbreaks and high disease activity. For further details of the most up-to-date vaccination recommendations, refer to CDC guidance.

Tetanus/Diphtheria/Pertussis (Tdap) Vaccine

As per the CDC, individuals ≥7 years should receive one dose of Tdap every 10 years. The FDA/ACIP approved a 3-dose series of Tdap/Tdap/Tdap or Tdap/Td/Td (tetanus/diphtheria) for individuals ≥7 years. For recipients of HCT, NCCN recommends administration of the 3-dose vaccine series, with the first dose 6 to 12 months post-HCT.

RSV Vaccine

The RSV vaccine is available for adults aged ≥60 years. However, its effectiveness in patients with cancer is unknown. The long-acting RSV monoclonal antibody (nirsevimab) is approved for infants <24 months of age to prevent RSV infection.

Travel Vaccines

Vaccines have variable risk and efficacy in patients receiving cancer care; therefore, the panel recommends consultation with an infectious disease expert before the administration of travel vaccines (eg, typhoid, yellow fever). Additional information on travel vaccines may be found in the CDC Yellow Book.

Vaccine Summary

Although efficacy data are lacking for the use of vaccines in patients with cancer, recommendations for their use are based on the principles of immunization and safety data. Persons receiving chemotherapy or radiation therapy for malignancies should not receive live vaccines for at least 3 months after cessation of therapy and until they are presumed to be immunocompetent.²⁹⁷ Live vaccines are contraindicated during treatment and for a period of at least 6 to 12 months in patients receiving IST (eg, blinatumomab, CAR T-cell therapy, monoclonal antibodies). These patients may also have a blunted response to inactivated vaccines. Certain live vaccines can be safely administered to household members of patients who are severely immunocompromised (eg, measles, mumps, rubella), whereas others cannot (eg, smallpox vaccine) because of the potential risk of transmission. The package insert for the vaccine should be reviewed prior to administration. The NCCN panel recommends that all household members be up to date on vaccinations.

Ideally, patients should be vaccinated at least 2 weeks before receiving cytotoxic therapy or IST; however, this timing is often not feasible in patients with cancer. In general, vaccination should not be given on the same day as cytotoxic therapy as cytotoxic therapy may reduce the proliferative lymphocytic responses required for protective immunity. In patients receiving chemotherapy, immunization between cytotoxic chemotherapy courses is likely to be associated with higher response rates than during chemotherapy administration.^298,299 Patients vaccinated <2 weeks before starting cytotoxic therapy or IST or while receiving these agents may have a limited response to vaccination. These patients should be revaccinated at least 3 months after therapy is discontinued and once immune competence has been restored.²⁹⁷

In summary, the NCCN panel recommends that patients with cancer receive the influenza, COVID-19, pneumococcal, meningococcal, and HPV vaccines (Figure 9). HCT recipients should also receive the inactivated vaccines for Tdap, Hib, hepatitis A and B, RZV, and polio (Figure 10 and Figure 11). The live vaccines for measles, mumps, rubella, and varicella may be given if no GVHD or ongoing immunosuppression is seen 2 years posttransplant in patients who are seronegative. Consultation with an infectious disease expert is recommended before administration of travel vaccines.

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INF-7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections, Version 3.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 9; 10.6004/jnccn.2024.0056

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INF-8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections, Version 3.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 9; 10.6004/jnccn.2024.0056

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INF-8A. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prevention and Treatment of Cancer-Related Infections, Version 3.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 9; 10.6004/jnccn.2024.0056