Myeloid growth factors use in cancer and treatment of chemotherapy toxicity.

Use of myeloid growth factors in cancer

1. Hematopoietic Growth Factors Granulocyte Colony Stimulating factor

2. What is Febrile Neutropenia ? Febrile neutropenia is defined as single temperature: ≥38.3 °C orally or ≥38.0 °C over 1 hour; and neutropenia: <500 neutrophils/ mcL or <1000 neutrophils/ mcL and a predicted decline to ≤500 neutrophils/ mcL over the next 48 hours

3. RISK ASSESSMENT FOR FEBRILE NEUTROPENIA • Disease • Chemotherapy regimen High-dose therapy Dose-dense therapy Standard-dose therapy • Patient risk factors • Treatment intent (curative vs. palliative)

4. PATIENT RISK FACTORS ASSESSMENT Prior chemotherapy or radiation therapy Persistent neutropenia Bone marrow involvement by tumor Recent surgery and/or open wounds Liver dysfunction (bilirubin >2.0) Renal dysfunction (creatinine clearance <50) Age >65 years receiving full chemotherapy dose intensity

5. Dose of GCSF Daily dose of 5 mcg/kg (rounding to the nearest vial size by institution-defined weight limits) until post-nadir absolute neutrophil count (ANC) recovery to normal or near-normal levels by laboratory standards. Start the next day or up to 3–4 days after completion of myelosuppressive chemotherapy and treat through post-nadir recovery

6. Pegfilgrastim - One dose of 6 mg Based on clinical trial data, pegfilgrastim can be administered the day after myelosuppressive chemotherapy (category 1) There should be at least 12 days between the dose of pegfilgrastim and the next cycle of chemotherapy Administration of pegfilgrastim up to 3–4 days after chemotherapy is also reasonable based on trials with filgrastim.

7. Caution should be exercised when administering prophylactic G-CSF in patients given concurrent chemotherapy and radiation. Randomized data have indicated a detrimental effect on toxic deaths with the use of GM-CSF during concurrent chemoradiotherapy. This was not observed in a more recent secondary analysis of the CONVERT trial, in which prophylactic G-CSF was allowed. The risks and benefits of G-CSF versus dose reduction or delay during modern chemoradiotherapy are uncertain at this time.

8. Allergic reactions Skin: rash, urticaria, facial edema Respiratory: wheezing, dyspnea Cardiovascular: hypotension, tachycardia, anaphylaxis Bleomycin-containing regimens: pulmonary toxicity Splenic rupture Acute respiratory distress syndrome Alveolar hemorrhage and hemoptysis Sickle cell crises (only in patients with sickle cell disease) Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)

9. Precautions Rare: vasculitis, Sweet syndrome Immunogenicity Adverse reactions Bone pain

10. Therapeutic Use of MGFs There is less evidence supporting the therapeutic use of MGFs for FN. While there are clinical benefits to G-CSF therapy for FN, such as shorter time to neutrophil recovery and shorter length of hospitalization, it remains unclear whether these benefits translate into a survival advantage. The NCCN Panel recommends that patients presenting with FN who are receiving or have previously received prophylactic filgrastim, tbo -filgrastim, or filgrastim biosimilars should continue G-CSF.

11. No studies address the therapeutic use of filgrastim for FN in patients who have already received prophylactic pegfilgrastim or a pegfilgrastim biosimilar. However, since pegfilgrastim and pegfilgrastim biosimilars are long-acting, those who have received these agents prophylactically should not be treated with additional G-CSF.

12. Pharmacokinetic data following treatment with pegfilgrastim demonstrate high levels during neutropenia and suggest that additional G-CSF use may not be beneficial. However, additional GCSF support may be considered in patients with prolonged neutropenia (beyond 12–14 days) as the pegylated products are unlikely to endure beyond this window. The NCCN Panel recommends an evaluation of risk factors for infection related complications or poor clinical outcome for patients presenting with FN who have not received prophylactic G-CSF

13. Features associated with poor outcome include age >65 years sepsis syndrome ANC <100 neutrophils/ mcL anticipated prolonged (>10 days) neutropenia pneumonia or other clinically documented infection invasive fungal infections hospitalization at the time of fever; and prior FN episode(s)

14. The goals of using MGFs to treat radiation-induced myelosuppression are to shorten the duration of severe neutropenia, minimize the severity of neutropenia-associated complications, and increase survival.