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 This is an original JCO publication from 2015. Please visit the JCO website to access the full article.


Recommendations for the Use of White Blood Cell Growth Factors

 

 Authors

Thomas J. Smith, Kari Bohlke, Gary H. Lyman, Kenneth R. Carson, Jeffrey Crawford, Scott J. Cross, John M. Goldberg, James L. Khatcheressian, Natasha B. Leighl, Cheryl L. Perkins, George Somlo, James L. Wade, Antoinette J. Wozniak, and James O. Armitage

 

THE BOTTOM LINE

Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update

Guideline Question

How should colony-stimulating factors (CSFs) be used in people with cancer?

Target Population

Adults or children with a solid tumor or lymphoma treated with chemotherapy

Target Audience

Medical oncologists, hematologists, oncology nurses, other clinicians who care for people with cancer, and patients

Methods

An Update Committee was convened to update clinical practice guideline recommendations based on a systematic review of the medical literature.

Key Points

See Summary of Recommendations Table below.

Additional Resources

More information, including clinical tools and resources, is available at www.asco.org/guidelines/wbcgf. Patient information is available at www.cancer.net. ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate.

 

 

SUMMARY OF RECOMMENDATIONS

Clinical Question

Recommendation

 Evidence Rating

Among adults treated with chemotherapy for a solid tumor or lymphoma, what factors should clinicians consider when selecting patients for primary prophylaxis of febrile neutropenia with a CSF?

Primary prophylaxis with a CSF starting with the first cycle and continuing through subsequent cycles of chemotherapy is recommended in patients who have an approximately 20% or higher risk for febrile neutropenia on the basis of patient-, disease-, and treatment-related factors. Primary CSF prophylaxis should also be given 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.

Type: Evidence-Based, Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

Among adults treated with chemotherapy for a solid tumor or lymphoma, what factors should clinicians use to select patients for secondary prophylaxis of febrile neutropenia with a CSF?Secondary prophylaxis with CSFs is recommended for patients who experienced a neutropenic complication from a previous 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.

Type: Evidence-Based, Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

Are there circumstances in which CSFs should be considered for the treatment of neutropenia among adults with cancer?Therapy for patients with afebrile neutropenia: CSFs should not be routinely used for patients with neutropenia who are afebrile.

Type: Evidence-Based, Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

Therapy for febrile patients with neutropenia: 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 that are predictive of poor clinical outcomes. High-risk features include expected prolonged (> 10 days) and profound (< 0.1 × 109 /L) neutropenia, age older than 65 years, uncontrolled primary disease, pneumonia, hypotension and multiorgan dysfunction (sepsis syndrome), invasive fungal infection, or being hospitalized at the time of the development of fever.

Type: Evidence-Based, Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

In what settings should CSFs be used in order to increase chemotherapy dose-density?Dose-dense regimens with CSF support should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Efficacy data support the use of CSFs with dose-dense chemotherapy in the adjuvant treatment of high-risk breast cancer, and with high dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin (HD-M-VAC) in urothelial cancer. There are limited and conflicting data on the value of dose-dense regimens with CSF support in non-Hodgkin lymphoma (NHL), and it cannot routinely be recommended at this time.

Type: Evidence-Based, Benefits Outweigh Harms

Evidence Quality: High for Breast Cancer and Lymphoma, Intermediate for Urothelial Cancer

Strength of Recommendation: Strong for Breast Cancer and Lymphoma, Moderate for Urothelial Cancer

What is the role of CSFs as adjuncts to progenitorcell transplantation?CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral-blood progenitor cells (PBPCs). Choice of mobilization strategy depends in part on type of cancer and type of transplantation.

Type: Evidence-Based, Benefits Outweigh Harms

Evidence Quality: Strong

Strength of Recommendation: High

CSFs should be administered after autologous stem cell transplantation to reduce the duration of severe neutropenia.

Type: Evidence-Based, Benefits Outweigh Harms

Evidence Quality: High

Strength of Recommendation: Strong

CSFs may be administered after allogeneic stem cell transplantation to reduce the duration of severe neutropenia.

Type: Evidence-Based

Evidence quality: Low

Strength of Recommendation: Weak

What is the role of CSFs in the setting of acute leukemia or myelodysplastic syndromes?The Update Committee did not provide recommendations regarding the use of CSFs in adults with acute myeloid leukemia or myelodysplastic syndromes. 
Should CSFs be avoided in patients receiving concomitant chemotherapy and radiation therapy?CSFs should be avoided in patients receiving concomitant chemotherapy and radiation therapy, particularly involving the mediastinum. In the absence of chemotherapy, therapeutic use of CSFs may be considered in patients receiving radiation therapy alone if prolonged delays secondary to neutropenia are expected.

Type: Evidence-Based

Evidence quality: High

Strength of Recommendation: Strong

Are there CSF recommendations that apply specifically to older adults, and that differ from recommendations in younger adults?Prophylactic CSF for patients with diffuse aggressive lymphoma age 65 years and older treated with curative chemotherapy (CHOP-R) should be considered, particularly in the presence of comorbidities.

Type: Evidence-Based, Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Moderate

How should CSFs be used in the pediatric population?The use of CSFs in pediatric patients will almost always be guided by clinical protocols. As in adults, the use of CSFs is reasonable for the primary prophylaxis of pediatric patients with a high likelihood of febrile neutropenia. Similarly, the use of CSFs for secondary prophylaxis or for therapy should be limited to high-risk patients.

Type: Evidence-Based, Benefits Outweigh Harms.

Evidence Quality: High

Strength of Recommendation: Strong

For pediatric indications in which dose-intense chemotherapy is known to have a survival benefit, such as Ewing’s sarcoma, CSFs should be used to enable the administration of these regimens.

Type: Evidence-Based; Benefits Outweigh Harms

Evidence quality: High

Strength of Recommendation: Strong

CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia (ALL) or nonrelapsed acute myeloid leukemia (AML) who do not have an infection.

Type: Informal Consensus

Evidence Quality: Intermediate

Strength of Recommendation: Moderate

What are recommendations for the initiation, duration, dosing, and administration of CSFs?FilgrastimFilgrastim should be started 1 to 3 days after the administration of myelotoxic chemotherapy. In the setting of high-dose therapy and autologous stem-cell rescue, filgrastim can be started 1 to 5 days after administration of high-dose therapy. Filgrastim should be continued until reaching an absolute neutrophil count (ANC) of at least 2 to 3 × 109 /L. For PBPC mobilization, filgrastim should be started at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis. 
In adults, the recommended filgrastim dose is 5 µg/kg per day for all clinical settings other than PBPC mobilization. In the setting of PBPC mobilization, a dose of 10 µg/kg per day may be preferable. The preferred route of filgrastim administration is subcutaneous. 
Filgrastim-sndzSame as for filgrastim. 
Tbo-filgrastimTbo-filgrastim should be started 1 to 3 days after the administration of myelotoxic chemotherapy. In adults, the recommended tbo-filgrastim dose is 5 µg/kg per day. The preferred route of tbo-filgrastim administration is subcutaneous. 
Pegfilgrastim6 mg should be given once, 1 to 3 days after chemotherapy if at all possible. Because some patients will not be able to return for a dose of pegfilgrastim as a result of distance or immobility, for instance, alternatives to consider may include self-administered filgrastim or tbo-filgrastim, or same-day pegfilgrastim, recognizing that although same-day pegfilgrastim is not as effective as later pegfilgrastim, it is better than no pegfilgrastim. Pegfilgrastim is also available in a timed auto-inject device that delivers 6mg of pegfilgrastim subcutaneously, 27 hours after it is placed on the skin and activated. Pegfilgrastim is not currently indicated for stemcell mobilization. The 6 mg formulation should not be used in infants, children, or small adolescents who weigh less than 45 kg 
SargramostimBecause GM-CSF has been licensed specifically for use in mobilization and after transplantation of autologous PBPCs, after autologous or allogeneic bone marrow transplantation, and for AML, the manufacturer’s instructions for administration are limited to those clinical settings. GM-CSF should be initiated on the day of bone marrow infusion and not less than 24 hours after the last chemotherapy and 12 hours after the most recent radiotherapy. GM-CSF should be continued until an ANC greater than 1.5 × 109 /L for 3 consecutive days is obtained. The drug should be discontinued early or the dose reduced by 50% if the ANC increases to greater than 20 × 109 /L. The recommended dose for adults is 250 µg/m2 per day. 
Do CSFs differ in efficacy?Pegfilgrastim, 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 the clinical situation. There have been no further data comparing G-CSF and GM-CSF since the 2006 update therefore there is no change in the recommendation regarding their therapeutic equivalency.

Type: Evidence-Based, Benefits Outweigh Harms

Evidence quality: High

Strength of recommendation: Strong

What is the role of CSFs in the treatment of radiation injury?Current recommendations for the management of patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death as a result of injury to other organs, includes the prompt administration of CSF or pegylated G-CSF.1-3

Type: Formal Consensus [by others], Benefits Outweigh Harms

Evidence Quality: Intermediate

Strength of Recommendation: Moderate

1. Dainiak N, Gent RN, Carr Z, et al: First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation. Disaster Med Public Health Prep 5:202-12, 2011

2. Dainiak N WJ, Armitage JO, et al, : The hematologist and radiation casualties, in Broudy VC PJ, Tricot GJ, (ed): American Society of Hematology Education Program Book. San Diego, CA, ASH, 2003, pp 473-488

3. Waselenko JK, MacVittie TJ, Blakely WF, et al: Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Ann Intern Med 140:1037-51, 2004

 

 

 

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