Chemotherapy-induced neutropenia and emerging agents for prevention and treatment: A review

Abstract

•Chemotherapy-induced neutropenia can lead to poor clinical outcomes.•CIN can lead to infections, hospitalizations, mortality, and lower chemotherapy dose intensity.•G-CSF agents have been the standard of care for the prevention of CIN for 30 years.•Emerging therapies will likely change the standard approach for CIN prevention. Cancer treatment with myelosuppressive chemotherapy puts patients at risk of developing chemotherapy-induced neutropenia (CIN). Neutropenia predisposes patients to potentially life-threatening complications, including febrile neutropenia (FN), antibiotic use, hospitalization, and increased mortality [[1]Lyman G.H. Febrile Neutropenia: An Ounce of Prevention or a Pound of Cure.J Oncol Pract. 2019; 15: 27-29https://doi.org/10.1200/jop.18.00750Crossref PubMed Google Scholar]. In addition, oncologists may reduce the dose of chemotherapy, which can lead to low relative dose intensity (RDI) and negatively impact treatment outcomes [[2]Lalami Y. Klastersky J. Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: An overview about well-established and recently emerging clinical data.Crit Rev Oncol Hematol. 2017; 120: 163-179https://doi.org/10.1016/j.critrevonc.2017.11.005Crossref PubMed Scopus (48) Google Scholar]. Granulocyte colony-stimulating factors (G-CSFs), which were first introduced for clinical use in the 1990s, reduced the incidence of these complications and improved patient outcomes [[3]Crawford J. Ozer H. Stoller R. Johnson D. Lyman G. Tabbara I. et al.Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer.N Engl J Med. 1991; 325: 164-170Crossref PubMed Google Scholar]. The need for daily injections was mitigated by development of the long-acting G-CSF pegfilgrastim [[4]Holmes F.A. Jones S.E. O’Shaughnessy J. Vukelja S. George T. Savin M. et al.Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer.Ann Oncol. 2002; 13: 903-909https://doi.org/10.1093/annonc/mdf130Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar], and the recent development of a wearable device reduces patient burden [[5]Jindal A. Kover J. Raduka V. O'Brien T.E. Incidence of Neutropenic Fever at a Safety Net Hospital in Cancer Chemotherapy Patients Receiving Prophylactic Pegfilgrastim Manual Injection Compared to the on-Body Auto-Injector.Blood. 2018; 132: 4709https://doi.org/10.1182/blood-2018-99-114282Crossref Google Scholar]. Cost has been partially mitigated by the introduction of biosimilars [6Dinan M.A. Hirsch B.R. Lyman G.H. Management of chemotherapy-induced neutropenia: measuring quality, cost, and value.J Natl Compr Canc Netw. 2015; 13: e1-7https://doi.org/10.6004/jnccn.2015.0014Crossref PubMed Scopus (32) Google Scholar, 7Schwartzberg L.S. Lal L.S. Balu S. Campbell K. Brekke L. Elliott C. et al.Incidence of febrile neutropenia during chemotherapy among patients with nonmyeloid cancer receiving filgrastim vs a filgrastim biosimilar.Clinicoecon Outcomes Res. 2018; 10: 493-500https://doi.org/10.2147/ceor.S168298Crossref PubMed Google Scholar]. However, financial burden, G-CSF–induced bone pain, and continued vulnerability to infection in the first week after chemotherapy remain as unmet medical needs [6Dinan M.A. Hirsch B.R. Lyman G.H. Management of chemotherapy-induced neutropenia: measuring quality, cost, and value.J Natl Compr Canc Netw. 2015; 13: e1-7https://doi.org/10.6004/jnccn.2015.0014Crossref PubMed Scopus (32) Google Scholar, 8Crawford J. Dale D.C. Kuderer N.M. Culakova E. Poniewierski M.S. Wolff D. et al.Risk and Timing of Neutropenic Events in Adult Cancer Patients Receiving Chemotherapy: The Results of a Prospective Nationwide Study of Oncology Practice.J Natl Compr Canc Netw. 2008; 6: 109-118https://doi.org/10.6004/jnccn.2008.0012Crossref PubMed Scopus (188) Google Scholar, 9D'Souza A. Jaiyesimi I. Trainor L. Venuturumili P. Granulocyte colony-stimulating factor administration: adverse events.Transfus Med Rev. 2008; 22: 280-290https://doi.org/10.1016/j.tmrv.2008.05.005Crossref PubMed Scopus (77) Google Scholar, 10Kubista E. Glaspy J. Holmes F.A. Green M.D. Hackett J. Neumann T. Bone pain associated with once-per-cycle pegfilgrastim is similar to daily filgrastim in patients with breast cancer.Clin Breast Cancer. 2003; 3: 391-398https://doi.org/10.3816/cbc.2003.n.003Abstract Full Text PDF PubMed Google Scholar, 11Moore D.C. Pellegrino A.E. Pegfilgrastim-Induced Bone Pain: A Review on Incidence, Risk Factors, and Evidence-Based Management.Ann Pharmacother. 2017; 51: 797-803https://doi.org/10.1177/1060028017706373Crossref PubMed Scopus (18) Google Scholar]. Several emerging therapies with mechanisms of action different from those of standard G-CSF agents are either recently approved or in late-stage development and have the potential to improve the management of CIN and FN. The duration and severity of neutropenia are major risk factors for the development of FN and for life-threatening infection [[12]Wood A.J.J. Pizzo P.A. Management of fever in patients with cancer and treatment-induced neutropenia.N Engl J Med. 1993; 328: 1323-1332Crossref PubMed Scopus (793) Google Scholar]. For regulatory and drug approval purposes, and to facilitate comparison across clinical trials, neutropenia is graded on a four-point scale (Table S1 in the Supplementary Material). Fever (temperature > 38 °C) in combination with severe neutropenia (absolute neutrophil count [ANC] < 500 cells/mm3) defines FN, while profound neutropenia is considered the most severe form of neutropenia and is defined as ANC < 100 cells/mm3 [13U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE)_Version 5.0. Updated November 27, 2017. Accessed June 15, 2021. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50.Google Scholar, 14Punnapuzha S, Edemobi PK, Elmoheen A. Febrile Neutropenia. In: StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2021, StatPearls Publishing LLC.; 2021.Google Scholar]. The clinical consequences of CIN include FN and resulting oral or intravenous antibiotic use, unplanned emergency department visits and hospitalizations, and possible death. Furthermore, the need for dose reductions and dose delays in subsequent chemotherapy cycles to help mitigate neutropenia can adversely impact patient outcomes [[2]Lalami Y. Klastersky J. Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: An overview about well-established and recently emerging clinical data.Crit Rev Oncol Hematol. 2017; 120: 163-179https://doi.org/10.1016/j.critrevonc.2017.11.005Crossref PubMed Scopus (48) Google Scholar]. When FN develops, initiation of empiric broad spectrum antibiotic use is indicated until either more specific coverage dictated by identification of the etiologic pathogen or until the neutrophil count recovers and fever resolves. Empiric antibiotics directed at normally commensal skin, gut, and oral flora are used [[15]Zimmer A.J. Freifeld A.G. Optimal Management of Neutropenic Fever in Patients With Cancer.J Oncol Pract. 2019; 15: 19-24https://doi.org/10.1200/jop.18.00269Crossref PubMed Scopus (0) Google Scholar]. FN typically develops in the first chemotherapy cycle, and incidence decreases from cycle 2 onward, likely in part due to chemotherapy dose reduction in cycle 2 in response to intra cycle ANC measurements of FN in cycle 1 [16Culakova E. Thota R. Poniewierski M.S. Kuderer N.M. Wogu A.F. Dale D.C. et al.Patterns of chemotherapy-associated toxicity and supportive care in US oncology practice: a nationwide prospective cohort study.Cancer Med. 2014; 3: 434-444https://doi.org/10.1002/cam4.200Crossref PubMed Scopus (66) Google Scholar, 17Kawatkar A.A. Farias A.J. Chao C. Chen W. Barron R. Vogl F.D. et al.Hospitalizations, outcomes, and management costs of febrile neutropenia in patients from a managed care population.Support Care Cancer. 2017; 25: 2787-2795https://doi.org/10.1007/s00520-017-3692-xCrossref PubMed Scopus (21) Google Scholar, 18Weycker D. Barron R. Kartashov A. Legg J. Lyman G.H. Incidence, treatment, and consequences of chemotherapy-induced febrile neutropenia in the inpatient and outpatient settings.J Oncol Pharm Pract. 2014; 20: 190-198https://doi.org/10.1177/1078155213492450Crossref PubMed Scopus (50) Google Scholar]. In a retrospective analysis of electronic health record data from 2131 patients with solid tumors or non-Hodgkin’s lymphoma (NHL) treated with chemotherapy during 2007–2010, 401 patients experienced a total of 458 FN episodes; 41% of the FN episodes occurred in cycle 1, and the incidence of FN decreased with each subsequent cycle (cycle 2: 17%; cycle 3: 13%; cycle 4: 10%) [[18]Weycker D. Barron R. Kartashov A. Legg J. Lyman G.H. Incidence, treatment, and consequences of chemotherapy-induced febrile neutropenia in the inpatient and outpatient settings.J Oncol Pharm Pract. 2014; 20: 190-198https://doi.org/10.1177/1078155213492450Crossref PubMed Scopus (50) Google Scholar]. In a 2003 analysis of patients with NHL treated in US community practices, more than half (59%) of FN hospitalizations occurred during the first two chemotherapy cycles [[19]Lyman G.H. Delgado D.J. Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma.Cancer. 2003; 98: 2402-2409https://doi.org/10.1002/cncr.11827Crossref PubMed Scopus (142) Google Scholar]. FN incidence varies across different tumor types [8Crawford J. Dale D.C. Kuderer N.M. Culakova E. Poniewierski M.S. Wolff D. et al.Risk and Timing of Neutropenic Events in Adult Cancer Patients Receiving Chemotherapy: The Results of a Prospective Nationwide Study of Oncology Practice.J Natl Compr Canc Netw. 2008; 6: 109-118https://doi.org/10.6004/jnccn.2008.0012Crossref PubMed Scopus (188) Google Scholar, 20Averin A. Silvia A. Lamerato L. Richert-Boe K. Kaur M. Sundaresan D. et al.Risk of chemotherapy-induced febrile neutropenia in patients with metastatic cancer not receiving granulocyte colony-stimulating factor prophylaxis in US clinical practice.Support Care Cancer. 2021; 29: 2179-2186https://doi.org/10.1007/s00520-020-05715-3Crossref PubMed Scopus (9) Google Scholar, 21Lyman G.H. Michels S.L. Reynolds M.W. Barron R. Tomic K.S. Yu J. Risk of mortality in patients with cancer who experience febrile neutropenia.Cancer. 2010; 116: 5555-5563https://doi.org/10.1002/cncr.25332Crossref PubMed Scopus (187) Google Scholar]. A retrospective analysis of patients who received a high-risk chemotherapy regimen and did not receive G-CSF prophylaxis revealed a similar incidence of FN in cycle 1 among patients with breast cancer, lung cancer, and NHL (7.5–8.8%), while no cases of FN were found among patients with colorectal cancer (Fig. 1). Differences in the incidence of FN were observed across intermediate-risk chemotherapy regimens in cycle 1 as well as throughout all treatment cycles (Fig. 1) [[20]Averin A. Silvia A. Lamerato L. Richert-Boe K. Kaur M. Sundaresan D. et al.Risk of chemotherapy-induced febrile neutropenia in patients with metastatic cancer not receiving granulocyte colony-stimulating factor prophylaxis in US clinical practice.Support Care Cancer. 2021; 29: 2179-2186https://doi.org/10.1007/s00520-020-05715-3Crossref PubMed Scopus (9) Google Scholar]. Across all cycles and tumor types, it is interesting that the risk of FN in the intermediate group with or without risk factors approaches 15–20% or greater, speaking to the potential to re-evaluate guidelines for G-CSF use in this population. Patients who develop FN are at an increased risk of morbidity and mortality [2Lalami Y. Klastersky J. Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: An overview about well-established and recently emerging clinical data.Crit Rev Oncol Hematol. 2017; 120: 163-179https://doi.org/10.1016/j.critrevonc.2017.11.005Crossref PubMed Scopus (48) Google Scholar, 17Kawatkar A.A. Farias A.J. Chao C. Chen W. Barron R. Vogl F.D. et al.Hospitalizations, outcomes, and management costs of febrile neutropenia in patients from a managed care population.Support Care Cancer. 2017; 25: 2787-2795https://doi.org/10.1007/s00520-017-3692-xCrossref PubMed Scopus (21) Google Scholar, 18Weycker D. Barron R. Kartashov A. Legg J. Lyman G.H. Incidence, treatment, and consequences of chemotherapy-induced febrile neutropenia in the inpatient and outpatient settings.J Oncol Pharm Pract. 2014; 20: 190-198https://doi.org/10.1177/1078155213492450Crossref PubMed Scopus (50) Google Scholar, 21Lyman G.H. Michels S.L. Reynolds M.W. Barron R. Tomic K.S. Yu J. Risk of mortality in patients with cancer who experience febrile neutropenia.Cancer. 2010; 116: 5555-5563https://doi.org/10.1002/cncr.25332Crossref PubMed Scopus (187) Google Scholar, 22Weycker D. Li X. Tzivelekis S. Atwood M. Garcia J. Li Y. et al.Burden of chemotherapy-induced febrile neutropenia hospitalizations in US clinical practice, by use and patterns of prophylaxis with colony-stimulating factor.Support Care Cancer. 2017; 25: 439-447https://doi.org/10.1007/s00520-016-3421-xCrossref PubMed Scopus (29) Google Scholar]. Development of FN predicted early and overall mortality (HR 1.15 and 1.35, respectively) in patients with solid tumors or NHL compared with propensity matched controls. In another study, the highest mortality incidence occurred in patients with lung cancer (35.6 deaths per 1000 person-months of treatment), followed by colorectal (9.00), NHL (8.22), ovarian (5.40), and breast cancer (2.19) [[21]Lyman G.H. Michels S.L. Reynolds M.W. Barron R. Tomic K.S. Yu J. Risk of mortality in patients with cancer who experience febrile neutropenia.Cancer. 2010; 116: 5555-5563https://doi.org/10.1002/cncr.25332Crossref PubMed Scopus (187) Google Scholar]. Development of FN may lead to unplanned emergency department evaluation and hospitalization that is inconvenient and expensive [[23]Fontanella C. Bolzonello S. Lederer B. Aprile G. Management of breast cancer patients with chemotherapy-induced neutropenia or febrile neutropenia.Breast Care (Basel). 2014; 9: 239-245https://doi.org/10.1159/000366466Crossref PubMed Scopus (34) Google Scholar]. Hospitalization rates vary by tumor type and comorbidity [17Kawatkar A.A. Farias A.J. Chao C. Chen W. Barron R. Vogl F.D. et al.Hospitalizations, outcomes, and management costs of febrile neutropenia in patients from a managed care population.Support Care Cancer. 2017; 25: 2787-2795https://doi.org/10.1007/s00520-017-3692-xCrossref PubMed Scopus (21) Google Scholar, 18Weycker D. Barron R. Kartashov A. Legg J. Lyman G.H. Incidence, treatment, and consequences of chemotherapy-induced febrile neutropenia in the inpatient and outpatient settings.J Oncol Pharm Pract. 2014; 20: 190-198https://doi.org/10.1177/1078155213492450Crossref PubMed Scopus (50) Google Scholar, 21Lyman G.H. Michels S.L. Reynolds M.W. Barron R. Tomic K.S. Yu J. Risk of mortality in patients with cancer who experience febrile neutropenia.Cancer. 2010; 116: 5555-5563https://doi.org/10.1002/cncr.25332Crossref PubMed Scopus (187) Google Scholar, 24Kuderer N.M. Dale D.C. Crawford J. Cosler L.E. Lyman G.H. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients.Cancer. 2006; 106: 2258-2266https://doi.org/10.1002/cncr.21847Crossref PubMed Scopus (828) Google Scholar]. Lung cancer has the highest risk for FN-related hospitalization (95.34 per 1000 person-months), followed by patients with ovarian (60.02), colorectal (56.80), NHL (51.52), and breast cancer (32.99) [[21]Lyman G.H. Michels S.L. Reynolds M.W. Barron R. Tomic K.S. Yu J. Risk of mortality in patients with cancer who experience febrile neutropenia.Cancer. 2010; 116: 5555-5563https://doi.org/10.1002/cncr.25332Crossref PubMed Scopus (187) Google Scholar]. The mean length of hospital stay for patients who develop FN varies from 4.1 to 7.9 days, and increases based on the number of major comorbidities [17Kawatkar A.A. Farias A.J. Chao C. Chen W. Barron R. Vogl F.D. et al.Hospitalizations, outcomes, and management costs of febrile neutropenia in patients from a managed care population.Support Care Cancer. 2017; 25: 2787-2795https://doi.org/10.1007/s00520-017-3692-xCrossref PubMed Scopus (21) Google Scholar, 24Kuderer N.M. Dale D.C. Crawford J. Cosler L.E. Lyman G.H. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients.Cancer. 2006; 106: 2258-2266https://doi.org/10.1002/cncr.21847Crossref PubMed Scopus (828) Google Scholar]. Mortality for patients hospitalized for FN is 10% and higher for patients who have multiple or severe comorbidities (∼20%) [2Lalami Y. Klastersky J. Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: An overview about well-established and recently emerging clinical data.Crit Rev Oncol Hematol. 2017; 120: 163-179https://doi.org/10.1016/j.critrevonc.2017.11.005Crossref PubMed Scopus (48) Google Scholar, 18Weycker D. Barron R. Kartashov A. Legg J. Lyman G.H. Incidence, treatment, and consequences of chemotherapy-induced febrile neutropenia in the inpatient and outpatient settings.J Oncol Pharm Pract. 2014; 20: 190-198https://doi.org/10.1177/1078155213492450Crossref PubMed Scopus (50) Google Scholar]. Dose reductions and delays in subsequent chemotherapy cycles are another consequence of FN. A lower RDI of chemotherapy negatively impacts outcomes in the curative setting [2Lalami Y. Klastersky J. Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: An overview about well-established and recently emerging clinical data.Crit Rev Oncol Hematol. 2017; 120: 163-179https://doi.org/10.1016/j.critrevonc.2017.11.005Crossref PubMed Scopus (48) Google Scholar, 25Nielson C.M. Bylsma L.C. Fryzek J.P. Saad H.A. Crawford J. Relative Dose Intensity of Chemotherapy and Survival in Patients with Advanced Stage Solid Tumor Cancer: A Systematic Review and Meta-Analysis.Oncologist. 2021; 26: e1609-e1618https://doi.org/10.1002/onco.13822Crossref PubMed Scopus (11) Google Scholar]. The incidence of RDI < 85% in 1579 patients with NHL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–based therapy was 53%, while the incidence of RDI < 85% among 2228 patients with early-stage breast cancer treated with various chemotherapeutic regimens was 26% overall, with the highest rate of RDI < 85% observed for non–dose-dense doxorubicin/cyclophosphamide + paclitaxel or docetaxel (AC-T) (51%) and the lowest rate of RDI < 85% observed for non–dose-dense AC (17%) [26Schwartzberg L.S. Saleh M. Whittaker S. Abella E. Severe neutropenia and relative dose intensity among patients<65 and ≥65 years with non-Hodgkin's lymphoma receiving CHOP-based chemotherapy.Support Care Cancer. 2014; 22: 1833-1841https://doi.org/10.1007/s00520-014-2157-8Crossref PubMed Scopus (7) Google Scholar, 27Weycker D. Barron R. Edelsberg J. Kartashov A. Lyman G.H. 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Identifying patients who have an increased risk of developing FN is a critical component of cancer patient management to prevent CIN-associated complications. The decision to use G-CSF agents as primary FN prophylaxis is based on the chemotherapy regimen–specific risk of FN development, and on patient-, disease-, and treatment-related risk factors (Table 1). Importantly, detection of asymptomatic CIN, which often occurs if routine or incidental blood counts are performed during chemotherapy treatment, is not a reason for FN treatment or dose reductions or dose delays.Table 1Risk factors for the development of CIN and FN 2Lalami Y. Klastersky J. Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: An overview about well-established and recently emerging clinical data.Crit Rev Oncol Hematol. 2017; 120: 163-179https://doi.org/10.1016/j.critrevonc.2017.11.005Crossref PubMed Scopus (48) Google Scholar, 29National Comprehensive Cancer Network. Hematopoietic growth factors: Version 4.2021. Updated May 20, 2021. Accessed September 10, 2021. https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf.Google Scholar, 30Aapro M.S. Bohlius J. Cameron D.A. Lago L.D. Donnelly J.P. Kearney N. et al.2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.Eur J Cancer. 2011; 47: 8-32https://doi.org/10.1016/j.ejca.2010.10.013Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar, 31Lyman G.H. Kuderer N.M. Crawford J. Wolff D.A. Culakova E. Poniewierski M.S. et al.Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy.Cancer. 2011; 117: 1917-1927https://doi.org/10.1002/cncr.25691Crossref PubMed Scopus (169) Google Scholar, 32Lyman G.H. Lyman C.H. Agboola O. Risk models for predicting chemotherapy-induced neutropenia.Oncologist. 2005; 10: 427-437https://doi.org/10.1634/theoncologist.10-6-427Crossref PubMed Scopus (250) Google Scholar, 33Smith T.J. Bohlke K. Lyman G.H. Carson K.R. Crawford J. Cross S.J. et al.Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update.J Clin Oncol. 2015; 33: 3199-3212https://doi.org/10.1200/JCO.2015.62.3488Crossref PubMed Scopus (511) Google Scholar.Treatment-relatedPatient-relatedDisease-related•Type of chemotherapy•Intensity of chemotherapy•No prior prophylactic antibiotics•No prophylactic G-CSF use•Prior chemotherapy or radiation therapy•Age > 65 years•Female gender•Poor performance status•≥1 comorbidity•Nutritional status•History of prior FN•Recent surgery and/or open wounds•Liver dysfunction•Renal dysfunction•Low WBC•Low hemoglobin levels•Cardiovascular disease•HIV infection•Advanced disease•Type of cancer•Bone marrow involvement•InfectionAbbreviations: CIN, chemotherapy-induced neutropenia; FN, febrile neutropenia; G-CSF, granulocyte colony-stimulating factor; HIV, human immunodeficiency virus; WBC, white blood cell count. Open table in a new tab Abbreviations: CIN, chemotherapy-induced neutropenia; FN, febrile neutropenia; G-CSF, granulocyte colony-stimulating factor; HIV, human immunodeficiency virus; WBC, white blood cell count. The primary factor associated with FN risk is the chemotherapy regimen. Chemotherapy regimens are classified as low, intermediate, and high FN risk. The National Comprehensive Cancer Network (NCCN) and the European Organisation for Research and Treatment of Cancer (EORTC) guidelines include extensive lists of widely used chemotherapy regimens categorized by malignancy and FN risk status [29National Comprehensive Cancer Network. Hematopoietic growth factors: Version 4.2021. Updated May 20, 2021. Accessed September 10, 2021. https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf.Google Scholar, 30Aapro M.S. Bohlius J. Cameron D.A. Lago L.D. Donnelly J.P. Kearney N. et al.2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.Eur J Cancer. 2011; 47: 8-32https://doi.org/10.1016/j.ejca.2010.10.013Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar]. American Society of Clinical Oncology (ASCO), EORTC, and NCCN guidelines recommend primary prophylaxis with a G-CSF agent starting with the first chemotherapy cycle and continuing through subsequent cycles with regimens at 20% or higher FN risk. For intermediate-risk chemotherapy regimens (10–20%), primary G-CSF prophylaxis is recommended in patients who have 1 or more risk factors, which should be considered rather than chemotherapy dose reductions in our opinion. Low FN risk regimens should not receive G-CSF prophylaxis. Risk reevaluation should occur with each subsequent chemotherapy cycle. If a patient experienced FN or a dose-limiting neutropenic event and had no G-CSF use in a prior cycle, secondary G-CSF prophylaxis should be strongly considered in subsequent cycles [29National Comprehensive Cancer Network. Hematopoietic growth factors: Version 4.2021. Updated May 20, 2021. Accessed September 10, 2021. https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf.Google Scholar, 30Aapro M.S. Bohlius J. Cameron D.A. Lago L.D. Donnelly J.P. Kearney N. et al.2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.Eur J Cancer. 2011; 47: 8-32https://doi.org/10.1016/j.ejca.2010.10.013Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar, 33Smith T.J. Bohlke K. Lyman G.H. Carson K.R. Crawford J. Cross S.J. et al.Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update.J Clin Oncol. 2015; 33: 3199-3212https://doi.org/10.1200/JCO.2015.62.3488Crossref PubMed Scopus (511) Google Scholar]. Many clinicians advocate for a more patient-specific, personalized risk assessment, finding the current group of guidelines minimally helpful [[34]Wijeratne D.T. Wright K. Gyawali B. Risk-Stratifying Treatment Strategies for Febrile Neutropenia—Tools, Tools Everywhere, and Not a Single One That Works?.JCO Oncology Practice. 2021; 17: 651-654https://doi.org/10.1200/op.21.00148Crossref PubMed Google Scholar]. Advanced technology using machine learning approaches may help clinicians more accurately assess risk and personalize interventions [[35]Peterson D.J. Ostberg N.P. Blayney D.W. Brooks J.D. Hernandez-Boussard T. 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