Neutropenia Treatment & Management

Medical care for patients with neutropenia is mostly supportive and based on the etiology, severity, and duration of the neutropenia. Fever and infections occurring as complications of neutropenia require specific treatment; see Antimicrobial Agents in Neutropenic Cancer Patients. Surgical care is not usually indicated but may be employed in certain contexts.

Go to Pediatric Autoimmune Neutropenia for complete information on this topic.

General measures to be taken include the following:

• Removal of any offending drugs or agents is the most important step in most cases involving drug exposure; if the identity of the causative agent is not known, stop all drugs until the etiology is established.

• Use careful oral hygiene to prevent infections of the mucosa and teeth; control oral and gingival lesion pain with saline and hydrogen peroxide rinses and local anesthetic gels and gargles.

• Avoid rectal temperature measurements and rectal examinations.

• Administer stool softeners for constipation.

• Use good skin care for wounds and abrasions; skin infections should be managed by a clinician with experience in the treatment of infection in neutropenic patients.

• Do not allow plants and dried or fresh flowers in the rooms of hospitalized neutropenic patients.

Start specific antibiotic therapy to combat infections. This often involves the use of third-generation cephalosporins or equivalents. Fever may be treated as an infection, as follows ^{[6, 7, 8, 9, 10]} :

• Cefepime, a carbapenem (eg, meropenem or imipenem-cilastatin), or piperacillin-tazobactam can be used as a single agent

• Agents from other antimicrobial classes (eg, aminoglycosides, fluoroquinolones, vancomycin) may be added for management of complications (eg, hypotension and pneumonia) or antimicrobial resistance (suspected or proven)

With blood culture results suspicious for resistant bacteria, early addition of the following antimicrobials may be considered:

• Methicillin-resistant Staphylococcus aureus (MRSA) - Vancomycin, linezolid, or, in the absence of evidence for pneumonia, daptomycin

• Vancomycin-resistant enterococcus (VRE) - Linezolid or daptomycin

• Extended-spectrum β-lactamase (ESBL)–producing gram-negative bacteria - A carbapenem

• Carbapenemase-producing organisms, including Klebsiella pneumoniae carbapenemase (KPC) - Polymyxin-colistin or tigecycline, or a newer β-lactam with activity against resistant gram-negative organisms as a less toxic and potentially more effective alternative

If the neutropenic patient’s fever does not respond within 4-5 days or if the fever recurs with the administration of broad-spectrum antibiotics after an initial afebrile interval, consider adding empiric antifungal coverage with amphotericin B (preferably lipid formulation), a broad-spectrum azole (eg, voriconazole), or an echinocandin (eg, caspofungin).

Special considerations in chemotherapy-related neutropenia

In adult patients with cancer who develop febrile neutropenia while undergoing chemotherapy, joint guidelines from the American Society of Clinical Oncology (ASCO) and the Infectious Diseases Society of America (IDSA) recommend using clinical criteria or a validated tool such as the Multinational Association of Support Care in Cancer (MASCC) risk index to determine whether outpatient therapy is appropriate. ^[5] Anticipated prolonged (> 7 days) and profound neutropenia (absolute neutrophil count [ANC] ≤100 cells/mm³ following cytotoxic chemotherapy are high-risk criteria. The MASCC Febrile Neutropenia Risk calculator also considers factors including hypotension, type of cancer being treated, and dehydration in order to determine risk of complications in patients with febrile neutropenia. A MASCC score of 20 or less indicates high risk, while a score of 21 or greater indicates low risk.

High-risk patients should be admitted to the hospital and started on empiric IV antibiotics. Low-risk patients (those who do not meet high-risk criteria) may be candidates for an outpatient course of oral antibiotics. For empiric outpatient therapy, the ASCO/IDSA guidelines recommend an oral fluoroquinolone plus amoxicillin/clavulanate (or clindamycin, if the patient is penicillin allergic), unless the patient was receiving fluoroquinolone prophylaxis before fever developed. Patients who remain febrile after 2 to 3 days of antibiotic therapy should be re-evaluated and considered for inpatient treatment. ^[5]

Myeloid growth factors—specifically, granulocyte colony-stimulating factors (G-CSFs) and granulocyte-macrophage colony-stimulating factor (GM-CSFs)—may shorten the duration of neutropenia in patients who have undergone chemotherapy.

G-CSFs are lineage-specific for the production of functionally active neutrophils and can also be used in patients with severe, chronic neutropenia. GM-CSFs stimulate the production of neutrophils, monocytes, and eosinophils. Filgrastim and pegfilgrastim are examples of G-CSFs; sargramostim is an example of a GM-CSF. These agents are typically administered no sooner than 24 hours after chemotherapy completion. Filgrastim is often the agent of choice if a G-CSF is chosen.

The availability of filgrastim has altered the management of agranulocytosis. It has been shown to shorten the period to recovery and the duration of infection when administered before infection is established. This agent is especially indicated in the management of congenital neutropenia, idiopathic severe chronic neutropenia (SCN), and cyclic neutropenia (CN) when serious infections are involved. If the condition is mild, with only neutropenia without a serious infection, filgrastim may be withheld.

Guidelines for use of myeloid growth factors issued by the National Comprehensive Cancer Network (NCCN) include recommendations that address the following areas ^[45] :

• Prophylactic use in chemotherapy patients at risk of neutropenia
• Therapeutic use for acute febrile neutropenia
• Therapeutic use for severe chronic neutropenia

Prophylactic therapy recommendations in the NCCN guidelines are based on evaluation of the individual’s risk of febrile neutropenia associated with chemotherapy. Risk assessment should take place before the initial cycle of chemotherapy and before each subsequent cycle. Disease type, chemotherapy dose regimen, and patient risk factors should be assessed, and the intention of chemotherapy (curative, life-extending, or symptom management) noted. ^[45]

Prophylactic use of G-CSF is recommended for patients at high risk (> 20%) of febrile neutropenia. For patients whose treatment is intended to be curative or life-extending, the recommendation is supported by class 1 evidence. CSF therapy may be considered in patients at intermediate risk (10-20%), but the NCCN acknowledges that this is a difficult decision that requires careful discussion with the patient. CSF therapy appears to increase the risk of developing acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and it is not recommended for patients at low risk (< 10%) of neutropenic fever. ^[45]

The NCCN guidelines state that there is less evidence for therapeutic use than for prophylactic use. If patients with acute neutropenic fever are receiving prophylactic filgrastim or sargramostim, the CSF treatment should be continued. Pegfilgrastim should be discontinued, as it is long-acting and evidence for its therapeutic benefits is lacking. If the patient is not receiving prophylactic CSF, their risk of infection complications or poor outcome should be assessed. CSF should be considered for patients at high risk. ^[45]

The NCCN guidelines affirm the effectiveness of G-CSF therapy for SCN, CN, and congenital neutropenia. Patients with cyclic or idiopathic neutropenia appear to benefit at lower doses of G-CSF than those with congenital neutropenia. Patients with severe congenital neutropenia, requiring high doses of G-CSF, seem to be at greater risk of AML and MDS. ^[45]

An American Society of Clinical Oncology (ASCO) guideline on the use of white blood cell growth factors includes the following strong recommendations based on high-quality evidence ^[46] :

• Primary prophylaxis with a CSF, starting with the first chemotherapy cycle and continuing through subsequent cycles, in patients who have an approximately 20% or higher risk for febrile neutropenia
• Primary CSF prophylaxis in patients receiving dose-dense chemotherapy, when considered appropriate; consideration should be given to alternative, equally effective, and safe chemotherapy regimens not requiring CSF support when available
• Secondary prophylaxis with a CSF for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose or treatment delay may compromise disease-free or overall survival or treatment outcome (in many clinical situations, dose reduction or delay may be a reasonable alternative)
• CSFs should not be routinely used for patients with neutropenia who are afebrile.
• CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. However, CSFs should be considered in patients with fever and neutropenia who are at high risk for infection-associated complications or who have prognostic factors predictive of poor clinical outcomes.
• Dose-dense regimens with CSF support should be used only if supported by convincing efficacy data or within an appropriately designed clinical trial. Efficacy data support the use of dose-dense chemotherapy in the adjuvant treatment of high-risk breast cancer. Data on the value of dose-dense regimens with CSF support in non-Hodgkin lymphoma are limited and conflicting, and this practice cannot routinely be recommended at this time.
• CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral-blood progenitor cells. Choice of mobilization strategy depends in part on type of cancer and type of transplantation.
• CSFs should be administered after autologous stem-cell transplantation to reduce the duration of severe neutropenia (the guideline also contains a weak recommendation for the administration of CSFs after allogeneic stem-cell transplantation)
• Pegfilgrastim, pegfilgrastim-jmdb, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related febrile neutropenia. The choice of agent depends on convenience, cost, and clinical situation.

European guidelines also recommend prophylactic treatment with G-CSFs in patients receiving chemotherapy regimens that pose a high risk of febrile neutropenia.With chemotherapy regimens associated with moderate risk, primary prophylaxis may also be advisable for cases in which patient-related factors increase the overall risk, or to maintain chemotherapy in cases where dose-dense or dose-intense chemotherapy strategies are used because of survival benefits, or reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis. ^[47]

Primary prophylaxis with biosimilar filgrastim has been shown to be cost-effective. ^[48]

Neutrophil (granulocyte) transfusions have undergone a cycle of popularity followed by disfavor. These transfusions are accompanied by many complications, including severe febrile reactions. Their use is controversial.

Although disappearing from clinical practice, granulocyte transfusions have some clinical usefulness in treating neonatal sepsis. Their usefulness in adults with neutropenia, in whom adequate increments of WBC counts are difficult to achieve, has not been demonstrated in randomized clinical trials. ^[49] Granulocyte transfusion could be considered in cases of gram-negative sepsis with no improvement in 24-48 hours.

Other measures that may be taken in the care of the patient with neutropenia include the following:

• Corticosteroid therapy (potentially effective in immune-mediated neutropenia)

• Correction of nutritional (eg, cobalamin or folic acid) deficiency if detected

• In cases caused by heavy metals such as gold, chelation with British anti-Lewisite (dimercaprol)

• Careful handwashing before and after direct contact with patients with neutropenia

• Meticulous care of indwelling venous catheters and avoidance of urinary catheters and other invasive maneuvers that violate natural infection barriers

In individuals with neutropenia and Felty syndrome who have recurrent life-threatening bacterial infections, splenectomy is the treatment of choice, though the response is often short lived. Systemic lupus associated with autoimmune agranulocytosis may also respond to splenectomy or to immunosuppressive therapy. Idiopathic autoimmune neutropenia may also respond to immune therapy. ^[12]

Indwelling central venous catheters should be removed in febrile neutropenic patients if septic thromboembolism is suspected. Other indications for catheter removal include the following:

• Corynebacterium jeikeium infection
• Infection with Candida species
• Polymicrobial infection
• Persistent fevers
• Pocket-space abscess
• Tunnel infections

In general, surgery should be avoided in a patient with neutropenia; however, surgical drainage of abscesses that have pus or watery exudate under pressure may occasionally be lifesaving. Perirectal abscesses and cholecystitis with cholangitis are examples of infections that, if left undrained, lead to polymicrobial sepsis, despite antibiotic therapy.

Neutropenic patients should follow the following dietary restrictions:

• Avoid raw and undercooked meat or well water.
• Commercial fruit juices, beer, milk, and milk products should be pasteurized.
• Do not consume aged cheese or cheese-based dressings.
• Avoid unwashed raw fruits and vegetables; these may contain large numbers of bacteria. All food should be cooked. Fresh flowers should be avoided as well.
• Outdated products and all moldy products should not be consumed

In patients with periodontitis and stomatitis, a soft or full liquid diet is indicated. Spicy and acidic foods should be avoided until recovery is complete.

Request a hematology consultation for review of the bone-marrow slides and peripheral blood smears to confirm the diagnosis and to assist in G-CSF dosing and evaluation.

Request an infectious disease consultation for advice and assistance in the selection of appropriate antibiotics, especially in patients with complicated infections or prolonged neutropenic fever that is not responding to standard therapy.

Obtain daily CBC counts with manual differential to monitor the neutropenic patient’s recovery from an etiologic agent or to monitor the neutropenia’s response to G-CSF or GM-CSF.

If septic shock occurs, the patient should be transferred to the ICU. Intubation may be required.