Cancer patients, particularly those with hematologic malignancies, usually have neutropenia, both disease-related and treatment-related, which makes those patients in danger of various types of infection. The way to prevent these patients from infection is prophylactic antibiotics uses. In this post we talk about how to manage neutropenia patients with cancer who are afebrile.

This post is based on the guideline of ASCO.

Assessing the risk of developing an FNE (febrile neutropenic episode)

Evidence data for the evaluation of outpatients is not available, therefore the ASCO Panel considered evidence from studies on inpatients or mixed populations.

Risk for developing an FNE should be systematically assessed (in consultation with infectious disease specialists as needed), including patient-, cancer-, and treatment-related factors.

Risk factors for FNE or for complications resulting form an FNE in oncology patients undergoing systemic chemotherapy are list in Table 1. These risk facors are grouped by characteristics of: patients and their health status, their underlying malignancy, and the chemotherapy regimen they are receiving. Studies cited in Table 1 and others have developed and tested models to predict likelihood of an FNE in the first or a subsequent chemotherapy cycle. On the basis of members’ expert opinion, the Panel recommends that patients starting a new chemotherapy regimen undergo an individualized but systematic assessment of risk for an FNE to evaluate the factors list in Table 1, involving consultation with local infectious disease experts as needed.

Table 1. Factors to Consider in Assessing Risk of and FNE in Patients Unergoing Cytotoxic Chemotherapy for Malignancy.

These risk factors in Table 1 are based on patient, cancer, and treatment modality.

Antibacterial Prophylaxis

Generally, the Panel suggests that clinicaians consider the use of antibacterial prophylaxis only for patients expected to experience profound neutropenia (defined as ANC < 100/μL) likely to last for ≥ 7 days. The Panel does not recommend routine antibacterial prophylaxis for patients with neutropenia that is less severe or of shorter duration. However, prophylaxis might be recommended for patients at high risk of mortality if an FNE occurs.

The literature serach found that antibacterial prophylaxis decreased mortality when compared with pooled controls receiving either placebo or no treatment. However, in these RCTs a majority of patients were undergoing either remission induction (or reinduction) for hematologic malignancy (mostly acute leukemia) or hematopoietic SCT (HSCT). In this population group their rates of febrile episodes, clinically documented infection, microbiologically documented infection, and bacteremia are high. Thus these patients were at high risk for FNE (febrile neutropenic episode).

Few RCTs of antibacterial prophylaxis focused on patients with cancer and neutropenia at low risk for an FNE or infection. In some studies about patients with solid tumors or lymphoma, the prophylaxis significantly decreased documented febrile episodes (core temperature > 38℃) attributed to infection in the first cycle and over the full course of chemotherapy. Also prolhylaxis also significant decreased rates of probable infection and hospitalization for infection, both in the first cycle and over the full course of chemotherapy. However, it did not yield a statistically significant decrease in rates of severe infection (infection-related sepsis syndrome, death, or both) or infection-related mortality.

A subset analysis in one meta-analysis pooled data from the RCT for patients with solid tumor or lymphoma reported a statistically significant decrease in all-cause mortality during the first month of chemotherapy. However, the absolute difference in 30-day mortality was modest and the prophylaxis did not significantly decrease all-cause mortality by the end of follow-up. These data suggest that it is not recommended to routinely use prophylactic antibacterial therapy in low-risk patients.

Thus, we recommend that clinicians limit use of antibacterial prophylaxis to patients at high risk for an FNE associated with prolonged severe neutropenia (ANC < 500/µL). The risk for FNE or infection are importantly determined by the expected duration and depth of neutropenia, and other factors in Table 1. However, because direct evidence is lacking, it is difficult to define risk thresholds for the two important variables above. Thus, ASCO Panel recommend that unless one or more other high-risk features of Table 1 are present, antibacterial prophylaxis should be limited to patients expected to have profound neutropenia (ANC < 100/µL) for at least 7 days.

Antifungal Prophylaxis

For the fungal infection, three meta-analyses reported that when compared with controls, systemic antifungal prophylaxis significantly decreased mortality attributed to fungal infections. Also the need for subsequent full-dose parenteral antifungal therapy was decreased and the incidence of systemic, invasive, and/or superficial fungal infections decreased too. Again, however, most patients randomly assigned in these RCTs were at high risk for IFI (invasive fungal infection) resulting from HSCT, induction chemotherapy for acute leukemia, or other treatments that caused lengthy durations of profound neutropenia.

The most recent review pooled data from 33 RCTs found a statistically significant decrease in fungal infection-related mortality and all-cause mortality at the end of follow-up. However, metaregression analysis showed statistically significant associations between the proportion of randomly assigned patients being treated for leukemia with the treatment effects of systemic antifungal prophylaxis in both overall mortality and risk for IFI.

Data from the most recent meta-analysis of RCTs of antifungal prophylaxis also showed that pooled IFI rates (either candidiasis or aspergillosis) among controls were approximately 6% across 24 studies of patients undergoing treatment for acute leukemia and > 10% across four studies of patients undergoing HSCT, each associated with lengthy duration of profound neutropenia. Thus, the ASCO Panel recommends limiting antifungal prophylaxis to patients at substantial risk for IFI (> 6% to 10%), which is profound neutropenia (ANC < 100//µL) for at least 7 days.

                                                                                                                                               Table 2. Risk Factors for Invasive Mold Infection

Risk Factors for IFI
  • Prolonged profound peutropenia (ANC < 100/µL for > 7 days) in the context of intensive remission-induction or reinduction therapy for acute leukemia in environments where the risk for invasive aspergillosis exceeds 6%
  • Prolonged (> 21 days) severe neutropenia (ANC < 500/µL), lymphocytopenia (ALC < 500/µL), or monocytopenia (AMC < 150/µL) among allogeneic HSCT recipients experiencing graft failure
  • Use of purine analogs (eg, fludarabine) to treat malignancy for pre-HSCT conditioning
  • Use of intensive immunosuppression for treating GVHD
  • Reactivation of cytomegalovirus
  • Iron overload states
  • A previous documented invasive mold infection
  • Environmental exposures associated with personal habits, outside activities, or indoor activities
Of note: many of these risk factors may interact to enhance the risk for mold infection.

Prophylaxis for Pneumocystis jirovecii Infection

Patients receiving chemotherapy regimens associated with a risk > 3.5% for pneumonia resulting from Pneumocystis jirovecii (PCP; eg, those with ≥ 20 mg of prednisone equivalents daily for ≥ 1 month or those based on purine analogs) are eligible for prophylaxis.

Retrospective analyses suggest those at greatest risk are patients undergoing intensive induction (or salvage reinduction) for acute leukemia, allogeneic bone marrow transplantation (particularly if receiving alemtuzumab), or treatment with either high-dose corticosteroids (eg, ≥ 20 mg of prednisone equivalents daily for ≥ 1 month) or purine analogs that deplete T cells such as fludarabine or cladribine. Additionally, a recent report suggests the regimen combining rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone every 2 weeks (R-CHOP-14) is associated with elevated risk for PCP (10% to 15%), although the regimen with the same drugs every 3 week (classical R-CHOP) is not. Another recent retrospective analysis suggests that CD4+ lymphocyte counts ≤ 200/µL predicted a higher risk (approximately 19%) for PCP in patients treated for B-cell non-Hodgkin lymphoma.

Prophylaxis for Reactivation of Hepatitis B Virus (HBV) Infection

Antiviral prophylaxis should be offered to patients know to be at substantial risk for reactivation of hepatitis B virus (HBV) infection.

Reactivation of HBV infection after treatment for malignancy has been reviewed extensively. Guidelines from several other organizations suggest that patients at risk for HBV reactivaton should be screened for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B core antigen (anti-HBc). Howver, ASCO Panel concluded that available evidence was insufficient to determine the net benefits and harms of routine screening for chronic HBV infection in all individuals with cancer about to receive (or already receiving) cytotoxic or immunosuppressive therapy. The Panel recommended a more targeted approach to HBV testing, using clinical judgment to select patients at risk who are about to receive or already receiving highly immunosuppressive treatments including, but not limited to, HSCT and regimens that include rituximab.

Three groups with a history of prior exposure to HBV are at risk: patients with chronic infection and viremia, chronic inactive carriers (positive for HBsAg for ≥ 6 months but with serum HBV DNA < 2,000 IU/mL and normal serum levels of hepatic transaminases), and those with immunity against HBV because of past exposure. Factors that may increase reactivation risk include male sex, younger age, hepatic transaminase levels > the normal range or HBV DNA > 3 × 105 copies/mL before cytotoxic therapy begins, dose-intense chemotherapy, and severe immunosuppression.

Prophylaxis for HSV and VZV

Evidence summarized in some revies suggests that most HSV (herpes simplex virus) or VZV (Varicella-Zoster virus) infections in patients undergoing treatment for malignancy are the result of reactivation of latent virus from prior exposure; new primary infections are uncommon.

In the absence of HSV prophylaxis, reactivation has been reported in 37% to 57% of patients undergoing intensive chemotherapy for hematologic malignancies and in 68% to 90% of those undergoing myeloablative allogeneic HSCT.

Reactivation of latent VZV, present in most adults, results in herpes zoster; complications may include postherpetic neuralgia, zoster ophthalmicus, scarring, or bacterial superinfection. Among patients with hematologic malignancies, VZV reactivaton is reportedly uncommon after imatinib for chronic myeloid leukemia (2.6%) but more frequent after fludarabine or alemtuzumab for chronic lymphocytic leukemia (10% to 15%), treatment for Hodgkin lymphoma or autologous HSCT (25%), and bortezomib for multiple myeloma (11% to 15%). VZV reactivation occurs in 30% to 60% of those who undergo allogeneic HSCT but is typically delayed until after engraftment. The median time to reactivation among such patients has been reported to be approximately 8 months, and approximately one in five may develop postherpetic neuralgia.

It is recommended that HSV or/and VZV seropositive patients undergoing therapy for certain hematologic mailignancies should be given prophylais to prevent reactivation of infection because of HSV.

Prophylaxis for Influenza

Seasonal influenza immunization is recommended for all patients undergoing treatment for malignancy and for all family and household contacts.