Febrile neutropenia, a common side effect of myelosuppressive chemotherapy in patients with cancer, can result in prolonged hospitalization and broad-spectrum antibiotic use, often prompting treatment delays or dose reductions of drug regimens. Prophylactic use of myeloid growth factors (mainly the colony-stimulating factors filgrastim and pegfilgrastim) in patients of heightened risk can reduce the severity and duration of febrile neutropenia. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myeloid Growth Factors provide recommendations on the use of these agents mainly in the oncology setting based on clinical evidence and expert consensus. This version includes revisions surrounding the issue of timing of pegfilgrastim administration. It also includes new sections on tbo-filgrastim, a recently approved agent that is biologically similar to filgrastim, and the role of myeloid growth factors in the hematopoietic cell transplant setting

Abstract

Febrile neutropenia, a common side effect of myelosuppressive chemotherapy in patients with cancer, can result in prolonged hospitalization and broad-spectrum antibiotic use, often prompting treatment delays or dose reductions of drug regimens. Prophylactic use of myeloid growth factors (mainly the colony-stimulating factors filgrastim and pegfilgrastim) in patients of heightened risk can reduce the severity and duration of febrile neutropenia. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myeloid Growth Factors provide recommendations on the use of these agents mainly in the oncology setting based on clinical evidence and expert consensus. This version includes revisions surrounding the issue of timing of pegfilgrastim administration. It also includes new sections on tbo-filgrastim, a recently approved agent that is biologically similar to filgrastim, and the role of myeloid growth factors in the hematopoietic cell transplant setting

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Neutropenia (<500 neutrophils/mcL or <1000 neutrophils/mcL and a predicted decline to ≤500/mcL over the next 48 h) and resulting febrile neutropenia (FN; ≥38.3°C orally or ≥38.0°C over 1 h) can be induced by myelosuppressive chemotherapy. FN, in turn, is a major dose-limiting toxicity of chemotherapy, often requiring prolonged hospitalization and broad-spectrum antibiotic use (reviewed by Lyman and Kuderer1). These can prompt dose reductions or treatment delays in subsequent chemotherapy cycles and compromise clinical outcome. Studies have shown that prophylactic use of colony-stimulating factors (CSFs) can reduce the risk, severity, and duration of FN, but the cost has prevented routine use for all patients receiving myelosuppressive chemotherapy. Selective use of CSFs in patients at increased risk for neutropenic complications may, however, enhance the cost-effectiveness.

The risk of FN is usually based on the treatment regimen and delivered dose intensity. A survey of the literature on randomized clinical trials of chemotherapy in patients with early-stage breast cancer and non-Hodgkin’s lymphoma (NHL) has shown, however, that the rates of myelosuppression and delivered dose intensity are underreported.2 When reported, the rates of myelosuppression with the same and similar regimens varied greatly, making it difficult to determine the actual risk for neutropenic complications associated with common chemotherapy regimens.2 Differences in the reported rates of neutropenic complications may relate to differences in study patient populations and the delivered dose intensity. Treatment dose intensity was reported with even less consistency, making it very difficult to interpret differences in reported rates of toxicity or treatment efficacy.

A review by Dale3 showed that approximately 25% to 40% of treatment-naïve patients develop FN with common chemotherapy regimens. Occurrence of FN may delay subsequent chemotherapy courses or result in dose reduction that may compromise treatment outcomes. Development of FN also increases diagnostic and treatment costs and often leads to longer hospital stays. In addition, correlations have been reported between changes in neutrophil counts and quality of life, as measured by physical functioning, vitality, and mental health.4

F1NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors, Version 2.2013

Version 2.2013, 08-02-13 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines#x000AE; and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 10; 10.6004/jnccn.2013.0148

F2NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors, Version 2.2013

Version 2.2013, 08-02-13 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines#x000AE; and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 10; 10.6004/jnccn.2013.0148

F3NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors, Version 2.2013

Version 2.2013, 08-02-13 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines#x000AE; and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 10; 10.6004/jnccn.2013.0148

F4NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors, Version 2.2013

Version 2.2013, 08-02-13 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines#x000AE; and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 10; 10.6004/jnccn.2013.0148

F5NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors, Version 2.2013

Version 2.2013, 08-02-13 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines#x000AE; and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 10; 10.6004/jnccn.2013.0148

F6NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors, Version 2.2013

Version 2.2013, 08-02-13 ©2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines#x000AE; and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 10; 10.6004/jnccn.2013.0148

Filgrastim and pegfilgrastim, both granulocyte-colony stimulating factors (G-CSFs), currently have FDA approval for use in the prevention of chemotherapy-induced neutropenia. In contrast, the labeled indication for sargramostim, a granulocyte-macrophage colony stimulating factor (GM-CSF), is limited to use after induction therapy for acute myeloid leukemia and in various stem cell transplantation settings. It should be noted that recommendations are based on evidence derived mainly from studies on G-CSFs. There is a lack of head-to-head comparative studies on the clinical benefits of G-CSFs and GM-CSFs.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myeloid Growth Factors (MGF) is focused on the use of CSFs in the cancer setting. Specifically, the guidelines address adult patients with solid tumors and nonmyeloid malignancies. Growth factors in the treatment of myeloid malignancies are discussed in the NCCN Guidelines for Myelodysplastic Syndromes (MDS) and the NCCN Guidelines for Acute Myeloid Leukemia (AML). To view the most recent versions of these guidelines, visit NCCN.org.

Benefits and Risks of MGFs

The prophylactic use of G-CSFs has been shown to reduce the incidence, length, and severity of chemotherapy-related neutropenia in small cell lung cancer, breast cancer, sarcoma, and NHL.5-16 G-CSFs also improved delivery of full chemotherapy dose intensity at the planned schedule, although this has not been generally shown to lead to better response or higher overall survival.5,7,9,12-15,17,18 However, in node-positive breast cancer19 and aggressive lymphoma,20 dose-dense regimens supported by G-CSFs improved disease-free and/or overall survival compared with conventional chemotherapy.

Meta-analyses have confirmed the efficacy of prophylactic CSFs in decreasing rates of infection21,22 and the risk of neutropenia.21,22 In a meta-analysis of 17 randomized trials of prophylactic G-CSFs including 3493 adult patients with solid tumor and lymphoma,23 G-CSF as primary prophylaxis reduces the risk of FN (relative risk [RR], 0.54; 95% CI, 0.43-0.67; P<.001) and improves relative dose intensity of the chemotherapy delivered (average difference between study arms, 8.4%; P=.001). For the first time, this analysis also reported a substantial reduction in risk of infection-related mortality (RR, 0.55; 95% CI, 0.33-0.90; P=.018) and all early deaths during chemotherapy (RR, 0.60; 95% CI, 0.43-0.83; P=.002). The survival advantage is confirmed in a recent systematic review by Lyman et al24 of 25 randomized controlled trials involving more than 12,000 patients undergoing chemotherapy with or without G-CSF support. With an average follow-up of 5 years, G-CSF was associated with 3.40% and 0.90 reduction in absolute and relative risk for all-cause mortality, respectively, although this comes with an increase in risk for AML and MDS (see later discussion). The degree of benefit correlated with chemotherapy dose intensity.

Over the past decade, the costs of inpatient hospitalization have escalated, changing the risk threshold on a pure cost basis from 40% to approximately 20%.25 Economic analyses of CSFs have yielded mixed results, depending on the context of use.26-30 However, the policy of this panel is to look primarily at issues of therapeutic efficacy and clinical benefit, rather than cost. The indication for prophylactic CSF use depends on the risk of FN or other neutropenic events that can potentially compromise treatment.

To date, the main consistently observed toxicity associated with G-CSF therapy was mild to moderate bone pain.31,32 This is usually effectively controlled by nonnarcotic analgesics. The meta-analysis by Kuderer et al23 confirmed a heightened risk of musculoskeletal pain associated with CSF (RR, 4.03; 95% CI, 2.15-7.52; P<.001).

Rare cases of splenic rupture with G-CSF use have also been reported, some of which were fatal.33 These cases occurred in patients and healthy donors in the stem cell transplantation setting. Some patients develop allergic reactions in the skin, the respiratory system, or the cardiovascular system (filgrastim only). Other warnings from the prescribing information include acute respiratory distress syndrome, alveolar hemorrhage, and hemoptysis.31,32,34 Sickle cell crisis, sometimes fatal, has been reported in patients with sickle cell disease, but not for patients with sickle cell trait.35-37 Similar toxicities are expected for filgrastim and pegfilgrastim, although not all toxicities have been reported with each preparation.

Although a potentially increased risk of AML/MDS with G-CSF administration has been suggested by epidemiologic studies, this was not observed in individual randomized trials.33 The recent analysis by Lyman et al24 reported an increase in absolute and relative risk of AML/MDS of 0.41% and 1.92, respectively, related to G-CSF. Whether the risk of AML/MDS is secondary to G-CSF or related to the higher total doses of chemotherapy cannot be determined from this meta-analysis. Overall mortality was nevertheless decreased.

Controversy has surrounded the use of G-CSFs for patients with Hodgkin lymphoma undergoing bleomycin-containing chemotherapy, especially ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). An increased risk of bleomycin pulmonary toxicity has been reported with G-CSF use for this disease in a retrospective study of 141 patients.38 In a systematic review of case reports by Azoulay et al,39 70 cases of G-CSF-related pulmonary toxicity were identified in patients with cancer with neutropenia; 36 patients had received bleomycin, but most of these had NHL and had also received drugs known to induce pulmonary toxicity (cyclophosphamide and/or methotrexate). This toxicity potential is unclear for BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), although bleomycin is given every 3 weeks in this regimen as opposed to every 2 weeks in ABVD. Clinicians should be alert to signs and symptoms of this complication for both regimens. An increase in bleomycin pulmonary toxicity has not been reported with G-CSF use in bleomycin-containing testicular cancer chemotherapy regimens.18

Prophylactic Use of MGFs

Risk Assessment

The guidelines begin with an evaluation of risk for chemotherapy-induced FN before the first cycle. The risk assessment involves varied components, including the disease type, chemotherapeutic regimen (high-dose, dose-dense or standard-dose therapy), patient risk factors, and treatment intent. Three categories based on the intent of chemotherapy have been designated by the NCCN panel, including curative/adjuvant therapy, treatment directed toward prolonging survival, and symptom management therapy. Based on the chemotherapy regimen and patient-related risk factors, the patient is assigned to an overall high-risk group (>20% risk of FN), an intermediate-risk group (10%-20% risk), and a low-risk group (<10% risk). Notably, no consensus nomogram for risk assessment currently exists. Although the NCCN panel outlines criteria to aid in assessment, independent clinical judgment should be exercised based on the patient’s situation. When determining the appropriate use of CSFs, in addition to assessing patient and treatment-related risk, consideration should be given to the intent of cancer treatment. For example, one criterion that identifies a high-risk patient is a previous neutropenic complication in the immediate previous cycle with no plan to reduce the dose intensity.

Chemotherapy Regimens and Risk of FN

The development of FN is a common dose-limiting toxicity of many single agents and combination chemotherapy regimens. This risk is directly related to the intensity of the chemotherapy regimen. Chemotherapy regimens that have an incidence of FN greater than 20% in clinical trials in chemotherapy-naïve patients are considered by the panel to be at high risk. It is emphasized that the type of chemotherapy regimen is only one component of the risk assessment, and must be combined with patient risk factors for an estimation of the overall risk of FN.

The algorithm includes lists of common chemotherapy regimens associated with a high risk (>20%) or intermediate risk (10%-20%) of FN development. These lists are not comprehensive but are meant to serve as examples only, because the exact risk will depend on the agent, dose, and the treatment setting. Some regimens, such as the RICE and CHOP-14 regimen for non-Hodgkin’s lymphoma, have only been tested with growth factor support.

Evens et al40 showed that standard chemotherapy for Hodgkin’s lymphoma (ABVD) can be safely administered at full dose without G-CSF support. However, this requires treatment with ABVD in some patients at the time of neutropenia. Until further evidence from larger prospective studies becomes available, prophylactic G-CSF use with ABVD can be considered after the risks and benefits are discussed with the patient.

Patient Risk Factors for Developing FN

Patient risk factors are an important consideration in estimating the overall risk of FN, particularly when chemotherapy regimens are considered an intermediate risk (reviewed by Lyman et al41). Patient factors may elevate the overall risk to a high-risk category, wherein prophylactic CSFs are more routinely recommended. For example, many regimens for breast and lung cancer are associated with an intermediate risk of neutropenic complications, and it is important to identify which of these patients would be considered at high risk. Even a low-risk regimen does not necessarily preclude the use of CSFs in a patient with high-risk factors.

Higher age, notably older than 65 years, is the most important risk factor for developing severe neutropenia (see NCCN Guidelines for Senior Adult Oncology).42-47 Other risk factors include previous chemotherapy or radiotherapy; preexisting neutropenia or tumor involvement in the bone marrow; poor performance status; comorbidities, including renal or liver dysfunction; and preexisting conditions, such as neutropenia and infection. Most of these have been confirmed as independent risk factors for neutropenic complications in a risk model developed by Lyman et al48 that was validated in a study population of 3760 patients with cancer beginning chemotherapy.

Patients at High Risk of FN: NCCN panel discussions have focused on defining a risk level of FN that would warrant routine use of prophylactic growth factors. The guidelines recommended prophylactic CSF if the risk of FN was 20% or greater. The most recent update of the ASCO guidelines and the European Organisation for Research and Treatment of Cancer (EORTC) both adopted the 20% threshold for considering routine prophylactic treatment.49,50

These consistent recommendations are based on the results of several large randomized trials that have documented that the risk of FN can be significantly reduced by primary prophylaxis when the risk of FN without prophylaxis is 20%. For example, Vogel et al8 reported on the results of a double-blind, randomized, placebo-controlled multicenter study to show whether first and subsequent cycle prophylactic CSF support with pegfilgrastim would significantly reduce FN in a regimen that had previously been associated with an expected FN incidence of 20%. This is the largest randomized study of prophylactic growth factor support that has been performed. Women with breast cancer received docetaxel at 100 mg/m2 every 3 weeks. A total of 465 women received a placebo injection and 463 women received pegfilgrastim, each administered 24 hours after chemotherapy in a double-blind study designed with FN as the primary end point. The placebo group had an overall incidence of FN of 17%. By contrast, the pegfilgrastim group had a 1% incidence. The incidence of hospitalization was reduced from 14% to 1%, and the use of intravenous anti-infectives was reduced from 10% to 2%, with all of these differences statistically significant (P<.001). In cycle 1, there was an 11% rate of FN in the first cycle for the placebo group versus less than 1% in the pegfilgrastim group. For cycles 2 through 4, the rate of FN was 6% in the placebo group compared with less than 1% in the pegfilgrastim group.

A second trial reported the results of 175 patients with small cell lung cancer who were randomized to receive prophylactic antibiotics with or without prophylactic G-CSF.6 In cycle 1, 20 patients (24%) in the antibiotics-only group developed FN, compared with 9 patients (10%) in the antibiotics plus FN group (P=.01). In cycles 2 to 5, the incidences of FN were similar in both groups (17% vs 11%). The authors concluded that primary FN prophylaxis added to primary antibiotic prophylaxis is effective in reducing FN and infections in patients with small cell lung cancer with the first cycle of chemotherapy. Furthermore, this strategy could be considered for other patients with cancer with a similar risk of FN.

The NCCN, ASCO, and EORTC guidelines all recognize a variety of special circumstances in which patients treated with relatively nonmyelosuppressive chemotherapy regimens may nonetheless be at high risk of FN from bone marrow compromise or comorbidity.

Prophylactic CSF is recommended for any patient considered at high risk, regardless of whether the treatment is intended to be curative, prolong survival, or manage symptoms.

Patients at Intermediate Risk of FN: The NCCN panel defines intermediate risk as a 10% to 20% probability of developing FN or a neutropenic event that would compromise treatment. In all 3 categories of treatment intent, the panel recommends individualized consideration of CSF use based on physician-patient discussion of the risk/benefit ratio of the likelihood of developing FN, the potential consequences of a neutropenic event, and the implications of reduced chemotherapy dose delivery. 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 from the chemotherapy regimen, other alternatives such as the use of less myelosuppressive chemotherapy or dose reduction, if of comparable benefit, should be explored.

Patients at Low Risk of FN: For low-risk patients, as defined by risk less than 10%, routine use of CSFs is not considered cost-effective, and alternative treatment options are appropriate.25,49,51,52 However, CSFs may be considered if the patient is receiving curative or adjuvant treatment and is at significant risk for serious medical consequences of FN, including death.

Evaluation of Subsequent Chemotherapy Cycles

After the first cycle, patient evaluation should be performed before each subsequent cycle to determine the risk categorization and treatment intent. If the patient experienced a previous episode of FN or a dose-limiting neutropenic event (a nadir or a day-of-treatment count impacting the planned dose of chemotherapy) during the previous cycle of treatment with the same dose and schedule planned for the current cycle, this patient is now in the high-risk group.

If the patient experiences such an episode despite receiving CSF, the panel recommends a chemotherapy dose reduction or change in treatment regimen, unless it will affect patient survival. If the patient does not develop FN or a dose-limiting neutropenic event and is thought to be benefiting from chemotherapy, the previous assessment should be repeated after each subsequent cycle.

Dosing and Administration

Currently used or approved MGFs for the prophylaxis of FN and maintenance of scheduled dose delivery include filgrastim, tbo-filgrastim, pegfilgrastim, and sargramostim, preferably given subcutaneously. Although data from randomized studies support the use of filgrastim, tbo-filgrastim, and pegfilgrastim in patients with solid malignancies, randomized studies of sargramostim have focused on its use after induction therapy for AML and in various stem cell transplantation settings. Therefore, when choosing among MGFs, filgrastim, tbo-filgrastim, and pegfilgrastim are considered category 1 recommendations, whereas sargramostim is considered a category 2B recommendation. NCCN panel members do not routinely recommend use of prophylactic antibiotics in these settings. In addition, the prophylactic use of CSFs in patients given concurrent chemotherapy and radiation has not been evaluated and is therefore not recommended.

Filgrastim

Initial doses of filgrastim are initiated the next day up to 3 to 4 days after completion of chemotherapy in a daily dose of 5 mcg/kg until postnadir absolute neutrophil count recovery is to normal or near-normal levels by laboratory standards. The dose may be rounded to the nearest vial size by institution-defined weight limits.

Tbo-filgrastim

As patents for oncology biologics begin to expire, the United States is developing an abbreviated regulatory pathway for the approval of similar follow-on formulations, termed biosimilars.53 The NCCN Biosimilars Work Group published a white paper identifying the challenges in the incorporation of these agents in health care practice.54

In August of 2012, the FDA announced the approval of tbo-filgrastim, described as “a leukocyte growth factor indicated for the reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.” Approval was based on 3 randomized clinical trials involving 680 cancer patients. One trial randomized 348 patients with breast cancer receiving docetaxel/doxorubicin therapy to tbo-filgrastim, filgrastim, or placebo.55 Tbo-filgrastim was equivalent to filgrastim and superior to placebo in reducing the duration of severe neutropenia and incidence of FN. Two other randomized studies of patients with lung cancer and non-Hodgkin’s lymphoma receiving chemotherapy also reported similar efficacy of tbo-filgrastim and filgrastim.56,57 Toxicities were similar between the 2 agents. A meta-analysis of the 3 trials concluded tbo-filgrastim to be non-inferior to filgrastim for the incidence of FN, irrespective of the myelotoxicity of the chemotherapy regimen.58 Studies in healthy subjects showed similar pharmacokinetic and pharmacodynamic profiles.59,60

Although tbo-filgrastim is available in the European Union as a biosimilar to filgrastim,50 it was approved by the FDA in an original biologic license application because the biosimilar approval process has not yet been finalized in the United States.

Pegfilgrastim

Because pegfilgrastim is longer-acting than filgrastim, a single injection of 6 mg is sufficient per chemotherapy cycle.

The NCCN panel discussed 2 issues that have emerged regarding the use of pegfilgrastim. The first is the timing of administration after chemotherapy. Because most clinical studies administer the agent the day after chemotherapy completion, this is a category 1 recommendation.32 Based on trials of filgrastim, panelists agreed that giving pegfilgrastim up to 3 to 4 days after chemotherapy is also reasonable. In addition, panelists pointed out that some institutions practise “same-day” pegfilgrastim, or administration of pegfilgrastim on a day in which patients receive chemotherapy, for logistical reasons and to minimize burdens on long-distance patients.61 The NCCN panel agreed that this strategy may be considered under certain circumstances. Retrospective studies in patients with gynecologic malignancies demonstrated the safety and efficacy of pegfilgrastim administered within 24 hours after chemotherapy.62,63 Burris et al64 reviewed data available in abstract form from 3 randomized phase II studies comparing same-day and next-day pegfilgrastim. Two of the studies, conducted in patients with breast cancer and lymphoma, showed a statistically insignificant trend toward longer duration of severe neutropenia for the same-day group.65,66 The third study, in patients with lung cancer, had an unexpected low rate of severe neutropenia (only 2 patients per group).67

The panel also discussed the use of pegfilgrastim in chemotherapy regimens of different cycle lengths. Use of pegfilgrastim after chemotherapy given every 3 weeks is a category 1 recommendation based on phase III clinical trials.8,68 Phase II studies demonstrated the efficacy of pegfilgrastim for chemotherapy regimens administered every 14 days.69-74 Insufficient data support dose and schedule of weekly regimens, and therefore these cannot be recommended.

Sargramostim

Insufficient evidence from randomized trials supports a category 1 recommendation for sargramostim in nonmyeloid malignancies. Sargramostim is indicated for use after induction chemotherapy in older adult patients with AML.75-77 Administration should start the next day or up to 3 to 4 days after completion of chemotherapy, and treatment should continue through postnadir recovery.

Therapeutic Use of MGFs

Compared with their prophylactic use, the therapeutic use of MGFs for FN as an adjunctive to antibiotics has less supporting evidence. In a Cochrane meta-analysis including 1518 patients from 13 trials, Clark et al78 reported a shorter length of hospitalization (hazard ratio [HR], 0.63; 95% CI, 0.49-0.82; P=.0006) and shorter time to neutrophil recovery (HR, 0.32; 95% CI, 0.23-0.46; P<.00001), but no improvement in overall survival associated with therapeutic CSF. An earlier meta-analysis by Berghmans et al79 again found no difference in mortality, but they were unable to assess other clinical benefits. Notably, Berghmans’ analysis did not include a multicenter trial that randomized 210 patients with solid tumors who developed chemotherapy-induced FN and had at least one high-risk factor to therapeutic G-CSF or placebo.80 The G-CSF arm showed a significantly shorter duration of grade 4 neutropenia (median, 2 vs 3 days; P=.0004), antibiotic therapy (median, 5 vs 6 days; P=.013), and hospital stay (median, 5 vs 7 days; P=.015).

Patients with FN who are receiving prophylactic filgrastim or sargramostim should continue with CSF therapy. However, because pegfilgrastim is long-acting, those who have received prophylactic pegfilgrastim should not be treated with additional CSF.81 Also, because a lack of evidence currently exists supporting the therapeutic use of pegfilgrastim, only filgrastim or sargramostim should be administered in the therapeutic setting. For patients who have not received prophylactic CSFs, the NCCN panel recommends an evaluation for risk factors for infection-related complications or poor clinical outcome, including old age (>65 years); sepsis syndrome; severe (ANC<100/l) or anticipated prolonged (>10 days) neutropenia; pneumonia; invasive fungal infection or other clinically documented infections; hospitalization; and prior episode of FN. If risk factors are present, CSFs should be considered.

MGFs in the Hematopoietic Cell Transplant Setting

MGFs are commonly administered in the transplant setting, either for mobilization of hematopoietic progenitor cells or as supportive care after transplantation.

Mobilization With Growth Factors

Mobilization of peripheral blood stem cells (PBSCs) by G-CSF has largely replaced bone marrow collection for autologous transplantation because of ease of collection, avoidance of general anesthesia, and more rapid recovery of blood counts.82 Most data are focused on filgrastim, although studies suggest that single-dose pegfilgrastim has similar efficacy.83 G-CSF can be administered as a single agent84 or as part of a chemomobilization regimen,85-87 starting on the day after completion of chemotherapy. Apheresis usually commences on the fourth or fifth day of G-CSF initiation when it is used as a single agent. After mobilization with chemotherapy plus growth factor, leukapheresis commences after a rise of the white blood count when the CD34+ cells are circulating. More recently, addition of the CXCR4 inhibitor plerixafor to chemomobilization has been shown to accelerate an increase in PBSC count.88-91 This may be used as a rescue strategy when PBSC yield is poor, or when the CD34+ cell count does not reach the target level. One retrospective analysis showed that pegfilgrastim resulted in a better PBSC yield than filgrastim, requiring less use of rescue plerixafor,92 but no randomized trials have been conducted.

G-CSF is also used to mobilize PBSCs in the allogeneic setting. Initially, there were concerns about normal donor toxicity and risk of graft-versus-host disease in the recipient, but studies have shown G-CSF to be well tolerated by donors, without an effect on long-term survival.93-95 The use of plerixafor in normal donors is currently being studied.

Studies using GM-CSF as a single mobilization agent or in sequential combination with G-CSF reported good yields of PBSC in normal donors.96-98

Growth Factors as part of Supportive Care After Transplant

Consensus is lacking on the use of growth factors in the posttransplant setting. G-CSF administration after high-dose chemotherapy and autologous PBSC transplantation has been shown to expedite neutrophil recovery in prospective randomized trials.99-103 However, results were mixed on the impact of G-CSF on duration of hospital stay, infections, and survival. A systematic review comparing filgrastim and pegfilgrastim in the autologous setting, including a randomized trial of 80 patients,104 concluded that the 2 are at least equally effective.105

Data are conflicting on G-CSF as a supportive care measure for allogeneic transplant recipients, with some studies associating G-CSF with worse clinical outcome.106 However, it has been used routinely after cord blood transplant, which has been associated with delayed recovery of blood counts.

GM-CSF has been shown to promote hematopoietic recovery after autologous bone marrow transplantation or delayed autologous engraftment.107,108 It has also been used for mobilization, but G-CSF use has been favored for this purpose.

Severe Chronic Neutropenia

These NCCN Guidelines are focused on chemotherapy-induced neutropenia in the cancer setting. Severe chronic neutropenia that requires G-CSF therapy is briefly discussed in this section. G-CSF is established as an effective treatment for cyclic, congenital, and idiopathic neutropenia (types of severe chronic neutropenia) based on a randomized controlled trial involving 123 patients.109 In this study, daily treatment with subcutaneously administered G-CSF normalized neutrophils in most patients and prevented fever, mouth ulcers, and infections. Subsequent observation studies show that patients with idiopathic and cyclic neutropenia generally respond to low-dose daily, alternate-day, or thrice-per-week subcutaneous G-CSF (1-3 mcg/kg/d). Patients with congenital neutropenia generally require somewhat higher doses (3-10 mcg/kg/d). All patients should have doses adjusted to maintain a blood neutrophil level in the normal or low normal range. Acute adverse effects include bone pain, arthralgias, and myalgias, which usually diminish in the first few weeks of treatment. The greatest concern is that patients diagnosed with severe congenital neutropenia, but not all patients with chronic neutropenia, are at risk of developing myelodysplasia and leukemia, with or without G-CSF treatment. More severely affected patients, as reflected by the requirement of higher doses of G-CSF, seem to be at greater risk. These considerations emphasize the importance of making a correct diagnosis and following these patients carefully. Currently, the only alternative therapy is hematopoietic stem cell transplantation. For further reading on chronic neutropenia, refer to the Web site developed by The Severe Chronic Neutropenia International Registry: http://depts.washington.edu/registry/index.html.

Individual Disclosures for the NCCN Penile Cancer Panel

T1

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