Colony Stimulating Factors

Colony stimulating factors are recombinant haemopoietic growth factors that stimulate production and release of neutrophils (and, for some, other cells). Granulocyte colony stimulating factor (G-CSF) shortens neutropenia after chemotherapy, treats severe chronic neutropenia and mobilises stem cells for collection. They reduce the duration and risk of febrile neutropenia but do not replace antibiotics.

Mechanism. G-CSF binds its receptor on myeloid progenitors, driving proliferation, differentiation and release from the marrow. Granulocyte-macrophage colony stimulating factor (GM-CSF) also acts on monocyte and dendritic lineages.

Members.

• Filgrastim and biosimilars; lenograstim (short-acting, daily).
• Pegfilgrastim (long-acting, once each cycle) and biosimilars.
• Sargramostim and molgramostim (GM-CSF).
• Plerixafor (CXCR4 antagonist) as a mobilising partner.

Pharmacokinetics. Filgrastim half-life 3 to 4 hours (neutrophil rise in 24 hours); pegfilgrastim cleared by neutrophils and lasts until neutrophil recovery.

Filgrastim. 5 micrograms/kg subcutaneously daily, starting 24 to 72 hours after chemotherapy, continuing until neutrophil recovery after the expected nadir (absolute count over 2 to 10 x 10^9/L, depending on local practice). Stem cell mobilisation: 10 micrograms/kg daily for 4 to 5 days before collection.

Pegfilgrastim. 6 mg subcutaneously once each chemotherapy cycle, at least 24 hours after chemotherapy and not within 14 days before the next cycle. Children under 45 kg: 100 micrograms/kg.

Lenograstim. 19.2 million units (150 micrograms)/m2 daily subcutaneously.

Sargramostim. 250 micrograms/m2 daily subcutaneously or intravenously; used after marrow transplantation and in acute myeloid leukaemia induction.

Severe chronic neutropenia. Filgrastim 5 micrograms/kg daily (idiopathic or cyclic) or 6 micrograms/kg twice daily (congenital), titrated to neutrophil count and infections.

Plerixafor. 240 micrograms/kg subcutaneously 11 hours before apheresis, with G-CSF, for poor mobilisers.

• First-line. Primary prophylaxis when the risk of febrile neutropenia is 20% or more (or 10 to 20% with age over 65, poor performance, prior neutropenia or other risk factors); secondary prophylaxis after a previous neutropenic complication.
• Alternative. Dose-dense regimens; treatment of febrile neutropenia in high-risk patients (pneumonia, hypotension, sepsis, expected prolonged neutropenia).
• Specialist. Stem cell mobilisation; severe chronic neutropenia; neutropenia after transplantation; acute radiation syndrome.
• Emergency. Radiation accident; otherwise not an emergency drug.

Selection. Prefer pegfilgrastim for convenience and filgrastim where daily injections are manageable or cost is the issue. Do not give within 24 hours before or after cytotoxic chemotherapy (short-acting) and do not give during radiotherapy to the chest.

Contraindications. Hypersensitivity to the product or to E. coli-derived proteins; severe congenital neutropenia with cytogenetic abnormality or myeloid leukaemia (relative); not given with or within 24 hours of cytotoxic chemotherapy (short-acting).

Serious adverse effects. Bone pain (common, treat with naproxen 250 to 500 mg twice daily or loratadine 10 mg daily); splenic rupture (left upper quadrant or shoulder pain); acute respiratory distress syndrome; capillary leak.

Other adverse effects. Glomerulonephritis; leucocytosis; sickle cell crisis in sickle cell disease or trait (avoid); Sweet syndrome; allergic reactions; secondary myelodysplasia and acute myeloid leukaemia with long-term use in congenital neutropenia.

Major interactions. Cytotoxic chemotherapy within 24 hours; lithium increases neutrophil release; plerixafor with G-CSF has additive effect; avoid concurrent radiotherapy of chest.

Common prescribing errors.

• Giving short-acting G-CSF within 24 hours of chemotherapy.
• Pegfilgrastim given too close to the next cycle.
• G-CSF in sickle cell disease.
• Continuing after count recovery.
• Using as a substitute for antibiotics in febrile neutropenia.

Special groups.

• Pregnancy: limited data; used if necessary.
• Breastfeeding: unlikely to pass; use if necessary.
• Children: same weight-based dosing; pegfilgrastim 100 micrograms/kg under 45 kg.
• Older adults: higher risk benefit; routine prophylaxis often warranted.
• Kidney: no adjustment.
• Liver: no adjustment.
• East Africa: sickle cell disease and trait are common, so ask about sickle status before use (including in patients on chemotherapy for lymphoma and leukaemia); cost and cold chain limit access; biosimilars may be the available form.

Monitoring. Full blood count with differential twice weekly during treatment and until recovery; spleen examination; respiratory symptoms; renal function.

Referral and escalation. Febrile neutropenia (fever 38.0 degrees Celsius or higher with neutrophils under 0.5 x 10^9/L: immediate broad-spectrum antibiotics); left upper quadrant pain; dyspnoea or infiltrates; sickle cell crisis.

Comparison with alternative classes. G-CSFs shorten neutropenia but do not improve cure rates and add cost; antibiotic prophylaxis, dose adjustment and supportive care are alternatives. Erythropoiesis stimulating agents and thrombopoietin receptor agonists act on different lineages.