How do chemotherapy and radiation affect myeloid progenitor cells?

Effects of Chemotherapy and Radiation on Myeloid Progenitor Cells

Both chemotherapy and radiation therapy significantly damage myeloid progenitor cells, leading to neutropenia and increased infection risk, with concurrent administration of these treatments causing particularly severe myelosuppression that may require supportive care but not prophylactic colony-stimulating factors.

Mechanisms of Myeloid Progenitor Cell Damage

• Chemotherapy and radiation primarily target rapidly dividing cells, including myeloid progenitor cells in the bone marrow, disrupting their proliferation and differentiation into mature neutrophils and other myeloid cells 1
• Colony-stimulating factors (CSFs) naturally regulate the production of neutrophils within bone marrow by affecting progenitor proliferation, differentiation, and end-cell functions 2
• Radiation therapy, with or without chemotherapy, significantly reduces neutrophil counts by damaging myeloid progenitors, with effects that may be partially reversed by CSFs 1
• The fraction of cycling progenitors can increase threefold with GM-CSF administration but decreases dramatically within one day of discontinuation, demonstrating the sensitivity of these cells to external factors 3

Clinical Consequences of Myeloid Progenitor Cell Damage

• Severe neutropenia (neutrophil count <500/mm³) commonly occurs following myelosuppressive chemotherapy, increasing the risk of febrile neutropenia and potentially life-threatening infections 1
• The incidence of febrile neutropenia ranges from 10-57% with standard chemotherapy regimens, with infection-related mortality up to 7% 1
• Myelosuppression may delay subsequent chemotherapy courses or result in dose reductions that could compromise treatment outcomes 1
• Infants receiving chemotherapy are at particularly high risk for neutropenic morbidity due to the immaturity of their hematopoietic and immune systems 1

Management of Chemotherapy-Induced Myelosuppression

• G-CSF (filgrastim) and pegfilgrastim are recommended (category 1) for prophylaxis of febrile neutropenia in high-risk patients receiving chemotherapy 1
• Initial doses of filgrastim should be administered 24-72 hours after completion of chemotherapy at 5 mcg/kg daily until post-nadir ANC recovery 1
• Pegfilgrastim can be administered as a single 6 mg dose 24 hours after completion of chemotherapy given every 3 weeks 1
• The subcutaneous route is preferred for all CSF agents 1

Special Considerations with Radiation Therapy

• CSFs should be avoided in patients receiving concurrent chemotherapy and radiation therapy, particularly involving the mediastinum 1
• When CSFs are used with concurrent chemoradiation, there is a significant risk of increased thrombocytopenia and pulmonary toxicity 1
• In a key study, patients receiving GM-CSF with concurrent chemoradiation had significantly higher rates of grade 3-4 platelet toxicity (54% and 35%) compared to control patients (12% and 6%) 1
• More toxic deaths (nine versus one, p<0.01) occurred in the GM-CSF arm, with most related to pulmonary toxicity 1
• In the absence of chemotherapy, therapeutic use of CSFs may be considered for patients receiving large-field radiation if prolonged delays due to neutropenia are expected 1

Long-term Risks and Complications

• There may be an increased risk of Myelodysplastic Syndrome (MDS) and/or Acute Myeloid Leukemia (AML) in patients with congenital neutropenia who receive G-CSF and in patients with breast and lung cancer who receive G-CSF with chemotherapy and/or radiation therapy 2
• The total dose of cyclophosphamide, number of chemotherapy cycles received before transplant, and total dose of mononuclear cells infused at transplant have been associated with secondary MDS/AML development 4
• Patients with severe congenital neutropenia appear to be at higher risk for developing myelodysplasia and leukemia, with or without G-CSF treatment 1

Emerging Approaches

• Ex vivo expansion of myeloid progenitor cells shows promise for overcoming bone marrow reconstitution delays after transplantation 5
• Cryopreserved ex vivo-expanded allogeneic myeloid progenitor cell products have demonstrated protective effects against lethal fungal infections in neutropenic animal models 6
• Infusion of ex vivo differentiated myeloid precursors may potentially shorten the period of neutropenia after high-dose chemotherapy and peripheral blood progenitor cell rescue 7

Practical Recommendations

• For patients receiving chemotherapy with high risk of febrile neutropenia (≥20%), primary prophylaxis with G-CSF is recommended 1
• For patients receiving concurrent chemoradiation, avoid prophylactic CSF use due to increased risk of thrombocytopenia and pulmonary toxicity 1
• For patients receiving radiation therapy alone with large fields, CSFs may be considered if prolonged neutropenia is expected 1
• Monitor patients receiving G-CSF for potential side effects including bone pain, arthralgias, and myalgias 1