Pharmacotherapy III

Fall 2012

1. Major host factors that predispose patients to infectious disease

2. Management of neutropenic fever

3. Site-specific infections (e.g. pneumonia, abdominal infections, catheter associated infections) in patients who have neutropenia or are who are otherwise significantly immunocompromized.

4. Prevention of infectious complications, including immunization and targeted antimicrobial prophylaxis.

Myelosuppression continues to be one of the most common dose limiting side effects with chemotherapeutic agents.

The timeline for myelosuppression is varied, but generally occurs within 7 to 10 days and recovers within 14 to 26 days.

Agents such as carmustine, lomustine, and mitomycin C have a delayed effect on bone marrow occurring in 4 to 6 weeks. Neutrophils and platelets are usually affected first because they have life spans measured in hours to days. Red blood cells have a lifespan of about 3 months, so they are among the last cell lines affected by chemo.

Neutropenia

NCCN definition: Low neutrophils, or neutropenia, is defined by mature and immature neutrophil counts dropping below 500/mm3. At this point the risk of infection increases significantly and continues to increase the longer neutropenia continues.

Infections in neutropenic patients are life threatening and challenging to diagnose because of the absence of white blood cell (WBC) dependent signs of infection...pus, abscesses, infiltrates on chest x-ray. This is where colony-stimulating factors (CSFs) can come into play. Neutropenia increases length of stay in the hospital and overall mortality.

The absolute neutrophil count (ANC) is equal to the product of the white blood cell count (WBC) and the fraction of polymorphonuclear cells (PMNs) and band forms noted on the differential analysis:

ANC = WBC (cells/microL) x percent (PMNs + bands) ÷ 100

Relation of absolute neutrophil count to risk of infection

Absolute neutrophil count/microL

Risk management

>1500 None 1000-1500 No significant risk of infection; fever can be managed on an outpatient basis 500-1000 Some risk of infection; fever can occasionally be managed on an outpatient basis <500 Significant risk of infection; fever should always be managed on an inpatient

basis with parenteral antibiotics; few clinical signs of infection <200 Very significant risk of infection; fever should always be managed on an inpatient

basis with parenteral antibiotics; few or no clinical signs of infection

Sargramostim (GM-CSF, Leukine), filgrastim (G-CSF, Neupogen), or pegfilgrastim (Neulasta) are often used prophylactically to shorten the duration and severity of neutropenia.

In addition to helping prevent infection, they also are used to allow the administration of subsequent chemotherapy courses on time. This improvement in dose density can translate to improved survival or tumor response, but not always. The decision to use CSFs needs to balance benefit and cost. Because CSFs are expensive and their use doesn't guarantee improved outcomes, their use is often regulated by institutional guidelines.

CSFs may be used for primary prevention to prevent febrile neutropenia...or for secondary prevention in patients who've already experienced febrile neutropenia with an earlier chemo cycle. Current American Society of Clinical Oncology (ASCO) guidelines advise against routine prophylaxis for all chemotherapy patients. Use for primary prevention is usually limited to patients who are being treated for lymphoma, adjuvant treatment for breast cancer, or testicular cancer (i.e., where cure is the intent). In these patients CSFs allow the administration of dose dense regimens without interruptions. In addition, primary prevention may benefit patients at high risk for the development of febrile neutropenia…elderly, pre-existing neutropenia, advanced cancer, comorbidities, etc. CSFs are used commonly in pediatric solid tumors, but are not recommend for hematologic malignancies for fear of worsening the disease.

When the risk of febrile neutropenia is greater than 20%, these agents are recommended for primary prevention to reduce the risk of hospitalization. Between a neutropenia risk of 10% and 20% primary prevention may be useful in the following situations:

Secondary prevention of neutropenia is often handled by reducing the dose of the chemotherapeutic agents or delaying cycles; however, when dose reduction or delay may impact a course of potentially curative chemotherapy CSFs are appropriate.

CSF use during an episode of febrile neutropenia is controversial. It may shorten the duration of hospital stay, but it isn't clear whether the cost outweighs the benefit. ASCO guidelines don't recommend routine use for febrile neutropenia, but do recognize that patients with pneumonia, fungal infections, or sepsis syndrome may benefit.

CSFs are administered subcutaneously starting 24 to 72 hours after a course of chemo ends. They can be given DURING a chemotherapy regimen if it is not myelosuppressive like vincristine, but this is controversial. Each product has a labeled dose per kg or m2, but rounding the dose to the nearest vial size reduces waste and simplifies dosing: filgrastim 300 mcg vial daily for patients <75 kg and 480 mcg daily for patients >75 kg; sargramostim 250 mcg vial daily for patients <60 kg and 500 mcg daily for patients >60 kg.

Pegfilgrastim (Neulasta) is the long-acting version of filgrastim and a single 6 mg subcutaneous dose replaces 5 to 10 injections of filgrastim or sargramostim. Package labeling recommends dosing CSFs until neutrophil counts are 10,000 cells/mm3, but this isn't necessary because the risk of infection is highest when neutrophils are less than 1,000/mm3. As a result, most only treat until neutrophil counts increase to 2,000 to 4,000/mm3. Most protocols will state a specific absolute neutrophil count goal. CSFs are generally well tolerated, although they can cause bone pain, but it's usually controllable with acetaminophen.

Thrombocytopenia

Low platelets or thrombocytopenia are also a problem after some chemotherapy regimens. The risk of serious bleeding increases significantly when platelet counts drop below 10,000/mm3, and platelet transfusions are indicated at this point. In addition, patients whose platelets do not recover to >75,000 to 100,000/mm3 may have their treatments postponed. In patients with non-hematologic malignancies who experience significant thrombocytopenia with chemotherapy, oprelvekin (IL-11) may be used to decrease the need for platelet transfusions. However, fluid retention (edema, dyspnea, pleural effusions, etc) can significantly limit the utility of oprelvekin. And most patients do not receive a good, durable response from it. Plus it's more costly than platelet transfusions, so its use is usually limited.

The definitions of fever and neutropenia (F&N) in NCCN clinical guidelines are consistent with those developed by the Infectious Diseases Society of America (IDSA) and the U.S. Food and Drug Administration (FDA) for evaluating antimicrobial therapy for F&N.

The NCCN guidelines define neutropenia as either an absolute neutrophil count (ANC) less than 500/mcL, or an ANC less than 1000/mcL and a predicted decline to 500/mcL or less over the

next 48 hours.

Fever is defined as a single temperature 38.3°C or more orally or 38.0°C or more over 1 hour in the absence of an obvious cause.

Although uncommon, a patient with neutropenia and signs or symptoms of infection (i.e., abdominal pain, severe mucositis, perirectal pain) without fever should be considered to have an active infection.

The concomitant administration of corticosteroids may also blunt the fever response and any localizing signs of infection.

Immunodeficiencies associated with primary malignancies Hematologic malignancies, myelodysplastic syndrome (MDS), Chronic lymphocytic leukemia

(CLL), Multiple myeloma Patients with advanced refractory malignancy have a greater risk of infectious complications

than those who respond to therapy Solid tumors may predispose the patient for infection because of anatomic factors. Patients undergoing surgery are at high risk as a result of the type of surgery, extent of tumor

burden, preoperative performance status and previous surgery, chemotherapy and radiation therapy.

Patients with advanced malignancy are commonly malnourished increases the risk of infection

Neutropenia the frequency and severity of infection are inversely proportional to the neutrophil count

(greatest when the neutrophil count is less than 100/mcL) The rate of decline of the neutrophil count and the duration of neutropenia are also critical

factors. Disruption of mucosal barrier Splenectomy and functional asplenia Corticosteroids and other lymphotoxic agents

Depend on the dose and duration of corticosteroids and use of immunosuppressive agents and the status of the malignancy.

Lymphocyte depleting agents increase the risk of common and opportunistic infectious disease. Hematopoietic stem cell transplantation (HSCT)

Autologous > allogeneic

Consider penicillin & TMP-SMX (GVHD)

Determining the potential sites and causative organisms of infections

Assessing the patient’s risk of developing and infections-related complications.

Site specific hx and physical examination should be performed promptly

Initial laboratory/radiology evaluationCBC with differential analysis, platelets, BUN, SCr, electrolytes, total

bilirubin, liver enzymes, renal function tests.O2 saturation, urinalysis, chest radiograph (depending on symptoms)

Cultures should be obtained during or immediately after completing the examination.2 blood samples should be cultured (peripheral and/or central)In some patients cultures of the anterior nares, oropharynx, urine,

stool, and rectum may be required. Also viral cultures, skin biopsy

Initial evaluation of fever & neutropeniaInitial evaluation of fever & neutropenia

Empiric antibiotics should be started soon after the time of presentationAll neutropenic patients should be treated empirically with broad

spectrum promptly at the first sign of infection (fever).Selection of initial therapyRecommended approaches:

IV antibiotic monotherapyIV antibiotic combination therapyOral antibiotic combination therapy (for low risk patients)

Initial empiric therapy for patients who are clinically instable (sepsis)

Prognostic factors in patients with bacteremiaClassification system for bacteremia in febrile neutropenic

patients: Complex, Simple (page 50 of the guideline)

Filgrastim and pegfilgrastimboth granulocyte-colony stimulating factors (G-CSF), currently have FDA approval for use in the prevention of

chemotherapy-induced neutropenia. Sargramostim,

a granulocyte-macrophage colony stimulating factor (GM-CSF),

labeled indication is limited to use following induction therapy for acute myeloid leukemia and in various stem cell transplantation settings

NCCN recommends routine use of CSFs for high-risk (>20%) patients to prevent development of febrile neutropenia (FN) in patients receiving treatment with curative intent, adjuvant therapy, or treatment expected to prolong survival & to improve QoL.

For intermediate risk (10-20% probability of developing FN or a neutropenic event that would compromise treatment), the panel recommends individualized consideration of CSF. When the intent of chemotherapy is designed to prolong survival or for symptom

management, the use of CSF is a difficult decision and requires careful discussion between the physician and patient.

If patient risk factors determine the risk, CSF is reasonable. If the risk is due to the chemotherapy regimen, other alternatives such as the use

of less myelosuppressive chemotherapy or dose reduction, if of comparable benefit, should be explored

For low-risk patients (<10% risk), routine use of CSFs is not recommended unless patient is receiving curative or adjuvant treatment & is at significant risk for serious medical consequences of FN, including death.

CSF is discontinued when neutrophil count reaches 2,000-4,000/mm3.