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

Open AccessPublished:June 21, 2022DOI:https://doi.org/10.1016/j.ctrv.2022.102427

      Highlights

      • 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.

      Keywords

      Introduction

      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 [
      • Lyman G.H.
      Febrile Neutropenia: An Ounce of Prevention or a Pound of Cure.
      ]. In addition, oncologists may reduce the dose of chemotherapy, which can lead to low relative dose intensity (RDI) and negatively impact treatment outcomes [
      • 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.
      ]. 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 [
      • 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.
      ]. The need for daily injections was mitigated by development of the long-acting G-CSF pegfilgrastim [
      • 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.
      ], and the recent development of a wearable device reduces patient burden [
      • 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.
      ]. Cost has been partially mitigated by the introduction of biosimilars [
      • Dinan M.A.
      • Hirsch B.R.
      • Lyman G.H.
      Management of chemotherapy-induced neutropenia: measuring quality, cost, and value.
      ,
      • Schwartzberg 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.
      ]. However, financial burden, G-CSF–induced bone pain, and continued vulnerability to infection in the first week after chemotherapy remain as unmet medical needs [
      • Dinan M.A.
      • Hirsch B.R.
      • Lyman G.H.
      Management of chemotherapy-induced neutropenia: measuring quality, cost, and value.
      ,
      • Crawford 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.
      ,
      • D'Souza A.
      • Jaiyesimi I.
      • Trainor L.
      • Venuturumili P.
      Granulocyte colony-stimulating factor administration: adverse events.
      ,
      • Kubista 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.
      ,
      • Moore D.C.
      • Pellegrino A.E.
      Pegfilgrastim-Induced Bone Pain: A Review on Incidence, Risk Factors, and Evidence-Based Management.
      ]. 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.

      Clinical consequences of CIN

      The duration and severity of neutropenia are major risk factors for the development of FN and for life-threatening infection [
      • Wood A.J.J.
      • Pizzo P.A.
      Management of fever in patients with cancer and treatment-induced neutropenia.
      ]. 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 [

      U.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.

      ,

      Punnapuzha S, Edemobi PK, Elmoheen A. Febrile Neutropenia. In: StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2021, StatPearls Publishing LLC.; 2021.

      ].
      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 [
      • 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.
      ]. 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 [
      • Zimmer A.J.
      • Freifeld A.G.
      Optimal Management of Neutropenic Fever in Patients With Cancer.
      ].

      Timing and incidence of FN development

      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 [
      • Culakova 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.
      ,
      • Kawatkar 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.
      ,
      • 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.
      ]. 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%) [
      • 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.
      ]. 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 [
      • 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.
      ].
      FN incidence varies across different tumor types [
      • Crawford 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.
      ,
      • 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.
      ,
      • 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.
      ]. 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) [
      • 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.
      ]. 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.
      Figure thumbnail gr1
      Fig. 1Incidence of FN Among Solid Tumor and NHL Patients Who Did Not Receive G-CSF Prophylaxis Treatment in the US at Four Health Systems (2009–2017). A retrospective analysis was conducted of 1457 metastatic cancer patients with solid tumors or NHL who received myelosuppressive chemotherapy from 2009 to 2017 at four US health systems. Patients were categorized according to the number of patient risk factors for FN and the risk of FN according to chemotherapy. The figure shows the incidence of FN among patients who did not receive G-CSF prophylaxis during a) cycle 1, or b) the entire treatment course. The figure is based on data from Averin et al, 2021.
      [
      • 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.
      ]
      Abbreviations: FN, febrile neutropenia; G-CSF, granulocyte colony-stimulating factor; IR, intermediate risk; LR, low risk; NHL, non-Hodgkin’s lymphoma; UR, unclassified risk; US, United States.

      Morbidity, mortality, hospitalizations, and chemotherapy delays and reductions

      Patients who develop FN are at an increased risk of morbidity and mortality [
      • 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.
      ,
      • Kawatkar 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • Weycker 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.
      ]. 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) [
      • 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.
      ].
      Development of FN may lead to unplanned emergency department evaluation and hospitalization that is inconvenient and expensive [
      • Fontanella C.
      • Bolzonello S.
      • Lederer B.
      • Aprile G.
      Management of breast cancer patients with chemotherapy-induced neutropenia or febrile neutropenia.
      ]. Hospitalization rates vary by tumor type and comorbidity [
      • Kawatkar 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • Kuderer 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.
      ]. 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) [
      • 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.
      ]. 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 [
      • Kawatkar 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.
      ,
      • Kuderer 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.
      ]. Mortality for patients hospitalized for FN is 10% and higher for patients who have multiple or severe comorbidities (∼20%) [
      • 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.
      ,
      • 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.
      ].
      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 [
      • 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.
      ,
      • Nielson 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.
      ]. 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%) [
      • Schwartzberg 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.
      ,
      • Weycker D.
      • Barron R.
      • Edelsberg J.
      • Kartashov A.
      • Lyman G.H.
      Incidence of reduced chemotherapy relative dose intensity among women with early stage breast cancer in US clinical practice.
      ]. Rates of dose delays and reductions have decreased over time. In a comparison of patients with aggressive B-cell NHL treated between 2006 and 2009 and 1993–2001, dose reductions decreased (21% compared with 35%), while the percent of patients achieving RDI ≥ 85% increased (68% vs 52%). This was attributed to increased G-CSF use among patients with NHL (75% vs 12%, respectively) and subsequent lower rates of FN (12% vs 21%) [
      • Lyman G.H.
      • Crawford J.
      • Tomita D.
      • Whittaker S.
      • Dale D.C.
      Changing patterns of chemotherapy relative dose intensity and supportive care for aggressive B-cell non-Hodgkin lymphoma.
      ].

      Prevention and treatment of CIN and FN

      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
      • 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.
      ,

      National 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.

      ,
      • Aapro 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.
      ,
      • Lyman 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.
      ,
      • Lyman G.H.
      • Lyman C.H.
      • Agboola O.
      Risk models for predicting chemotherapy-induced neutropenia.
      ,
      • Smith 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.
      .
      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
      • Infection
      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 [

      National 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.

      ,
      • Aapro 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.
      ]. 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 [

      National 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.

      ,
      • Aapro 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.
      ,
      • Smith 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.
      ]. Many clinicians advocate for a more patient-specific, personalized risk assessment, finding the current group of guidelines minimally helpful [
      • Wijeratne D.T.
      • Wright K.
      • Gyawali B.
      Risk-Stratifying Treatment Strategies for Febrile Neutropenia—Tools, Tools Everywhere, and Not a Single One That Works?.
      ]. Advanced technology using machine learning approaches may help clinicians more accurately assess risk and personalize interventions [
      • Peterson D.J.
      • Ostberg N.P.
      • Blayney D.W.
      • Brooks J.D.
      • Hernandez-Boussard T.
      Machine Learning Applied to Electronic Health Records: Identification of Chemotherapy Patients at High Risk for Preventable Emergency Department Visits and Hospital Admissions.
      ].
      Filgrastim was the first G-CSF–based myeloid growth factor approved as a FN-prophylactic agent in 1991 [
      • 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.
      ] Subsequently, filgrastim biosimilars were developed and approved for clinical use, including tbo-filgrastim, filgrastim-sndz, and filgrastim-aafi [
      • Schwartzberg 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.
      ,

      National 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.

      ,
      • Awad M.
      • Singh P.
      • Hilas O.
      Zarxio (filgrastim-sndz): The first biosimilar approved by the FDA.
      ,

      Chen B, Nagai S, Armitage JO, Witherspoon B, Nabhan C, Godwin AC, et al. Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada. Oncologist. 2019;24(4):537-548. doi:10.1634/theoncologist.2018-0341.

      ]. Filgrastim and its biosimilars are rapidly cleared from the body by renal filtration, with a circulation half-life of approximately 4–8 h, and therefore require daily dosing until neutrophil recovery. The duration of G-CSF administration for optimal effect should be more than five days and up to eleven days or until post-nadir recovery [

      National 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.

      ,
      • Clemons M.
      • Fergusson D.
      • Simos D.
      • Mates M.
      • Robinson A.
      • Califaretti N.
      • et al.
      A multicentre, randomised trial comparing schedules of G-CSF (filgrastim) administration for primary prophylaxis of chemotherapy-induced febrile neutropenia in early stage breast cancer.
      ,
      • Scott S.D.
      • Chrischilles E.A.
      • Link B.K.
      • Delgado D.J.
      • Fridman M.
      • Stolshek B.S.
      Days of prophylactic filgrastim use to reduce febrile neutropenia in patients with non-Hodgkin's lymphoma treated with chemotherapy.
      ]. Daily dosing is inconvenient and a burden to patients [
      • Gawade P.L.
      • Li S.
      • Henry D.
      • Smith N.
      • Belani R.
      • Kelsh M.A.
      • et al.
      Patterns of granulocyte colony-stimulating factor prophylaxis in patients with cancer receiving myelosuppressive chemotherapy.
      ,
      • van der Auwera P.
      • Platzer E.
      • Xu Z.-X.
      • Schulz R.
      • Feugeas O.
      • Capdeville R.
      • et al.
      Pharmacodynamics and pharmacokinetics of single doses of subcutaneous pegylated human G-CSF mutant (Ro 25–8315) in healthy volunteers: comparison with single and multiple daily doses of filgrastim.
      ]; therefore, to avoid the inconvenience of daily administration, pharmacologic approaches were taken to increase the retention of G-CSF in the circulation, including adding an inert, polyethylene glycol tail to G-CSF (PEGylation), conjugation to either the Fc fraction of monoclonal antibodies or transferrin, fusion to human albumin, and circularization. PEGylation, which increases the size of the molecule and prevents renal excretion, has been most successful [
      • Kumari M.
      • Sahni G.
      • Datta S.
      Development of Site-Specific PEGylated Granulocyte Colony Stimulating Factor With Prolonged Biological Activity.
      ]. PEGylation increases the serum half-life of G-CSF by up to 42 h, enabling the dosing schedule to be 1 dose per cycle [
      • Crawford J.
      Once-per-cycle pegfilgrastim (Neulasta) for the management of chemotherapy-induced neutropenia.
      ]. The first PEGylated G-CSF agent approved for use was pegfilgrastim in 2002 [

      Drug approval package: Neulasta (pegfilgrastim) injection US Food & Drug Administration. Updated January 2002. Accessed September 23, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/125031_0000_NeulastaTOC.cfm.

      ]. Subsequently, several long-acting biosimilar molecules have become available, including pegfilgrastim-jmdb, pegfilgrastim-cbqv, pegfilgrastim-bmez, and pegfilgrastim-apgf [
      • Selby C.
      • Peyton-Thomas B.
      • Eslami P.
      Pegfilgrastim Biosimilars: Where Are We Now?.
      ].
      Post chemotherapy timing of G-CSF administration is critical to its benefit [
      • Weycker D.
      • Bensink M.
      • Lonshteyn A.
      • Doroff R.
      • Chandler D.
      Risk of chemotherapy-induced febrile neutropenia by day of pegfilgrastim prophylaxis in US clinical practice from 2010 to 2015.
      ,
      • Weycker D.
      • Li X.
      • Figueredo J.
      • Barron R.
      • Tzivelekis S.
      • Hagiwara M.
      Risk of chemotherapy-induced febrile neutropenia in cancer patients receiving pegfilgrastim prophylaxis: does timing of administration matter?.
      ]. NCCN guidelines specify that G-CSF agents should be administered once per cycle of treatment between day 1 and day 4 after chemotherapy [

      National 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.

      ]. Same-day administration is suboptimal [
      • Barnes G.
      • Pathak A.
      • Schwartzberg L.
      G-CSF utilization rate and prescribing patterns in United States: associations between physician and patient factors and GCSF use.
      ,
      • Lyman G.H.
      • Allcott K.
      • Garcia J.
      • Stryker S.
      • Li Y.
      • Reiner M.T.
      • et al.
      The effectiveness and safety of same-day versus next-day administration of long-acting granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced neutropenia: a systematic review.
      ,
      • Schuman S.I.
      • Lambrou N.
      • Robson K.
      • Glück S.
      • Myriounis N.
      • Pearson J.M.
      • et al.
      Pegfilgrastim dosing on same day as myelosuppressive chemotherapy for ovarian or primary peritoneal cancer.
      ], and administration of filgrastim on day 8 is not effective [
      • Crawford J.
      • Kreisman H.
      • Garewal H.
      • Jones S.E.
      • Shoemaker D.
      • Pupa M.R.
      • et al.
      The impact of Filgrastim schedule variation on hematopoietic recovery post-chemotherapy.
      ]. Prophylactic antibiotics are not recommended for standard chemotherapy regimens for most solid tumors [

      National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections. Updated June 5, 2020. Accessed June 18, 2021. https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf.

      ].

      COVID-19 pandemic

      The recent COVID-19 pandemic significantly impacted cancer care. Accordingly, NCCN and the European Society of Medical Oncology provided short-term recommendations to reduce the need for hospitalizations and frequent visits to outpatient centers through expanded prophylactic G-CSF use to intermediate-risk patients and self-administration of G-CSF [
      • Griffiths E.A.
      • Alwan L.M.
      • Bachiashvili K.
      • Brown A.
      • Cool R.
      • Curtin P.
      • et al.
      Considerations for Use of Hematopoietic Growth Factors in Patients With Cancer Related to the COVID-19 Pandemic.
      ,

      European Society of Medical Oncology. Supportive care strategies during the COVID-19 pandemic. Accessed June 18, 2021. https://www.esmo.org/guidelines/cancer-patient-management-during-the-covid-19-pandemic/supportive-care-in-the-covid-19-era.

      ]. It is unclear how these short-term recommendations will impact long-term patient management.

      Benefits and limitations of G-CSF agents

      Reduction in clinical sequelae of FN

      G-CSF–based agents act to demarginate mature neutrophils into the peripheral blood and accelerate the maturation of committed neutrophil precursors in the bone marrow (Fig. 2) [
      • Theyab A.
      • Algahtani M.
      • Alsharif K.F.
      • Hawsawi Y.M.
      • Alghamdi A.
      • Alghamdi A.
      • et al.
      New insight into the mechanism of granulocyte colony-stimulating factor (G-CSF) that induces the mobilization of neutrophils.
      ]. Clinically, this manifests as an elevated neutrophil count in the first 4 days after G-CSF initiation and delaying the time point of the neutrophil nadir to day 7 or 8 after chemotherapy, reducing the depth of the nadir, and achieving neutrophil recovery by day 14 after chemotherapy. As a result, G-CSF agents decrease the risk of FN and documented infections, and reduce the need for antibiotics and hospitalizations [
      • 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.
      ], which was the basis for FDA approval. Subsequent studies show G-CSF agents reduce the incidence of FN among patients who are at risk of developing FN [
      • Clark O.A.
      • Lyman G.H.
      • Castro A.A.
      • Clark L.G.
      • Djulbegovic B.
      Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials.
      ,
      • Kuderer N.M.
      • Dale D.C.
      • Crawford J.
      • Lyman G.H.
      Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review.
      ,

      Mhaskar R, Clark OA, Lyman G, Engel Ayer Botrel T, Morganti Paladini L, Djulbegovic B. Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database Syst Rev. 2014(10):CD003039. doi:10.1002/14651858.CD003039.pub2.

      ,
      • Wang L.
      • Baser O.
      • Kutikova L.
      • Page J.H.
      • Barron R.
      The impact of primary prophylaxis with granulocyte colony-stimulating factors on febrile neutropenia during chemotherapy: a systematic review and meta-analysis of randomized controlled trials.
      ], decrease hospitalization time, and improve neutrophil recovery [
      • Clark O.A.
      • Lyman G.H.
      • Castro A.A.
      • Clark L.G.
      • Djulbegovic B.
      Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials.
      ,

      Mhaskar R, Clark OA, Lyman G, Engel Ayer Botrel T, Morganti Paladini L, Djulbegovic B. Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database Syst Rev. 2014(10):CD003039. doi:10.1002/14651858.CD003039.pub2.

      ]. In addition, G-CSF agents improve overall survival after chemotherapy, as shown by recent meta-analyses that included studies with at least 2 years of follow-up [
      • Lyman G.H.
      • Dale D.C.
      • Culakova E.
      • Poniewierski M.S.
      • Wolff D.A.
      • Kuderer N.M.
      • et al.
      The impact of the granulocyte colony-stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials.
      ,
      • Lyman G.H.
      • Yau L.
      • Nakov R.
      • Krendyukov A.
      Overall survival and risk of second malignancies with cancer chemotherapy and G-CSF support.
      ].
      Figure thumbnail gr2
      Fig. 2MOA for G-CSF, Trilaciclib, and Plinabulin in Preventing CIN and FN. Emerging agents for the prevention of CIN and FN have different mechanisms of action than G-CSF agents (including F-627 and eflapegrastim) (A), which act by promoting the demargination of peripheral blood neutrophils and accelerating the maturation of HSPC to neutrophils. Trilaciclib (B) is a CDK4/6 inhibitor that blocks cell cycle progression in G1, thereby limiting the cytotoxicity of chemotherapy in HSPC, but having no impact on CDK4/6 independent tumors. Plinabulin (C) binds to a differentiated pocket of β-tubulin and protects HSPC in the bone marrow from the cytotoxic effects of chemotherapy, thereby allowing neutrophil production to proceed normally. Abbreviations: CIN, chemotherapy induced neutropenia; FN, febrile neutropenia; G-CSF, granulocyte colony-stimulating factor; HSPC, hematopoietic stem and progenitor cell; MOA, mechanism of action; G, gap; M, mitosis; S, synthesis.

      Clinical problems associated with G-CSF use

      The primary adverse event (AE) associated with all approved G-CSF products is bone pain, which occurs in 25–83% of patients [
      • D'Souza A.
      • Jaiyesimi I.
      • Trainor L.
      • Venuturumili P.
      Granulocyte colony-stimulating factor administration: adverse events.
      ,

      National 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.

      ,
      • Tigue C.C.
      • McKoy J.M.
      • Evens A.M.
      • Trifilio S.M.
      • Tallman M.S.
      • Bennett C.L.
      Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project.
      ,
      • Lapidari P.
      • Vaz-Luis I.
      • Di Meglio A.
      Side effects of using granulocyte-colony stimulating factors as prophylaxis of febrile neutropenia in cancer patients: A systematic review.
      ]. The mechanism of G-CSF–induced bone pain is likely due to bone marrow expansion, activation of pro-inflammatory circuits, and sensitization of peripheral nerve fibers to pain stimuli [
      • Lapidari P.
      • Gbenou A.
      • Havas J.
      • Martin E.
      • Pistilli B.
      • Martin A.-L.
      • et al.
      Long-term patient reported outcomes and hematologic toxicity among patients who received Granulocyte-Colony Stimulating Factors during chemotherapy for early breast cancer.
      ]. Prophylactic antihistamine, nonsteroidal anti-inflammatory agents, and acetaminophen may be helpful in treating G-CSF–induced bone pain; however, there is limited evidence of their benefit [
      • Lambertini M.
      • Del Mastro L.
      • Bellodi A.
      • Pronzato P.
      The five “Ws” for bone pain due to the administration of granulocyte-colony stimulating factors (G-CSFs).
      ]. Other reported side effects associated with G-CSF agents include headache (15–70%), nausea and/or vomiting (3–18%), fever/chills/sweats (0–27%), fatigue (9–59%), skin reaction (1–3%), and myalgias (13–68%), though these side effects may reflect the adverse effects of chemotherapy with which the G-CSF agents are used [
      • D'Souza A.
      • Jaiyesimi I.
      • Trainor L.
      • Venuturumili P.
      Granulocyte colony-stimulating factor administration: adverse events.
      ,

      National 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.

      ]. An increased risk of secondary malignancies, most commonly acute myeloid leukemia and myelodysplastic syndrome, has also been reported following G-CSF administration (relative risk 1.85, P < 0.01) [
      • Lyman G.H.
      • Yau L.
      • Nakov R.
      • Krendyukov A.
      Overall survival and risk of second malignancies with cancer chemotherapy and G-CSF support.
      ].

      Underutilization in clinical practice

      FN prophylaxis is often underutilized in real-world clinical practice in patients receiving high-risk and intermediate-risk chemotherapy regimens [
      • Barnes G.
      • Pathak A.
      • Schwartzberg L.
      G-CSF utilization rate and prescribing patterns in United States: associations between physician and patient factors and GCSF use.
      ]. In one retrospective study of patients with solid tumors or lymphoma treated between 2009 and 2017, G-CSF was administered to 48.5% of high-risk patients (of whom 7.8% developed FN) and 13.9% of intermediate-risk patients who had one risk factor of FN (of whom 4.8% developed FN) [
      • 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.
      ]. In another retrospective analysis of similar patients treated between 2013 and 2017, 76% of high-risk patients received prophylactic G-CSF, while only 28% of intermediate-risk patients received G-CSF prophylaxis. Among intermediate-risk patients, there was no difference in G-CSF use among those who did or did not have ≥ 1 risk factor for FN. In this cohort, 8.5% of patients received G-CSF prophylaxis on the same day as completion of chemotherapy, which may negate G-CSF benefit [
      • Gawade P.L.
      • Li S.
      • Henry D.
      • Smith N.
      • Belani R.
      • Kelsh M.A.
      • et al.
      Patterns of granulocyte colony-stimulating factor prophylaxis in patients with cancer receiving myelosuppressive chemotherapy.
      ]. Underutilization of G-CSF prophylaxis may result from patient financial concerns, noncompliance, physician concerns regarding reimbursement, and a lack of awareness of guideline recommendations [
      • Hawkins A.
      • Murphy A.
      • McNamara M.
      • Gawade P.L.
      • Belani R.
      • Kelsh M.A.
      A Survey of Oncologists' Perceptions and Opinions Regarding the Use of Granulocyte Colony-Stimulating Factors.
      ].
      Financial concerns are a potential issue for both the patient and their treating physician, as G-CSF administration leads to additional medical costs beyond intended care. In general, biologics (filgrastim, pegfilgrastim) are associated with a high cost, which can limit accessibility for many patients [
      • Dinan M.A.
      • Hirsch B.R.
      • Lyman G.H.
      Management of chemotherapy-induced neutropenia: measuring quality, cost, and value.
      ,

      National 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.

      ]. However, these financial burdens may be reduced by administering G-CSF biosimilar products, which have been shown to provide significant savings in cost-efficiency analyses in both the US and European G5 countries [
      • Aapro M.
      • Cornes P.
      • Abraham I.
      Comparative cost-efficiency across the European G5 countries of various regimens of filgrastim, biosimilar filgrastim, and pegfilgrastim to reduce the incidence of chemotherapy-induced febrile neutropenia.
      ,
      • Blayney D.W.
      • Silver S.M.
      Cancer Biosimilars-A Regulatory Success So Far, but Value Still to Be Determined.
      ,
      • McBride A.
      • Balu S.
      • Campbell K.
      • Bikkina M.
      • MacDonald K.
      • Abraham I.
      Expanded access to cancer treatments from conversion to neutropenia prophylaxis with biosimilar filgrastim-sndz.
      ,
      • McBride A.
      • Campbell K.
      • Bikkina M.
      • MacDonald K.
      • Abraham I.
      • Balu S.
      Cost-efficiency analyses for the US of biosimilar filgrastim-sndz, reference filgrastim, pegfilgrastim, and pegfilgrastim with on-body injector in the prophylaxis of chemotherapy-induced (febrile) neutropenia.
      ].

      Emerging agents for prevention and treatment of CIN and FN

      Given the limitations of G-CSF, additional prevention and treatment options are needed for CIN and FN. Emerging agents recently approved, those in regulatory review, or in late-stage development may change the treatment landscape for CIN and FN. Key data for the emerging agents are presented in Table 2, and the ongoing clinical studies are described in Table 3.
      Table 2Key data for emerging agents for the prevention and treatment of CIN.
      Data P-values are included if published.
      DrugStudy (Name and/or NCT Identifier)PhasePopulation (N)TreatmentMean DSN C1
      Severe neutropenia = grade 4.
      SN
      Severe neutropenia = grade 4.
      FNHospitalization Rate
      TrilaciclibNCT03041311

      Daniel et al, 2020
      • McBride A.
      • Campbell K.
      • Bikkina M.
      • MacDonald K.
      • Abraham I.
      • Balu S.
      Cost-efficiency analyses for the US of biosimilar filgrastim-sndz, reference filgrastim, pegfilgrastim, and pegfilgrastim with on-body injector in the prophylaxis of chemotherapy-induced (febrile) neutropenia.
      2ES-SCLC (N = 107)Trilaciclib (240 mg/m2 QD D1–3) prior to carboplatin D1 + etoposide D1-3 + atezolizumab D1
      Carboplatin AUC 5 + etoposide 100 mg/m2 + atezolizumab 1200 mg.
       → atezolizumab maintenance D1 Q21D
      0 vs 4 days (P < 0.0001)1.9% vs 49.1% (P < 0.001)1.9% vs 5.7%

      (P = 0.3105)
      3.8% vs 11.3% (P = 0.1287)
      Placebo (240 mg/m2 QD D1–3) prior to carboplatin D1 + etoposide D1–3 + atezolizumab D1
      Carboplatin AUC 5 + etoposide 100 mg/m2 + atezolizumab 1200 mg.
       → atezolizumab maintenance D1 Q21D
      NCT02514447

      Hart et al, 2021
      • Daniel D.
      • Kuchava V.
      • Bondarenko I.
      • Ivashchuk O.
      • Reddy S.
      • Jaal J.
      • et al.
      Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled Phase II trial.
      1b/2aES-SCLC (N = 61)Trilaciclib (240 mg/m2 QD D1–3) prior to (≤4h) topotecan D1-5
      Topotecan 1.5 mg/m2.
      Q21D
      2 vs 7 days (P < 0.0001)40.6% vs 75.9% (P = 0.016)6.3% vs 17.9%9.4% vs 21.4%

      (P = 0.1879)
      Placebo (240 mg/m2 QD D1–3) prior to (≤4h) topotecan D1–5
      Topotecan 1.5 mg/m2.
      Q21D
      NCT02499770

      Weiss et al, 2019
      • Hart L.L.
      • Ferrarotto R.
      • Andric Z.G.
      • Beck J.T.
      • Subramanian J.
      • Radosavljevic D.Z.
      • et al.
      Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study.
      1b/2ES-SCLC (N = 122)Trilaciclib (200 or 240 mg/m2 QD D1–3) prior to carboplatin D1 + etoposide D1–3
      Carboplatin AUC 5 + etoposide 100 mg/m2.
      0 vs 3 days (P ≤ 0.001)5% vs 43% (P ≤ 0.0001)3% vs 8%Not reported
      Placebo (200 or 240 mg/m2 QD D1–3) prior to carboplatin AUC 5 D1 + etoposide D1–3
      Carboplatin AUC 5 + etoposide 100 mg/m2.
      NCT02978716

      Tan et al, 2019
      • Weiss J.M.
      • Csoszi T.
      • Maglakelidze M.
      • Hoyer R.J.
      • Beck J.T.
      • Domine Gomez M.
      • et al.
      Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.
      2TNBC (N = 102)Group 1: Gemcitabine + carboplatin D1,8
      Gemcitabine 1000 mg/m2 + carboplatin AUC 2.
      0.8 vs 1.5 vs 1.0 days (P = 0.705)26% vs 36% vs 23% (P = 0.705)3% vs 3% vs 0%Not reported
      Group 2: Trilaciclib 240 mg/m2 D1, 8 + gemcitabine + carboplatin D1, 8
      Gemcitabine 1000 mg/m2 + carboplatin AUC 2.
      Group 3: Trilaciclib 240 mg/m2 D1, 2, 8, 9 + gemcitabine + carboplatin D2, 9
      Gemcitabine 1000 mg/m2 + carboplatin AUC 2.
      PlinabulinPROTECTIVE-1/NCT03102606

      Blayney et al, 2021
      • Tan A.R.
      • Wright G.S.
      • Thummala A.R.
      • Danso M.A.
      • Popovic L.
      • Pluard T.J.
      • et al.
      Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial.
      3Breast, lung, and prostate cancer patients (intermediate FN risk) (N = 105)Docetaxel D1
      Docetaxel 75 mg/m2.
       + plinabulin 40 mg D1 + placebo D2
      Equal DSNNot reported0% vs 1.89%3.84% vs 1.89%
      Docetaxel D1
      Docetaxel 75 mg/m2.
       + placebo D1 + pegfilgrastim 6 mg D2
      PROTECTIVE-2/NCT03294577

      Blayney et al, 2021; Shi et al, 2021
      • Blayney D.W.
      • Shi Y.
      • Bondarenko I.
      • Ogenstad S.
      • Zhang Q.
      • Du L.
      • et al.
      Head-to-head comparison of single agent (SA) plinabulin (Plin) versus pegfilgrastim (Peg) for the prevention of chemotherapy-induced neutropenia (CIN) in the phase 3 trial PROTECTIVE-1.
      ,
      • Blayney D.W.
      • Shi Y.
      • Adamchuk H.
      • Feng D.
      • Zhang Q.
      • Du L.
      • et al.
      Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention.
      3Breast cancer (N = 221)Docetaxel/doxorubicin/cyclophosphamide
      Docetaxel 75 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2.
      D1 + plinabulin 40 mg D1 + pegfilgrastim 6 mg D2
      1.2 vs 1.5 (P = 0.03)
      Study met the primary endpoint of improvement in percentage of patients with DSN C1 = 0 (31.5% vs 13.6%, P = 0.0015).
      21.62% vs 46.36% (P = 0.0001) (profound neutropenia C1)3.6% vs 6.3% (P = 0.36)75% vs 100%
      Docetaxel/doxorubicin/cyclophosphamide
      Docetaxel 75 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2.
      D1 + pegfilgrastim 6 mg D2
      PROTECTIVE-1/NCT04345900

      Blayney et al, 2020
      • Shi Y.
      • Blayney D.W.
      • Adamchuk H.
      • Zhang Q.
      • Du L.
      • Huang L.
      • et al.
      Chemotherapy induced profound neutropenia (PN) in patients (pt) with breast cancer (BC) after chemotherapy and plinabulin (Plin) plus pegfilgrastim (Peg) combination versus (vs) peg alone: Final phase 3 results from protective-2 (BPI-2358-106).
      2NSCLC (N = 55)Docetaxel D1
      Docetaxel 75 mg/m2.
       + plinabulin 5, 10, 20 mg/m2 D1
      0.36 vs 0.15 days (P = 0.76)
      Reported for 20 mg/m2 dose of plinabulin.
      Not reportedn = 1
      One case of FN was reported for 20 mg/m2 dose of plinabulin, which led to patient withdrawal. It is not clear whether FN events occurred in other treatment arms.
      14% vs 15 %
      Reported for 20 mg/m2 dose of plinabulin.
      Docetaxel D1
      Docetaxel 75 mg/m2.
       + pegfilgrastim 6 mg D2
      F-627
      F-627 data is presented based on data posted in Clinicaltrials.gov. Data are not published in a peer-reviewed journal or congress.
      NCT03252431

      Clinicaltrials.gov
      • Blayney D.W.
      • Zhang Q.
      • Feng J.
      • Zhao Y.
      • Bondarenko I.
      • Vynnychenko I.
      • et al.
      Efficacy of plinabulin vs pegfilgrastim for prevention of chemotherapy-induced neutropenia in adults with non-small cell lung cancer: A phase 2 randomized clinical trial.
      3Breast cancer (N = 393)Docetaxel + cyclophosphamide D1
      Docetaxel 75 mg/m2 + cyclophosphamide 600 mg/m2.
       + F-627 20 mg D2 C1–4
      0.2 vs 0.2 days11.7% vs 11.7% (C1)3% vs 0.5%Not reported
      Docetaxel + cyclophosphamide D1
      Docetaxel 75 mg/m2 + cyclophosphamide 600 mg/m2.
       + pegfilgrastim 6 mg D2 C1–4
      NCT02872103

      Clinicaltrials.gov

      Neulasta-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy. Clinicaltrials.gov. Updated May 7, 2021. Accessed September 9, 2021. https://clinicaltrials.gov/ct2/show/results/NCT03252431.

      3Breast cancer (N = 122)Docetaxel + doxorubicin D1
      Chemotherapy doses not provided.
       + F-627 20 mg D2 C1–4
      1.3 vs 3.9 days69.9% vs 94.9%4.8% vs 28.2%Not reported
      Docetaxel + doxorubicin D
      Chemotherapy doses not provided.
       + placebo 20 mg D2 C1 + F-627 20 mg D2 C2–4
      EflapegrastimADVANCE/NCT02643420

      Schwartzberg et al, 2020

      Placebo-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy. Clinicaltrials.gov. Updated May 5, 2021. Accessed September 9, 2021. https://clinicaltrials.gov/ct2/show/results/NCT02872103.

      3Breast cancer (N = 406)Docetaxel + cyclophosphamide D1
      Docetaxel 75 mg/m2 + cyclophosphamide 600 mg/m2.
       + eflapegrastim 13.2
      13.2 mg eflapegrastim is equivalent to 3.6 mg G-CSF.
      mg D2
      0.20 vs 0.35 days (P = 0.013)15.8% vs 24.3% (P = 0.034)2% vs 1% (P = 0.435)Not reported
      Docetaxel + cyclophosphamide D1
      Docetaxel 75 mg/m2 + cyclophosphamide 600 mg/m2.
       + pegfilgrastim 6 mg D2
      RECOVER/NCT02953340

      Cobb et al, 2020
      • Schwartzberg L.S.
      • Bhat G.
      • Peguero J.
      • Agajanian R.
      • Bharadwaj J.S.
      • Restrepo A.
      • et al.
      Eflapegrastim, a long-acting granulocyte-colony stimulating factor for the management of chemotherapy-induced neutropenia: results of a phase III trial.
      3Breast cancer (N = 237)Docetaxel + cyclophosphamide D1
      Docetaxel 75 mg/m2 + cyclophosphamide 600 mg/m2.
       + eflapegrastim 13.2
      13.2 mg eflapegrastim is equivalent to 3.6 mg G-CSF.
      mg D2
      0.31 vs 0.39 days (P = 0.0001)20.3% vs 23.5%0.8% vs 3.4% (P = 0.370)Not reported
      Docetaxel + cyclophosphamide D1
      Docetaxel 75 mg/m2 + cyclophosphamide 600 mg/m2.
       + pegfilgrastim 6 mg D2
      Abbreviations: AUC, area under the curve; C, cycle; CIN, chemotherapy-induced neutropenia; D, day; DSN, duration of severe neutropenia; ES-SCLC, extensive-stage small-cell lung cancer; FN, febrile neutropenia; G4, grade 4; h, hours; m2, millimeter square; mg, milligram; NSCLC, non-small cell lung cancer; Q21D, every 21 days; QD, once daily; SN, severe neutropenia; TNBC, triple-negative breast cancer; vs, versus.
      a Data P-values are included if published.
      b Severe neutropenia = grade 4.
      c Carboplatin AUC 5 + etoposide 100 mg/m2 + atezolizumab 1200 mg.
      d Topotecan 1.5 mg/m2.
      e Carboplatin AUC 5 + etoposide 100 mg/m2.
      f Gemcitabine 1000 mg/m2 + carboplatin AUC 2.
      g Docetaxel 75 mg/m2.
      h Docetaxel 75 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2.
      i Study met the primary endpoint of improvement in percentage of patients with DSN C1 = 0 (31.5% vs 13.6%, P = 0.0015).
      j Reported for 20 mg/m2 dose of plinabulin.
      k One case of FN was reported for 20 mg/m2 dose of plinabulin, which led to patient withdrawal. It is not clear whether FN events occurred in other treatment arms.
      l F-627 data is presented based on data posted in Clinicaltrials.gov. Data are not published in a peer-reviewed journal or congress.
      m Docetaxel 75 mg/m2 + cyclophosphamide 600 mg/m2.
      n Chemotherapy doses not provided.
      o 13.2 mg eflapegrastim is equivalent to 3.6 mg G-CSF.
      Table 3Key ongoing studies in the prevention of CIN and FN.
      Based on search conducted on September 10, 2021, on Clinicaltrials.gov database.
      DrugStudyPhasePopulationTreatmentPrimary EndpointKey Secondary Endpoints
      TrilaciclibPRESERVE1 (NCT04607668)3mCRCFOLFOXIRI/bevacizumab + trilaciclib vs placeboDSN C1 and occurrence of severe neutropenia during inductionQoL, PFS, OS
      PRESERVE2 (NCT04799249)3mTNBCGemcitabine/carboplatin + trilaciclib vs placeboOSQoL, PFS, myeloprotective effects
      NCT049028853ES-SCLCCarboplatin/etoposide or topotecan + trilaciclib vs placeboPK, safety, DSN C1Incidence of severe neutropenia, G-CSF treatment, febrile neutropenia, antibiotics use, ORR, DCR
      PRESERVE3 (NCT04887831)2Advanced/metastatic bladder cancerChemotherapy +/– trilaciclib followed by avelumabPFSResponse rates, incidence of severe neutropenia
      PRESERVE4 (NCT04863248)2NSCLCDocetaxel + trilaciclib vs placeboOSPFS, ORR, incidence of severe neutropenia, G-CSF treatment, FN, DSN
      EflapegrastimNCT045704232Pediatric patients with solid tumors or lymphomasMyelosuppressive therapy + eflapegrastimTEAEsIncidence of severe neutropenia and FN, time to ANC recovery, PK
      NCT041878981Breast cancerDocetaxel/cyclophosphamide + eflapegrastim (same day dosing)DSN C1Incidence of neutropenia, time to recovery of severe neutropenia, incidence of G3 FN, incidence of neutropenic complications, PK
      Abbreviations: ANC, absolute neutrophil count; C1, cycle 1; CIN, chemotherapy-induced neutropenia; DCR, duration of complete response; DSN, duration of severe neutropenia; ES-SCLC, extensive-stage small-cell lung cancer; FN, febrile neutropenia; FOLFOXIRI, folinic acid, 5-fluorouracil, oxaliplatin and irinotecan; G3, grade 3; G-CSF, granulocyte-colony stimulating factor; mCRC, metastatic colorectal cancer; mTNBC, metastatic triple-negative breast cancer; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; QoL, quality-of-life; TEAEs, treatment-emergent adverse event.
      a Based on search conducted on September 10, 2021, on Clinicaltrials.gov database.

      Trilaciclib - (G1 Therapeutics, Inc)

      Trilaciclib is one in a class of small-molecule inhibitors of cyclin-dependent kinase 4/6 (CDK4/6). Trilaciclib is United States Food & Drug Administration (US FDA) approved to reduce chemotherapy-induced bone marrow suppression in adults with extensive stage small lung cancer (ES-SCLC) after platinum/etoposide-based or topotecan-based chemotherapy. FDA approval was based on data from three randomized placebo-controlled phase 2 studies, in which trilaciclib reduced the incidence of severe neutropenia and the duration of severe neutropenia (DSN) in chemotherapy cycle 1 in patients with ES-SCLC (Table 2) [

      US FDA. FDA Approves Drug to Reduce Bone Marrow Suppression Caused by Chemotherapy. Updated February 12, 2021. Accessed August 25, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-reduce-bone-marrow-suppression-caused-chemotherapy.

      ,

      COSELA (trilaciclib) prescribing information [Internet]. G1 Therapeutics. Updated February 2021. Accessed August 25, 2021. https://www.g1therapeutics.com/cosela/pi/.

      ]. Trilaciclib is recommended by NCCN guidelines as an option to decrease the incidence of chemotherapy-induced myelosuppression in ES-SCLC [

      National 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.

      ].
      In preclinical studies, trilaciclib induced transient and reversible G1 cell cycle arrest of murine and human hematopoietic stem and progenitor cells (HSPCs) and protected murine HSPCs from chemotherapy-induced exhaustion [
      • He S.
      • Roberts P.J.
      • Sorrentino J.A.
      • Bisi J.E.
      • Storrie-White H.
      • Tiessen R.G.
      • et al.
      Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion.
      ]. Since trilaciclib functions as a HSPC protective agent, trilaciclib is administered a few hours prior to chemotherapy. In the trilaciclib clinical trials, the G-CSF rescue rate for neutropenia was 10–50% [
      • Daniel D.
      • Kuchava V.
      • Bondarenko I.
      • Ivashchuk O.
      • Reddy S.
      • Jaal J.
      • et al.
      Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled Phase II trial.
      ,
      • Hart L.L.
      • Ferrarotto R.
      • Andric Z.G.
      • Beck J.T.
      • Subramanian J.
      • Radosavljevic D.Z.
      • et al.
      Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study.
      ,
      • Weiss J.M.
      • Csoszi T.
      • Maglakelidze M.
      • Hoyer R.J.
      • Beck J.T.
      • Domine Gomez M.
      • et al.
      Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.
      ,
      • Weiss J.
      • Goldschmidt J.
      • Zoran A.
      • Dragnev K.H.
      • Pritchett Y.
      • Morris S.R.
      • et al.
      Myelopreservation and reduced use of supportive care with trilaciclib in patients with small cell lung cancer.
      ].
      Trilaciclib results in dose-proportional pharmacokinetics in healthy volunteers [
      • He S.
      • Roberts P.J.
      • Sorrentino J.A.
      • Bisi J.E.
      • Storrie-White H.
      • Tiessen R.G.
      • et al.
      Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion.
      ] and was well tolerated across the clinical development program, with no reports of bone pain and fewer grade 3 or higher AEs than placebo-treated groups, primarily due to fewer hematologic toxicities [
      • Daniel D.
      • Kuchava V.
      • Bondarenko I.
      • Ivashchuk O.
      • Reddy S.
      • Jaal J.
      • et al.
      Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled Phase II trial.
      ,
      • Hart L.L.
      • Ferrarotto R.
      • Andric Z.G.
      • Beck J.T.
      • Subramanian J.
      • Radosavljevic D.Z.
      • et al.
      Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study.
      ,
      • Weiss J.M.
      • Csoszi T.
      • Maglakelidze M.
      • Hoyer R.J.
      • Beck J.T.
      • Domine Gomez M.
      • et al.
      Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.
      ,
      • Weiss J.
      • Goldschmidt J.
      • Zoran A.
      • Dragnev K.H.
      • Pritchett Y.
      • Morris S.R.
      • et al.
      Myelopreservation and reduced use of supportive care with trilaciclib in patients with small cell lung cancer.
      ]. The most common AEs attributed to trilaciclib were fatigue (9.6%), nausea (7.7%), anemia (5.8%), and infusion-related reactions (5.8%) [
      • Daniel D.
      • Kuchava V.
      • Bondarenko I.
      • Ivashchuk O.
      • Reddy S.
      • Jaal J.
      • et al.
      Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled Phase II trial.
      ].
      In addition to the benefits of trilaciclib observed in the neutrophil population (Table 2) [
      • Daniel D.
      • Kuchava V.
      • Bondarenko I.
      • Ivashchuk O.
      • Reddy S.
      • Jaal J.
      • et al.
      Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled Phase II trial.
      ,
      • Hart L.L.
      • Ferrarotto R.
      • Andric Z.G.
      • Beck J.T.
      • Subramanian J.
      • Radosavljevic D.Z.
      • et al.
      Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study.
      ,
      • Weiss J.M.
      • Csoszi T.
      • Maglakelidze M.
      • Hoyer R.J.
      • Beck J.T.
      • Domine Gomez M.
      • et al.
      Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.
      ], it has also demonstrated myelopreservation against additional hematopoietic lineages. A pooled analysis of the three phase 2 studies that led to its approval revealed significant decreases in grade 4 neutropenia and G-CSF administration, as well as grade 3/4 anemia and thrombocytopenia, red blood cell (RBC) transfusion on/after week 5, and erythropoiesis-stimulating agents administration. Improvements were also observed in quality of life (QoL) [
      • Weiss J.
      • Goldschmidt J.
      • Andric Z.
      • Dragnev K.H.
      • Gwaltney C.
      • Skaltsa K.
      • et al.
      Effects of Trilaciclib on Chemotherapy-Induced Myelosuppression and Patient-Reported Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer: Pooled Results from Three Phase II Randomized, Double-Blind, Placebo-Controlled Studies.
      ]. Similarly, a composite endpoint analysis of five adverse hematologic events among the same studies confirmed the benefit of trilaciclib as a myeloprotective agent, with improvements observed in all-cause chemotherapy dose reductions, FN, prolonged severe neutropenia, and RBC transfusions on/after week 5 [
      • Dómine Gómez M.
      • Csőszi T.
      • Jaal J.
      • Kudaba I.
      • Nikolov K.
      • Radosavljevic D.
      • et al.
      Exploratory composite endpoint demonstrates benefit of trilaciclib across multiple clinically meaningful components of myeloprotection in patients with small cell lung cancer.
      ]. However, these benefits may be tumor- or chemotherapy type–dependent, as no improvement in gemcitabine/carboplatin-induced myelosuppression was observed among patients with triple-negative breast cancer treated with trilaciclib as compared with placebo in a phase 2 study, though benefits in progression-free survival and overall survival did occur in the trilaciclib cohort [
      • Tan A.R.
      • Wright G.S.
      • Thummala A.R.
      • Danso M.A.
      • Popovic L.
      • Pluard T.J.
      • et al.
      Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial.
      ,

      O'Shaughnessy J, Wright G, Thummala A, Danso M, Popovic L, Pluard R, et al. Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: Final analysis of a randomized phase 2 trial. Presented at the 2020 Virtual Meeting of the San Antonio Breast Cancer Symposium December 8-11, 2020 Abstract PD1-06. doi:https://www.abstractsonline.com/pp8/#!/9223/presentation/714.

      ].

      Plinabulin - phase 3 (BeyondSpring, Inc.)

      Plinabulin is a small non-G-CSF molecule that binds to a differentiated pocket of β-tubulin and prevents microtubule polymerization [
      • Wang Y.
      • Zhang H.
      • Gigant B.
      • Yu Y.
      • Wu Y.
      • Chen X.
      • et al.
      Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery.
      ]. Similar to trilaciclib, plinabulin is also being investigated as both a CIN reducing agent and as an antitumor agent. In preclinical studies in rats, plinabulin reduced neutropenia induced by multiple types of chemotherapy regimens; however, the mechanism of action of plinabulin is different than standard G-CSF agents. Compared to pegfilgrastim, plinabulin administration with chemotherapy resulted in a delayed rise in ANC levels and no increase in bone marrow or plasma G-CSF in rats and mice. Rather, plinabulin increased the number of lineage−/Sca1+/c-Kit+ (LSK) cells when co-administered with docetaxel, suggesting that plinabulin may have a chemotherapy protective effect on HSPCs [
      • Tonra J.R.
      • Lloyd G.K.
      • Mohanlal R.
      • Huang L.
      Plinabulin ameliorates neutropenia induced by multiple chemotherapies through a mechanism distinct from G-CSF therapies.
      ]. Plinabulin also demonstrated antitumor activity against several human tumor cell lines, including colorectal, prostate, breast, non-small cell lung cancer (NSCLC), multiple myeloma, and leukemia cell lines [
      • Nicholson B.
      • Lloyd G.K.
      • Miller B.R.
      • Palladino M.A.
      • Kiso Y.
      • Hayashi Y.
      • et al.
      NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent.
      ,
      • Singh A.V.
      • Bandi M.
      • Raje N.
      • Richardson P.
      • Palladino M.A.
      • Chauhan D.
      • et al.
      A novel vascular disrupting agent plinabulin triggers JNK-mediated apoptosis and inhibits angiogenesis in multiple myeloma cells.
      ]. These antitumor effects were attributed to direct cancer cell killing, anti-angiogenesis, increased dendritic cell maturation, and CD8 T cell priming against tumor cells [
      • Singh A.V.
      • Bandi M.
      • Raje N.
      • Richardson P.
      • Palladino M.A.
      • Chauhan D.
      • et al.
      A novel vascular disrupting agent plinabulin triggers JNK-mediated apoptosis and inhibits angiogenesis in multiple myeloma cells.
      ,
      • Kashyap A.S.
      • Fernandez-Rodriguez L.
      • Zhao Y.
      • Monaco G.
      • Trefny M.P.
      • Yoshida N.
      • et al.
      GEF-H1 signaling upon microtubule destabilization is required for dendritic cell activation and specific anti-tumor responses.
      ].
      In a phase 1 study of 13 patients with advanced NSCLC, plinabulin had a tolerable safety profile when combined with docetaxel. The most common AEs in > 10% of patients were fatigue, pain, nausea, diarrhea, and vomiting. Serious adverse events considered likely related to plinabulin were grade 3 nausea, grade 3 vomiting, and grade 2 dehydration (1 case each). Unlike standard G-CSF agents, there were no reports of bone pain [
      • Millward M.
      • Mainwaring P.
      • Mita A.
      • Federico K.
      • Lloyd G.K.
      • Reddinger N.
      • et al.
      Phase 1 study of the novel vascular disrupting agent plinabulin (NPI-2358) and docetaxel.
      ]. Data from the phase 2 PROTECTIVE-1 study in NSCLC revealed that plinabulin administration results in similar ANC recovery and DSN when compared to pegfilgrastim (Table 2). Similar protective benefits against CIN in patients with solid tumors were observed in the phase 3 randomized PROTECTIVE-2 studies, which compared plinabulin + pegfilgrastim versus pegfilgrastim alone (Table 2), as well as the phase 3 DUBLIN-3 study in patients with NSCLC treated with docetaxel + plinabulin or placebo as a cancer treatment agent [
      • Blayney D.W.
      • Shi Y.
      • Bondarenko I.
      • Ogenstad S.
      • Zhang Q.
      • Du L.
      • et al.
      Head-to-head comparison of single agent (SA) plinabulin (Plin) versus pegfilgrastim (Peg) for the prevention of chemotherapy-induced neutropenia (CIN) in the phase 3 trial PROTECTIVE-1.
      ,
      • Blayney D.W.
      • Shi Y.
      • Adamchuk H.
      • Feng D.
      • Zhang Q.
      • Du L.
      • et al.
      Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention.
      ,
      • Shi Y.
      • Blayney D.W.
      • Adamchuk H.
      • Zhang Q.
      • Du L.
      • Huang L.
      • et al.
      Chemotherapy induced profound neutropenia (PN) in patients (pt) with breast cancer (BC) after chemotherapy and plinabulin (Plin) plus pegfilgrastim (Peg) combination versus (vs) peg alone: Final phase 3 results from protective-2 (BPI-2358-106).
      ,
      • Blayney D.W.
      • Zhang Q.
      • Feng J.
      • Zhao Y.
      • Bondarenko I.
      • Vynnychenko I.
      • et al.
      Efficacy of plinabulin vs pegfilgrastim for prevention of chemotherapy-induced neutropenia in adults with non-small cell lung cancer: A phase 2 randomized clinical trial.
      ,
      • Feinsten T.
      • Han B.
      • Shi Y.
      • Feng D.
      • Mitchell D.
      • Lelorier Y.
      • et al.
      DUBLIN-3 (BPI-2358-103): A global phase (Ph) III trial with the plinabulin/docetaxel (Plin/Doc) combination vs. Doc in 2nd/3rd Line NSCLC patients (pts) with EGFR-wild type (wt) progressing on a prior platinum-based regimen.
      ]. Importantly, both PROTECTIVE-1 and PROTECTIVE-2 confirmed that patients treated in the plinabulin cohorts, as monotherapy, or in combination with pegfilgrastim, have early onset of ANC protection in week 1 after chemotherapy, have less bone pain, and a better QoL than do patients in the control cohorts [
      • Blayney D.W.
      • Shi Y.
      • Bondarenko I.
      • Ogenstad S.
      • Zhang Q.
      • Du L.
      • et al.
      Head-to-head comparison of single agent (SA) plinabulin (Plin) versus pegfilgrastim (Peg) for the prevention of chemotherapy-induced neutropenia (CIN) in the phase 3 trial PROTECTIVE-1.
      ,
      • Blayney D.W.
      • Shi Y.
      • Adamchuk H.
      • Feng D.
      • Zhang Q.
      • Du L.
      • et al.
      Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention.
      ,
      • Shi Y.
      • Blayney D.W.
      • Adamchuk H.
      • Zhang Q.
      • Du L.
      • Huang L.
      • et al.
      Chemotherapy induced profound neutropenia (PN) in patients (pt) with breast cancer (BC) after chemotherapy and plinabulin (Plin) plus pegfilgrastim (Peg) combination versus (vs) peg alone: Final phase 3 results from protective-2 (BPI-2358-106).
      ,
      • Blayney D.W.
      • Zhang Q.
      • Feng J.
      • Zhao Y.
      • Bondarenko I.
      • Vynnychenko I.
      • et al.
      Efficacy of plinabulin vs pegfilgrastim for prevention of chemotherapy-induced neutropenia in adults with non-small cell lung cancer: A phase 2 randomized clinical trial.
      ,
      • Mohanlal R.
      • Lelorier Y.
      • Mitchell D.
      • Huang L.
      • Blayney D.W.
      Impact of adding plinabulin to pegfilgrastim for the prevention of TAC chemotherapy (Chemo) induced neutropenia (CIN), on patient quality of life (QoL).
      ]. Furthermore, similar to trilaciclib, plinabulin is also administered on the same day as chemotherapy, 30 min after chemotherapy use, which could alleviate the burden associated with daily or post-chemotherapy G-CSF administration [
      • Blayney D.W.
      • Shi Y.
      • Bondarenko I.
      • Ogenstad S.
      • Zhang Q.
      • Du L.
      • et al.
      Head-to-head comparison of single agent (SA) plinabulin (Plin) versus pegfilgrastim (Peg) for the prevention of chemotherapy-induced neutropenia (CIN) in the phase 3 trial PROTECTIVE-1.
      ].
      Recently, the US FDA issued a complete response letter denying the approval of plinabulin in combination with G-CSF for CIN prevention. The FDA suggested an additional clinical trial to fulfill the substantial evidence required to support the CIN indication [

      BeyondSpring. BeyondSpring Pharmaceuticals receives complete response letter from the FDA for plinabulin new drug application for prevention of chemotherapy-induced neutropenia (CIN). Updated December 1, 2021. Accessed December 15, 2021. https://beyondspringpharma.com/beyondspring-pharmaceuticals-receives-complete-response-letter-from-the-fda-for-plinabulin-new-drug-application-for-prevention-of-chemotherapy-induced-neutropenia-cin/.

      ]. Plinabulin has received breakthrough therapy designation for the prevention of CIN by China’s National Medical Products Administration [

      The ASCO Post. FDA Pipeline: Priority Reviews in Multiple Myeloma, Cervical Cancer, Neutropenia, and Myelofibrosis. Updated June 23, 2021. Accessed September 23, 2021, 2021. https://ascopost.com/news/june-2021/fda-pipeline-priority-reviews-in-multiple-myeloma-cervical-cancer-neutropenia-and-myelofibrosis/.

      ]. In addition to the anti-cancer effect seen in the initial plinabulin clinical trial of docetaxel and plinabulin, preliminary positive results from a confirmatory phase 3 trial in NSCLC were recently reported [
      • Han B.
      • Shi Y.-K.
      • Feinstein T.
      • Feng D.
      • Mitchell D.
      • Lelorier Y.
      • et al.
      LBA48 DUBLIN-3 (BPI-2358-103): A global phase (Ph) III trial with the plinabulin/docetaxel (Plin/Doc) combination vs. Doc in 2nd/3rd Line NSCLC patients (pts) with EGFR-wild type (wt) progressing on a prior platinum-based regimen.
      ,
      • Heist R.S.
      • Aren O.R.
      • Mita A.C.
      • Polikoff J.
      • Bazhenova L.
      • Lloyd G.K.
      • et al.
      Randomized phase 2 trial of plinabulin (NPI-2358) plus docetaxel in patients with advanced non-small cell lung cancer (NSCLC).
      ].

      F-627 (efbemalenograstim alpha) – Phase 3 (Evive Biotech)

      F-627 is a recombinant human granulocyte-colony stimulating factor (rhG-CSF) dimer that is linked to an immunoglobulin G2 (IgG2)-Fc fragment. It is considered a long-acting G-CSF molecule that allows for once-per-cycle therapy for the preventive management of neutropenia and is administered on the day after chemotherapy [

      Neulasta-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy. Clinicaltrials.gov. Updated May 7, 2021. Accessed September 9, 2021. https://clinicaltrials.gov/ct2/show/results/NCT03252431.

      ,

      Placebo-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy. Clinicaltrials.gov. Updated May 5, 2021. Accessed September 9, 2021. https://clinicaltrials.gov/ct2/show/results/NCT02872103.

      ,

      Evive Biotech. Evive Biotech meets primary and secondary endpoints in global phase III clinical trial for their novel chemotherapy-induced neutropenia treatment. Evive Biotech. Updated July 7, 2020. Accessed December 14, 2020. https://www.evivebiotech.com/press_releases/evive-biotech-meets-primary-and-secondary-endpoints-in-global-phase-iii-clinical-trial-for-their-novel-chemotherapy-induced-neutropenia-treatment/.

      ]. In preclinical studies in monkeys in comparison to pegfilgrastim, F-627 treatment resulted in stronger ANC responses and similar pharmacokinetic parameters, despite a 2.5-fold lower relative molar dose with F-627 [
      • Hu Z.T.
      • Huang Z.H.
      • Cen X.B.
      • Wang T.
      • Zhuang K.
      • Yang H.Z.
      • et al.
      F-627, a G-CSF Dimer, Stimulated a More Rapid Neutrophil Recovery In Cyclophosphamide-Treated Monkeys Compared to Monomer Rhg-CSFs.
      ].
      Currently, limited data are published regarding the clinical activity of F-627. In phase 3 trials in patients with breast cancer treated with docetaxel + doxorubicin or docetaxel + cyclophosphamide, F-627 provided protection against severe neutropenia and FN when compared to placebo or pegfilgrastim, respectively (Table 2) [

      Neulasta-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy. Clinicaltrials.gov. Updated May 7, 2021. Accessed September 9, 2021. https://clinicaltrials.gov/ct2/show/results/NCT03252431.

      ,

      Placebo-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy. Clinicaltrials.gov. Updated May 5, 2021. Accessed September 9, 2021. https://clinicaltrials.gov/ct2/show/results/NCT02872103.

      ]. Adverse events in the F-627 cohort occurring in > 5% of patients were leukocytosis (7.1%), asthenia (6.6%), bone pain (15.7%), and arthralgia (6.1%) [

      Neulasta-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy. Clinicaltrials.gov. Updated May 7, 2021. Accessed September 9, 2021. https://clinicaltrials.gov/ct2/show/results/NCT03252431.

      ]. The US FDA recently accepted the biologics license application for F-627 based on the data from phase 3 trials [

      Evive Biotech. Evive Biotech meets primary and secondary endpoints in global phase III clinical trial for their novel chemotherapy-induced neutropenia treatment. Evive Biotech. Updated July 7, 2020. Accessed December 14, 2020. https://www.evivebiotech.com/press_releases/evive-biotech-meets-primary-and-secondary-endpoints-in-global-phase-iii-clinical-trial-for-their-novel-chemotherapy-induced-neutropenia-treatment/.

      ,

      Evive Biotech. U.S. FDA Accepts Biologics License Application for Ryzneuta™. Updated May 28, 2021. Accessed August 25, 2021. https://www.evivebiotech.com/press_releases/u-s-fda-accepts-biologics-license-application-for-ryzneuta/.

      ].

      Eflapegrastim – Phase 3 (Spectrum Pharmaceuticals)

      Eflapegrastim is a long-acting hematopoietic growth factor, consisting of rhG-CSF analog conjugated to a human aglycosylated IgG4 Fc fragment via a short polyethylene glycol linker [
      • Cobb P.W.
      • Moon Y.W.
      • Mezei K.
      • Láng I.
      • Bhat G.
      • Chawla S.
      • et al.
      A comparison of eflapegrastim to pegfilgrastim in the management of chemotherapy-induced neutropenia in patients with early-stage breast cancer undergoing cytotoxic chemotherapy (RECOVER): A Phase 3 study.
      ]. In preclinical studies, the Fc fragment of eflapegrastim bound to FcRn in cell lines, resulting in FcRn-mediated transcytosis. This was associated with higher serum and bone marrow concentrations of eflapegrastim than pegfilgrastim in rats at the same administered dose. These results translated to a shorter duration of neutropenia when eflapegrastim was administered 24 h post-chemotherapy compared to pegfilgrastim. Furthermore, eflapegrastim significantly reduced the duration of neutropenia in rats when administered concomitantly with chemotherapy or up to 5 h post-chemotherapy, suggesting that same-day dosing of eflapegrastim with chemotherapy may be possible [
      • Barrett J.A.
      • Choi J.
      • Lakshmikanthan S.
      • Kim Y.-Y.
      • Greene D.
      • Kolli P.
      • et al.
      Eflapegrastim's enhancement of efficacy compared with pegfilgrastim in neutropenic rats supports potential for same-day dosing.
      ].
      In two separate phase 3 clinical trials in patients with early-stage breast cancer treated with standard docetaxel/cyclophosphamide (ADVANCE and RECOVER), eflapegrastim demonstrated noninferiority and comparable safety at a lower G-CSF dose versus pegfilgrastim (Table 2) [
      • Schwartzberg L.S.
      • Bhat G.
      • Peguero J.
      • Agajanian R.
      • Bharadwaj J.S.
      • Restrepo A.
      • et al.
      Eflapegrastim, a long-acting granulocyte-colony stimulating factor for the management of chemotherapy-induced neutropenia: results of a phase III trial.
      ,
      • Cobb P.W.
      • Moon Y.W.
      • Mezei K.
      • Láng I.
      • Bhat G.
      • Chawla S.
      • et al.
      A comparison of eflapegrastim to pegfilgrastim in the management of chemotherapy-induced neutropenia in patients with early-stage breast cancer undergoing cytotoxic chemotherapy (RECOVER): A Phase 3 study.
      ]. A pooled analysis of the studies confirmed that eflapegrastim significantly reduced the risk of severe neutropenia compared to pegfilgrastim in the overall population and in patients > 75 kg, and resulted in similar safety profile as pegfilgrastim [

      Schwartzberg LS, Bhat G, Restrepo A, Hlalah O, Mehmi I, Moon YW, et al. Pooled efficacy analysis from two phase 3 studies in patients receiving eflapegrastim, a novel, long-acting granulocyte-colony stimulating factor, following TC for early-stage breast cancer. Poster Presented at the Virtual San Antonio Breast Cancer Symposium. 2020;Abstract PS9-59. doi:https://www.abstractsonline.com/pp8/#!/9223/presentation/1323.

      ]. In both phase 3 studies, eflapegrastim treatment resulted in a similar incidence of bone pain compared to pegfilgrastim (eflapegrastim 32–34% vs pegfilgrastim 32–38%). The incidence of additional AEs associated with G-CSF agents were likewise comparable between the treatment arms, including rates of musculoskeletal AEs, injection site reactions, and hypersensitivity-type reactions [
      • Schwartzberg L.S.
      • Bhat G.
      • Peguero J.
      • Agajanian R.
      • Bharadwaj J.S.
      • Restrepo A.
      • et al.
      Eflapegrastim, a long-acting granulocyte-colony stimulating factor for the management of chemotherapy-induced neutropenia: results of a phase III trial.
      ,
      • Cobb P.W.
      • Moon Y.W.
      • Mezei K.
      • Láng I.
      • Bhat G.
      • Chawla S.
      • et al.
      A comparison of eflapegrastim to pegfilgrastim in the management of chemotherapy-induced neutropenia in patients with early-stage breast cancer undergoing cytotoxic chemotherapy (RECOVER): A Phase 3 study.
      ].

      Conclusions

      The development of CIN can lead to clinical consequences that can negatively impact patient outcomes [
      • 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.
      ]. While the approval and widespread use of prophylactic G-CSF agents has reduced the clinical consequences of FN, they are also associated with several limitations, including side effects, late onset of action, lack of convenience due to daily dosing of short-acting agents, challenges with insurance approvals and reimbursement, and inadequate risk stratification tools [
      • Dinan M.A.
      • Hirsch B.R.
      • Lyman G.H.
      Management of chemotherapy-induced neutropenia: measuring quality, cost, and value.
      ,
      • D'Souza A.
      • Jaiyesimi I.
      • Trainor L.
      • Venuturumili P.
      Granulocyte colony-stimulating factor administration: adverse events.
      ,
      • Wijeratne D.T.
      • Wright K.
      • Gyawali B.
      Risk-Stratifying Treatment Strategies for Febrile Neutropenia—Tools, Tools Everywhere, and Not a Single One That Works?.
      ,
      • Gawade P.L.
      • Li S.
      • Henry D.
      • Smith N.
      • Belani R.
      • Kelsh M.A.
      • et al.
      Patterns of granulocyte colony-stimulating factor prophylaxis in patients with cancer receiving myelosuppressive chemotherapy.
      ]. The advent of biosimilar G-CSF products has helped alleviate financial burdens for some patients by improving access, while maintaining the efficacy and safety profile of the originator molecules. However, the recent approval of trilaciclib as a myeloprotective agent for ES-SCLC, and the continued development of plinabulin, F-627, and eflapegrastim are likely to improve the strategies for preventing CIN and FN in the future. In particular, the alternative mechanisms of action of trilaciclib and plinabulin may offer several advantages over standard G-CSF therapy, including same-day dosing as chemotherapy, limited to no bone pain, and potential antitumor activity. Additional studies may further define the role of these emerging agents as the new standard of care for CIN and FN prevention in solid tumors in combination with chemotherapeutic regimens.
      Source(s) of support (in the form of grants, equipment, drugs, or all of these): Medical writing support was provided by Rebecca Bigelow (Publication Practice Counsel™; Truposha LLC), which was funded by BeyondSpring, Inc. Authors retained full control of content and other publication-related decisions.

      CRediT authorship contribution statement

      Douglas W. Blayney: Writing – review & editing. Lee Schwartzberg: Writing – review & editing.

      Declaration of Competing Interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DB reports research funding (institution) from BeyondSpring; consulting fees from TG Therapeutics, Biotheranostics, Bristol Myers Squibb, Incyte Pharmaceuticals, Lilly, Merck, and Innovate Science Solutions; honoraria/speaker role from BeyondSpring; advisory role for Madorra; serves on the Board of Directors for Artelo Biosciences; stocks from Artelo Biosciences, Madorra. LS reports research funding (institution) from Amgen; consulting fees from Pfizer, Myriad, Genentech, Odonate, Amgen, Spectrum, Napo, Lilly, Bristol Myers Squibb, Helsinn, Bayer, BeyondSpring, AstraZeneca, Seagen, Sanofi, and Coherus; honoraria/speaker role from Coherus, PUMA, Merck, Seagen, and Pfizer.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

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